Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C([O-])([O-])=O.[K+].[K+].[CH2:17](Br)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C(#N)C>[CH2:17]([O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCBr
Reactant: Oc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCCCCOc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.8 %

Procedure:
4-Hydroxyindole (500 mg, 3.76 mmol), K2CO3 (1.04 g, 7.51 mmol), and n-nonylbromide (817 mg, 3.94 mmol) was dissolved in acetonitrile (10 mL) and stirred at 25° C. for 10 min in a 250 mL round bottom flask. The reaction mixture was refluxed for 24 h and cooled to 25° C. The reaction mixture filtered to remove insoluble impurities and solvent evaporated under reduced pressure. The residue was purified by flash chromatography eluting with 100% hexanes and 30% EtOAc/hexanes to afford 4-nonyloxyindole as pale yellow solid (847 mg, 87%). Rf=0.8 (30% EtOAc/hexanes).
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(C)=O>[C:22]1([CH2:21][CH2:20][O:12][C:10]2[CH:9]=[CH:8][C:6]3[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]=3[CH:11]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCCc1ccccc1
Reactant: N#Cc1nc2ccc(O)cc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1nc2ccc(OCCc3ccccc3)cc2s1
Temperature: 25 °C
Yield: 50.2 %

Procedure:
A suspension of 2-cyano-6-hydroxybenzothiazole (1.00 g, 5.68 mmol) in acetone (5 mL) was prepared in a 100-mL 2-necked round-bottomed flask fitted with a reflux condenser. Anhydrous potassium carbonate (1.18 g, 8.52 mmol) was added to the reaction mixture and the suspension turned to a yellow solution. Then (2-bromoethyl)benzene (1.37 g, 0.88 mL, 7.38 mmol) was added and the reaction mixture was heated at reflux for using a heated stir plate and oil bath. Progress of the reaction was monitored by HPLC analysis of reaction aliquots. After 15 h of reflux the reaction was about 40% complete. Additional (2-bromoethyl)benzene (0.5 equivalents, 2.84 mmol) and potassium carbonate (0.5 equivalents, 2.84 mmol) were added periodically during the course of two days until the starting material was consumed. The reaction mixture was allowed to cool to ambient temperature and then filtered to remove inorganic salts. The filtrate was concentrated by rotoevaporation to provide 2.2 g of a crude oil. The crude product was purified by flash chromatography on silica gel using an initial mobile phase consisting of a mixture of 9:1 heptane-ethyl acetate. The mobile phase was adjusted to a mixture of 5:1 heptane-ethyl acetate, and then adjusted to a mixture of 7:3 heptane-ethyl acetate to provide 800 mg (50% yield) of the desired product as an off-white foam. The structure was confirmed by 1H NMR analysis in DMSO-d6.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=O)[CH3:2].[CH3:14][O:15][CH:16]([O:19][CH3:20])[CH2:17][NH2:18].[BH4-].[Na+]>C(O)C>[CH3:14][O:15][CH:16]([O:19][CH3:20])[CH2:17][NH:18][CH2:7][C:6]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1
Reactant: CCOc1cc(C=O)ccc1OC
Reactant: COC(CN)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1cc(CNCC(OC)OC)ccc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-ethoxy-4-methoxybenzaldehyde (3.6 g, 20 mmol) in ethanol (15 ml) is added to 2,2-dimethoxyethylamine (21 mmol) and the mixture heated at reflux for 2 hours. After cooling to room temperature, sodium borohydride (0.794 g, 21 mmol) is added and the mixture stirred at room temperature overnight. Ethanol is removed by evaporation and water added, followed by extraction with ethyl acetate. The organic extracts are combined, washed with water, brine, dried over magnesium sulfate and evaporated to give (2,2-dimethoxy-ethyl)-(3-ethoxy-4-methoxy-benzyl)-amine, [MH]+ 270. The intermediate (2.70 g, 10 mmol) is suspended in 6N HCl (50 ml), glyoxylic acid (0.88 g, 12 mmol) is added and the mixture heated for 1 hour at 100° C. After cooling to room temperature, methanol (30 ml) is added and the mixture filtered and characterised as the methyl ester M+ 276. The filtrate is treated with lithium hydroxide (10 mmol) in THF-methanol-water overnight. After evaporation of the solvents, the crude product is partitioned between water and dichloromethane. The aqueous phase is washed with dichloromethane and evaporated to dryness to afford (7-ethoxy-6-methoxy-isoquinolin-4-yl)-acetic acid lithium salt which is used for xanthine formation without further characterisation.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])[CH2:3][CH2:4][OH:5].N1C=CC=CC=1.[C:21](Cl)(Cl)=[O:22]>C(Cl)Cl>[Si:8]([O:7][CH2:6][C@H:2]1[CH2:3][CH2:4][O:5][C:21](=[O:22])[NH:1]1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](N)CCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CCOC(=O)N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (3R)-3-amino-4-{[tert-butyl(dimethyl)silyl]oxy}butan-1-ol (2.63 g, 12 mmol) in DCM (100 mL) at 0° C. was added pyridine (3 mL) followed by phosgene (20% solution in toluene, 1.9 M, 8.5 mL) dropwise and the mixture was stirred for 30 min and allowed to warm to rt, and quenched with water. The layers were separated and the water layer extracted with DCM once. The organic layers were dried over MgSO4, filtered and concentrated. The desired product (4R)-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1,3-oxazinan-2-one was obtained from crystallization from ether/hexanes at −20° C. as a light yellow solid. 1H NMR (400 MHz, CDCl3) 5.52 (br s, 1H), 4.38-4.33 (m, 1H), 4.28-4.22 (m, 1H), 3.70-3.59 (m, 2H), 3.46 (t, 1H), 1.97-1.93 (m, 1H), 1.72-1.67 (m, 1H), 0.91 (s, 9H), 0.90 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH3:13])[CH:7]=[CH:6]2.[Br:14]N1C(=O)CCC1=O>C(#N)C>[Br:14][C:4]1[C:3]([O:2][CH3:1])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8]([CH3:13])=[N:9]2
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2nc(C)ccc2c1
Solvent: CC#N
Product: COc1ccc2nc(C)ccc2c1Br
Temperature: 25 °C
Reaction time: 6 h
Yield: 98.4 %

