Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C@H:7]2[CH2:9][C@H:8]2[CH2:10][CH2:11][OH:12])[CH2:3][CH2:2]1.ClC1C=NC(N2CCC([C@H]3C[C@H]3CCO)CC2)=NC=1.Cl[C:33]1[N:38]=[CH:37][C:36]([CH2:39][CH3:40])=[CH:35][N:34]=1>>[CH2:39]([C:36]1[CH:35]=[N:34][C:33]([N:1]2[CH2:6][CH2:5][CH:4]([C@H:7]3[CH2:9][C@H:8]3[CH2:10][CH2:11][OH:12])[CH2:3][CH2:2]2)=[N:38][CH:37]=1)[CH3:40]
Reactant: OCC[C@@H]1C[C@@H]1C1CCNCC1
Reactant: CCc1cnc(Cl)nc1
Agent: OCC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1
Product: CCc1cnc(N2CCC([C@H]3C[C@H]3CCO)CC2)nc1

Procedure:
2-{(1S,2R)-2-[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanol was synthesized from 2-((1S,2R)-2-(piperidin-4-yl)cyclopropyl)ethanol according to the method described for 2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanol employing 2-chloro-5-ethylpyrimidine. MS (ESI) m/z 276.1 (M+H).
Reaction SMILES: [H-].[Na+].[C:3]1([NH:9][C:10]2[S:14][N:13]=[N:12][C:11]=2[C:15]([NH2:17])=[O:16])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].[K+].[Br-]>CN(C=O)C>[C:24]1([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:3][NH:9][C:10]2[S:14][N:13]=[N:12][C:11]=2[C:15]([NH2:17])=[O:16])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NC(=O)c1nnsc1Nc1ccccc1
Reactant: CCCCCCCCCCCCCCBr
Agent: [Br-]
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1nnsc1NCCCCCCCCCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice-cooled suspension of NaH (19 mg, 60 wt % in oil, 0.46 mmole) in 3 mL of DMF was added 5-phenylamino-[1,2,3]thiadiazole-4-carboxylic acid amide (100 mg, 0.46 mmole). The mixture was stirred at room temperature for 1 h. 1-Bromotetradecane (131 mg, 0.47 mmole) was then added to the reaction mixture which was cooled in an ice bath. The reaction was carried out overnight with stirring and then quenched with a mixture of 5 mL of saturated aqueous NH4Cl, 5 mL of saturated aqueous NaCl and 10 mL EtOAc. The aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layers were dried with anhydrous Na2SO4, concentrated and then purified by preparative TLC with hexane:EtOAc (1:1) as the eluant. A white powder product was obtained (122 mg, 66%). m.p. 79-81° C. 1H NMR (ppm, CDCl3): 7.60-7.44 (m, 5 H), 7.20 (s, br., 1 H), 5.63 (s, br., 1 H), 2.96 (t, 2 H), 1.43-1.00 (m, 24 H), 0.88 (t, 3 H). FTIR (cm−1, KBr pellet): 3386, 3299, 2918, 2851, 1674, 1657, 1600, 1527, 1503, 1384, 1299, 999, 766, 743, 693.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[F:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([F:21])=[C:16]([F:22])[C:15]=1[OH:23].C([O-])([O-])=O.[K+].[K+].C(#N)C>O>[F:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([F:21])=[C:16]([F:22])[C:15]=1[O:23][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: Oc1c(F)c(F)cc(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: N#Cc1cc([N+](=O)[O-])ccc1Oc1c(F)c(F)cc(F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
In a 250 ml single-neck flask equipped with a magnetic stirrer and a reflux condenser fitted with a nitrogen bubbler were placed 9.13 g (0.050 moles) of 2-chloro-5-nitrobenzonitrile, 8.55 (0.0515 moles) of 2,3,5,6-tetrafluorophenol, 7.10 g (0.0515 moles) of anhydrous K2CO3, and 75 ml of acetonitrile. The mixture was heated to reflux and held there for 3 hrs. The reaction mixture was then cooled to room temperature and diluted with 150 ml of deionized water. The product separated as a solid. The solid was filtered off, washed thoroughly with water, and air-dried. The air-dried solid was recrystallized from 300 ml of absolute ethanol to give 11.36 g (73% yield) of purified 2-(2,3,5,6-tetrafluorophenoxy)-5-nitrobenzonitrile, mp 152.5°-154.5° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([CH:22]=[CH:23][N:24]=2)[C:18]([O:20][CH3:21])=[O:19])=[CH:11][C:10]=1[C:25]#[N:26])C1C=CC=CC=1.CC1C(C)=C(C)C(C)=C(C)C=1>FC(F)(F)C(O)=O>[C:25]([C:10]1[CH:11]=[C:12]([C:15]2[CH:16]=[C:17]([CH:22]=[CH:23][N:24]=2)[C:18]([O:20][CH3:21])=[O:19])[CH:13]=[CH:14][C:9]=1[OH:8])#[N:26]
Reactant: COC(=O)c1ccnc(-c2ccc(OCc3ccccc3)c(C#N)c2)c1
Agent: Cc1cc(C)c(C)c(C)c1C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccnc(-c2ccc(O)c(C#N)c2)c1

