Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].[CH3:2]I.[Cl:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:8][CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]=1[CH:21]=[O:22].[Cl-].[NH4+]>O.O1CCCC1.C(OCC)C>[Cl:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:8][CH:7]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:6]=1[CH:21]([OH:22])[CH3:2]
Reactant: O=CC1=C(Cl)c2ccccc2OC1c1ccccc1
Reactant: CI
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CC(O)C1=C(Cl)c2ccccc2OC1c1ccccc1
Temperature: 0 °C

Procedure:
2.88 g magnesium is allowed to react with 16.82 g methyl iodide in 80 ml refluxing dry diethylether. After disappearance of magnesium, one adds a solution of 21.4 g 4-chloro-3-formyl-flav-3-ene in 100 ml of a mixture of diethylether and tetrahydrofuran. After cooling to 0° C., a solution of 12.68 g ammonium chloride in 160 ml water is added. The two phases are separated and the aqueous solution is extracted with 50 ml diethyl ether. The combined organic phases are washed with 50 ml water, dried over magnesium sulfate and evaporated. The crude solid is crystallized in hexane. A racemate of one diastereomer of 4-chloro-3-(α-hydroxyethyl)-flav-3-ene is obtained as yellow crystals; m.p. 111°-113° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][N:6]=1)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:24][CH:25]([F:27])[F:26])(=O)=O.[Li+].[OH-].Cl>C(OCC)(=O)C.C1COCC1.CN(C=O)C>[F:26][CH:25]([F:27])[CH2:24][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([OH:2])=[O:4])=[N:6][CH:7]=1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc(O)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(OCC(F)F)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.8 %

Procedure:
To a mixture of 5-hydroxy-2-pyridinecarboxylic acid methyl ester (0.253 mL, 2.122 mmol), cesium carbonate (1.11 g, 3.40 mmol) and DMF (4.25 mL) was added 2,2-difluoroethyl trifluoromethanesulfonate (0.682 mL, 3.18 mmol). The reaction was stirred at ambient temperature for 3 hrs. The reaction was partitioned between water and ethyl acetate. The organic portion was concentrated and the residue was treated with 5 mL of THF and LiOH (Aq. 2N) (3.18 mL, 6.37 mmol). The reaction was stirred at ambient temperature for 16 hrs. The reaction was treated with 6N HCl until the pH reached ˜2 and then diluted with ethyl acetate. The organic portion was dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (370 mg, 1.821 mmol, 86%) as a tan solid. MS m/z=204.1 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:19])[NH:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)O)C.C[O-].[Na+]>C1(C)C=CC=CC=1>[CH3:18][O:17][C:11]1[CH:10]=[C:9]([CH:7]2[O:19][C:4](=[O:3])[NH:5][CH2:6]2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: CCOC(=O)NCC(O)c1ccc(OC)c(OC)c1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(C2CNC(=O)O2)cc1OC
Yield: 80 %