Procedure:
A solution of 6-methoxy-2-methylquinoline (177 g, 1.02 mol) in acetonitrile (1.77 L) was cooled to 0-3° C. followed by portion-wise addition of N-bromosuccinimide (200 g, 1.12 mol) over a period of 30 min while maintaining the same temperature. The resulted brown slurry was warmed to ambient temperature and stirred for an additional 6 h. The reaction was then quenched by a 10% NaHSO3 solution (211 mL). The reaction mixture was concentrated to a volume of 600 mL then slowly poured into 0.1 N NaOH (2.5 L). The slurry (pH=9) was stirred at room temperature for 1 h then filtered, washed with water (2×1 L) and dried in a vacuum oven to give 253 g (98.6%) of the title compound as a brown solid.
Reaction SMILES: CCN(CC)CC.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[N:13]1([NH2:19])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>C(Cl)Cl>[N:13]1([NH:19][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: CS(=O)(=O)Cl
Reactant: NN1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NN1CCOCC1
Temperature: 25 °C

Procedure:
Using the adapted Tozer procedure of Example 1, NEt3 (2.8 mL) and methanesulfonyl chloride Compound 1i (2.3 g, 20.0 mmol) were added to a solution of morpholin-4-ylamine Compound 11a (2.1 g, 20.0 mmol) in 20 mL of CH2Cl2 at 0° C. under a N2 atmosphere. The mixture was stirred and warmed to ambient temperature over a 2 hr period, then the reaction was quenched with water (10 mL). The organic layer was diluted with CH2Cl2 (60 mL) and washed with water and brine, separated and dried with anhydrous Na2SO4, then filtered and concentrated in vacuo to afford N-morpholin-4-yl-methanesulfonamide Compound 11b as an oil.
Reaction SMILES: F[C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].O.O.O.O.O.O.O.O.O.[S-2:21].[Na+].[Na+].C(=O)(O)[O-].[Na+].O>ClCCl>[NH2:4][C:3]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:2]=1[SH:21]
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Reactant: [S-2]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Nc1cc([N+](=O)[O-])ccc1S
Temperature: 125 °C
Yield: 100.8 %

