Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)#[N:20].CS(C)=O.[OH-].[Na+]>O>[Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[O:27][C:24]1[CH:25]=[CH:26][C:21]([C:19]#[N:20])=[CH:22][CH:23]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccc(Oc2ccc([N+](=O)[O-])c(Oc3ccccc3)c2Cl)cc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 14.2 gm of 2,3-dichloro-6-nitro-1-phenoxy-benzene, 6.5 gm of 4-cyano-phenol, 40 ml of dimethylsulfoxide and 50 ml of 10 N sodium hydroxide was stirred for 3 hours at 100° C. Thereafter, the reaction mixture was diluted with water, the aqueous mixture was extracted with chloroform, the organic extract solution was dried, and the chloroform was distilled off. The residue was purified by passing it through a silicagel column and recrystallizing it from ethanol, yielding 11 gm (60.2% of theory) of the colorless crystalline title compound, m.p. 140°-142° C.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH:12]1[CH:16]=[CH:15][N:14]=[N:13]1.CN[C@@H]1CCCC[C@H]1NC>CN(C=O)C.O.[Cu]I>[N:12]1[N:13]([C:2]2[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[N:14]=[CH:15][CH:16]=1
Reactant: Cc1ccc(I)c(C(=O)O)c1
Reactant: c1c[nH]nn1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Temperature: 120 °C

Procedure:
A solution of 2-iodo-5-methylbenzoic acid (4.0 g, 15.3 mmol) in DMF (10 mL) was treated with 1,2,3-triazole (2.1 g, 30.5 mmol), CsCO3 (9.95 g, 30.5 mmol), CuI (0.145 g, 0.76 mmol) and trans-N,N′-dimethylcyclohexane-1,2-diamine (0.43 g, 3.05 mmol). The mixture was heated at 120° C. for 10 min in a microwave reactor. The reaction was cooled to room temperature, diluted with water, and washed with EtOAc. The aqueous phase was acidified with 1N HCl and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by gradient elution on SiO2 (0 to 10% MeOH in water with 0.1% AcOH) to give the faster eluting 2-(2H-1,2,3-triazol-2-yl)-5-methylbenzoic acid A-5, followed by the undesired regioisomer isomer, 1-(2H-1,2,3-triazol-2-yl)-5-methylbenzoic acid. Data for A-5: 1HNMR (500 MHz, DMSO-d6) d 12.98 (br s, 1H), 8.04 (s, 2H), 7.72-7.45 (m, 3H), 2.41 (s, 3H) ppm.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)C=C.Cl[C:16]1[CH:21]=CC=C[C:17]=1Cl>>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:13][C:14]=1[CH2:21][CH:16]=[CH2:17]
Reactant: Clc1ccccc1Cl
Reactant: C=CCOc1ccc(C(=O)OC)cc1
Product: C=CCc1cc(C(=O)OC)ccc1O
Temperature: 183 °C
Yield: 91 %

Procedure:
A solution of 15.05 g (78.3 mmol) of the product of Step A in 25 mL of 1,2-dichlorobenzene was magnetically stirred and refluxed (183° C.) under an argon atmosphere for 18 hours. At this point, the reaction mixture was cooled to room temperature and applied to a 6 cm diameter by 18 cm silica gel flash chromatography column and eluted with 25% ethyl acetate-hexane to separate the 1,2-dichlorobenzene, then with 40% ethyl acetate-hexane to elute the product. The product fractions were concentrated in vacuo and the residual oil was crystallized from hexane to afford 13.70 g (91%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[Cl:11])=[CH:5][CH:4]=1.C(OC([NH:28][C:29]([CH3:34])([CH3:33])[C:30](=[S:32])[NH2:31])=O)(C)(C)C.O>CN(C)C=O>[ClH:11].[NH2:28][C:29]([C:30]1[S:32][C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:31]=1)([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(N)=S
Reactant: COc1ccc(C(=O)C(Cl)c2ccc(OC)cc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2nc(C(C)(C)N)sc2-c2ccc(OC)cc2)cc1
Product: Cl
Temperature: 70 °C
Reaction time: 6 h
Yield: 81.8 %