Procedure:
3 mmol of 2-(3,4-dimethoxyphenyl)-2-hydroxyethylcarbamic acid ethyl ester is suspended with 4 mmol of sodium methylate in 12 ml. of toluene and heated for 2 hours to a bath temperature of 110° under the exclusion of moisture. During this step, methanol and ethanol are distilled off. The toluene is then withdrawn under vacuum, the residue is taken up in 50 ml. of chloroform and distributed over 10 ml. of water. After drying, filtration, and concentration of the organic phase, the mixture is recrystallized from methanol, thus obtaining an 80% yield of 5-(3,4-dimethoxyphenyl)-2-oxazolidinone, m.p. 114°-117°.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]([C:14]1[CH:15]=[C:16]([C:26]([CH3:30])([CH3:29])[C:27]#[N:28])[CH:17]=[C:18]([CH2:20][N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)[CH:19]=1)[CH3:13].C(N(CC)CC)C>ClCCl.O>[C:12]([C:14]1[CH:15]=[C:16]([C:26]([CH3:30])([CH3:29])[C:27]#[N:28])[CH:17]=[C:18]([CH2:20][N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)[CH:19]=1)(=[O:11])[CH3:13]
Reactant: CC(O)c1cc(Cn2cncn2)cc(C(C)(C)C#N)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(=O)c1cc(Cn2cncn2)cc(C(C)(C)C#N)c1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A solution of oxalyl chloride (0.12 ml) in dichloromethane (2 ml) was stirred and cooled to 70° while dimethyl sulphoxide (0.12 ml) was added dropwise. The solution was stirred for 2 minutes, then 2-[3-(1-hydroxyethyl)-5-(1H-1,2,4-triazol-1-ylmethyl)phenyl]-2-methylpropiononitrile, (0.18 g), was added, and the temperature was kept at -70° for 10 minutes. Triethylamine (0.2 ml) was added, and the mixture was allowed to warm to room temperature. Water (15 ml) was added, and the mixture was extracted three times with dichloromethane. The extracts were combined, dried and evaporated to dryness, and the residue was purified by flash column chromatography, eluting with methanol:chloroform (1:99 by volume) to give 2-[3 acetyl-5-(1H-1,2,4-triazol-1 ylmethyl)phenyl]-2-methylpropiononitrile. Nmr in deuteriochloroform; δ 8.2(1H,s), 8.02(2H,m), 7.8(1H,m), 7.64(1H,m), 5.45(2H,s), 2.6 (3H,s), 1.75(6H,s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[CH2:11][O:10]2)=[C:4]([Cl:17])[CH:3]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:24]([O:26][C:27](=[O:28])[C:19]=12)=[O:25]>O1CCCC1>[Cl:17][C:4]1[CH:3]=[C:2]([NH:1][C:27]([C:19]2[C:20]([C:24]([OH:26])=[O:25])=[CH:21][CH:22]=[CH:23][N:18]=2)=[O:28])[CH:7]=[CH:6][C:5]=1[CH2:8][N:9]1[C:13](=[O:14])[C:12]([CH3:15])([CH3:16])[CH2:11][O:10]1
Reactant: O=C1OC(=O)c2ncccc21
Reactant: CC1(C)CON(Cc2ccc(N)cc2Cl)C1=O
Solvent: C1CCOC1
Product: CC1(C)CON(Cc2ccc(NC(=O)c3ncccc3C(=O)O)cc2Cl)C1=O
Yield: 34.1 %

Procedure:
This compound was prepared in a manner analogous to that of Example 1, Step C, using 4.0 grams (0.016 mole) of 2-[(4-amino-2-chlorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone and 2.3 grams (0.016 mole) of 2,3-pyridinedicarboxylic anhydride in 175 mL of tetrahydrofuran. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to a residual oil. The oil was crystallized by dissolving it in ethanol and adding diethyl ether until precipitation occurred. The solid was recrystallized in the same manner to yield 2.2 grams of 2-[[2-chloro-4-[(3-carboxy-2-pyridinyl)carbonylamino]phenyl]methyl]-4,4-dimethyl-3-isoxazolidinone; m.p. 94°-96° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Cl:11][S:12](O)(=[O:14])=[O:13]>>[CH3:10][O:9][C:4]1[CH:5]=[C:6]([CH3:8])[C:7]([S:12]([Cl:11])(=[O:14])=[O:13])=[C:2]([CH3:1])[CH:3]=1
Reactant: O=S(=O)(O)Cl
Reactant: COc1cc(C)cc(C)c1
Product: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1

Procedure:
A solution of 3,5-dimethylanisole (102.5 g, 753 mmol) in MC (1,000 ml) was cooled to 0° C. A solution of chlorosulfonic acid (251 ml, 3.763 mmol) in MC (250 ml) was added dropwise to this solution. After a reaction time of 10 min, the reaction solution was introduced into an ice bath (1,000 ml), the phases were separated and extraction was carried out once more with MC (250 ml). The combined organic phases were washed with water (1,000 ml) and saturated sodium chloride solution (1,000 ml), dried over Na2SO4 and concentrated. The product was purified by column chromatography over silica gel (heptane/MC 5:1). Yield: 63.5 g, 36%
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[C:5]([C:7]([O:9]CC)=[O:8])[N:6]=1.[OH-].[Na+]>CO.O>[NH2:1][C:2]1[S:3][C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[C:5]([C:7]([OH:9])=[O:8])[N:6]=1
Reactant: CCOC(=O)c1nc(N)sc1-c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1nc(C(=O)O)c(-c2ccncc2)s1
Temperature: 25 °C
Yield: 79.8 %