Procedure:
2-Fluoro-5-nitroaniline (1 g, 6.41 mmol), sodium sulfide nonahydrate (1.7 g, 7.05 mmol), sodium bicarbonate (600 mg, 7.05 mmol) and water (15 mL) were combined and heated in the microwave at 125° C. for 5 min. After cooling, dichloromethane was added, and the organic layer was washed with 2M aqueous hydrochloric acid and then brine. The combined organic layers were dried over anhydrous MgSO4 and evaporated to afford 1.1 g (33%) of the title compound.
Reaction SMILES: [CH:1]([NH:4][C:5](=[NH:7])[CH3:6])([CH3:3])[CH3:2].Br[C:9](=[CH:18]OC)[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11].C(N(CC)CC)C.S(=O)(=O)(O)O>C(O)(C)C>[C:10]([C:9]1[N:4]([CH:1]([CH3:3])[CH3:2])[C:5]([CH3:6])=[N:7][CH:18]=1)(=[O:11])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=N)NC(C)C
Reactant: COC=C(Br)C(=O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cc1ncc(C(=O)c2ccccc2)n1C(C)C
Temperature: 80 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
In a 300 mL-volume glass vessel equipped with a stirrer, a thermometer and a dropping funnel, the isopropyl alcohol solution containing 16.2 g (0.162 mol) of N-isopropylacetamidine (which was prepared in the same manner as in Reference Example 1), 26.0 g (0.108 mol) of 2-bromo-3-methoxy-1-phenyl-2-propen-1-one and 16.4 g (0.162 mol) of triethylamine were placed. The mixture was heated to 80° C. under stirring for 8 hours for carrying out reaction. After the reaction was complete, 80 mL of sulfuric acid (2 mol/L) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The concentrate was washed with methyl isobutyl ketone, and the aqueous portion was taken out. The aqueous portion was made basic by adding an aqueous 48% sodium hydroxide, while the mixture was kept at a temperature of not higher than 40° C. The aqueous basic portion was subjected to extraction with methyl isobutyl ketone, and the extracted portion was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluant: hexane/ethyl acetate=2/1) to give 2.47 g (yield: 10%) of 5-benzoyl-1-isopropyl-2-methylimidazole as pale yellow liquid.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]([OH:8])=O)(=[O:4])=[O:3].[Cl:9][C:10]1[CH:11]=[C:12]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][C:33]=3[O:35][C@@H:36]([CH3:40])[CH2:37][NH:38][CH3:39])[N:28]=[CH:27][N:26]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>>[Cl:9][C:10]1[CH:11]=[C:12]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][C:33]=3[O:35][C@@H:36]([CH3:40])[CH2:37][N:38]([CH3:39])[C:6](=[O:8])[CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])[N:28]=[CH:27][N:26]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: CS(=O)(=O)CC(=O)O
Reactant: CNC[C@H](C)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: C[C@@H](CN(C)C(=O)CS(C)(=O)=O)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 61 %

Procedure:
The procedure described in Example 1 was repeated using methanesulfonylacetic acid and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(1S)-1-methyl-2-(methylamino)ethoxy]quinazolin-4-amine (obtained as described for the R-antipode in Example 2.3, preparation of starting materials) to give the title compound in 61% yield; NMR spectrum (DMSO-d6) 1.38 (d, 3H), 2.95 (s, 3H), 3.15 (s, 3H), 3.37 (dd, 1H), 4.30 (m, 1H), 4.41 (d, 2H), 5.11 (m, 1H), 5.29 (s, 2H), 7.24 (m, 2H), 7.30 (d, 1H), 7.35 (m, 1H), 7.57 (d, 1H), 7.64 (dd, 1H), 7.70 (t, 1H), 7.86 (dt, 1H), 8.11 (d, 1H), 8.45 (s, 1H), 8.58 (d, 1H), 9.88 (s, 1H); Mass Spectrum MH+ 570.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH3:21])=[O:5])[CH3:2].[Br:22]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.O>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:21][Br:22])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1CBr
Temperature: 25 °C
Yield: 99 %