Procedure:
A mixture of 1,2-bis(4-methoxyphenyl)-2-chloroethanone (5.00 g) and 2-tert-butyloxycarbonylamino-2-methylpropanethioamide (4.50 g) in dimethylformamide (25 ml) was stirred at 70° C. for 6 hours. After allowing to cool to the ambient temperature, the reaction mixture was dropped into water. The precipitates were collected by filtration. The resulting residue (6.28 g) was dissolved with dichloromethane (120 ml), and stirred at 2° C. To the reaction mixture was added 1,4-dioxan solution of 4N hydrogen chloride (60 ml), and stirred at ambient temperature for 1 hour. The resulting residue was evaporated in vacuo. The residue was added iso-propyl ether (300 ml) and stirred at 2° C. for 3 hours. The resulting precipitate was collected by filtration and washed with iso-propyl ether, to give 2-(1-amino-1-methylethyl)-4,5-bis(4-methoxyphenyl)thiazole hydrochloride (5.5 g).
Reaction SMILES: [C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([OH:10])[C:8]#[CH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1[CH:19]=[C:20](O)[C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2>>[C:11]1([C:7]2([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:10][C:20]3[C:21]4[C:26]([CH:27]=[C:18]([CH3:17])[C:19]=3[CH:9]=[CH:8]2)=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C#CC(O)(c1ccccc1)c1ccccc1
Reactant: Cc1cc(O)c2ccccc2c1
Product: Cc1cc2ccccc2c2c1C=CC(c1ccccc1)(c1ccccc1)O2

Procedure:
The procedure of Step 2 of Example 1 was followed except that 1,1-diphenyl-2-propyn-1-ol was used in place of 1,1-bis(4-methoxyphenyl)-2-propyn-1-ol and 3-methyl-1-hydroxynaphthalene was used in place of methyl-1,4-dihydroxy-2-naphthoate to produce 2,2-diphenyl-5-methyl-[2H]-naphtho[1,2-b]pyran.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].C(N(CC)CC)C.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1.CC(C)=O>ClCCl>[OH:4][CH2:3][CH2:2][N:1]([CH2:21][C:20]1[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1)[CH2:5][CH2:6][OH:7]
Reactant: COc1ccc(CCl)cc1
Reactant: OCCNCCO
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: ClCCl
Product: COc1ccc(CN(CCO)CCO)cc1
Temperature: 2.5 °C
Yield: 94.7 %

Procedure:
25 gms (0.2380 moles) of diethanolamine and 60 ml (0.4312 moles) triethylamine in 75 ml dichloromethane were taken in a reaction vessel and cooled to 0-5° C. with stirring. 40 gms (0.2554 moles) of p-methoxy benzyl chloride in 50 ml of dichloromethane was added thereto slowly. Further, the reaction mass was stirred with dichloromethane and maintained at a temperature of 25-30° C. for about 16 hours. The resulting solution was concentrated to get a residue. 200 ml of acetone was added to the residue, cooled to 0-5° C. for about one hour and filtered. The filtrate was concentrated to obtain the title compound as an oil (50.8 gms).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.C(N(CC)CC)C.[CH2:25]([N:27]=[C:28]=[O:29])[CH3:26]>C1(C)C=CC=CC=1>[CH2:11]([C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([NH:1][C:28]([NH:27][CH2:25][CH3:26])=[O:29])[S:3][C:4]=2[CH:10]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Nc1nc2ccc(Cc3ccccc3)cc2s1
Reactant: CCN=C=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1nc2ccc(Cc3ccccc3)cc2s1
Temperature: 95 °C
Yield: 54.8 %

Procedure:
A suspension of 2-amino-6-benzyl-benzothiazole (0.040 g, 0.17 mmol), triethylamine (0.104 mL, 0.77 mmol, 4.5 eq), and ethyl isocyanate (0.049 mL, 0.64 mmol, 3.8 eq) in 1 mL toluene was heated at about 95° C. for about 16 hours. The precipitate was filtered off, washed with Et2O and MeOH, and dried under vacuum to give the desired compound 0.029 g (56%). LC/MS 312.3 (M+1); LC retention time 2.62 min.
Reaction SMILES: C1([C@@H](N2CCCC2)CO)C=CC=CC=1.[C:15]1([C@H:21](O)[CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:29][NH:30][C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=1>>[C:15]1([C@H:21]([N:30]([C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)[CH3:29])[CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O[C@H](CN1CCCC1)c1ccccc1
Reactant: CNc1ccc(C(=O)OC)cc1
Agent: OC[C@@H](c1ccccc1)N1CCCC1
Product: COC(=O)c1ccc(N(C)[C@H](CN2CCCC2)c2ccccc2)cc1
Yield: 52 %

