Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=O)[NH:14][CH:15]=[N:16]2)=[C:11]([O:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:29])=O.C(N(C(C)C)CC)(C)C>ClCCCl>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:29])=[N:14][CH:15]=[N:16]2)=[C:11]([O:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2cc(OCc3ccccc3)cc(OC3CCOCC3)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Clc1ncnc2cc(OCc3ccccc3)cc(OC3CCOCC3)c12
Temperature: 80 °C

Procedure:
A mixture of 7-benzyloxy-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one (9 g), phosphoryl chloride (2.8 ml), di-isopropylethylamine (11.4 ml) and 1,2-dichloroethane (130 ml) was stirred and heated to 80° C. for 3 hours. The mixture was evaporated to give 7-benzyloxy-4-chloro-5-tetrahydropyran-4-yloxyquinazoline which was used without further purification.
Reaction SMILES: C(=O)(O)[O-].[Na+].[Br:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[C:9]([O:14][CH3:15])[CH:8]=1.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>O.O1CCOCC1>[Br:6][C:7]1[CH:13]=[CH:12][C:10]([NH:11][C:17](=[O:18])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:9]([O:14][CH3:15])[CH:8]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1cc(Br)ccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(Br)ccc1NC(=O)OCc1ccccc1
Reaction time: 0.08 h
Yield: 74.3 %

Procedure:
A solution of sodium bicarbonate (3.12 g, 0.0371 mol) in water (35 mL) was added to a solution of 4-bromo-2-methoxyaniline (3.00 g, 0.0148 mol) in dioxane (50 mL). The resulting mixture was stirred for 5 minutes and benzyl chloroformate (3.8 g, 0.022 mol) was added dropwise over 3 minutes. The reaction mixture was for two hours, then dioxane was removed under reduced pressure and the water phase was extracted twice with ethyl acetate (100 mL each). The combined organic extracts were dried over magnesium sulfate and after filtration concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica using ethyl acetate/n-heptane (5:95) as mobile phase to yield benzyl N-(4-bromo-2-methoxyphenyl)carbamate (3.75 g, 0.011 mol) as a white solid: 1H NMR (DMSO-d6, 400 MHz) 8.72 (s, 1H), 7.61 (d, 1H), 7.38 (m, 5H), 7.20 (s, 1H), 7.10 (d, 1H), 5.14 (s, 2H), 3.81 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH2:6][C:7]([CH3:13])([CH3:12])[CH2:8]2)=[C:4]([CH3:14])[C:3]=1[CH:15]1[CH2:20][C:19](=[O:21])[CH2:18][C:17](=[O:22])[CH2:16]1.C(O[C:28](=[O:31])[CH2:29]C)(=O)CC.C[N:33]([C:35]1[CH:40]=[CH:39][CH:38]=CN=1)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH2:6][C:7]([CH3:13])([CH3:12])[CH2:8]2)=[C:4]([CH3:14])[C:3]=1[CH:15]1[CH2:20][C:19](=[O:21])[C:18]([C:35](=[N:33][O:31][CH2:28][CH3:29])[CH2:40][CH2:39][CH3:38])=[C:17]([OH:22])[CH2:16]1
Reactant: CN(C)c1ccccn1
Reactant: Cc1c(Cl)c(C2CC(=O)CC(=O)C2)c(C)c2c1CC(C)(C)C2
Reactant: CCC(=O)OC(=O)CC
Solvent: Cc1ccccc1
Product: CCCC(=NOCC)C1=C(O)CC(c2c(C)c3c(c(C)c2Cl)CC(C)(C)C3)CC1=O

