Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15](=O)[C:16]#[C:17][CH2:18][O:19][CH3:20])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:29][NH2:30].O>CCO>[CH2:1]([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:16]=[C:17]([CH2:18][O:19][CH3:20])[NH:30][N:29]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCC#CC(=O)[C@H]1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)CC1
Reactant: NN
Solvent: CCO
Solvent: O
Product: COCc1cc([C@H]2CC[C@H](N(Cc3ccccc3)Cc3ccccc3)CC2)n[nH]1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
A stirred solution of 13E (150 mg, 0.399 mmol) in EtOH (2 mL) was treated with hydrazine (0.116 mL, 2.397 mmol), and stirred overnight at 75° C. Upon cooling, water was added, the mixture was stirred for 1 h, the resulting white solid was collected by filtration and air dried to yield 13F (125 mg, 80% yield). MS (ES): m/z=390.3 [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 7.31 (d, 4H, J=7.0 Hz); 7.18-7.25 (m, 4H); 7.14 (t, 2H, J=7.3 Hz); 5.92 (s, 11H); 4.35 (s, 2H); 3.58 (s, 4H); 3.30 (s, 3H); 2.44-2.55 (m, 2H); 1.89-2.01 (m, 4H); 1.23-1.50 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][NH:11][CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][C:17]1[CH:25]=[C:24]([CH3:26])[C:20]([C:21](O)=[O:22])=[CH:19][N:18]=1>>[C:1]([O:5][C:6]([N:8]1[CH:9]2[CH2:15][CH2:14][CH:13]1[CH2:12][N:11]([C:21]([C:20]1[CH:19]=[N:18][C:17]([NH2:16])=[CH:25][C:24]=1[CH3:26])=[O:22])[CH2:10]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(N)ncc1C(=O)O
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Product: Cc1cc(N)ncc1C(=O)N1CC2CCC(C1)N2C(=O)OC(C)(C)C
Yield: 55.3 %

Procedure:
Following general amide formation method 1, 3,8-Diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (279 mg, 1.31 mmol, 1.0 eq) was combined with 6-Amino-4-methylnicotinic acid (200 mg, 1.31 mmol, 1.0 eq) to give 3-(6-Amino-4-methyl-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (251 mg) in 55% yield. MS m/z 347.0 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=[O:13])[CH2:10][C:9](=[O:14])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1(OC2C=CC=CC=2)C=CC=CC=1.C(Cl)Cl.[Pd]>[C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=[C:9]([OH:14])[CH:10]=[C:11]([OH:13])[CH:12]=1
Reactant: O=C1CC(=O)CC(c2ccccc2)C1
Agent: [Pd]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Product: Oc1cc(O)cc(-c2ccccc2)c1
Temperature: 230 °C
Reaction time: 2.5 h

Procedure:
A mixture of 5-phenyl-1,3-cyclohexanedione (2.5 g, 13 mM) and 10% Pd/C (0.5 g) in phenyl ether (30 mL) was heated to 230° C. over 30 minutes and held at 230° C. for 2.5 hours. The reaction was cooled, taken up in CH2Cl2 and filtered through Dicalite. The filtrate was concentrated and the residue purified by chromatography (CH2Cl2, then 5-10% EtOAc/CH2Cl2) to give the desired product.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][N:8]=1.[CH2:17]([O:19][P:20]([O:24]CC)[O:21][CH2:22][CH3:23])[CH3:18].O>C(OCC)(=O)C>[CH2:17]([O:19][P:20]([CH2:2][C:3]1[CH:16]=[CH:15][CH:14]=[C:5]([O:6][C:7]2[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][N:8]=2)[CH:4]=1)(=[O:24])[O:21][CH2:22][CH3:23])[CH3:18]
Reactant: CCOP(OCC)OCC
Reactant: Cc1ccnc(Oc2cccc(CCl)c2)c1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOP(=O)(Cc1cccc(Oc2cc(C)ccn2)c1)OCC
Temperature: 150 °C
Reaction time: 16 h
Yield: 39.3 %