Procedure:
A mixture of ethyl 2-amino-5-(4-pyridyl)-4-thiazolecarboxylate (5.0 g) and sodium hydroxide (1.6 g) in a mixture of methanol (50 ml) and water (10 ml) was stirred at ambient temperature for an hour. The reaction mixture was evaporated in vacuo and the residue was dissolved in water. The aqueous solution was adjusted to pH 5 with 10% hydrochloric acid. The precipitate was collected by filtration and dried over phosphorus pentoxide in vacuo to afford 2-amino-5-(4-pyridyl)-4-thiazolecarboxylic acid (3.54 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]2[CH2:15][CH:14]([O:16][C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])[CH2:13][N:12]2[C:25]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:28]=2)=O)=[O:10])=[CH:4][CH:3]=1.[H-].[Na+]>CN(C)C=O.O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:10])[N:11]3[CH2:15][CH:14]([O:16][C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH2:13][N:12]3[C:25]=2[C:27]2[CH:32]=[CH:31][N:30]=[C:29]([O:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:28]=2)=[CH:4][CH:3]=1
Reactant: O=C(OC1CN(C(=O)Cc2ccc(F)cc2)N(C(=O)c2ccnc(Oc3ccccc3)n2)C1)N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(OC1Cn2c(-c3ccnc(Oc4ccccc4)n3)c(-c3ccc(F)cc3)c(=O)n2C1)N1CCOCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
A solution of morpholine-4-carboxylic acid 1-[2-(4-fluorophenyl)acetyl]-2-(2-phenoxypyrimidine-4-carbonyl)-pyrazolidin-4-yl ester, 42, (154 mg, 0.287 mmol) in dimethylformamide (3 mL) is added dropwise to a −10° C. suspension of sodium hydride (16.4 mg of a 60% dispersion in mineral oil, 0.410 mmol) in tetrahydrofuran (3 mL). After 1 hour at −10° C., the reaction was warmed to 0° C. for 2 hours. The orange-colored solution is then quenched by slowly adding saturated NH4Cl (400 μL). The cooling bath is removed, and the solution allowed to warm to room temperature. The reaction mixture is concentrated in vacuo and the resulting residue is dissolved in THF (25 mL) and filtered through a pad of Celite. The filtrate is concentrated in vacuo and the residue purified by Prep HPLC to afford 47 mg (32% yield) of the desired product as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.46 (d, J=4.9 Hz, 1H), 7.47-7.18 (m, 9H), 7.08 (t, J=8.7 Hz, 2H), 6.89 (d, J=4.9 Hz, 1H), 5.66 (m, 1H), 4.16 (m, 2H), 4.02 (d, J=12.9 Hz, 1H), 3.87 (dd, J=12.9, 5.1 Hz, 1H), 3.79-3.30 (m, 8H); HRMS m/z calcd for C27H25FN5O5 (MH+) 518.1840, found 518.1815.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:8][OH:9].N1C=CN=C1.C(N(CC)CC)C.[S:22](Cl)(Cl)=[O:23]>ClCCl>[S@@:22]1(=[O:23])[N:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]2[CH2:8][O:9]1
Reactant: O=S(Cl)Cl
Reactant: OC[C@@H]1CCCCN1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[S@@]1OCC2CCCCN21
Temperature: 2.5 °C
Reaction time: 0.75 h