Procedure:
This was prepared from the mixture of 2-(R)-phenyl-2-(pyrrolidin-1-yl)ethanol and 1-(S)-phenyl-2-(pyrrolidin-1-yl)ethanol and methyl 4-methylaminobenzoate in 52% yield according to a procedure similar to that described in Example 1 (i).
Reaction SMILES: CC[N:3](C(C)C)C(C)C.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13](F)[CH:12]=1>CS(C)=O>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13]([CH:12]=1)[NH2:3]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Solvent: CS(C)=O
Product: Nc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 19 h

Procedure:
Amino-(4-methoxyphenyl)-methylpolystyrene (loading 1.69 mmol/g, 7.00 g, 11.8 mmol) was soaked in DMSO in a peptide vessel for 30 min. The solvent was then drained. DIEA (11.3 mL, 65.1 mmol) in DMSO (88 mL) was added to the resin, followed by 4-chloro-2-fluoronitrobenzene (10.4 g, 59.2 mmol). The mixture was shaken at room temperature for 19 h, at which point it was drained. The resin was washed with DMSO (3×), EtOH (3×), DMF (3×), MeOH (3×) and DCM (3×). It was then dried under vacuum overnight. A small sample (approx. 10 mg) was treated with 23:2:75 (v/v/v) TFA/H2O/DCM (0.5 mL) for ca. 1 h. The solution containing the released material was concentrated and analyzed with LC/MS. UV (254 nm): 97% @ 5.65 min. MS: m/e 171 (M−1).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH:10]1([SH:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[CH3:8][C:6]1[CH:7]=[C:2]([S:16][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:3]=[C:4]([CH3:9])[CH:5]=1
Reactant: SC1CCCCC1
Reactant: Cc1cc(C)cc(I)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: Cc1cc(C)cc(SC2CCCCC2)c1
Yield: 70.8 %

Procedure:
The general procedure in example 39 was followed. 5-Iodo-m-Xylene (144 μL, 1.0 mmol), cyclohexylmercaptan (122 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-propanol (1.0 mL) were used to obtain the cyclohexyl 3,5-dimethylphenyl sulfide (156 mg, 71% yield) as colorless oil. Column chromatographic solvent (hexane). Rf=0.4 (hexane). 1H NMR (CDCl3, 300 MHz) δ 6.99 (s, 2 H), 6.82 (s, 1 H), 3.02-3.10 (m, 1 H), 2.28 (s, 6 H), 1.96-2.00 (m, 2 H), 1.74-1.77 (m, 2 H), 1.56-1.63 (m, 1 H), 1.21-1.42 (m, 4 H). 13C NMR (CDCl3, 75 MHz) δ 138.4, 134.7, 129.7, 128.7, 46.8, 33.8, 26.5, 26.2, 21.6. IR (neat, cm−1) 3088, 3060, 3012, 2962, 2867. MS (EI) m/z (relative intensity) 220 (40), 138 (100), 105 (30). Anal Cald for C14H20S, Cald. C: 76.30, H: 9.15; Found C: 76.30, H: 9.17.
Reaction SMILES: C(OC(N[C@:7]([CH2:35][CH2:36]CC)([C:15]([N:17]1[CH2:34][CH2:33][CH2:32][C@H:18]1[C:19]([NH:21][C@H:22]([CH:30]=[O:31])[CH2:23][CH2:24][CH2:25][NH:26][C:27](=[NH:29])[NH2:28])=[O:20])=O)CC1C=CC=CC=1)=O)C.Cl.[CH2:40]([O:42][C:43]([NH:45][C@:46](CCCC)([C:54](N1CCC[C@H]1C(OCC1C=CC=CC=1)=O)=[O:55])[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:44])[CH3:41]>>[CH2:40]([O:42][C:43]([NH:45][C@H:46]([C:54]([C@@:18]1([C:19]([NH:21][C@H:22]([CH:30]=[O:31])[CH2:23][CH2:24][CH2:25][NH:26][C:27](=[NH:29])[NH2:28])=[O:20])[CH2:32][CH2:33][CH2:34][N:17]1[CH2:15][CH2:7][CH2:35][CH3:36])=[O:55])[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:44])[CH3:41]
Reactant: CCCC[C@@](Cc1ccccc1)(NC(=O)OCC)C(=O)N1CCC[C@H]1C(=O)N[C@H](C=O)CCCNC(=N)N
Reactant: CCCC[C@@](Cc1ccccc1)(NC(=O)OCC)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Product: CCCCN1CCC[C@]1(C(=O)N[C@H](C=O)CCCNC(=N)N)C(=O)[C@H](Cc1ccccc1)NC(=O)OCC

