Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([NH:4][CH2:5][CH2:6][C:7]1[C:11]2[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:10]=2[NH:9][CH:8]=1)=[O:3].B.[OH-].[K+].[C:21](OC(=O)C)(=[O:23])[CH3:22]>FC(F)(F)C(O)=O.N1C=CC=CC=1.O>[C:21]([N:9]1[C:10]2[C:11](=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[CH:7]([CH2:6][CH2:5][NH:4][C:2](=[O:3])[CH3:1])[CH2:8]1)(=[O:23])[CH3:22]
Reactant: COc1ccc2[nH]cc(CCNC(C)=O)c2c1
Reactant: CC(=O)OC(C)=O
Agent: B
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)C(CCNC(C)=O)CN2C(C)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution, cooled to 0° C., of melatonin (1 mmol) in trifluoroacetic acid (2 ml) is added dropwise borane (2 eq, 1M solution in THF) . The mixture is stirred for 30 min at 0° C. followed by dropwise addition of water (1.5 ml), and the medium is left stirring for 1 h at room temperature. The mixture is then brought to pH=10 using 2N potassium hydroxide solution and is then extracted with dichloromethane. The crude product is separated on a column of flash silica (25/75/5 acetone/dichloromethane/methanol) and 110 mg of N-[2-(5-methoxyindolin-3-yl)ethyl]acetamide are obtained, which product is then acetylated with acetic anhydride in pyridine to give N-[2-(1-acetyl-5-methoxyindolin-3-yl)ethyl]acetamide.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.[C:10]1(O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(O)C1CCOCC1
Reactant: Oc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Oc1ccccc1)C1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.7 %

Procedure:
Tetrahydropyran-4-carboxylic acid (1.00 g, 7.69 mmol), phenol (651 mg, 6.92 mmol), and PyBOP (4.40 g, 8.45 mmol) were dissolved in DMF (15 mL). To the solution was added triethylamine (2.36 mL, 16.9 mmol), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was successively washed with saturated sodium bicarbonate aqueous solution and brine, and dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:2) to give phenyl tetrahydropyran-4-carboxylate (1.28 g, 81%).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=[CH2:2].[F:12][C:13]1[C:18](O)=[C:17]([F:20])[C:16]([F:21])=[C:15]([F:22])[C:14]=1[F:23].C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C.O1CCCC1>[CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][C:18]2[C:17]([F:20])=[C:16]([F:21])[C:15]([F:22])=[C:14]([F:23])[C:13]=2[F:12])=[O:8])=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C=Cc1ccc(C(=O)O)cc1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=Cc1ccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1
Reaction time: 1 h
Yield: 93.4 %

Procedure:
In a mixture solvent of 500 mL of ethyl acetate and 150 mL of tetrahydrofuran were dissolved 50 g of 4-vinylbenzoic acid and 62.1 g of pentafluorophenol, and the solution was ice-cooled. To the solution was added 69.65 g of dicyclohexylcarbodiimide, and the mixture was stirred under ice-cooling for 1 hour and then at room temperature for 1 hour. Precipitated dicyclohexylurea was filtered off and the filtrate was concentrated under a reduced pressure. To the residue was added 150 mL of hexane, and precipitated dicyclohexylurea was filtered off. Then, the filtrate was concentrated under a reduced pressure to give 99 g of pentafluorophenyl 4-vinylbenzoate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15]([CH3:16])=[N:14][N:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[C:8]=2[N:9]=[C:10](Br)[CH:11]=1)=[O:5])[CH3:2].[CH3:23][O:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15]([CH3:16])=[N:14][N:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[C:8]=2[N:9]=[C:10]([C:30]2[CH:31]=[CH:32][C:27]([O:26][CH2:25][O:24][CH3:23])=[CH:28][CH:29]=2)[CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(Br)nc2c1c(C)nn2C1CCCCO1
Reactant: COCOc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(-c2ccc(OCOC)cc2)nc2c1c(C)nn2C1CCCCO1
Temperature: 85 °C
Reaction time: 1 h
Yield: 107.1 %