Procedure:
To a solution of (S)-1-Piperidin-2-yl-methanol hydrochloride (3.43 g, 22.63 mmol), imidazole (6.1 g, 88.72 mmol) and triethylamine (7.33 g, 72.42 mmol) in anhydrous dichloromethane (120 mL) at 0-5° C. was added a solution of thionyl chloride (3.2 g, 25.86 mmol) in anhydrous dichloromethane (10 mL) over a period of 45 min. The reaction mixture was stirred at 0-5° C. for 45 min, partitioned with H2O and the aqueous layer was extracted with dichloromethane (2×150 mL). The combined organic layer was washed with H2O, dried over Na2SO4, and concentrated in vacuo to give an orange liquid. Flash column chromatography purification (silica gel, 2% EtOAc in dichloromethane) afforded the title product as a clear, colorless liquid (1.31 g, 36%).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[NH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34].C[O-].[Na+]>>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:29])[C:5]([C:3]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[C:10]1=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1ncc2c(cc(-c3ccncc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2c(cc(-c3ccncc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 84 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-pyridin-4-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (29 mg, 0.075 mmol), β-alanine (868 mg, 9.7 mmol) and NaOMe solution (15 mL, 7.5 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in water and washed several times with ether. The aqueous layer was acidified to pH about 3-4 with 1 M HCl, and the resulting precipitate was isolated by filtration to give 28 mg of the title compound as a bright yellow solid. MS: (+) m/z 445.26 (M+1).
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:11](F)[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[CH:1]1([CH2:7][NH:8][C:9]2[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:11]([N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1cc(Nc2ccccc2)c(F)cc1NCC1CCCCC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2cc(NCC3CCCCC3)c([N+](=O)[O-])cc2Nc2ccccc2)CC1
Yield: 78.7 %

Procedure:
A solution of N4-cyclohexylmethyl-2-fluoro-5-nitro-N1-phenyl-benzene-1,4-diamine (0.23 g, 0.66 mmol), N-methylpiperazine (0.22 mL, 1.97 mmol) and N,N′-diisopropylethylamine (0.34, 1.97 mmol) in DMF (3.0 mL) was stirred at 100° C. under an inert atmosphere for 16 h. The reaction mixture was transferred to a separatory funnel containing water. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with water, brine and dried over MgSO4. The solution was filtered through diatomaceous earth and the solvent was evaporated. The resulting dark red residue was flash chromatographed (5% MeOH/CH2Cl2) to give N4-cyclohexylmethyl-2-(4-methyl-piperazin-1-yl)-5-nitro-N1-phenyl-benzene-1,4-diamine as a red foam (0.22 g, 80.7% yield). M+, 424
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC(Cl)(Cl)Br.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH2:30][C:31]([OH:33])=O.[NH2:34][C:35]1[CH:40]=[C:39]([CH3:41])[CH:38]=[C:37]([CH3:42])[N:36]=1>O1CCCC1>[CH3:41][C:39]1[CH:38]=[C:37]([CH3:42])[N:36]=[C:35]([NH:34][C:31](=[O:33])[CH2:30][C:26]2[S:25][CH:29]=[CH:28][CH:27]=2)[CH:40]=1
Reactant: O=C(O)Cc1cccs1
Reactant: Cc1cc(C)nc(N)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Br
Solvent: C1CCOC1
Product: Cc1cc(C)nc(NC(=O)Cc2cccs2)c1

Procedure:
9.22 g of triphenylphosphine, 6.93 ml of trichlorobromomethane, 5 g of 2-thienylacetic acid and 8.50 g of 2-amino-4,6-dimethylpyridine are dissolved in 120 ml of tetrahydrofuran. The mixture is brought to reflux and filtered, and the filtrate is concentrated; the residue is chromatographed on silica gel, eluting with dichloromethane, and the product obtained is recrystallized from isopropyl ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:33])=[C:5]([C:24]([O:31][CH3:32])=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:8]=1.[CH3:34][Si](C=[N+]=[N-])(C)C.C(O)(=O)C>CO>[CH3:1][O:2][C:3]1[C:4]([CH3:33])=[C:5]([C:24]([O:31][CH3:32])=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([O:13][CH3:34])=[O:12])=[C:9]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:8]=1
Reactant: COc1c(C)c(Cc2ccc(C(=O)O)c(OCc3ccccc3)c2)c(OC)c(OC)c1OC
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
4-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-benzyloxybenzoic acid (525 mg, 1.1615 mmol) was dissolved in methanol (20 ml), trimethylsilyl diazomethane (15.9 g, 10% solution in hexane, 13.9473 mmol) was added thereto under cooling with ice and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added acetic acid (2 ml) and the mixture was allowed to stand so as to decompose an excessive reagent. The reaction solution was concentrated to give the title compound (530 mg, 1.1373 mmol, 98%).
Reaction SMILES: [ClH:1].[CH2:2]([N:4]([C:11]1[CH:16]=[C:15]([CH3:17])[N:14]=[C:13](OCC)[CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:3].C(=O)([O-])[O-].[Na+].[Na+].Cl.[CH2:28]([CH2:30][NH2:31])[OH:29]>O.C(OCC)(=O)C>[ClH:1].[CH2:2]([N:4]([C:11]1[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]([NH:31][CH2:30][CH2:28][OH:29])[CH:12]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH3:3]
Reactant: NCCO
Reactant: CCOc1cc(N(CC)c2ccccc2)cc(C)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCN(c1ccccc1)c1cc(C)nc(NCCO)c1
Yield: 24 %