Procedure:
4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester (1.6 g, 5.00 mmol) is dissolved into chloroform (50 mL) then N-bromosuccinimide (1.0 g, 5.5 mmol) and 2,2′-azobisisobutyronitrile (0.412 g, 2.5 mmol) are added and the reaction is heated to reflux. The reaction is monitored by TLC until no starting material remained. The reaction is allowed to cool to room temperature, then diluted with more chloroform (100 mL). Water (50 mL) is added and the two phases are separated. The organic layer is washed with brine, then dried over anhydrous sodium sulfate. The material is then concentrated and further purified using flash column chromatography to yield 1.97 g or 99% yield.
Reaction SMILES: [Cl:1][C:2]1[C:15]([CH2:16][N:17]2[CH2:36][CH2:35][C:20]3([O:25][CH2:24][CH2:23][N:22]([C:26]([C:28]4[N:29]=[C:30]([CH2:33][CH3:34])[S:31][CH:32]=4)=[O:27])[CH2:21]3)[CH2:19][CH2:18]2)=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][CH2:5][O:6][CH2:7][CH2:8][C:9]([OH:11])=O.CCN(C(C)C)C(C)C.[CH3:46][O:47][CH:48]([O:56][CH3:57])[CH2:49][NH:50][CH:51]1[CH2:55][CH2:54][CH2:53][CH2:52]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:1][C:2]1[C:15]([CH2:16][N:17]2[CH2:18][CH2:19][C:20]3([O:25][CH2:24][CH2:23][N:22]([C:26]([C:28]4[N:29]=[C:30]([CH2:33][CH3:34])[S:31][CH:32]=4)=[O:27])[CH2:21]3)[CH2:35][CH2:36]2)=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][CH2:5][O:6][CH2:7][CH2:8][C:9]([N:50]([CH:51]1[CH2:55][CH2:54][CH2:53][CH2:52]1)[CH2:49][CH:48]([O:56][CH3:57])[O:47][CH3:46])=[O:11]
Reactant: COC(CNC1CCCC1)OC
Reactant: CCc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCOCCC(=O)O)c4Cl)CC3)C2)cs1
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: ClCCl
Product: CCc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCOCCC(=O)N(CC(OC)OC)C5CCCC5)c4Cl)CC3)C2)cs1
Reaction time: 1 h
Yield: 95 %

Procedure:
To a solution of 3-(2-chloro-3-((4-(2-ethylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)phenethoxy)propanoic acid (9.8 g) in DCM (100 mL) was added Hunig's Base (9.58 mL). The reaction was stirred for 10 mins before the addition of N-(2,2-dimethoxyethyl)cyclopentanamine (4.12 g) followed by HATU (7.65 g). After 1 h, the reaction mixture was diluted with DCM (200 mL) and washed with saturated sodium bicarbonate (300 mL) followed by water (300 mL). The DCM solution was dried over Na2SO4, filtered and evaporated in vacuo. The crude product was purified by silica chromatography, eluting with 2 to 5% 7N/NH3/methanol in dichloromethane to afford 3-(2-chloro-3-((4-(2-ethylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)phenethoxy)-N-cyclopentyl-N-(2,2-dimethoxyethyl)propanamide (12.0 g) as a pale yellow gum.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:4]([C:5](F)=[O:6])[C:3]=1[C:14](F)=[O:15].FC1(F)C2C(=C(F)C(F)=C(F)C=2F)C(=O)[O:19]1.C(=O)([O-])O.[Na+]>>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:4]2[C:5](=[O:19])[O:6][C:14](=[O:15])[C:3]=12
Reactant: O=C(F)c1c(F)c(F)c(F)c(F)c1C(=O)F
Reactant: O=C1OC(F)(F)c2c(F)c(F)c(F)c(F)c21
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Yield: 72.5 %

Procedure:
Into a 100 ml glass reactor equipped with a reflux condenser and a stirrer, 50 g (0.207 mol) of the mixture (1:1) of the 3,4,5,6-tetrafluorophthaloyldifluoride and the 3,3,4,5,6,7-hexafluoro-1-[3H]-isobenzofuranone of Example 2, and 17.4 g (0.207 mol) of sodiumhydrogen carbonate were charged, and the mixture was reacted at 130° C. for 5 hours with vigorous stirring. Then the reaction mixture was separated by distillation to obtain 33.0 g of tetrafluorophthalic anhydride. The yield was 72.5%.
Reaction SMILES: [C:1]1([NH:7][C:8](=[S:18])[NH:9]/[N:10]=[CH:11]/[C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[C:1]1([NH:7][C:8]2[S:18][C:11]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)=[N:10][N:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: S=C(N/N=C/c1cccnc1)Nc1ccccc1
Agent: Cl[Fe](Cl)Cl
Solvent: O
Solvent: CCO
Product: c1ccc(Nc2nnc(-c3cccnc3)s2)cc1
Temperature: 95 °C
Reaction time: 2 h
Yield: 25.1 %