Procedure:
2-(3-Chloromethyl-phenoxy)-4-methyl-pyridine (5.16 g, 22 mmol) from Step 2 was treated neat with triethylphosphite (4.68 mL, 27.3 mmol) and heated to 150° C. After 16 h, the reaction mixture was cooled to room temperature and partioned between water and ethyl acetate. The organic layer was separated and the aqueous was extracted again with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a residue. The residue was purified by silica gel chromatography (30-60%, EtOAc:DCM) to afford the desired product (2.9 g, 40% yield) as a thick oil.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH3:12].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: Oc1ccc(I)cc1
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1ccc(I)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
A suspension of 4-iodophenol (3 g, 13.64 mmol), 1-bromopropane (1.845 g, 15.00 mmol), and sodium carbonate (7.54 g, 54.5 mmol) in DMF (30 mL) was stirred at 80° C. for 4 hrs. The reaction mixture was diluted with water (250 mL) and extracted with EtOAc (3×75 mL). The combined organic extracts were washed with 0.5M NaOH (2×50 mL), and water (2×50 mL), and then dried over MgSO4. The solvent was removed. The crude product (3.11 g) was obtained, which was directly used for the next reaction without further purification. 1H NMR (400 MHz, chloroform-d) δ 7.61-7.53 (m, 2H), 6.74-6.67 (m, 2H), 3.90 (t, J=6.5 Hz, 2H), 1.88-1.76 (m, 2H), 1.05 (t, J=7.4 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:16]([O:18][C:19]([C:21]1[NH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([OH:30])=[CH:25][CH:24]=2)=[O:20])[CH3:17]>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1.CCOC(C)=O>[CH2:16]([O:18][C:19]([C:21]1[NH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([O:30][C:2]1[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=1)=[CH:25][CH:24]=2)=[O:20])[CH3:17]
Reactant: CCOC(=O)c1cc2cc(O)ccc2[nH]1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2cc(Oc3ccnc4cc(OC)c(OC)cc34)ccc2[nH]1
Temperature: 180 °C

Procedure:
A mixture of 4-chloro-6,7-dimethoxy-quinoline (0.4 g, 1.8 mmol), 5-hydroxy-1H-indole-2-carboxylic acid ethyl ester (0.37 g, 1.8 mmol, Biosynth AG) and DMAP (0.22 g, 1.8 mmol, Aldrich) in toluene (in a microwave tube) was heated in a microwave (Personal Chemistry, Emrys Optimizer) at 180° C. for 2 h. The mixture was cooled to RT and diluted with 30 mL of EtOAc. The solution was washed with 10 mL of brine twice, dried over Na2SO4 and concentrated in vacuo. The residue was further purified with silica gel column chromatography (50% to 100% EtOAc in hexanes) to provide a white foam as the desired compound. MS (ESI pos. ion) m/z: 393 (M+H). Calc'd Exact Mass for C22H20N2O5: 392.40.
Reaction SMILES: C(OC(=O)[NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:17]=2)=[CH:11][N:10]=1)=S)C.[Cl-].O[NH3+].C([N:38](CC)C(C)C)(C)C.C(O)C>CO>[NH2:38][C:6]1[N:8]=[C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([NH:23][C:24](=[O:25])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH:17]=3)=[CH:11][N:10]2[N:5]=1
Reactant: CCOC(=O)NC(=S)Nc1ccc(Oc2ccc(Cl)c(NC(=O)OC(C)(C)C)c2)cn1
Reactant: CCN(C(C)C)C(C)C
Agent: [Cl-]
Agent: [NH3+]O
Solvent: CCO
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cc(Oc2ccc3nc(N)nn3c2)ccc1Cl
Yield: 94.2 %