Procedure:
4-(N-ethylanilino)-2-ethoxy-6-methylpyridine hydrochloride (0.584 g, 2 mM) in ethanolamine (5 ml) was heated under argon at 180° C. for 24 hours. The solution was cooled, diluted with water (50 ml), basified with aqueous sodium carbonate solution and extracted with methylene chloride (4×10 ml). The organic extracts were combined, dried (MgSO4) and evaporated to give a gum. This gum was triturated with ether to give, 4-(N-ethylanilino)-2-hydroxy-6-methylpyridine as a white solid (0.05 g) which was collected by filtration. The filtrate was evaporated and the residue was purified by flash column chromatography, eluting successively with methanol/methylene chloride (1:19 v/v), methanol/methylene chloride, (1:9 v/v/) and methanol/methylene chloride/0.88d aqueous NH4OH (20:80:1 v/v) to give a gum. This gum was dissolved in ethyl acetate and treated with etheral hydrogen chloride to give a gum which solidified on standing. The solid was washed with ether to give 4-(N-ethylanilino)-2-(2-hydroxyethylamino)-6-methylpyridine hydrochloride (0.15 g, 24% yield); m.p. 190° C.; microanalysis, found C, 62.2; H, 7.5; N, 13.7%; C16H22N3OCl requires: C, 62.4; H, 7.15; N, 13.6%; NMR: 1.1-1.2 (3H, t, CH3), 2.23(3H, s, CH3), 3.2-3.32(2H, q, CH2), 3.5-3.6(2H, t, CH2), 3.7-3.85(2H, q, CH2), 5.7(1H, s, CH), 5.9(1H, s, CH), 7.2-7.6(5H, complex, aromatic), 4.7-5.1(1H, broad, OH), 12.4(1H, NH).
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][OH:6].CCN(C(C)C)C(C)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl>[CH3:16][S:17]([O:6][CH2:5][CH2:4][CH2:3][S:2][CH3:1])(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: CSCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CSCCCOS(C)(=O)=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(methylthio)propan-1-ol in dichloromethane (0.2 M) was added sequentially at −78° C. Hunig's base (1.3 eq.) and methanesulfonyl chloride (1.3 eq.). The resulting reaction mixture was stirred at −78° C. for 1 h and then warmed slowly to RT. The reaction was quenched with sat. aq. NH4Cl and then extracted with ether. The combined organic extracts were washed with water and brine, dried over MgSO4, and filtered. Concentrated of the filtrate in vacuo afforded the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[CH:13](O)=[O:14]>>[NH:10]1[CH:11]=[CH:12][C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][CH:13]=[O:14])=[CH:7][CH:6]=2)=[N:9]1
Reactant: O=CO
Reactant: Nc1ccc(-c2cc[nH]n2)cc1
Product: O=CNc1ccc(-c2cc[nH]n2)cc1

Procedure:
A solution of 3-(4-aminophenyl)-1-H-pyrazole (10 g) in formic acid (100 ml) was refluxed for 4 hours and evaporated to dryness. The residue was dissolved in water, and the solution was filtered through charcoal. The filtrate was made basic to give 9.5 g of N-[4-(pyrazol-3-yl)-phenyl]-formamide; M.p. 139°-141° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[O:29])[C:15]#[C:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]/[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:28])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCOC(C)=O.CCCCCC>ClCCCl>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([C:15]1[C:27]2[C:22](=[C:23]([Cl:28])[CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]2[CH2:19][CH2:18][CH2:17][C:16]=12)=[O:29])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCCCCC(=O)C#CCCC/C=C/c1ccccc1Cl
Solvent: ClCCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCCCCC(=O)c1c2c(cc3c(Cl)cccc13)CCC2
Yield: 97.4 %

