Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][C:6]([CH2:22][OH:23])=[CH:7][C:8]1([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[F:21])[CH2:10][CH2:9]1.C1C=CC=CC=1>N1C=CC=CC=1>[C:1]([O:23][CH2:22][C:6]([F:5])=[CH:7][C:8]1([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][C:12]=2[F:21])[CH2:10][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: OCC(F)=CC1(c2ccc(C(F)(F)F)cc2F)CC1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC(=O)OCC(F)=CC1(c2ccc(C(F)(F)F)cc2F)CC1
Yield: 99 %

Procedure:
The method of Example 17 was repeated using acetyl chloride (0.7 ml), 1-(2-fluoro-3-hydroxyprop-1-enyl)-1-(2-fluoro-4-trifluoromethylphenyl)cyclopropane (Example 13) (0.37 g), benzene (20 ml) and pyridine (0.12 ml) to yield the title compound (0.43 g, 99%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]O)=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:42]>ClCCl>[CH2:1]([O:3][C:4]([CH:6]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][Br:42])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C(Oc1ccc(CO)cc1)c1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)C(Oc1ccc(CBr)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
28.6 g (0.1 mol) of 4-(α-ethoxycarbonyl-benzyloxy)benzyl alcohol are dissolved in 300 ml of dichloromethane and mixed with 31.6 g (0.12 mol) of triphenylphosphine. Whilst cooling with ice, a solution of 40.0 g (0.12 mol) of carbon tetrabromide in 100 ml of dichloromethane is added dropwise. The mixture is stirred for 30 minutes at ambient temperature and then concentrated by evaporation. The residue is purified over a silica gel column (particle size: 0.063-0.02 mm), using as eluant first petroleum ether and then mixtures of petroleum ether and ethyl acetate of increasing polarity (9:1 and 8:2). The unified fractions are evaporated down in vacuo.
Reaction SMILES: Br[CH2:2][C:3]#[N:4].C(N(CC)C(C)C)(C)C.[N:14]([CH2:17][CH:18]([S:32][S:33][CH3:34])[CH2:19][C@H:20]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:21]([OH:23])=[O:22])=[N+:15]=[N-:16]>C(#N)C>[C:3]([CH2:2][O:23][C:21](=[O:22])[C@@H:20]([NH:24][C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:19][CH:18]([S:32][S:33][CH3:34])[CH2:17][N:14]=[N+:15]=[N-:16])#[N:4]
Reactant: N#CCBr
Reactant: CSSC(CN=[N+]=[N-])C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CSSC(CN=[N+]=[N-])C[C@H](NC(=O)OC(C)(C)C)C(=O)OCC#N
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.7 %

Procedure:
Bromoacetonitrile (45 μl, 0.669 mmol) and N,N-diisopropylethylamine (58 μl, 0.334 mmol) were added to a solution of (S)-5-azido-2-tert-butoxycarbonylamino-4-methyldisulfanyl-pentanoic acid (Compound 35) (75 mg, 0.223 mmol) in acetonitrile (2 ml), and the reaction solution was stirred at room temperature for 5 hours. The reaction mixture was extracted with ethyl acetate/saturated ammonium chloride, and the organic layer was washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford (S)-5-azido-2-tert-butoxycarbonylamino-4-methyldisulfanyl-pentanoic acid cyanomethyl ester (Compound 36) (81 mg, 97%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[N:18][C:17]([NH2:20])=[C:16]([C:21](=[O:29])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.CO.C(Cl)Cl>[NH2:20][C:17]1[C:16]([C:21]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[O:29])=[N:15][C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:19][N:18]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cnc(N)c(C(=O)Nc3ccccn3)n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Nc1ncc(N2CCNCC2)nc1C(=O)Nc1ccccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73 %