Procedure:
To a solution of 8.02 g of the 5-(6-chloro-2,2,4,7-tetramethylindan-5-yl)-cyclohexane-1,3-dione in 100 ml of absolute toluene was added 12.8 ml of propionic anhydride. After refluxing for 4 hours, toluene and excess propionicanhydride were evaporated under reduced pressure to afford a residue. To the solution of the residue in 100 ml of toluene was added 0.61 g of dimethylaminopyridine and refluxed for 20 hours. The reaction mixture was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography to afford 10.1 g of the title compound as yellow solid.
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:16]=[C:15](C(O)=O)[C:14](NC3C=CC(C)=CC=3)=[CH:13][C:9]=2[C:10](O)=[O:11])=[CH:3][CH:2]=1.ClC1C=CC([NH:34][C:35]2[CH:43]=[C:42](C(O)=O)[C:41](NC3C=CC(Cl)=CC=3)=[CH:40][C:36]=2[C:37](O)=[O:38])=CC=1>>[CH:1]1[CH:6]=[C:5]2[C:10]([C:9]3[C:8]([NH:7][C:4]2=[CH:3][CH:2]=1)=[CH:16][C:15]1[C:37]([C:36]2[C:35]([NH:34][C:14]=1[CH:13]=3)=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:38])=[O:11]
Reactant: Cc1ccc(Nc2cc(C(=O)O)c(Nc3ccc(C)cc3)cc2C(=O)O)cc1
Reactant: O=C(O)c1cc(Nc2ccc(Cl)cc2)c(C(=O)O)cc1Nc1ccc(Cl)cc1
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Temperature: 125 °C
Reaction time: 0.42 h

Procedure:
A stirred vessel is charged with 1000 parts of polyphosphoric acid containing 85.0% P2O5. Then 75 parts of 2,5-di(4-toluidino)terephthalic acid and 60 parts of 2,5-di(4-chloroanilino)terephthalic acid are introduced at 90° C. with stirring over 25 minutes. During this addition the temperature rises to 120° C. The mixture is heated to 125° C. and stirred at 125° C. for 1 hour, and ring closure takes place to form the quinacridone. The reaction mixture is subsequently metered into a static mixer, model Kenics KMR (length: 10 cm, diameter: 9 mm, 8 elements, supplier: H. Ott, Neckargmünd) with a throughput of 3.3 parts by volume per hour in a volume flow of 27 parts by volume per hour of 70% strength phosphoric acid at 95° C. and is hydrolyzed in 0.9 second (a precipitate is formed). During hydrolysis, the temperature rises to 118° C. Following the hydrolysis the phosphoric acid strength is 77.7%. This gives 4905 parts of crude pigment suspension. After cooling to 60° C., the crude pigment suspension is filtered off with suction, washed to neutrality with water and dried at 80° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:7]=[C:6]([CH3:17])[C:3]=1[CH:4]=[O:5].N1C=CC=CC=1.[O:24](S(C(F)(F)F)(=O)=O)[S:25]([C:28]([F:31])([F:30])[F:29])(=O)=[O:26]>ClCCl.[Cl-].[Na+].O>[CH:4]([C:3]1[C:6]([CH3:17])=[CH:7][C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[CH:9][C:2]=1[O:1][S:25]([C:28]([F:31])([F:30])[F:29])(=[O:26])=[O:24])=[O:5]
Reactant: Cc1cc(OC2CCCCO2)cc(O)c1C=O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: Cc1cc(OC2CCCCO2)cc(OS(=O)(=O)C(F)(F)F)c1C=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 69.9 %

Procedure:
To a solution of 2-hydroxy-6-methyl-4-(tetrahydro-pyran-2-yloxy)-benzaldehyde (8.70 g, 36.8 mmol) and pyridine (14.56 g, 184.1 mmol) in dichloromethane (40 mL) was slowly added Tf2O (15.58 g, 55.2 mol) at −10 to 0° C. The mixture was stirred at 0° C. for 3 hours. The mixture was diluted with cold brine and extracted with 50% EtOAc/hexane. The organic extracts were washed with brine, dried and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (EtOAc/hexane=1:4) to give pure product (9.48 g, 69.3%). 1H NMR (400 MHz, CDCl3) δ ppm 10.35 (s, 1H), 6.86-7.03 (m, 2H), 5.53 (t, J=2.93 Hz, 1H), 3.79 (m, 1 H), 3.55-3.71 (m, 1H), 2.65 (s, 3H), 1.84-2.05 (m, 3 H), 1.51-1.78 (m, 3 H). MS (ESI) m/z=369 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[NH:34][C@H:35]([CH2:38][OH:39])[CH2:36][CH3:37])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][N:9]=1.C(N(CC)CC)C.Cl[C:57](Cl)([O:59]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl.[Cl-].[Na+].O>[F:48][C:2]([F:1])([F:47])[C:3]1[CH:4]=[C:5]([CH:40]=[C:41]([C:43]([F:44])([F:45])[F:46])[CH:42]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[N:34]1[C@@H:35]([CH2:36][CH3:37])[CH2:38][O:39][C:57]1=[O:59])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][N:13]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2N[C@@H](CC)CO)nc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2N2C(=O)OC[C@@H]2CC)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 227.1 %