Procedure:
To a 10-20 mL microwave irradiation vial equipped with a stir bar was added compound 11 (0.35 g, 0.81 mmol) in DCE (13 mL). The reaction was irradiated with stirring at 180° C. for 180 min until complete by TLC (AcOEt/n-hexane 0.5:9.5). The solution turned golden in color. The mixture was then transferred to a vial, concentrated under reduced pressure, and dried under vacuum to yield the title compound as a brown oil (0.34 g, 97% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:25]2[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=2)[C:5]2[N:6]([N:8]=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20][N:19]=4)[CH2:14][CH2:13]3)[N:10]=2)[CH:7]=1.Cl[C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33]>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([C:25]2[CH2:26][CH2:27][N:28]([C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])[CH2:29][CH:30]=2)[C:5]2[N:6]([N:8]=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20][N:19]=4)[CH2:14][CH2:13]3)[N:10]=2)[CH:7]=1
Reactant: Cc1cc(C2=CCNCC2)c2nc(NC3CCN(c4cc(C)ncn4)CC3)nn2c1
Reactant: CC(C)OC(=O)Cl
Solvent: ClCCl
Product: Cc1cc(C2=CCN(C(=O)OC(C)C)CC2)c2nc(NC3CCN(c4cc(C)ncn4)CC3)nn2c1

Procedure:
Prepared in analogy to example 164b, starting from 6-methyl-N-(1-(6-methylpyrimidin-4-yl)piperidin-4-yl)-8-(1,2,3,6-tetrahydropyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine and isopropyl chloroformate. The title compound was obtained as a colorless solid (yield: 32%) after column chromatography on silica gel using a gradient from methylene chloride to a mixture of methylene chloride/methanol 19:1 (v/v) as eluent. MS ISP (m/e): 491.3 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): (ppm)=8.51 (s, 1H), 8.04 (s, 1H), 7.16 (br s, 1H), 7.11 (s, 1H), 6.41 (s, 1H), 4.97 (sept, 1H), 4.39 (d, 1H), 4.31 (br d, 2H), 4.21 (br s, 2H), 3.96 (m, 1H), 3.72 (t, 1H), 3.18 (t, 2H), 2.63 (br s, 2H), 2.37 (s, 3H), 2.34 (s, 3H), 2.21 (br d, 2H), 1.53 (m, 2H), 1.26 (d, 6H).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][CH:16]([C:36]1[N:37](C(OC(C)(C)C)=O)[CH:38]=[C:39]([CH2:41][C:42]([CH3:46])([CH3:45])[CH2:43][CH3:44])[N:40]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[N:26][N:27](C(OC(C)(C)C)=O)[CH:28]=2)=[CH:20][CH:19]=1)=O)(C)(C)C>>[CH3:45][C:42]([CH3:46])([CH2:43][CH3:44])[CH2:41][C:39]1[N:40]=[C:36]([CH:16]([NH2:15])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:28]=[N:27][NH:26][CH:25]=3)=[CH:22][CH:23]=2)[NH:37][CH:38]=1
Reactant: CCC(C)(C)Cc1cn(C(=O)OC(C)(C)C)c(C(Cc2ccc(-c3cnn(C(=O)OC(C)(C)C)c3)cc2)NC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Product: CCC(C)(C)Cc1c[nH]c(C(N)Cc2ccc(-c3cn[nH]c3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (2 mL) was added to neat tert-butyl 4-(4-{2-[(tert-butoxycarbonyl)amino]-2-[1-(tert-butoxycarbonyl)-4-(2,2-dimethylbutyl)-1H-imidazol-2-yl]ethyl}phenyl)-1H-pyrazole-1-carboxylate. After stirring at ambient temperature for 1 h, the reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and 10% aqueous sodium hydroxide. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo to afford the title compound. (M+H) found: 338.