Procedure:
Tert-butyl-4-[5-amino-6-(2-pyridylcarbamoyl)pyrazin-2-yl]piperazine-1-carboxylate (5.43 g, 13.59 mmol) was suspended in DCM (50 mL) and stirred at 0° C. during addition of TFA (10 ml). The reaction mixture was warmed to RT over 2 hours but analysis showed little deprotection. The reaction was treated with a further 30 ml of TFA and stirred at RT for 15 minutes. The mixture was concentrated under reduced pressure to give a dark red oil which was dissolved in MeOH/DCM and azeotroped with toluene to give an intense orange solid which was filtered, washed with ether and dried under high vacuum (5.41 g, 73% Yield).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:16])[NH:7][C:8]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:9][N:10]=1)[CH2:3][CH3:4].[CH3:17][C:18]1([C:25](Cl)=[O:26])[CH2:23][CH2:22][CH:21]([CH3:24])[CH2:20][CH2:19]1>>[CH:11]1([C:8]2[NH:7][C:6](=[O:16])[C:5]([CH:2]([NH:1][C:25]([C:18]3([CH3:17])[CH2:23][CH2:22][CH:21]([CH3:24])[CH2:20][CH2:19]3)=[O:26])[CH2:3][CH3:4])=[N:10][N:9]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC1CCC(C)(C(=O)Cl)CC1
Reactant: CCC(N)c1nnc(C2CCCC2)[nH]c1=O
Product: CCC(NC(=O)C1(C)CCC(C)CC1)c1nnc(C2CCCC2)[nH]c1=O

Procedure:
In analogy to the procedure for Example 36A, 150 mg (0.67 mmol) 6-(1-aminopropyl)-3-cyclopentyl-1,2,4-triazin-5(4H)-one, 130 mg (0.74 mmol) 1,4-dimethylcyclohexanecarbonyl chloride and proportionate amounts of the other reagents are used. The crude product is used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[NH2:11][C:5]1[CH:4]=[CH:3][C:2]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: Nc1ccc(Br)cc1C(=O)O
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccc(-c2ccccc2)cc1C(=O)O
Temperature: 80 °C
Reaction time: 15 h

Procedure:
1 g (4.62 mmol) of 5-bromoanthranilic acid (Fluka Buchs, Switzerland) and 6.94 ml 1M K2CO3 are stirred in 10 ml DMF. Argon gas is bubbled through the solution. 50 mg tetrakis-triphenylphosphin-palladium (Fluka) and 846 mg (6.94 mmol) phenylboronic acid (Fluka, Buchs, Switzerland) are added. The reaction mixture is stirred for 15 h at 80° C. (tlc-control). The solvent is evaporated, and 50 ml 4N NaOH are added to the residue. The aqueous phase is washed three times with ethyl acetate. Hydrochloric acid is added to the water phase until pH=7 is reached and the aqueous phase is extracted four times with ethyl acetate. After drying the organic phase with MgSO4, the solvent is evaporated and the residue crystallized from CH2Cl2-methanol-hexane. mp: 245° C. (dec.); MS: 214 (M++1); HPLC: tret=9.74 min (Grad 1).
Reaction SMILES: [O:1]1CCC(=O)C1.Cl.CNC.[C-]#N.[K+].[CH3:14][N:15]([CH3:23])[C:16]1([C:21]#[N:22])[CH2:20][CH2:19]C[CH2:17]1>O>[CH3:14][N:15]([CH3:23])[C:16]1([C:21]#[N:22])[CH2:20][CH2:19][O:1][CH2:17]1
Reactant: O=C1CCOC1
Reactant: CN(C)C1(C#N)CCCC1
Agent: CNC
Agent: Cl
Agent: [C-]#N
Solvent: O
Product: CN(C)C1(C#N)CCOC1
Yield: 88 %

Procedure:
The title compound (6.54 g, 88%) was prepared from dihydro-3(2H)-furanone D44 (4.54 g, 0.053 mol), dimethylamine hydrochloride (4.9 g, 0.06 mol) and potassium cyanide (3.5 g, 0.054 mol) in water (100 ml) in a similar manner to that described in D1. 1H NMR (CDCl3) δ: 2.15 (1H, m), 2.33 (6H, s), 2.44 (1H, m), 3.69 (1H, d), 4.02-4.13 (2H, m), 4.17 (1H, m).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([OH:9])[N:3]=1.CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>CN(C=O)C.C(OCC)C>[F:8][C:7]1[C:2]([N:1]=[CH:12][N:13]([CH3:15])[CH3:14])=[N:3][C:4]([OH:9])=[N:5][CH:6]=1
Reactant: COC(OC)N(C)C
Reactant: Nc1nc(O)ncc1F
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN(C)C=Nc1nc(O)ncc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 92 %