Procedure:
Powdered iron(III) chloride hexahydrate (5.1 g, 19 mmol, 4.0 equiv) was added to a stirred suspension of (E)-4-phenyl-1-(pyridin-3-ylmethylene)thiosemicarbazide (1.2 g, 4.7 mmol, 1.0 equiv) in absolute ethanol (47 mL) at 23° C. The resulting dark brown suspension was heated to 95° C. and stirred for 2 h. The cooled reaction mixture was concentrated by rotary evaporation. The residue was diluted with a 1M solution of sodium hydroxide (200 mL) and extracted with dichloromethane (8×75 mL). The combined organic layers were dried (Na2SO4), gravity-filtered, and concentrated by rotary evaporation to afford the title compound as a tan solid (300 mg, 25%): mp 252-255° C.; IR (KBr thin film) 3460 (w), 3260 (w), 3198 (w), 2921 (w), 2851 (w), 2788 (w), 1620 (m), 1566 (m), 1501 (s) cm−1; 1H NMR (300 MHz, DMSO-d6) δ 10.65 (s, 1H), 9.05 (d, J=2 Hz, 1H), 8.67 (dd, J=5, 2 Hz, 1H), 7.66 (m, 2H), 7.56 (dd, J=8, 5 Hz, 1H), 7.38 (m, 2H), 7.05 (m, 1H); ESIMS m/z 255 ([M+H]+). Precursors N-methyl-5-[4-(trifluoromethyl)pyridin-3-yl]-1,3,4-thiadiazol-2-amine, N-methyl-5-[4-(trifluoromethyl)pyridin-3-yl]-1,3,4-thiadiazol-2-amine, N-methyl-5-pyrimidin-5-yl-1,3,4-thiadiazol-2-amine, 5-(6-chloropyridin-3-yl)-N-methyl-1,3,4-thiadiazol-2-amine, 5-(5-fluoropyridin-3-yl)-N-methyl-1,3,4-thiadiazol-2-amine, 5-(5-chloropyridin-3-yl)-N-methyl-1,3,4-thiadiazol-2-amine, N-methyl-5-(2-methylpyrimidin-5-yl)-1,3,4-thiadiazol-2-amine, N,N-dimethyl-5-[5-(methylamino)-1,3,4-thiadiazol-2-yl]pyrimidin-2-amine, N-methyl-5-[5-(trifluoromethyl)pyridin-3-yl]-1,3,4-thiadiazol-2-amine, N-methyl-5-pyridin-4-yl-1,3,4-thiadiazol-2-amine, and N-methyl-5-(5-methylpyridin-3-yl)-1,3,4-thiadiazol-2-amine were prepared as described in Example 3.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[CH:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1)=[C:2]=[S:3].[NH2:26][CH:27]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[CH2:28][OH:29]>O1CCCC1>[OH:29][CH2:28][CH:27]([NH:26][C:2]([NH:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[CH:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1)=[S:3])[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1
Reactant: COc1ccc(C(N)CO)cc1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(CO)NC(=S)Nc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-(4-isothiocyanato-phenyl)-1-(4-trifluoromethoxy-phenyl)-1H-1,2,4-triazole (1.09 g, 2.70 mmol) in tetrahydrofuran (7 mL) was added 2-amino-2-(4-methoxyphenyl)ethanol (0.506 g, 3.30 mmol) (Reggelin, M. et al., Synlett, 2012, 23, 1095-1098). The reaction was stirred overnight at room temperature. The reaction mixture was concentrated and the residue was recrystallized with petroleum ether providing the title compound as a white solid (1.42 g, 81%): 1H NMR (300 MHz, CDCl3) δ 7.96 (s, 1H), 7.72-7.57 (m, 2H), 7.27 (s, 1H), 7.23-7.14 (m, 2H), 6.87-6.72 (m, 4H), 6.64-6.56 (m, 2H), 6.38-6.22 (m, 3H), 5.05 (s, 1H), 3.47-3.28 (m, 2H), 3.20 (s, 3H); ESIMS m/z 530 ([M+H]+).
Reaction SMILES: Br.Br.[OH:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.Cl[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=3)[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: Oc1ccc(N2CCNCC2)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Oc1ccc(N2CCN(c3ccc(C(F)(F)F)cn3)CC2)cc1
Temperature: 80 °C
Reaction time: 9 h
Yield: 57.3 %