Procedure:
Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-((S)-1-hydroxymethyl-propyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (102 mg) is dissolved in methylene chloride (1.5 ml) and thereto is added triethylamine (31 μl), followed by an addition of triphosgene (17 mg) under water-cooling, and the mixture is stirred at room temperature overnight. To the reaction mixture is added a saturated brine, 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 purified by column chromatography (hexane:ethyl acetate=9:1→7:3) to give ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-((S)-4-ethyl-2-oxo-oxazolidin-3-yl)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (94 mg). MS (m/z): 723 [M+H]+
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH2:11][CH2:12][N:13]=2)=[CH:5][CH:4]=1.[C:14](NC1C=CC=CC=1)(=[O:19])[CH2:15][C:16]([CH3:18])=[O:17]>>[CH3:1][N:2]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:10][CH2:11][CH2:12][N:13]=2)=[CH:7][CH:8]=1)[C:14](=[O:19])[CH2:15][C:16]([CH3:18])=[O:17]
Reactant: CC(=O)CC(=O)Nc1ccccc1
Reactant: CNc1ccc(C2=NCCO2)cc1
Product: CC(=O)CC(=O)N(C)c1ccc(C2=NCCO2)cc1

Procedure:
This compound was prepared by treating 4-aminobenzonitrile with a slight excess, on a molar equivalents basis, of methyl iodide in tetrahydrofuran solvent for 4 hrs at room temperature. Removal of the THF and other volatiles, followed by recrystallization, gave a 76% yield of 4-(N-methyl)aminobenzonitrile, mp 85-87° C. Using Example 1 procedure, the aforesaid substituted nitrile was treated with ethanolamine to obtain a 70% yield of 2-[4-(N-methyl) aminophenyl]oxazoline, mp 145-147° C. Following the Example 6 procedure, the aforesaid compound was treated with TDO to form the oxazoline shown below, having a methyl group attached to the nitrogen in the acetoacetanilide segment. The product was recrystallized from ethyl acetate, mp 102-105° C. Elemental analysis, FT-IR, exhibiting 1726 (C—O) and 1635 (—C═N—) cm−1 absorptions, and with 1H NMR confirmed the below drawn structure.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH2:9][S:10][CH3:11])=[CH:4][N:3]=1.[N:12]#[C:13][NH2:14].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C1COCC1>[F:8][C:7]1[CH:6]=[C:5]([CH2:9][S:10]([CH3:11])=[N:14][C:13]#[N:12])[CH:4]=[N:3][C:2]=1[Cl:1]
Reactant: CSCc1cnc(Cl)c(F)c1
Reactant: N#CN
Solvent: Ic1ccccc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CS(Cc1cnc(Cl)c(F)c1)=NC#N
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
To a stirred solution of 2-chloro-3-fluoro-5-methylthiomethylpyridine (1.7 g, 8.9 mmol) and cyanamide (3.7 g, 8.9 mmol) in THF (15 mL) cooled to 0° C. was added iodobenzene diacetate (2.86 g, 8.9 mmol) in one portion and the resulting mixture was stirred at 0° C. for 1 h and then at room temperature for 2 h. The solvent was removed in vacuo and the resulting mixture was purified on silica gel using 60% acetone in hexane to give 1.828 g of [1-(5-fluoro-6-chloropyridin-3-yl)methyl](methyl)-λ4-sulfanylidenecyanamide as an off-white solid in 89% yield. LC-MS calcd. for C8H7ClFN3S [M+1]+: 232.69. Found: 232.04.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]2[C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[CH2:8][CH2:9][C:10]=2[CH:11]=1.[NH2:16][NH2:17]>N1C=CC=CC=1>[NH:16]([C:2]1[N:3]=[N:4][C:5]2[C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[CH2:8][CH2:9][C:10]=2[CH:11]=1)[NH2:17]
Reactant: Clc1cc2c(nn1)-c1ccccc1CC2
Reactant: NN
Solvent: c1ccncc1
Product: NNc1cc2c(nn1)-c1ccccc1CC2