Procedure:
To a degassed mixture of 1.68 g 6-bromo-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester, 1.00 g 4-(methoxymethoxy)-phenylboronic acid and 0.70 g potassium carbonate in DME/water (v/v=2/1, 24 mL) at r.t. and under Ar-atmosphere 70 mg palladium(0) bis(tri-tert-butylphosphine) was added and the mixture was stirred at 85° C. for 1 h. To the mixture water and ethyl acetate were added, the phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. 2.08 g (100%) of the title compound were obtained.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[C:15]([NH2:20])[CH:16]=[CH:17][CH:18]=3)N=CC=2)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[Cl:25][C:26]1[CH:43]=[CH:42][C:41]([CH2:44][NH:45][C:46](=[O:51])[C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:40][C:27]=1[C:28]([O:30]C1C=CC([N+]([O-])=O)=CC=1)=O.C[N:53]([CH:55]=O)[CH3:54]>>[Cl:25][C:26]1[CH:43]=[CH:42][C:41]([CH2:44][NH:45][C:46](=[O:51])[C:47]([CH3:48])([CH3:49])[CH3:50])=[CH:40][C:27]=1[C:28]([NH:20][C:15]1[C:16]2[C:54](=[C:10]([NH:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=3)[CH:19]=[CH:18][CH:17]=2)[N:53]=[CH:55][CH:14]=1)=[O:30]
Reactant: Nc1cccc2c(Nc3cccc(C(F)(F)F)c3)ccnc12
Reactant: CN(C)C=O
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2ccnc3c(Nc4cccc(C(F)(F)F)c4)cccc23)c1
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-(3-(trifluoromethyl)phenyl)quinoline-4,8-diamine (Intermediate-12, 80 mg, 0.264 mmol) in DMF (2 mL) was added NaH (26 mg, 0.65 mmol, 60% in mineral oil) at 0° C. and the reaction mixture was stirred at 0-5° C. for 30 minutes. Then a solution of 4-nitrophenyl 2-chloro-5-(pivalamidomethyl)benzoate (Intermediate-13, 123 mg, 0.314 mmol) in DMF (1 mL) was added to the reaction mixture at 0° C. and the reaction mixture was stirred at 0° C.—rt for 2 h. Then the reaction mixture was quenched with water and was extracted with EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 15 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.92 (s, 1H), 9.07 (s, 1H), 8.86 (d, J=4.8 Hz, 1H), 8.21-8.18 (m, 2H), 7.80-7.57 (m, 3H), 7.59-7.54 (m, 5H), 7.39 (d, J=8.4 Hz, 1H), 7.25 (d, J=7.2 Hz, 1H), 4.32 (d, J=6.0 Hz, 2H), 1.19 (s, 9H); MS [M+H]+: 555.25.
Reaction SMILES: O1CCC[CH2:2]1.[Br:6][C:7]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([CH:15]([OH:17])[CH3:16])=[CH:9][C:8]=1[O:18][CH3:19].[H-].[Na+].IC>O>[Br:6][C:7]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([CH:15]([O:17][CH3:2])[CH3:16])=[CH:9][C:8]=1[O:18][CH3:19]
Reactant: COc1cc(C(C)O)cc(OC)c1Br
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COc1cc(C(C)OC)cc(OC)c1Br
Reaction time: 0.17 h