Procedure:
Methyl 2-[4(benzyloxy)-3-cyanophenyl]isonicotinate and pentamethylbenzene were heated under reflux temperature in trifluoroacetic acid to obtain methyl 2-(3-cyano-4-hydroxyphenyl)isonicotinate. F: 255.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([OH:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25].O>C(Cl)Cl>[C:1]([O:5][C:6]([NH:7][C@@H:8]1[CH2:9][CH2:10][C@H:11]([O:14][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:12][CH2:13]1)=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](OS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100.8 %

Procedure:
A solution of cis (4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester (1.00 g, 4.70 mmol) in DCM (10 mL) was treated with triethylamine (1.29 mL, 9.30 mmol) and the mixture was cooled to 0° C. Methanesulfonyl chloride (0.54 mL, 7.00 mmol) was added dropwise and the mixture was stirred at 0° C. for 15 minutes. Water was added and the phases were separated. The aqueous phase was extracted with DCM (×2) and the combined organic phase was washed with saturated sodium hydrogen carbonate solution, and brine, dried with sodium sulfate and concentrated under vacuum to give 1.39 g (quant) of Cis methanesulfonic acid 4 tert-butoxycarbonylamino-cyclohexyl ester as a peach coloured solid which was used without further purification. 1H NMR (400 MHz, CDCl3) δ: 4.89 (m, 1H), 4.46 (br s, 1H), 3.53 (br s, 1H), 3.01 (s, 3H), 2.05 (m, 2H), 1.84-(m, 2H), 1.73 (m, 2H), 1.58 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: Cl.O[CH2:3][C:4]1[N:5]=[CH:6][NH:7][CH:8]=1.S(Cl)(Cl)=O.[CH3:13][C:14]1([CH3:25])[CH2:23][CH:22]([CH3:24])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15]1>CN(C=O)C>[CH3:13][C:14]1([CH3:25])[CH2:23][CH:22]([CH3:24])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]1[CH2:3][C:4]1[N:5]=[CH:6][NH:7][CH:8]=1
Reactant: CC1CC(C)(C)Nc2ccccc21
Reactant: OCc1c[nH]cn1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC1CC(C)(C)N(Cc2c[nH]cn2)c2ccccc21
Reaction time: 2 h
Yield: 39 %