Procedure:
3-Chloro-5,6-dihydrobenzo[h]cinnoline was heated at 100° C. in a mixture of anhydrous pyridine (30 mL) and anhydrous hydrazine (5 mL) for 3.25 h. The solvent was removed under vacuum and the residue was partitioned between chloroform and 1M aqueous potassium carbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was triturated with diethyl ether and filtered to give 3-hydrazinyl-5,6-dihydrobenzo[h]cinnoline as a beige solid; 1H NMR (DMSO-d6, 300 MHz) 8.17 (d, 1H), 7.91 (br s, 1H), 7.28 (m, 3H), 6.87 (s, 1H), 4.34 (br s, 2H), 2.92 (m, 4H) ppm; 13C NMR (DMSO-d6, 75 MHz) 162.49, 147.92, 137.95, 137.39, 132.97, 128.87, 128.75, 127.56, 123.59, 110.55, 28.01, 27.66; MS (ES) 213 (M+H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([CH3:25])[CH:17]=2)=[N:4][NH:3]1.[C:26](N1C=CN=C1)([N:28]1[CH:32]=[CH:31][N:30]=[CH:29]1)=[O:27].[O:38]1CCCC1>O>[CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([CH3:25])[CH:17]=2)=[N:4][N:3]1[C:26]([OH:27])=[O:38].[N-:28]1[CH:32]=[CH:31][N:30]=[CH:29]1
Reactant: Cc1cc(C2=NNC(C)Cc3cc4c(cc32)OCO4)ccc1[N+](=O)[O-]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C1CCOC1
Solvent: O
Product: Cc1cc(C2=NN(C(=O)O)C(C)Cc3cc4c(cc32)OCO4)ccc1[N+](=O)[O-]
Product: c1c[n-]cn1
Reaction time: 20 h
Yield: 82 %