Procedure:
To a magnetically stirred solution of 4-amino-5-fluoro-pyrimidin-2-ol* (4.00 g, 31.0 mmol) in DMF (100 mL) was added N,N-dimethylformamide dimethyl acetal (4.00 g, 34.0 mmol). The mixture was stirred at room temperature for 72 h, diluted with diethyl ether (200 mL), and filtered. The solid product was washed with heptane to give the title compound (5.23 g, 92% yield) as a white solid: mp 240-243° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.7 (bs, 1H), 8.59 (s, 1H), 7.7 (d, J=5.6 Hz, 1H), 3.18 (s, 3H), 3.06 (s, 3H); HPLC-MS (ESI) m/z 185 (M+H)+, 183 (M−H)−. *4-amino-5-fluoro-pyrimidin-2-ol can be purchased commercially.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([CH:18]3[CH2:20][CH2:19]3)=O)=[CH:12][CH:11]=2)[N:3]=[CH:2]1.Cl.[NH2:22][OH:23]>C(O)C>[NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16](=[N:22][OH:23])[CH:18]3[CH2:20][CH2:19]3)=[CH:12][CH:11]=2)[N:3]=[CH:2]1
Reactant: O=C(c1ccc(OCCCc2c[nH]cn2)cc1)C1CC1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: ON=C(c1ccc(OCCCc2c[nH]cn2)cc1)C1CC1

Procedure:
1.2 mmol of cyclopropyl 4-(3-(1H-imidazol-4-yl)propyloxy)phenyl ketone (Example 61) and 2.4 mmol of hydroxylamine hydrochloride in 20 ml of anhydrous ethanol are heated at 60° C. for 5 hours. The mixture is treated as described in Example 138, but isolated in the form of the free base.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:6][CH:5]=[CH:4][C:3]=1[C:13]1(O)[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]1.[OH-].[Na+]>>[F:1][C:2]1[C:7]([O:8][C:9]([F:10])([F:11])[F:12])=[CH:6][CH:5]=[CH:4][C:3]=1[C:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH:14]=1
Reactant: CCCN1CCC(O)(c2cccc(OC(F)(F)F)c2F)CC1
Agent: [Na+]
Agent: [OH-]
Product: CCCN1CC=C(c2cccc(OC(F)(F)F)c2F)CC1
Temperature: 100 °C
Yield: 78.6 %

Procedure:
A mixture of 4-[2-fluoro-3-(trifluoromethoxy)phenyl]-1-propyl-piperidin-4-ol (0.83 g, 2.6 mmol) and polyphosphoric acid (10 ml) was heated at 100° C. for 2 h. The mixture was poured on to ice and was basified with 5 M sodium hydroxide. The mixture was extracted with ethylacetate (3×100 ml) and the combined organic phases was dried (MgSO4), filtered and evaporated to dryness to give the title compound (0.62 g). MS m/z (rel. intensity, 70 eV) 303 (M+, 24), 275 (14), 274 (bp), 147 (7), 133 (6).
Reaction SMILES: [NH:1]([C:11]([O:13][CH2:14][CH:15]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].FC(F)(F)C(O)=O.C([SiH](C(C)C)C(C)C)(C)C.[OH:45][C:46]([CH2:48][CH2:49][CH2:50][CH2:51][C@H:52]1[C@@H:60]2[C@@H:55]([NH:56][C:57]([NH:59]2)=[O:58])[CH2:54][S:53]1)=O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN1C(=O)CCC1>[NH:1]([C:11]([O:13][CH2:14][CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22]2[C:27]1=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:12])[C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:46]([CH2:48][CH2:49][CH2:50][CH2:51][C@H:52]1[C@@H:60]2[C@@H:55]([NH:56][C:57]([NH:59]2)=[O:58])[CH2:54][S:53]1)=[O:45]
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reactant: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CC(C)[SiH](C(C)C)C(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reaction time: 1 h