Procedure:
In 10 ml of ethanol was dissolved 2.0 g (11.5 millimoles) of 1,2-dihydro-2,2,4-trimethylquinoline, and 0.4 g of 10% Pd-C was added to the solution and reaction was carried out at 60° C. in a hydrogen atmosphere for 7 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to obtain 1.8 g (the yield was 89%) of 2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline in the form of a light-brown oil. To 0.5 g (3.7 millimoles) of 4-hydroxymethylimidazole hydrochloride was added 3 ml of thionyl chloride and reaction was carried out at 50° C. for 2 hours. The excess of thionyl chloride was removed by distillation under reduced pressure. The residue was dissolved in 10 ml of DMF and a solution of 1.1 g (6.3 millimoles) of 2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline in 5 ml of DMF was added to the above solution at 100° C. Reaction was carried out for 1 hour. DMF was removed from the reaction mixture by distillation under reduced pressure. An aqueous solution of sodium hydrogen-carbonate was added to the residue and the mixture was extracted with dichloromethane. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain a light-green oil. The oil was purified by the silica gel column chromatography (developing solvent; ethyl acetate) to obtain 0.35 g (the yield was 39%) of 4-[1-(2,2,4-trimethyl-1,2,3,4-tetrahydroquinolyl)methyl]imidazole in the form of a colorless crystal. Reaction was carried out in the same manner as described in Example 3 by using 4-[1-(2,2,4-trimethyl-1,2,3,4-tetrahydroquinolyl)methyl]imidazole to obtain 0.35 g (the yield was 30%) of intended compound No. 8 in the form of a light-brown oil.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([N:19]([C:21](=[O:23])[CH3:22])[OH:20])[CH3:18])[C:12]=1[Cl:24].Cl.[NH2:27][NH2:28]>[Cl-].[Na+].O>[C:21]([N:19]([OH:20])[CH:17]([C:13]1[C:12]([Cl:24])=[C:11]([NH:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:27][NH2:28])=[O:2])[CH:16]=[CH:15][CH:14]=1)[CH3:18])(=[O:23])[CH3:22]
Reactant: NN
Reactant: COC(=O)c1ccccc1Nc1cccc(C(C)N(O)C(C)=O)c1Cl
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC(=O)N(O)C(C)c1cccc(Nc2ccccc2C(=O)NN)c1Cl
Temperature: 25 °C
Yield: 69 %

Procedure:
2[[3-[1-(Acetylhydroxyamino)ethyl]-2-chlorophenyl]amino]benzoic acid methyl ester (4.0 g, 11.0 mmoles) is suspended in neat hydrazine (30 mL) and stirred at room temperature. When all solid is dissolved (approximately 10 minutes after addition) the reaction mixture is diluted with 300 mL of cold brine. The pH of the solution is lowered to pH 7 by the addition of concentrated HCl. The precipitate is collected by filtration and recrystallized from EtOAc to give 2-[[3-[1-(acetylhydroxyamino]ethyl]-2-chlorophenyl]amino]benzoic acid hydrazide (2.8 g, 69%); m.p. 193°-195° C.
Reaction SMILES: C(O)(=O)/C=C/C(O)=O.[S:9]1[CH:13]=[C:12]([CH2:14][N:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[N:17]=[C:16]2[NH:24][CH:25]2[CH2:29][CH2:28][N:27](C(OCC)=O)[CH2:26]2)[N:11]=[CH:10]1.[BrH:35]>O>[BrH:35].[BrH:35].[NH:27]1[CH2:28][CH2:29][CH:25]([NH:24][C:16]2[N:15]([CH2:14][C:12]3[N:11]=[CH:10][S:9][CH:13]=3)[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[N:17]=2)[CH2:26]1
Reactant: CCOC(=O)N1CCC(Nc2nc3cccnc3n2Cc2cscn2)C1
Agent: Br
Agent: O=C(O)/C=C/C(=O)O
Solvent: O
Product: c1cnc2c(c1)nc(NC1CCNC1)n2Cc1cscn1
Temperature: 100 °C
Reaction time: 22 h
Yield: 79.4 %

Procedure:
A mixture of 157.0 parts of ethyl 3-[[3-(4-thiazolylmethyl)-3H-imidazo[4,5-b]pyridin-2-yl]amino]-1-pyrrolidinecarboxylate (E)-2-butenedioate(2:3) and 870 parts of a hydrobromic acid solution 48% in water was stirred for 22 hours at 100° C. After cooling, the precipitate was filtered off and washed with water. The filtrate was evaporated. The residue was taken up three times in methylbenzene and the solvent was evaporated each time. The oily residue was stirred in 2-propanone. The precipitate was filtered off and the filtrate was evaporated. The residue was taken up in boiling ethanol. The clear solution was filtered and the filtrate was allowed to crystallize over weekend while stirring. The crystallized product was filtered off, washed with ethanol and dried in vacuo at 50° C., yielding 106.5 parts (79.4%) of N-(3-pyrrolidinyl)-3-(4-thiazolylmethyl)-3H-imidazo[4,5-b]pyridin-2-amine dihydrobromide; mp. 260.5° C. (compound 38).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH2:7][N:6]1[C:20](=O)[CH2:21][C:22](=[O:24])[CH3:23])=[O:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH2:7][N:6]1[C:20](=[S:35])[CH2:21][C:22](=[O:24])[CH3:23])=[O:4]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)CC(C)=O
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=S)CC(C)=O