Procedure:
A mixture of 3.37 g (10.0 millimoles) of (±)-7,8-dihydro-8-methyl-5-(3-methyl-4-nitro-phenyl)-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepine, 1.95 g (12.0 millimoles) of 1,1′-carbonyl-diimidazole and 75 ml of anhydrous tetrahydrofurane is stirred under boiling for 20 hours. The reaction mixture is cooled with icecold water. The precipitated product is filtered and washed with 50 ml of diethyl ether. Thus 3.55 g of the desired product are obtained, yield 82%, mp.: 223–226° C.
Reaction SMILES: O.[CH3:2][O:3][C:4]([C:6]1[CH:7]=[C:8]([CH:12]([C:15]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:16])[C:13]#[N:14])[CH:9]=[CH:10][CH:11]=1)=[O:5].BrBr.C(=O)(O)[O-:27].[Na+]>C(Cl)Cl>[C:18]1([CH:17]2[C:15](=[O:16])[C:12]([C:8]3[CH:9]=[CH:10][CH:11]=[C:6]([C:4]([O:3][CH3:2])=[O:5])[CH:7]=3)=[C:13]([NH2:14])[O:27]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C([O-])O
Reactant: COC(=O)c1cccc(C(C#N)C(=O)Cc2ccccc2)c1
Agent: BrBr
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cccc(C2=C(N)OC(c3ccccc3)C2=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In this example 0.4 g of water was admixed with 6.5 g of (3-methoxycarbonylphenyl)-benzylcarbonyl-acetonitrile in about 40 ml of methylene chloride at room temperature. 1.1 ml of bromine in about 10 ml of methylene chloride was added dropwise at room temperature. After addition of the bromine, the reaction mixture was mixed with saturated aqueous sodium bicarbonate and stirred for about 1/2 hour at room temperature, resulting in a two-phase liquid mixture. The phases were separated. The aqueous phase was extracted three times with methylene chloride. The combined extracts and methylene chloride phase were washed twice with saturated aqueous sodium bicarbonate, dried over magnesium sulfate and concentrated by evaporation affording an oily residue. The residue was triturated with a mixture of ethyl ether and petroleum ethers affording 5.0 g of the title compound as a solid.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)#[CH:7].Cl[Si:15](Cl)([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[N:16]([CH2:19][CH3:20])[CH2:17][CH3:18].[Cu](C#N)C#N>O1CCCC1>[CH2:17]([N:16]([Si:15]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])([C:7]#[C:6][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:1]#[C:2][C:3]1[CH:4]=[CH:4][CH:3]=[CH:2][CH:1]=1)[CH2:19][CH3:20])[CH3:18]
Reactant: CCN(CC)[Si](Cl)(Cl)N(CC)CC
Reactant: C#Cc1ccccc1
Reactant: [Li]CCCC
Agent: N#C[Cu]C#N
Solvent: C1CCOC1
Product: CCN(CC)[Si](C#Cc1ccccc1)(C#Cc1ccccc1)N(CC)CC
Reaction time: 1.5 h
Yield: 93 %

Procedure:
1.6 N normal butyl lithium 205 ml was dropwise added to a solution comprising 33 ml of ethynylbenzene and 300 ml of tetrahydrofuran (hereinafter abbreviated as THF) at 0° C. under nitrogen gas flow, and stirring was continued for 1.5 hour. Dichlorobis(diethylamino)silane 36.5 g and 672 mg of copper cyanide were added to the resulting solution, and stirring was continued at room temperatures for 20 minutes to carry out the reaction. Solid matters precipitated in the reaction liquid were removed by filtering, and then the filtrate was concentrated. Water was added to this concentrate to extract the product with ether. This ether extraction layer was washed with water and then dried on magnesium sulfate. An ether component of this liquid was distilled off, and then the residue was refined by distillation to obtain 52 g of bis(diethylamino)-bis(phenyethynyl)silane. The yield was 93%.
Reaction SMILES: [NH2:1][C:2](=[N:39][C:40]([O:42][CH2:43][C:44]([CH3:46])=[CH2:45])=[O:41])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@@H:10]([C:27]2[NH:31][C:30](=[O:32])[N:29]([C:33]3[N:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[N:28]=2)[C:11]2[C:12]([F:26])=[C:13]([CH:21]=[C:22]([O:24][CH3:25])[CH:23]=2)[O:14][CH2:15][CH2:16][O:17][C:18](=[O:20])[CH3:19])=[CH:5][CH:4]=1.Cl[CH2:48][O:49][C:50](=[O:57])[C:51]([CH3:56])([CH3:55])[CH2:52][O:53][CH3:54].C(=O)([O-])[O-].[Rb+].[Rb+].CN(C)C(=O)C>O.C(OCC)(=O)C>[C:18]([O:17][CH2:16][CH2:15][O:14][C:13]1[C:12]([F:26])=[C:11]([C@@H:10]([NH:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([NH2:1])=[N:39][C:40]([O:42][CH2:43][C:44]([CH3:46])=[CH2:45])=[O:41])=[CH:8][CH:7]=2)[C:27]2[N:31]=[C:30]([O:32][CH2:48][O:49][C:50](=[O:57])[C:51]([CH3:56])([CH3:55])[CH2:52][O:53][CH3:54])[N:29]([C:33]3[N:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[N:28]=2)[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=1)(=[O:20])[CH3:19]
Reactant: COCC(C)(C)C(=O)OCCl
Reactant: C=C(C)COC(=O)N=C(N)c1ccc(N[C@@H](c2nn(-c3ncccn3)c(=O)[nH]2)c2cc(OC)cc(OCCOC(C)=O)c2F)cc1
Agent: O=C([O-])[O-]
Agent: [Rb+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: C=C(C)COC(=O)N=C(N)c1ccc(N[C@@H](c2nc(OCOC(=O)C(C)(C)COC)n(-c3ncccn3)n2)c2cc(OC)cc(OCCOC(C)=O)c2F)cc1
Temperature: 85 °C
Reaction time: 1.25 h
Yield: 45.8 %