Procedure:
By methods substantially equivalent to those described in Example 39, 1.47 g of EtOCO-Phe(αn-Bu)-Pro-Arg-H.HCl was prepared from EtOCO-Phe(αn-Bu)-Pro-OBzl (TLC Rf =0.74, 50% ethyl acetate:hexanes). EtOCO-Phe(αn-Bu)-Pro-Arg-H.HCl was purified by RPHPLC (98/2 (A/B), 60 min; to 85/15 (A/B), 300 min).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[N:8]=[CH:7][CH:6]=[CH:5]2.[C:13]([O-:16])(=[O:15])[CH3:14].[Br-].[C:18]([Zn+2])([CH3:21])([CH3:20])[CH3:19]>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:18]([O:15][C:13](=[O:16])[CH2:14][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[N:8]=[CH:7][CH:6]=[CH:5]2)([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1cc2ncccc2cc1Br
Reactant: CC(=O)[O-]
Reactant: CC(C)(C)[Zn+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Product: Cc1cc2ncccc2cc1CC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
To 1.02 g of 6-bromo-7-methyl-quinoline were added a solution of 20 ml of tert-butylzincbromide acetate and 0.58 g of Pd(PPh3)4. The mixture was placed in the microwave reactor for 30 min to achieve a temperature of 120° C. (repeated for 3 times.). Purification via flash column chromatography returned the title compound (3.2 g, 68%). 1H NMR (CDCl3, 300 MHz) δ 8.84 (m, 1H), 8.07 (m, 1H), 7.89 (s, 1H), 7.63 (s, 1H), 7.31 (m, 1H), 3.72 (s, 2H), 2.51 (s, 3H), 1.46 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:6]([N:7]([CH2:20][C:21]#[CH:22])[C:8](=[O:19])[CH2:9][N:10](C)[C:11](=O)OC(C)(C)C)=[CH:5][N:4]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[N:3]=1.FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[C:6]([N:7]([CH2:20][C:21]#[CH:22])[C:8](=[O:19])[CH2:9][NH:10][CH3:11])=[CH:5][N:4]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[N:3]=1
Reactant: C#CCN(C(=O)CN(C)C(=O)OC(C)(C)C)c1cn(-c2cccnc2)nc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C#CCN(C(=O)CNC)c1cn(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
To a solution of tert-butyl (2-((3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(prop-2-yn-1-yl)amino)-2-oxoethyl)(methyl)carbamate (0.47 g, 1.16 mmol) in DCM (1.16 ml) was added 2,2,2-trifluoroacetic acid (1.16 ml) and the reaction mixture was stirred at ambient temperature for 1 h. To the mixture was added toluene and then the reaction was concentrated to dryness. The oil was redissolved in DCM and saturated NaHCO3 solution was added. The phases were separated and the aqueous phase was extracted with DCM. The organic layers were combined, the solvent evaporated, and the residue purified using silica gel chromatography (0-15% MeOH/DCM) to afford the title compound as yellow oil (0.258 g, 0.849 mmol, 73%): IR (thin film) 1696 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.98 (d, J=2.6 Hz, 1H), 8.64 (dd, J=4.7, 1.3 Hz, 1H), 8.19 (s, 1H), 8.06 (ddd, J=8.3, 2.6, 1.4 Hz, 1H), 7.47 (dd, J=8.3, 4.7 Hz, 1H), 4.48 (s, 2H), 3.49 (s, 2H), 2.49 (s, 3H), 2.28 (t, J=2.5 Hz, 1H); ESIMS m/z 304 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]([N:13]([CH2:18][CH:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:14][CH2:15][CH2:16][OH:17])([C:9]([F:12])([F:11])[F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O[C:33]1[CH:40]=[CH:39][C:36]([CH:37]=[O:38])=[CH:35][CH:34]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]([N:13]([CH2:18][CH:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH2:14][CH2:15][CH2:16][O:17][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=[O:38])=[CH:35][CH:34]=1)([C:9]([F:11])([F:12])[F:10])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: OCCCN(CC(c1ccccc1)c1ccccc1)C(Cl)(c1ccccc1)C(F)(F)F
Reactant: O=Cc1ccc(O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=Cc1ccc(OCCCN(CC(c2ccccc2)c2ccccc2)C(Cl)(c2ccccc2)C(F)(F)F)cc1
Yield: 43 %