Procedure:
To a tetrahydrofuran (100 mL) solution of 1-(4-bromo-3,5-dimethoxyphenyl)ethanol (7.24 g, 27.7 mmol) was added sodium hydride (1.33 g, 33.2 mmol) at 0° C., and the mixture was stirred for 10 minutes. To the mixture was added dropwise iodomethane (1.90 mL, 30.5 mmol), and the mixture was stirred at room temperature for one hour. After the reaction was completed, water was added to the reaction mixture while cooling on ice, which was extracted with ethyl acetate and dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-heptane/ethyl acetate: 10/1 then 1/4) to obtain the title compound (7.39 g, 26.9 mmol).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][N:11]=1.BrC1C=CC(Br)=CN=1.O1C2C=CC=CC=2C=C1B(O)O.[C:37]1(B(O)O)[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][CH:38]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([C:45]2[C:46]3[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:42]=[CH:43][CH:44]=2)=[CH:12][N:11]=1
Reactant: Brc1ccc(-c2cc3ccccc3o2)nc1
Reactant: OB(O)c1cccc2ccccc12
Agent: Brc1ccc(Br)nc1
Agent: OB(O)c1cc2ccccc2o1
Product: c1ccc2oc(-c3ccc(-c4cccc5ccccc45)cn3)cc2c1

Procedure:
It is easy to synthesis the following compound in the same manner as in Example 1 except that 2-(benzofuran-2-yl)-5-bromopyridine was synthesized from 2,5-dibromopyridine (made by Tokyo Kasei Kogyo K.K.) and 2-benzofuranboronic acid (made by Aldrich Co.) and is reacted with 1-naphthylboronic acid (made by Tokyo Kasei Kogyo) to obtain 2-(benzofuran-2-yl)-5-(naphthalene-1-yl)pyridine, which is used instead of 2-(5-trifluoromethylpyridine-2-yl)benzofuran.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.Cl.[Cl:18][C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][C:29]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[C:22]([NH:24][CH2:25][CH3:26])=[O:23].[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[Cl:18][C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][C:29]=1[N:30]1[CH2:31][CH2:32][N:33]([CH2:2][C:3]2[CH:12]=[N:11][C:10]3[N:9]4[CH2:13][CH2:14][CH2:15][C@H:8]4[C:7](=[O:16])[NH:6][C:5]=3[CH:4]=2)[CH2:34][CH2:35]1)[C:22]([NH:24][CH2:25][CH3:26])=[O:23]
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Reactant: CCNC(=O)c1ccc(N2CCNCC2)c(Cl)c1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)c(Cl)c1
Temperature: 105 °C
Yield: 35.3 %

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (100 mg, 0.456 mmol), 3-chloro-N-ethyl-4-(piperazin-1-yl)benzamide hydrochloride (139 mg, 0.456 mmol), (cyanomethyl)trimethylphosphonium iodide (166 mg, 0.684 mmol) and N,N-diisopropylethylamine (0.398 ml, 2.281 mmol) were suspended in propiononitrile (Volume: 1.370 ml) and heated in a closed vial at 90-120° C. for 4 h. The reaction mixture became a dark brown solution. It was cooled to room temperature, concentrated in vacuo, dissolved in DMSO (2 mL) and purified using HPLC (basic, 10-95% ACN in water). The fractions were concentrated in vacuo and the resulting solid was recrystallized from water-methanol (5:1, 6 mL) and dried in vacuum to afford (S)-3-chloro-N-ethyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (75.6 mg, 0.161 mmol, 35.3% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03 (t, J=7.20 Hz, 3 H) 1.76-1.93 (m, 3 H) 2.06-2.17 (m, 1 H) 2.44-2.51 (m, 4 H) 2.96 (br. s., 4 H) 3.14-3.23 (m, 2 H) 3.28-3.38 (m, 3 H) 3.46-3.58 (m, 1 H) 3.88-3.97 (m, 1 H) 6.92 (d, J=2.02 Hz, 1 H) 7.10 (d, J=8.34 Hz, 1 H) 7.56 (d, J=1.77 Hz, 1 H) 7.70 (dd, J=8.34, 2.02 Hz, 1 H) 7.81 (d, J=2.27 Hz, 1 H) 8.37 (t, J=5.43 Hz, 1 H) 10.38 (s, 1 H). [M+H] calc'd for C24H29ClN6O2, 469; found, 469.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][C:15]=2[C:23]([F:26])([F:25])[F:24])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.[Cl:56][C:57]1[CH:68]=[CH:67][C:60]2[NH:61][C:62]([C@@H:64]([NH2:66])[CH3:65])=[N:63][C:59]=2[CH:58]=1>CN1C(=O)CCC1>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:66][C@H:64]([C:62]3[NH:61][C:60]4[CH:67]=[CH:68][C:57]([Cl:56])=[CH:58][C:59]=4[N:63]=3)[CH3:65])=[O:20])=[CH:16][C:15]=2[C:23]([F:26])([F:24])[F:25])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)cc2C(F)(F)F)CC1
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN1CCCC1=O
Product: C[C@H](NC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C(F)(F)F)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1f from 4-(4-N-Boc-piperazin-1-yl)-3-trifluoromethyl-benzoic acid, TBTU, NMM and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in NMP and subsequent purification by chromatography on silica gel (eluant: petroleum ether/ethyl acetate=50:50).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:9]([NH:12][C:13]#[N:14])(=[O:11])[CH3:10].[Na]>CN(C)C=O>[CH2:2]([N:12]([C:13]#[N:14])[C:9](=[O:11])[CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCBr
Reactant: CC(=O)NC#N
Agent: [Na]
Solvent: CN(C)C=O
Product: CCCCCCCN(C#N)C(C)=O