Procedure:
In the same manner as in Example 23-1 and using ethyl{[(5-{3-[(tert-butoxycarbonyl)amino]-4-chlorophenoxy}pyridin-2-yl)amino]carbonothioyl}carbamate (7.23 g, 15.5 mmol), hydroxylammonium chloride (7.64 g, 0.110 mol), N,N-diisopropylethylamine (13.5 mL, 77.4 mmol), ethanol (50 mL) and methanol (50 mL) as starting materials, the title compound (5.49 g, 92%) was obtained as a white solid.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@H:11]([OH:23])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(Cl)Cl.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>>[CH3:34][S:35]([O:23][C@H:11]1[CH2:12][C@@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:18])[C@@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:10]1)(=[O:37])=[O:36]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@H](O)C[C@@H]1O[Si](C)(C)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@H](OS(C)(=O)=O)C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (1S,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl-(dimethyl)silyl]oxy}methyl)cyclopentanol (2.02 g, 0.00560 mol) in CH2Cl2 (55.0 mL, 0.858 mol) at 0° C. was added triethylamine (1.8 mL, 0.013 mol) and methanesulfonyl chloride (0.650 mL, 0.00840 mol) under an atmosphere of nitrogen. The mixture was stirred at 0° C. for 30 minutes, and then warmed to 23° C. for 1 hour. The reaction was quenched by addition of saturated aqueous sodium bicarbonate, extracted with DCM, dried (Na2SO4), filtered and concentrated to give 2.66 g (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH3:27][C:28]([CH3:42])([CH3:41])[C:29]([NH:31][CH2:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][CH:34]=1)=[O:30]>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:38][CH2:37][C:36]1[CH:39]=[CH:40][C:33]([CH2:32][NH:31][C:29](=[O:30])[C:28]([CH3:41])([CH3:27])[CH3:42])=[CH:34][CH:35]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(CN)cc1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Product: CC(C)(C)C(=O)NCc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Yield: 75.9 %

Procedure:
Use a method similar to the General Procedure 1-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (299 mg, 0.704 mmol) and 4-[(2,2-dimethyl-propionylamino)-methyl]-benzylamine (310 mg, 1.41 mmol). Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (3:2) to obtain 7-chloro-6-{4-[(2,2-dimethyl-propionylamino)-methyl]-benzylamino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow oil (265 mg, 76%). MS (ES+) m/z: 496 (M+H)+.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[N:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:41][C:42]1[CH:47]=[CH:46][C:45](O)=[CH:44][CH:43]=1>C1COCC1>[Br:41][C:42]1[CH:47]=[CH:46][C:45]([O:21][CH2:20][CH2:19][C:16]2[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=2)=[CH:44][CH:43]=1
Reactant: Oc1ccc(Br)cc1
Reactant: OCCc1ccncc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Brc1ccc(OCCc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
Diethyl azodicarboxylate (4.44 mL, mmol, 40%) was slowly added to a solution of 2-pyridin-4-yl-ethanol (1.00 g, 8.12 mmol), triphenylphosphine (2.56 g, 9.74 mmol), and 4-bromophenol (1.40 g, 8.12 mmol) in THF (40.6 mL) at 0° C. under nitrogen. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was quenched with water (150 mL) and extracted with ethyl acetate (200 mL). The organics were washed with 1N aqueous NaOH (100 mL) and brine (100 mL). The organics were dried (Na2SO4), filtered, and concentrated. The crude material was crystallized with ether:heptanes (1:1, ˜25 mL) and the solid was removed via filtration and washed with ether:heptanes. The combined filtrates were concentrated and further purified via flash chromatography using an Analogix SF25-40 g column and ethyl acetate in heptane (0-30%) as the eluant to afford the title compound as a clear liquid (1.20 g, 46.2%). LC-MS m/z 278.4 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.11 (t, 2H) 4.19 (t, J=6.44 Hz, 2H) 6.77 (d, J=8.98 Hz, 2H) 7.22-7.26 (m, 2H) 7.38 (d, J=4.69 Hz, 2H) 8.54-8.57 (m, 3H)
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[C:12]([CH3:14])([CH3:13])[C:11]2[C:6](=[CH:7][C:8]([CH2:15][CH3:16])=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:19][CH2:20][C@H:21]([OH:23])[CH3:22]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:15]([C:8]1[CH:7]=[C:6]2[C:11]([C:12]([CH3:13])([CH3:14])[C:4]3[CH:3]=[CH:2][N:19]([CH2:20][C@H:21]([OH:23])[CH3:22])[C:5]=32)=[CH:10][CH:9]=1)[CH3:16]
Reactant: C[C@@H](O)CN
Reactant: CCc1ccc2c(c1)C(=O)C(CC=O)C2(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1ccc2c(c1)-c1c(ccn1C[C@@H](C)O)C2(C)C
Reaction time: 0.75 h
Yield: 91.1 %