Procedure:
A mixture of 6.82 g (20 mmol) of 1-(4-hydroxyphenyl)piperazine dihydrobromide, 3.36 g (18.5 mmol) of 2-chloro-5-trifluoromethylpyridine, 2.91 g (21 mmol) of powdered K2CO3 and 76 ml of absolute DMF was warmed to 80° C., and 460 mg of powdered K2CO3 were added with stirring at 80° C. in each case after 10 minutes, after a further 25 minutes and after a further 60 minutes (a total of 1.38 g (10 mmol) of K2CO3), and the mixture was stirred for a further 9 hours at 80° C. After removing the DMF by distillation in vacuo, the residue was taken up in CH2Cl2 /water, the phases were separated after thorough mixing, and the aqueous solution was extracted three times with CH2Cl2. The combined CH2Cl2 extracts were dried, filtered and evaporated in vacuo. The residue (6 g) was dissolved in boiling methanol. The turbid solution formed was filtered through kieselguhr under suction, concentrated to half the volume, and cooled in an ice bath. The crystals which precipitated out were filtered off under suction and dried. The filtrate, after further concentration and cooling, precipitated further crystalline substance, which was filtered off under suction and recrystallized from a little methanol. In this fashion, 3.43 g (=57.4% yield) of 1-(4-hydroxyphenyl)-4-(5-trifluoromethylpyrid-2-yl)piperazine, melting point 178°-79° C., were obtained.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]([O:7][CH2:8]SC1C=CC=CC=1)=[O:6])[CH3:2].S(Cl)([Cl:19])(=O)=O.C1CCCCC=1>C(Cl)Cl>[CH2:1]([O:3][CH2:4][C:5]([O:7][CH2:8][Cl:19])=[O:6])[CH3:2]
Reactant: CCOCC(=O)OCSc1ccccc1
Reactant: O=S(=O)(Cl)Cl
Solvent: C1=CCCCC1
Solvent: ClCCl
Product: CCOCC(=O)OCCl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.7 %

Procedure:
To a solution of (phenylthio)methyl 2-ethoxyacetate (17.28 g, 76 mmol) in CH2Cl2 (200 mL) at 0° C. was added a solution of sulfuryl chloride (7.36 mL, 92 mmol) in CH2Cl2 (50 mL) over a period of 15 min, and the reaction was stirred at room temperature for 90 min. The reaction was again cooled to 0° C. and treated with a second portion of sulfuryl chloride (7.36 mL, 92 mmol) in CH2Cl2 (50 mL) over a period of 15 min. The reaction was then warmed to 30° C., stirred for 1 hour, and then cooled back to 0° C. A solution of cyclohexene (24.5 mL, 242 mmol) in CH2Cl2 (50 mL) was added over a period of 10 min, during which gas evolution was observed. The reaction was stirred at room temperature for 90 min, stored at −20° C. overnight, and purified by vacuum distillation to give the target compound as a slightly yellow oil (11.33 g, 97%): by 58° C. at 6.8 mm Hg; 1H NMR (400 MHz, CDCl3) δ 5.77 (s, 2H), 4.16 (s, 2H), 3.62 (q, J=7.0 Hz, 2H), 1.27 (t, J=7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 168.81, 68.59, 67.77, 67.48, 14.96.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:27])[C:6]1[CH:15]=[C:14]([O:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)[CH:13]=[C:8]([C:9]([O:11]C)=[O:10])[CH:7]=1.Cl>O.CCO>[CH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[CH:26][C:17]=1[O:16][C:14]1[CH:13]=[C:8]([C:9]([OH:11])=[O:10])[CH:7]=[C:6]([CH:15]=1)[C:5]([OH:27])=[O:4]
Reactant: COC(=O)c1cc(Oc2ccc3ccccc3c2)cc(C(=O)OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(Oc2ccc3ccccc3c2)cc(C(=O)O)c1
Temperature: 25 °C

Procedure:
A solution of LiOH (1.5 mmol) in water (1 ml) was added to 5-(naphthalene-2-yloxy)-isophthalic acid dimethylester (0.5 mmol) suspended in 5 ml EtOH. The mixture was stirred at room temperature. The reaction was monitored by TLC until completion. 2.5 ml 1 M HCl solution was added and the precipitation was collected. The product was used in next step without further purification.