Procedure:
Fmoc-Lys (mtt)-Resin was stirred with a mixture of 1% trifluoroacetic acid (TFA) and 0.1% triisopropylsilane (TIS) in DCM at 0° C. for 30 min and then for one hour at room temperature. Then, the resin was washed with NMP and DCM, and dried in vacuum. 2.68 gr. of loaded resin were obtained. This resin was then swelled with 25 ml NMP in the Presence of 930 mg Biotin, 1.44 gr. O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluophosphate (HBTU), 513 mg N-hydroxybenzotriazole (HOBt) and 1 ml of diisopropylethylamine (DIEA). The reaction was stirred for 4.5 hr. Then, the resin was washed with NMP and DCM, and dried in vacuum. 2.8 gr. of Fmoc-Lys(Biotin)-resin were obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:43])[CH:7]=[C:8]([NH:10][C:11](=[O:42])[C:12]2[CH:17]=[C:16]([Cl:18])[C:15]([O:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][C:21]=3[C:26]([N:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]([CH:38]4[CH2:40][CH2:39]4)[CH2:30][CH2:29]3)=[O:27])=[CH:14][C:13]=2[Cl:41])[CH:9]=1)=[O:4].O.O.[OH-].[Li+].Cl>O1CCOCC1.C(OCC)(=O)C>[Cl:41][C:13]1[CH:14]=[C:15]([O:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][C:21]=2[C:26]([N:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]([CH:38]3[CH2:40][CH2:39]3)[CH2:30][CH2:29]2)=[O:27])[C:16]([Cl:18])=[CH:17][C:12]=1[C:11]([NH:10][C:8]1[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[N:6]([CH3:43])[CH:7]=1)=[O:42]
Reactant: COC(=O)c1cc(NC(=O)c2cc(Cl)c(Oc3ccncc3C(=O)N3CCN(C4CC4)c4ccccc43)cc2Cl)cn1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(NC(=O)c2cc(Cl)c(Oc3ccncc3C(=O)N3CCN(C4CC4)c4ccccc43)cc2Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
To a solution of 0.10 g (0.16 mmol) 4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester (Example 41) in 1 mL dioxane were added 1 mL water and 0.008 g (0.19 mmol) lithiumhydroxide monohydrate. The resulting suspension was stirred for 2 hours at room temperature, then heated to 80° C. for 5.5 hours. Another 0.001 g (0.024 mmol) lithiumhydroxide monohydrate were added and the reaction mixture was heated for another 1.5 hours at 80° C. After stirring at room temperature for 64 hours the reaction mixture was poured on 1M aqueous hydrochloric acid and ethyl acetate and the layers were separated. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was dissolved in N,N-dimethylformamide, filtered over a syringe microfilter and purified by preparative HPLC (Phenomenex Gemini column) with a gradient of acetonitrile:water (containing 0.05% formic acid) (10:90 to 98:2) to give the title compound as a light brown solid (0.034 g, 35%). MS (ESI): m/z=606.13 [M+H]+.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:8][S:9]([OH:12])(=O)=O.O=S(=O)=O>ClC1C=CC=CC=1Cl>[CH:6]1[C:1]([OH:7])=[CH:2][CH:3]=[C:4]([S:9]([C:4]2[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=2)(=[O:12])=[O:8])[CH:5]=1
Reactant: Oc1ccccc1
Reactant: O=S(=O)(O)O
Agent: O=S(=O)=O
Solvent: Clc1ccccc1Cl
Product: O=S(=O)(c1ccc(O)cc1)c1ccc(O)cc1
Yield: 93 %

Procedure:
188 g of phenol were reacted with 89 g of 65% strength oleum in the presence of 272 g of o-dichlorobenzene analogously to Example 1. When the reaction had ended, the 4,4'-dihydroxydiphenyl sulfone formed was filtered off directly from the reaction mixture with suction. 234 g of reaction product were obtained, which corresponds to a yield of 93% of theory, based on the phenol. The content of 4,4'-dihydroxydiphenyl sulfone (high performance liquid chromatography) was 79% by area.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.[C:12](O)(=[O:22])[C:13]1[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:15]([OH:17])=[O:16]>C(Cl)Cl>[C:15]([C:14]1[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=1[C:12]([NH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)=[O:22])([OH:17])=[O:16]
Reactant: O=C(O)c1ccccc1C(=O)O
Reactant: NCCCSc1ccncc1
Solvent: ClCCl
Product: O=C(O)c1ccccc1C(=O)NCCCSc1ccncc1
Yield: 92.3 %