Procedure:
In analogy to the procedure described in example 192 g, (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-(3-oxo-butyryl)-pyrrolidine-2-carboxylic acid methyl ester was reacted with Lawesson's reagent to give the title compound as red solid. MS (ESI): m/z=404.1 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([Cl:18])[C:6]2[O:10][CH:9]([CH2:11][NH:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][C:7]=2[CH:17]=1.[C:19](Cl)([Cl:21])=[O:20]>C(OCC)(=O)C>[Cl:2][C:3]1[CH:4]=[C:5]([Cl:18])[C:6]2[O:10][CH:9]([CH2:11][N:12]([CH2:13][CH2:14][CH2:15][CH3:16])[C:19]([Cl:21])=[O:20])[CH2:8][C:7]=2[CH:17]=1
Reactant: O=C(Cl)Cl
Reactant: CCCCNCC1Cc2cc(Cl)cc(Cl)c2O1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCN(CC1Cc2cc(Cl)cc(Cl)c2O1)C(=O)Cl
Reaction time: 4 h

Procedure:
A thoroughly stirred suspension of 26 g (0.0838 mole) of N-(5,7-dichloro-2,3-dihydrobenzofuran-2-ylmethyl)-N-butylamine hydrochloride in 250 ml of dry ethyl acetate was gassed with phosgene at 50° C. After 4 hours, the suspended material had dissolved. The mixture was evaporated down under reduced pressure, at 50° C. and under 0.5 mbar in the final stage. 27 g of N-(5,7-dichloro-2,3-dihydrobenzofuran-2-ylmethyl)-N-butylcarbamyl chloride were obtained as a colorless oil, which was reacted further without additional purification.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][CH:11]([CH2:23][CH3:24])[CH:12]([C:14]1[O:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1)[OH:13].[C:25]([O:29][C:30](=[O:32])N)([CH3:28])([CH3:27])[CH3:26]>C(Cl)Cl>[C:25]([O:29][C:30](=[O:32])[NH:10][CH:11]([CH:12]([C:14]1[O:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1)[OH:13])[CH2:23][CH3:24])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(N)=O
Reactant: CCC(N)C(O)c1nc2ccccc2o1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(NC(=O)OC(C)(C)C)C(O)c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
DIPEA (0.35 ml, 2 mmol) and di-tret-butyl dicarbonate (355 mg, 1.63 mmol) were added to a solution of 2-Amino-1-benzooxazol-2-yl-butan-1-ol (320 mg, 1.55 mmol) in dry methylene chloride (10 ml) and stirred at room temperature for 4 hrs. The reaction was quenched with saturated aqueous NH4Cl and the pH was adjusted to neutral. Oraganic layer separated and the aqueous layer extracted with methylene chloride. The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure to give, 1-(Benzooxazol-2-yl-hydroxy-methyl)-propyl]-carbamic acid tert-butyl ester (500 mg).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[Cl:20][C:21]1[CH:26]=[C:25](Cl)[N:24]=[CH:23][N:22]=1>C(O)C>[Cl:20][C:21]1[N:22]=[CH:23][N:24]=[C:25]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)[CH:26]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: C1CC2(CCN1)OCCO2
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Clc1cc(N2CCC3(CC2)OCCO3)ncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
To a solution of 1,4-dioxa-8-azaspiro[4,5]decane (9.02 g) and diisopropylethylamine (9.77 g) in ethanol (30 ml) was added 4,6-dichloropyrimidine (9.88 g), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, and the residue was diluted with dichloromethane (150 ml). The mixture was washed with 0.3N sodium hydroxide solution and saturated brine, dried and concentrated, and the residue was crystallized from diethylether to give colorless crystals of 8-(6-chloropyrimidine-4-yl)-1,4-dioxa-8-azaspiro[4,5]decane (15.84 g).
Reaction SMILES: C([Li])CCC.[S:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1.CON(C)[C:18](=[O:20])[CH3:19]>C1COCC1>[S:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:18](=[O:20])[CH3:19]
Reactant: CON(C)C(C)=O
Reactant: c1ccc2scnc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)c1nc2ccccc2s1
Temperature: -78 °C
Reaction time: 3 h
Yield: 38.1 %