Procedure:
36.0 g (0.20 mol) of 1-bromoheptane are added dropwise to a solution of 21.2 g (0.20 mol) of sodium acetylcyanamide in 50 ml of dimethylformamide at 85° C. The mixture is allowed to after-react for 2 hours and the NaBr is filtered off with suction at room temperature. The filtrate is treated with 50 ml of H2O and the mixture is extracted with cloroform. The solvent is separated off on a rotary evaporator and the crude product is distilled over a rotating belt column to give 24.3 g (66.7% of theory) of pure product of boiling point 124° C./18 mbar.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[Cl-].[Mg+2].[Cl-].N1C=CC=CC=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1>C(Cl)Cl>[CH2:8]([O:7][C:1](=[O:6])[CH:2]([C:19]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)=[O:26])[C:3](=[O:4])[CH3:5])[CH3:9]
Reactant: O=C(Cl)c1ccncc1
Reactant: CCOC(=O)CC(C)=O
Agent: [Cl-]
Agent: [Mg+2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C(C(C)=O)C(=O)c1ccncc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 46.7 %

Procedure:
8 g (61.5 mmol) of ethyl acetoacetate were dissolved in 280 ml of CH2Cl2, the solution was cooled at 0° C. and successively were added 6.00 g (63.3 mmol) of anhydrous magnesium chloride, 10 ml (124 mmol) of pyridine and 13.4 g (94.73 mmol) of isonicotinoyl chloride. The yellow suspension was stirred 1 h under ice cooling and 18 h at room temperature. The reaction mixture was poured into crashed ice and extracted twice with CH2Cl2. The organic phases were washed with brine, dried over magnesium sulfate, and evaporated. The residue was purified by column chromatography (n-heptane:EtOAc 1:4) to afford the title compound as light yellow oil (6.75 g, 47%). MS: 236.0 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:8][CH2:7][C@@H:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:5][CH2:4]1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[CH3:17][S:18]([O:1][CH2:2][CH:3]1[CH2:4][CH2:5][C@H:6]([NH:9][C:10]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:16])[CH2:7][O:8]1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC(CO)OC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCC(COS(C)(=O)=O)OC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
tert-Butyl [(3S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]carbamate (331 mg, 1.43 mmol) in dichloromethane (5 mL) was treated with methanesulfonyl chloride (0.222 mL, 2.87 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h, then concentrated and partitioned between ethyl acetate and water. The organic phase was concentrated and purified on silica gel (eluting with a gradient of 0 to 50% ethyl acetate in hexanes) to give the desired product (0.38 g, 86%). LCMS calculated for C8H16NO6S (M-t-Bu+H)+: m/z=254.1. Found: 254.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:12]1([C:18]2[O:19][CH2:20][CH:21]([OH:30])[CH:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:23]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([O:30][CH:21]2[CH2:20][O:19][C:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:23][CH:22]2[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OC1COC(c2ccccc2)=NC1c1ccccc1
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Solvent: ClCCCl
Product: O=C(Nc1ccc(Cl)c(Cl)c1)OC1COC(c2ccccc2)=NC1c1ccccc1
Yield: 75.5 %