Procedure:
A solution of 340 mg (2.02 mmol) of 4-(3-aminopropylthio)pyridine and 738 mg (4.98 mmol) of anhydrous phthalic acid in 5 ml of methylene chloride was stirred at room temperature for 30 minutes. The resulting crystals were filtered and dried to obtain 590 mg of the desired compound (92.3%, colorless powder), mp: 151.0°-153.3° C.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[Na+].[CH:9]1([C:15]#[N:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C1(C)C=CC=CC=1>C(O)(C)C>[OH:3][NH:2][C:15]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[NH:16]
Reactant: NO
Reactant: N#CC1CCCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: N=C(NO)C1CCCCC1
Reaction time: 0.21 h

Procedure:
To a solution of 1.9 g (27.4 mmol) of hydroxylamine hydrochloride in 22 mL of isopropyl alcohol, 3.3 g (40.3 mmol) of sodium bicarbonate was added. The resulting mixture was stirred at 25° C. to 30° C. for 10-15 min. 2.0 g (18.3 mmol) of cyclohexanecarbonitrile was added and stirred at 80° C. to 85° C. for 3-4 h. After the reaction period, the reaction mass was cooled to 25° C. to 30° C., filtered and washed with 10 mL of isopropyl alcohol. The filtrate was collected and distilled out completely to obtain a crude residue. The residue was chased with 5 mL of toluene, to yield the title compound.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].Cl[C:6]1[C:11]([C:12]#[N:13])=[CH:10][N:9]=[CH:8][CH:7]=1.C(N(C(C)C)CC)(C)C.CO>C(O)(C)C>[OH:2][CH2:1][CH2:3][NH:4][C:6]1[C:11]([C:12]#[N:13])=[CH:10][N:9]=[CH:8][CH:7]=1
Reactant: NCCO
Reactant: N#Cc1cnccc1Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: N#Cc1cnccc1NCCO
Temperature: 25 °C
Yield: 73.5 %

Procedure:
A mixture of ethanolamine (0.60 mL, 10.0 mmol), 4-chloronicotinonitrile (1.38 g, 10.0 mmol) and diisopropylethylamine (1.74 mL, 10.0 mmol) in isopropanol was heated at reflux for 2.5 hours. It was cooled to room temperature and loaded on to a 50 g SCX-2 cartridge preconditioned with methanol. The cartridge was eluted with methanol and then with a 2M solution of ammonia in methanol. Collecting appropriate fractions followed by evaporation of solvents gave the title compound as a beige solid (1.20 g, 74%). 1H NMR (d6-DMSO, 400 MHz) 8.40 (s, 1H), 8.21 (d, J=6.3 Hz, 1H), 6.94 (bs, 1H), 6.77 (d, J=6.3 Hz, 1H), 4.84 (bs, 1H), 3.55 (t, J=6.0 Hz, 2H), 3.31 (dt, J=6.0 Hz, 6.0 Hz, 2H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2N=N1.ON1C2C=CC=CC=2N=N1.NC1C=CC=CC=1.[N:45]1([C:51]2[N:52]=[C:53]([CH2:58][C:59]([O-])=[O:60])[NH:54][C:55](=[O:57])[CH:56]=2)[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1.[Na+]>CN(C)C=O>[N:45]1([C:51]2[N:52]=[C:53]([CH2:58][C:59]([NH:8][C:12]3[CH:11]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:60])[NH:54][C:55](=[O:57])[CH:56]=2)[CH2:46][CH2:47][O:48][CH2:49][CH2:50]1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Nc1ccccc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.9 %