Procedure:
Butyllithium (10.2 mL, 16.3 mmol, 1.6 M, 1.1 Eq) was added dropwise to a stirred solution of benzothiazole (1.6 mL, 14.8 mmol, 1.0 Eq) in anhydrous THF (15 mL) at −78° C. under nitrogen. The resultant solution was stirred at −78° C. for one hour. N-Methoxy-N-methylacetamide (1.7 mL, 16.3 mmol, 1.1 Eq) was added in one portion and the reaction stirred at −78° C. for 3 hours. The resultant solution was allowed to warm to room temperature overnight. The reaction was quenched by the addition of 1M HCl (10 mL) and extracted with ethyl acetate (3×15 mL). The combined organic extracts were dried over solid MgSO4 and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (10% ethyl acetate in hexanes) to give the title compound as a yellow solid (1.0 g, 39% yield): 1H NMR (400 Mhz, CDCl3) δ 2.85 (3H, s), 7.54-7.62 (2H, m), 8.01 (1H, d), 8.21 (1H, d); MS: ES+ 178.0 (100%).
Reaction SMILES: CS[C:3]1[N:4]([CH2:15][CH2:16][CH3:17])[C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:6][N:7]=1>[Ni].C(O)C>[CH2:15]([N:4]1[C:5]([C:8]2[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=2)=[CH:6][N:7]=[CH:3]1)[CH2:16][CH3:17]
Reactant: CCCn1c(-c2ccc(O)cc2)cnc1SC
Agent: [Ni]
Solvent: CCO
Product: CCCn1cncc1-c1ccc(O)cc1
Yield: 61 %

Procedure:
A mixture of 12 parts of 4-[2-(methylthio)-1-propyl-1H-imidazol-5-yl]phenol, 10 parts of Raney-nickel catalyst and 80 parts of ethanol is stirred and refluxed for 2 hours. The Raney-nickel is filtered off and the filtrate is stirred and refluxed for 2 hours with another 10 parts of Raney-nickel catalyst. The Raney-nickel catalyst is filtered off and the filtrate is evaporated, yielding 5.5 parts (61%) of 4-(1-propyl-1H-imidazol-5-yl)phenol; mp. 160° C.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:1]1([O:11][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1cccc2ccccc12
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)COc1cccc2ccccc12
Yield: 80 %

Procedure:
432 g 1-naphthol, 602 g ethyl 2-bromoacetate, 276 g potassium carbonate and 2.160 l. ethanol are refluxed for 18 hours, the precipitate filtered, the solvent evaporated under reduced pressure and the residue recrystallized from petroleum ether. The ester, which melts at 52° C., is obtained with an 80% yield.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=2)[CH2:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)([CH3:13])[CH3:12])=[N:7][CH:8]=1)[CH3:2].S(Cl)([Cl:36])(=O)=O>C(OCC)C>[Cl:36][C:18]1[CH:19]=[C:14]([C:11]([CH3:13])([CH3:12])[CH2:10][N:9]([C:6]2[N:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][N:7]=2)[CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][C:29]([F:31])([F:32])[F:30])=[CH:26][CH:27]=2)[CH:15]=[CH:16][C:17]=1[OH:20]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCc1cnc(N(Cc2ccc(OC(F)(F)F)cc2)CC(C)(C)c2ccc(O)cc2)nc1
Solvent: CCOCC
Product: CCc1cnc(N(Cc2ccc(OC(F)(F)F)cc2)CC(C)(C)c2ccc(O)c(Cl)c2)nc1
Yield: 24.9 %