Procedure:
Under nitrogen atmosphere, a mixture of acetic acid 2-{3-[(R)-{4-[amino(2-methylallyloxycarbonylimino)methyl]phenylamino}-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]-triazol-3-yl)methyl]-2-fluoro-5-methoxyphenoxyl}ethyl ester (1.0 g, 1.57 mmol), 3-methoxy-2,2-dimethylpropionic acid chloromethyl ester (598 mg, 3.31 mmol), rubidium carbonate (255 mg, 1.10 mmol), and N,N-dimethylacetamide (20 mL) was stirred at 85° C. for 75 minutes. After cooling to room temperature, ethyl acetate (100 mL) and water (100 mL) were added to the reaction mixture. The organic layer was collected, sequentially washed with water (100 mL) and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (mixed solvent of heptane-ethyl acetate) to obtain the captioned compound (560 mg) as a solid.
Reaction SMILES: C(OC([NH:11][C@@H:12]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]2[N:23]([CH3:24])[N:22]=[CH:21][C:20]=2[NH:25][C:26]([C:28]2[N:29]=[C:30]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([CH:47]=[CH2:48])[C:42]=3[F:49])[S:31][C:32]=2[NH:33]C(=O)OC(C)(C)C)=[O:27])[CH2:14][CH2:13]1)=O)C1C=CC=CC=1.[H][H].B(Br)(Br)Br.C(Cl)Cl>CO>[NH2:33][C:32]1[S:31][C:30]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][CH3:48])[C:42]=2[F:49])=[N:29][C:28]=1[C:26]([NH:25][C:20]1[CH:21]=[N:22][N:23]([CH3:24])[C:19]=1[N:15]1[CH2:16][CH2:17][CH2:18][C@@H:12]([NH2:11])[CH2:13][CH2:14]1)=[O:27]
Reactant: [H][H]
Reactant: C=Cc1cccc(-c2nc(C(=O)Nc3cnn(C)c3N3CCC[C@@H](NC(=O)OCc4ccccc4)CC3)c(NC(=O)OC(C)(C)C)s2)c1F
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CCc1cccc(-c2nc(C(=O)Nc3cnn(C)c3N3CCC[C@@H](N)CC3)c(N)s2)c1F
Reaction time: 2 h

Procedure:
tert-butyl N-[4-[[5-[(4R)-4-(benzyloxycarbonylamino)azepan-1-yl]-1-methyl-pyrazol-4-yl]carbamoyl]-2-(2-fluoro-3-vinyl-phenyl)thiazol-5-yl]carbamate (51 mg, 0.086 mmol) was dissolved in methanol (50 mL) and hydrogenated on H-Cube at 60° C. and 50 bar hydrogen pressure to reduce the double bond. The solution was concentrated and the residue was dissolved in DCM (5 mL). 1.0M solution of boron tribromide in methylene chloride (0.35 ml, 0.35 mmol) was added and the mixture was stirred for 2 h. The solvent was distilled off and the residue was purified via reverse phase HPLC to afford 383. MS (ESI) m/z: 458.3 [M+H+].
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7]CC)=O)[CH2:3][CH2:2]1.[F:12][C:13]([F:22])([F:21])[C:14]1[CH:15]=[C:16](Br)[CH:17]=[CH:18][CH:19]=1.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[F:12][C:13]([F:22])([F:21])[C:14]1[CH:15]=[C:16]([N:1]2[CH2:2][CH2:3][CH:4]([C:5]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:7])[CH2:10][CH2:11]2)[CH:17]=[CH:18][CH:19]=1
Reactant: FC(F)(F)c1cccc(Br)c1
Reactant: CCOC(=O)C1CCNCC1
Reactant: C1COCCN1
Product: O=C(C1CCN(c2cccc(C(F)(F)F)c2)CC1)N1CCOCC1