Procedure:
A solution of 2.3 g of (RS)-2-(2-oxoethyl)-6-ethyl-3,3-dimethyl-1-indanone and 80 mg of p-toluenesulfonic acid in 90 ml of anhydrous toluene was heated on a water separator. A solution of 3.0 g of (R)-1-amino-2-propanol in 40 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (diethyl ether/hexane 3:2). 2.45 g (91%) of (R)-1-(7-ethyl-4,4-dimethyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a red oil.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(Br)(Br)(Br)[Br:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][Br:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CC(=O)Oc1ccc(CO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(=O)Oc1ccc(CBr)cc1
Yield: 79 %

Procedure:
To the solution of 4-hydroxymethylphenol acetate (2.50 g, 15.0 mmol) and carbon tetrabromide (5.97 g, 18.0 mmol) in 40 ml of methylene chloride was added triphenylphosphine (4.73 g, 180 mmol) under nitrogen. The resultant mixture was stirred for 3 hours. The product was purified by flash chromatography using heptane/ethyl acetate (90/10-80/20) as eluent in a yield of 79%.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH:7]=[CH2:8])[CH:2]1[O:4][CH2:3]1.[CH3:9][SiH:10]1[O:17][SiH:16]([CH3:18])[O:15][SiH:14]([CH3:19])[O:13][SiH:12]([CH3:20])[O:11]1>COCCOCCOC.[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[O:4]1[CH2:3][CH:2]1[CH2:1][O:5][CH2:6][CH2:7][CH2:8][Si:16]1([CH3:18])[O:17][Si:10]([CH2:8][CH2:7][CH2:6][O:5][CH2:1][CH:2]2[O:4][CH2:3]2)([CH3:9])[O:11][Si:12]([CH2:8][CH2:7][CH2:6][O:5][CH2:1][CH:2]2[O:4][CH2:3]2)([CH3:20])[O:13][Si:14]([CH2:8][CH2:7][CH2:6][O:5][CH2:1][CH:2]2[O:4][CH2:3]2)([CH3:19])[O:15]1
Reactant: C[SiH]1O[SiH](C)O[SiH](C)O[SiH](C)O1
Reactant: C=CCOCC1CO1
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: COCCOCCOC
Product: C[Si]1(CCCOCC2CO2)O[Si](C)(CCCOCC2CO2)O[Si](C)(CCCOCC2CO2)O[Si](C)(CCCOCC2CO2)O1
Temperature: 100 °C

Procedure:
Allyl glycidyl ether (57.1 g, 0.5 moles) was added to a 250 mL 3-neck flask, equipped with a stirrer, dropping funnel, internal thermometer and condenser, and heated to 100° C. After the addition of 1 mL of a 1 weight percent solution of hexachloroplatinic acid in diethylene glycol dimethyl ether, 24.0 g (0.1 moles) of 2,4,6,8-tetramethylcyclotetrasiloxane were added very rapidly with vigorous stirring, the internal temperature rising to 195° C. After the addition of 2,4,6,8-tetramethylcyclotetrasiloxane, stirring was continued until the temperature of the reaction product had dropped to 130° C. Unreacted portions of the allyl glycidyl ether and 2,4,6,8-tetramethylcyclotetrasiloxane were removed by stirring the reaction mixture at 60°-70° C. at a vacuum of 0.1 hPa, produced by an oil pump. The slightly yellowish crude product (77.8%), nD20 : 1.4633, was subjected to a fractional vacuum distillation using a packed column. The compound (21) distilled at about 335° C. and 1 hPa as a clear, viscous liquid, the greater portion polymerizing. nD20 : 1,4668.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[N:7]([CH3:13])[C:8]([CH2:11]Cl)=[N:9][CH:10]=1)=[O:5].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[CH3:2][O:3][C:4]([C:6]1[N:7]([CH3:13])[C:8]([CH2:11][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[N:9][CH:10]=1)=[O:5]
Reactant: COC(=O)c1cnc(CCl)n1C
Reactant: C1COCCN1
Agent: Cl
Product: COC(=O)c1cnc(CN2CCOCC2)n1C

Procedure:
Using 2-chloromethyl-3-methyl-3H-imidazole-4-carboxylic acid methyl ester hydrochloride and morpholine, the title compound was obtained as light brown solid (>98% yield). MS: m/e=240(M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12]([OH:14])[CH3:13])[CH2:11][O:10]1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26](=O)[NH:25][CH:24]=[N:23]2)=[CH:18][CH:17]=1.ClC1C=CC(N2C(=O)N([C@H](C)[C@]3(C4C=CC(F)=CC=4F)OC3)C=N2)=CC=1>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[C:26]([O:14][C@@H:12]([C@@:9]3([C:3]4[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=4[F:1])[CH2:11][O:10]3)[CH3:13])=[N:25][CH:24]=[N:23]2)=[CH:20][CH:21]=1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: O=c1[nH]cnn1-c1ccc(Cl)cc1
Agent: C[C@@H](n1cnn(-c2ccc(Cl)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](Oc1ncnn1-c1ccc(Cl)cc1)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 19.1 %