Procedure:
To a solution of 3-[(Chloro-trifluoromethyl-benzyl)-diphenylethyl-amino]-propan-1-ol (0.500 g, 1.12 mmol) in toluene (4 ml) at ambient temperature was added 4-Hydroxy-benzaldehyde (0.213 g, 1.74 mmol) under Argon with stirring. The mixture was treated with polymer bound PPh3 (0.594 g, 1.782 mmol). After 15 minutes of stirring, the mixture was treated with DIAD (0.273 mL, 1.387 mmol) and was stirred at ambient temperature overnight. The reaction mixture was filtered then concentrated, in-vacuo, to dryness. The oil was dissolved in DMSO and was purified via reverse-phase HPLC to yield the title compound (0.266 g, 43%); MS (ES+) m/e 553 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[C:14]([N+:18]([O-:20])=[O:19])[C:15]=1[O:16][CH3:17])[C:6](N1C=CN=C1)=[O:7].[C:21](=[N:24][OH:25])([NH2:23])[CH3:22]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[C:14]([N+:18]([O-:20])=[O:19])[C:15]=1[O:16][CH3:17])[C:6]([O:25][N:24]=[C:21]([NH2:23])[CH3:22])=[O:7]
Reactant: CC(N)=NO
Reactant: COc1cc(C(=O)n2ccnc2)cc([N+](=O)[O-])c1OC
Solvent: CN(C)C=O
Product: COc1cc(C(=O)ON=C(C)N)cc([N+](=O)[O-])c1OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
10.0 g of 1-(3,4-dimethoxy-5-nitrobenzoyl)imidazole in 50 ml of dimethylformamide are treated with 6.95 g of acetamidoxime, whereupon the mixture is stirred at 70° for 1 hour. After cooling, the mixture is poured into 500 ml of ice-water and stirred for 30 minutes. The separated crystals are filtered under suction and washed with water. After crystallization from ethyl acetate there is obtained N'-[(3,4-dimethoxy-5-nitrobenzoyl)oxy]acetamidine in the form of colorless crystals of m.p. 165°-166°.
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[F:5][C:6]1([F:15])[CH2:11][CH2:10][N:9]([C:12]([NH2:14])=[S:13])[CH2:8][CH2:7]1.[C:16]1([C:22](=O)[CH2:23][C:24](=O)[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])(=O)C.[Na+]>CO>[CH2:28]([O:27][C:25]([C:24]1[CH:23]=[C:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:4]=[C:3]2[N:14]=[C:12]([N:9]3[CH2:8][CH2:7][C:6]([F:5])([F:15])[CH2:11][CH2:10]3)[S:13][C:2]=12)=[O:26])[CH3:29]
Reactant: N#CCCl
Reactant: CCOC(=O)C(=O)CC(=O)c1ccccc1
Reactant: NC(=S)N1CCC(F)(F)CC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1cc(-c2ccccc2)nc2nc(N3CCC(F)(F)CC3)sc12
Yield: 86.7 %

Procedure:
Chloroacetonitrile (0.32 mL, 5.06 mmol) was added to a solution of 4,4-difluoropiperidinothiocarboxamide (839 mg, 4.66 mmol) prepared above in methanol (15 mL), followed by heating overnight under reflux. The reaction solution was concentrated, and the residue was dissolved in acetic acid (15 mL), followed by addition of commercially available ethyl 4-phenyl-2,4-dioxobutyrate (1.03 g, 4.68 mmol) and sodium acetate (573 mg, 6.99 mmol) thereto. The mixture was heated for 1.5 hr under reflux in an argon atmosphere. The reaction solution was concentrated, and the residue was put into a saturated aqueous solution of sodium hydrogen carbonate. The precipitated crystals were collected by filtration, washed with water, and dried to obtain 2-(4,4-difluoropiperidino)-5-phenyl-7-thiazolo[4,5-b]pyridinecarboxylic acid ethyl ester (1.63 g, 4.04 mmol) as a brown powder.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([N+:18]([O-:20])=[O:19])[CH:10]=[CH:11][C:12]=3[OH:17])[C:7](=[O:21])[C:6]=2[C:5]([N+:22]([O-:24])=[O:23])=[CH:4][CH:3]=1.[C:25]1([O:31][CH3:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>B(O)(O)O.S(=O)(=O)(O)O>[OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([N+:18]([O-:20])=[O:19])[CH:10]=[C:11]([C:28]4[CH:29]=[CH:30][C:25]([O:31][CH3:32])=[CH:26][CH:27]=4)[C:12]=3[OH:17])[C:7](=[O:21])[C:6]=2[C:5]([N+:22]([O-:24])=[O:23])=[CH:4][C:3]=1[C:28]1[CH:29]=[CH:30][C:25]([O:31][CH3:32])=[CH:26][CH:27]=1
Reactant: COc1ccccc1
Reactant: O=C1c2c(O)ccc([N+](=O)[O-])c2C(=O)c2c([N+](=O)[O-])ccc(O)c21
Agent: O=S(=O)(O)O
Agent: OB(O)O
Product: COc1ccc(-c2cc([N+](=O)[O-])c3c(c2O)C(=O)c2c(O)c(-c4ccc(OC)cc4)cc([N+](=O)[O-])c2C3=O)cc1
Temperature: 0 °C
Yield: 77.5 %