Procedure:
3,4-Dichlorophenyl isocyanate (1.15 g) is added at a temperature in the region of 20° C. to a solution, maintained under an argon atmosphere, of (4RS, 5RS)-2,4-diphenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (1.52 g) in 1,2-dichloroethane (20 cc). The solution obtained is heated to reflux for 6 hours and then concentrated to dryness under reduced pressure (2.7 kPa). After recrystallization in acetonitrile, (4RS, 5RS)-5-(3,4-dichlorophenylcarbamoyloxy)-2,4-diphenyl-5,6-dihydro-4H-1,3-oxazine (2 g), m.p. 184° C., is obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[C:5]([C:12]#[N:13])=[CH:4][N:3]=1.[N:14]1([CH2:20][CH2:21][NH:22][S:23]([C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.Cl.CCOCC>CC(O)CC>[N:14]1([CH2:20][CH2:21][NH:22][S:23]([C:26]2[CH:27]=[CH:28][C:29]([NH:30][C:2]3[N:7]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[C:5]([C:12]#[N:13])=[CH:4][N:3]=3)=[CH:31][CH:32]=2)(=[O:25])=[O:24])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC(C)Oc1nc(Cl)ncc1C#N
Reactant: Nc1ccc(S(=O)(=O)NCCN2CCCCC2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CCC(C)O
Product: CC(C)Oc1nc(Nc2ccc(S(=O)(=O)NCCN3CCCCC3)cc2)ncc1C#N
Temperature: 70 °C
Reaction time: 18 h
Yield: 2.6 %

Procedure:
To a stirred suspension of 2-chloro-4-isopropoxy-5-cyanopyrimidine (Method 26; 505 mg, 2.56 mmol) and 4-[N-(2-piperidinoethyl)sulphamoyl]aniline (Method 43; 362 mg, 1.28 mmol) in 2-butanol (10 ml) was added 1M HCl in ether (3.6 ml, 3.6 mmol). The reaction was warmed to 70° C. and stirred for 18 hours. The reaction was filtered and the solvent removed under reduced pressure to yield a yellow solid. This solid was partitioned between DCM (40 ml) and 2M sodium hydroxide (40 ml). The phases were separated and the aqueous layer was extracted with DCM (30 ml). The organic phases were combined and washed with water (30 ml) and brine (30 ml). Solvent was removed under reduced pressure and the resulting solid was recrystallized from methanol to give the title compound (15 mg). NMR: 1.35 (m, 2H), 1.45 (m, 10H), 2.25 (m, 6H), 2.85 (m, 2H), 5.45 (m, 1H), 7.30 (br s, 1H), 7.80 (d, 2H), 7.90 (d, 2H),8.75 (s, 1H), 10.60 (br s, 1H); m/z 444.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:17][CH3:18])=[C:4]([C:12]([CH3:16])([CH3:15])[C:13]#[N:14])[CH:5]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:7]=1.Cl[C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21].C(N(CC)C(C)C)(C)C>C1COCC1>[C:8]([C:6]1[CH:5]=[C:4]([C:12]([C:13]#[N:14])([CH3:16])[CH3:15])[C:3]([O:17][CH3:18])=[C:2]([NH:1][C:20](=[O:21])[O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])[CH:7]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: COc1c(N)cc(C(C)(C)C)cc1C(C)(C)C#N
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(NC(=O)OCC(Cl)(Cl)Cl)cc(C(C)(C)C)cc1C(C)(C)C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(3-amino-5-tert-butyl-2-methoxyphenyl)-2-methylpropanenitrile (0.050 g, 0.202 mmol) in THF (0.6 mL), 2,2,2-trichloroethyl chloroformate (0.052 g, 0.245 mmol) and N,N-diisopropylethylamine (0.053 mL, 0.304 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=0/100-30/70) to obtain 0.086 g (quantitative) of the captioned compound.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[N:6][N:7]2[C:12]([N:13]([CH3:20])C3C=CC=CC=3)=[N:11][C:10]([S:21][CH3:22])=[N:9][C:8]=12)([CH3:3])[CH3:2].[C:23]1([C:29]2[CH:36]=[CH:35][C:32](CN)=[CH:31][CH:30]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CO>[CH:1]([C:4]1[CH:5]=[N:6][N:7]2[C:12]([NH:13][CH2:20][C:32]3[CH:35]=[CH:36][C:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:30][CH:31]=3)=[N:11][C:10]([S:21][CH3:22])=[N:9][C:8]=12)([CH3:3])[CH3:2]
Reactant: NCc1ccc(-c2ccccc2)cc1
Reactant: CSc1nc(N(C)c2ccccc2)n2ncc(C(C)C)c2n1
Solvent: CO
Product: CSc1nc(NCc2ccc(-c3ccccc3)cc2)n2ncc(C(C)C)c2n1