Procedure:
In the same manner as in Reference Example 5, starting from 1.34 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl] ethanol and 1.15 g of 2-(4-chlorophenyl)-3(2H,4H)-1,2,4-triazolone, 2-(4-chlorophenyl)-4-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-3(2H,4H)-1,2,4-triazolone (519 mg) and 424 mg of (2R)-2-[(1R)-1-[1-(4-chlorophenyl)-1H-1,2,4-triazol-5-yloxy]ethyl]-2-(2,4-difluorophenyl)oxirane were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][C:11](Cl)=[CH:12][C:13]=2[CH3:14])=[CH:4][CH:3]=1.C(OCC)(=O)NN.BrC1C=CC(C2C(C)=[CH:32][C:33]3[N:34]([C:36](=[O:39])NN=3)[N:35]=2)=CC=1>C(O)CCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]3[N:10]([C:36](=[O:39])[N:34]([CH2:33][CH3:32])[N:35]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc2n[nH]c(=O)n2nc1-c1ccc(Br)cc1
Reactant: Cc1cc(Cl)nnc1-c1ccc(Br)cc1
Agent: CCOC(=O)NN
Solvent: CCCCO
Product: CCn1nc2cc(C)c(-c3ccc(Br)cc3)nn2c1=O

Procedure:
A mixture comprising 328 g. of 3-(p-bromophenyl)-6-chloro-4-methylpyridazine (U.S. Pat. No. 4,092,311), 242 g. of ethyl carbazate and 2 liters of butanol is stirred at reflux for 4 days, then cooled in an ice bath. The resulting solid is collected by filtration and air dried, giving 269 g. of 6-(p-bromophenyl)-7-methyl-1,2,4-triazolo[4,3-b]pyridazin-3(2H)-one.
Reaction SMILES: [CH3:1][N:2]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:3]1[N:8]=[CH:7][CH:6]=[C:5]([C:9]#[N:10])[N:4]=1.[C:19](OC)(=[O:27])[C:20]1[C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[SH:22].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:3]1[N:8]=[CH:7][CH:6]=[C:5]([C:9]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19](=[O:27])[N:10]=2)[N:4]=1
Reactant: CN(CC(=O)OC(C)(C)C)c1nccc(C#N)n1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN(CC(=O)OC(C)(C)C)c1nccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 47.6 %

Procedure:
tert-Butyl [methyl(6-cyano-2-pyrimidinyl)amino]acetate (1.63 g, 6.56 mmol) and methyl thiosalicylate (3.31 g, 19.7 mmol) were dissolved in toluene (50 ml), and triethylamine (2.76 ml, 19.7 mmol) was added thereto. The mixture was refluxed for 18 hrs. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (1.20 g, 39%) as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.CO[CH:17]1[CH2:21][CH2:20][CH:19](OC)O1.C>C1(C)C=CC=CC=1.C(O)(=O)C>[N:1]1([C:2]2[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=2)[CH:17]=[CH:21][CH:20]=[CH:19]1
Reactant: CCOC(=O)C=Cc1ccc(N)cc1
Reactant: COC1CCC(OC)O1
Agent: C
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C=Cc1ccc(-n2cccc2)cc1