Procedure:
9.9 g of 1,8-dihydroxy-4,5-dinitroanthraquinone are dissolved in a mixture of 15.6 g of boric acid and 228 g of 100 percent sulphuric acid. The solution obtained is cooled down to -10° to 0° C. and 7.4 g of anisole are added dropwise. The temperature is maintained for a further 1 hour at 0° C. and then the mixture is poured onto 240 g of ice and heated to reflux for 4 hours. The solid is filtered off with suction, washed with water to neutrality and dried at 60° C. 12.6 g of 1,8-dihydroxy-2,7-di(4-methoxyphenyl)-4,5-dinitroanthraquinone, corresponding to a yield of 77% of theory, are obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:14])=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[S:8][CH2:7][CH2:6][C:5]2=[O:13].[BH4-].[Na+].Cl>CO>[Br:1][C:2]1[C:3]([CH3:14])=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[S:8][CH2:7][CH2:6][CH:5]2[OH:13]
Reactant: Cc1cc(Br)c(C)c2c1SCCC2=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(Br)c(C)c2c1SCCC2O
Reaction time: 2 h
Yield: 0 %

Procedure:
In a 100-ml eggplant type flask, 5.0 g (18.4 mol) of 6-bromo-5,8-dimethylthiochroman-4-one as a halogenated thiochroman-4-one compound was dissolved in 30 ml of methanol, and 0.35 g (9.2 mmol, 0.5 equivalent) of sodium borohydride as a reducing agent was added at room temperature. The reaction mixture was stirred for 2 hours, then, diluted hydrochloric acid was added, and the mixture was extracted with ethyl acetate. An organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then solvent was distilled off to give 0.49 g (yield 95%) of 6-bromo-5,8-dimethylthiochroman-4-ol.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[CH2:25][CH2:24][C:21]2([CH2:23][CH2:22]2)[CH:20]([OH:26])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[CH2:25][CH2:24][C:21]2([CH2:23][CH2:22]2)[C:20](=[O:26])[CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)C(O)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC2(CC2)C(=O)C1
Reaction time: 0.25 h
Yield: 102 %

Procedure:
To a solution of oxalyl chloride (42.35 ml, 0.480 mol) in CH2Cl2 (910 ml) was added a solution of dimethylsulfoxide (68.24 ml, 0.961 mol) in CH2Cl2 (910 ml) at −70° C. within 45 min. The solution was stirred for 15 min and a solution of 4-hydroxy-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester (91.00 g, 0.400 mol) in CH2Cl2 (910 ml) was added within 40 min keeping the internal temperature at below −60° C. The mixture was stirred for 35 min and triethylamine (280.4 ml, 2.00 mol) was added at below −60° C. within 10 min. The cooling bath was removed and the yellow suspension was stirred for 1 h then quenched with water (1.4 l). The organic phase was separated, washed with water (3×1 l) and sat. aq. NaCl solution (3 l) and evaporated. The residual orange powder was dissolved in TBME (1.40 l), the turbid solution filtered (Hyflo Speedex) to remove some insoluble material and the clear filtrate evaporated to provide crude 4-oxo-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester as yellow powder (91.9 g). The material was re-dissolved in TBME (300 ml) and purified by filtration over silica gel (700 g) using a 3:1 heptane/TBME mixture (6.5 l). Evaporation and drying (10 mbar, 40° C.) afforded 4-oxo-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester as whitish powder (80.58 g, 89%), GC purity 100a %.