Procedure:
370 mg of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, 113 mg of 1-hydroxybenzotriazole and 0.140 ml of aniline are added to a solution of 200 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of Example 1 in 3 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 3 hours, and then concentrated under reduced pressure. Water and ethyl acetate are added and the resulting mixture is thus stirred for 30 minutes. The precipitate formed is filtered off and dried in a rotary evaporator. After purification by silica column chromatography, eluent: dichloromethanemethanol 90/10, 161 mg of 2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]-N-phenylacetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[H-].[Na+].Br[CH:16]([C:18]1[N:23]2[N:24]=[CH:25][N:26]=[C:22]2[N:21]=[CH:20][CH:19]=1)[CH3:17]>COCCOC>[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][CH:16]([C:18]2[N:23]3[N:24]=[CH:25][N:26]=[C:22]3[N:21]=[CH:20][CH:19]=2)[CH3:17])=[CH:8][CH:9]=1
Reactant: CC(Br)c1ccnc2ncnn12
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(Oc1ccc(OC(F)(F)F)cc1)c1ccnc2ncnn12
Reaction time: 0.5 h

Procedure:
A solution of 4-trifluoromethoxyphenol (1.78 g) in dry 1,2-dimethoxyethane was added slowly to a stirred suspension of sodium hydride (0.48 g) in dry 1,2-dimethoxyethane (35 ml). The mixture was stirred for 30 minutes, then a solution of 7-(1-bromoethyl)-1,2,4-triazolo[1,5-a]pyrimidine (2,27 g, prepared in a similar manner to that described in Example 6 above) in dry 1,2-dimethoxyethane (85 ml) was added dropwise. The reaction mixture was stirred for 4 hours at room temperature. The sodium bromide was removed from the mixture by filtration. The solvent was evaporated from the mixture and the residue was dissolved in dichloromethane and washed with 200 ml of a 5% aqueous solution of sodium hydroxide followed by water. The organic layer was dried over magnesium sulphate. Evaporation of the solvent afforded a crude product which was purified by column chromatography on silica gel using as eluent a mixture of petroleum ether and ethyl acetate (in the ratio 6:4 respectively), followed by recrystallisation from a mixture of ethyl acetate and hexane to give 7-[1-(4-trifluoromethoxyphenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine. Yield 2.69 g, (m.p. 91°-93° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](Br)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+].Cl.C(=O)([O-])O.[Na+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10]([O:16][C:17]2[CH:27]=[CH:26][CH:25]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:18]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cccc(O)c1
Reactant: Brc1ncccc1OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(Oc2ncccc2OCc2ccccc2)c1
Temperature: 140 °C

Procedure:
3-Benzyloxy-2-bromopyridine (8 g, 30 mmol) and ethyl 3-hydroxybenzoate (13.3 g, 80 mmol) are dissolved in DMF (50 ml), and thereto are added potassium carbonate (28 g, 0.2 mol) and cuprous bromide (11.5 g, 80 mmol). The mixture is heated under reflux at 140° C. for one hour. After being allowed to cool, the reaction solution is acidified with a 15% aqueous hydrochloric acid solution (50 ml), and then neutralized with a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate (300 ml×2). The organic layer is washed with a saturated brine (200 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: ethyl acetate/hexane) to give 3-benzyloxy-2-(3-ethoxycarbonylphenoxy)pyridine as a pale yellow oil.
Reaction SMILES: C(OC([N:8]([CH:10]1[CH2:14][CH2:13][N:12]([S:15]([C:18]2[C:19]3[C:20]([Br:29])=[CH:21][N:22]=[C:23]([Cl:28])[C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:17])=[O:16])[CH2:11]1)[CH3:9])=O)(C)(C)C.Cl.C[OH:32]>>[OH:32][C:23]1[C:24]2[CH:25]=[CH:26][CH:27]=[C:18]([S:15]([N:12]3[CH2:13][CH2:14][CH:10]([NH:8][CH3:9])[CH2:11]3)(=[O:17])=[O:16])[C:19]=2[C:20]([Br:29])=[CH:21][N:22]=1.[ClH:28]
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(S(=O)(=O)c2cccc3c(Cl)ncc(Br)c23)C1
Reactant: CO
Agent: Cl
Product: CNC1CCN(S(=O)(=O)c2cccc3c(O)ncc(Br)c23)C1
Temperature: 60 °C
Reaction time: 30 h

Procedure:
Intermediate 24 (168 mg) obtained in Step A mentioned above is added with 10% hydrogen chloride/methanol (4 ml), and the mixture is stirred at 60° C. for 30 hours. The solvent is evaporated under reduced pressure to obtain the title compound as hydrochloride (123 mg (predictive yield)).