Procedure:
The title compound was prepared from commercially available ethyl isonipecotate, 3-(trifluoromethyl)-bromobenzene as the aryl halide, and morpholine as the secondary amine utilizing general procedures A and B described above. 1H NMR (300 MHz, CDCl3) 1H NMR (CDCl3) δ 7.34 (dd, J=7.6, 8.6 Hz, 1H), 7.11-7.05 (m, 3H), 3.80 (m, 1H), 3.76 (m, 1H), 3.70-3.54 (m, 8H), 2.81 (dt, J=2.7, 12.4 Hz, 2H), 2.67-2.57 (m, 1H), 2.09 (dd, J=4.2, 13.4 Hz, 1H), 2.00 (dd, J=4.0, 11.7 Hz, 1H), 1.85 (m, 1H), 1.81 (m, 1H). ESI MS: 343.4 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:19][CH2:18][NH:17][CH2:16][C:15]3=[O:20])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[Br:28][C:29]1[CH:30]=[C:31]([S:35](Cl)(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1>ClCCl>[Br:28][C:29]1[CH:30]=[C:31]([S:35]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH:10]3[CH2:11][CH2:12][N:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[CH2:8][CH2:9]3)[C:15](=[O:20])[CH2:16]2)(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: O=C1CNCCN1CC1CCN(c2ccncc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CN(S(=O)(=O)c2cccc(Br)c2)CCN1CC1CCN(c2ccncc2)CC1
Yield: 26 %

Procedure:
To a solution of 1-[1-(4-pyridyl)-4-piperidylmethyl]-2-piperazinone (2.74 g) and triethylamine (1.67 ml) in dichloromethane (50 ml) was added dropwise at 0° C. 3-bromobenzenesulfonyl chloride (2.56 g), and the mixture was stirred at 0° C. for 1 hour. The reaction solution was diluted with dichloromethane, was washed with water and saturated brine, dried (MgSO4) and concentrated, and the residue was purified with silica gel column chromatography (acetone:methanol=9:11:1) and washed with water to give colorless crystals of 4-(3-bromobenzenesulfonyl)-1-[1-(4-pyridyl)-4-piperidylmethyl]-2-piperazinone (1.28 g). A part of the crystals were treated with hydrochloric acid to give colorless crystals of the title compound as hydrochloride.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[Cl:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([Cl:17])[C:8]=1[NH:18][NH2:19].[OH-].[Na+]>ClCCl>[Cl:6][C:7]1[CH:12]=[C:11]([C:13]([F:15])([F:14])[F:16])[CH:10]=[C:9]([Cl:17])[C:8]=1[NH:18][NH:19][C:3](=[O:4])[CH2:2][Cl:1]
Reactant: O=C(Cl)CCl
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(CCl)NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 20 °C
Reaction time: 8.5 h
Yield: 91 %

Procedure:
A solution of chloroacetyl chloride (2.3 ml, 1.08 equivalents) in anhydrous dichloromethane (30 ml) was added during 30 minutes to a stirred solution of 2,6-dichloro-4-trifluoromethylphenylhydrazine (6.1 g, 24.89 mmol) in anhydrous dichloromethane (60 ml) maintaining between 5 and 12° C. under an argon atmosphere. The mixture was then stirred for 5-12 hours at 20° C. A solution of sodium hydroxide (11.2 ml of 10%) and dichloromethane were added and the organic phase washed (water), dried (magnesium sulfate) and evaporated to give the title compound (7.25 g) as a white solid, NMR 4.05 (s, 2H), 6.77 (s, 1H), 7.47 (s, 2H), 8.6 (s, 1H). The yield was 91%.