Procedure:
To a solution 4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}-1,1-dimethylethyl)phenol (300 mg; 0.67 mmol) in ethyl ether (0.1M) was added sulfuryl chloride (0.060 ml; 0.74 mmol). After 10 minutes an additional 0.3 eq of sulfuryl chloride were added. Stirred 20 more minutes. Partitioned between ethyl acetate and dilute sodium bicarbonate solution. Organic phase was washed with saturated brine, dried over sodium sulfate and concentrated. Purification by radial chromatography on silica gel using a dichloromethane-hexane gradient (30–90%) provided the title compound (80 mg; 25% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]1([C:11]([OH:13])=[O:12])[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C.O>[CH2:1]([O:3][C:4]1([C:11]([O:13][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:12])[CH2:5][CH2:6][C:7](=[O:10])[CH2:8][CH2:9]1)[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC1(C(=O)O)CCC(=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC1(C(=O)OCc2ccccc2)CCC(=O)CC1
Temperature: 60 °C
Yield: 78.2 %

Procedure:
To a solution of 1-ethoxy-4-oxocyclohexanecarboxylic acid (0.777 g, 4.17 mmol) in DMF (15 mL) was added potassium carbonate (1.153 g, 8.35 mmol) followed by benzyl bromide (0.546 mL, 4.59 mmol). The mixture was heated at 60° C. for 18 h, then cooled to rt. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (2×30 mL). The organic layers were washed with water (3×30 mL), then with brine and dried over magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography using a 0-25% ethyl acetate in hexanes gradient and a 24 g silica gel column to give benzyl 1-ethoxy-4-oxocyclohexanecarboxylate (0.9 g, 3.26 mmol, 78% yield) as a light-yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ=7.40-7.32 (m, 5H), 5.21 (s, 2H), 3.48 (q, J=6.9 Hz, 2H), 2.65-2.54 (m, 2H), 2.39-2.27 (m, 4H), 2.20-2.09 (m, 2H), 1.24 (t, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])(=O)[CH3:2].[BH4-].[Na+].[C:16](O)(=O)C.O>O1CCCC1>[CH2:1]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:16])=[O:11])[CH3:2]
Reactant: COC(=O)CCCCCNC(C)=O
Reactant: CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCNCCCCCC(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Crude methyl 6-acetylamino-hexanoate (5.19 g) is dissolved in tetrahydrofuran (50 ml) and thereto is added sodium borohydride (5.03 g). The reaction solution is heated under reflux and thereto is added dropwise acetic acid (7.6 ml) and the mixture is heated under reflux for 1 hour and 30 minutes. To the reaction solution is added water under ice-cooling and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is dissolved in ethanol (30 ml) and thereto is added a 4N-hydrochloric acid in ethyl acetate (7.6 ml) and the mixture is stirred at room temperature overnight. To the reaction solution are added a 2N-aqueous sodium hydroxide solution and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give ethyl 6-ethylamino-hexanoate (1.74 g) as a crude product. MS (m/z): 188 [M+H]+
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([CH2:21][NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:15]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:13][C:14]1[CH:19]=[CH:18][C:17]2[O:20][C:1](=[O:2])[N:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:21][C:16]=2[CH:15]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Oc1ccc(Br)cc1CNc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C1Oc2ccc(Br)cc2CN1c1ccccc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 99.6 %

Procedure:
Step 2 Carbonyldiimidazole (0.874 g, 5.39 mmol) and DMAP (0.088 g, 0.719 mmol) were added to a solution of 4-bromo-2-((phenylamino)methyl)phenol (1.00 g, 3.60 mmol) in DCM (100 mL) and the resulting mixture was stirred at rt for 60 h. The mixture was diluted with hexanes (100 mL), washed with NaHCO3 (aq) (2×25 mL), 1 M hydrochloric acid (25 mL) and brine (25 mL), dried and filtered through a pad of silica gel. The solids were rinsed with 1:1 EtOAc-hexane and the filtrate was concentrated to give 6-bromo-3-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazin-2-one as a white solid (1.09 g, 100%). 1H NMR (400 MHz, DMSO-d6) δ 7.41-7.56 (3H, m), 7.30-7.41 (3H, m), 7.21-7.29 (1H, m), 7.01 (1H, d, J=8.80 Hz), 4.80 (2H, s). Mass spectrum m/z 304, 306 (M+H)+.