Procedure:
A solution of ethyl 4-aminocinnamate (1 g) and 2,5-dimethoxytetrahydrofuran (0.677 ml) in toluene (3 ml) and acetic acid (3 ml) was refluxed for 5 hours with removing methane. After cooling, the mixture was washed with water twice and saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo. The residue was purified with column chromatography eluting with n-hexane-ethyl acetate to give ethyl 4-(1-pyrrolyl)cinnamate (740 mg) as colorless crystals.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:17]2[CH:22]=[C:21]([NH:23][C:24]([C:26]3[C:31]([CH3:32])=[CH:30][C:29]([C:33]#[N:34])=[CH:28][N:27]=3)=[O:25])[CH:20]=[CH:19][C:18]=2[F:35])([CH:14]([F:16])[F:15])[N:13]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:17]2[CH:22]=[C:21]([NH:23][C:24]([C:26]3[C:31]([CH3:32])=[CH:30][C:29]([C:33]#[N:34])=[CH:28][N:27]=3)=[O:25])[CH:20]=[CH:19][C:18]=2[F:35])([CH:14]([F:16])[F:15])[N:13]=1
Reactant: Cc1cc(C#N)cnc1C(=O)Nc1ccc(F)c([C@]2(C(F)F)COCC(NC(=O)OC(C)(C)C)=N2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C#N)cnc1C(=O)Nc1ccc(F)c([C@]2(C(F)F)COCC(N)=N2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of ((R)-5-{5-[(5-cyano-3-methyl-pyridine-2-carbonyl)-amino]-2-fluoro-phenyl}-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamic acid tert-butyl ester (23 g, 45.77 mmol) in DCM (615 ml) was added under argon TFA (23 ml, 302.27 mmol) below 25° C. After stirring for 18 h at 25° C., another TFA (12 ml, 151.13 mmol) was added. After stirring at 25° C. for another 6 h, cooled down to −5° C., quenched by 12.5% NH3 aqueous solution (110 ml). The DCM phase was collected and water (100 ml) was added. The DCM of the diphase solution was removed to provide a yellowish suspension. Filtered and dried to provide the title compound as yellowish crystals. ESIMS: 404 [(M+H)+]; 1H NMR (400 MHz, DMSO-d6): 10.72 (s, 1H), 8.96 (s, 1H), 8.38 (s, 1H), 7.99 (dd, 1H), 7.81 (m, 1H), 7.18 (d, 1H), 6.17 (br s, 2H), 6.15 (t, 1H), 3.98 (m, 4H), 2.53 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[N:17]([CH3:34])[C:18]([CH2:21][N:22]([CH2:30][CH2:31][O:32][CH3:33])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19][N:20]=4)[S:15][C:8]=23)=[C:4]([F:37])[CH:3]=1.[C:38]1([CH2:44][C:45]([N:47]=[C:48]=[S:49])=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CCO.C1(C)C=CC=CC=1>[F:37][C:4]1[CH:3]=[C:2]([NH:1][C:48]([NH:47][C:45](=[O:46])[CH2:44][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[S:49])[CH:36]=[CH:35][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[N:17]([CH3:34])[C:18]([CH2:21][N:22]([CH2:30][CH2:31][O:32][CH3:33])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19][N:20]=3)[S:15][C:8]=12
Reactant: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)n1C)C(=O)OC(C)(C)C
Reactant: O=C(Cc1ccccc1)N=C=S
Solvent: Cc1ccccc1
Solvent: CCO
Product: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)c3s2)n1C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.8 %

Procedure:
To a solution of 46 (375 mg, 0.711 mmol) in a mixture of EtOH (5 mL) and toluene (5 mL) at RT was added phenylacetyl isothiocyanate (189 mg, 1.066 mmol) and the reaction mixture was stirred at RT for 3 hours. The mixture was concentrated to dryness then purified by column chromatography (eluent a gradient of 80% EtOAc in hexane to EtOAc), to afford 47 (400 mg, 80%) as a red solid. MS (m/z): 705.2 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][C:5]#[N:6].[N:11]([O-])=O.[Na+]>Cl>[C:5]([C:4]1[C:3]2[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=2)[NH:1][N:11]=1)#[N:6]
Reactant: O=N[O-]
Reactant: N#CCc1ccccc1N
Agent: Cl
Agent: [Na+]
Product: N#Cc1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of o-aminobenzyl cyanide (0.5 g) in aqueous hydrochloric acid 1N (9.6 mL), was treated with a solution of aqueous sodium nitrite 1N (3.85 mL). After stirring at room temperature for 15 minutes, the reaction mixture was filtered. The solid was recrystallised from ethanol to give the title compound (0.4 g) as a yellow solid, m.p. 138-140° C. 1H NMR [(CD3)2SO]: δ 7.89 (d, 1H, J=7.7 Hz); 7.76 (d, 1H, J=7.9 Hz); 7.48 (t, 1H); 7.41 (t, 1H).