Procedure:
In a sealed tube, a solution of 8-isopropyl-4-(N-methyl-N-phenylamino)-2-(methylsulfanyl)pyrazolo[1,5-a]-1,3,5-triazine (114 mg, 0.36 mmol) and of 4-phenylbenzylamine (100 mg, 0.55 mmol) is heated at 140° C. for 24 h. After cooling, the solvent is evaporated off. The crude compound collected is purified by flash chromatography (EP/Et2O 9:1) so as to give IIa.1 (95 mg, 67%). Mp=134-135° C. (MeOH). 1H NMR (300 MHz, CDCl3): δ 7.75 (s, 1H, Harom), 7.59-7.56 (m, 4H, Harom), 7.45-7.34 (m, 5H, Harom), 6.93 (bs, 1H, NH), 4.85 (d, 2H, J=5.7 Hz, CH2), 3.18 (hept, 1H, J=7.2 Hz, CH), 2.58, (s, 3H, CH3), 1.33 (d, 6H, J=7.2 Hz, 2 CH3). MS (EST): m/z 390 (MH′).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH:40]=[CH:41][C:42]=1[NH:43][C:44]([NH:46][CH:47]1[CH2:49][CH2:48]1)=[O:45])[O:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH:27]3[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]3)=[C:20]([C:23]#[N:24])[CH:21]=2)[N:16]=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>O>[Cl:8][C:9]1[CH:10]=[C:11]([O:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH2:26][CH:27]4[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]4)=[C:20]([C:23]#[N:24])[CH:21]=3)[N:16]=[CH:15][CH:14]=2)[CH:40]=[CH:41][C:42]=1[NH:43][C:44]([NH:46][CH:47]1[CH2:49][CH2:48]1)=[O:45]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cc3nccc(Oc4ccc(NC(=O)NC5CC5)c(Cl)c4)c3cc2C#N)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: N#Cc1cc2c(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)ccnc2cc1OCC1CCNCC1
Reaction time: 1 h
Yield: 99.5 %

Procedure:
After adding trifluoroacetic acid (2.5 ml) to tert-butyl 4-(((4-(3-chloro-4-((cyclopropylamino)carbonyl)aminophenoxy)-6-cyano-7-quinolyl)oxy)methyl)-1-piperidinecarboxylate (501 mg, 0.846 mmol) at room temperature, the mixture was stirred for 1 hour. The reaction solution was diluted with water (35 ml) while cooling in an ice water bath, and then sodium bicarbonate (3.5 g) was gradually added for neutralization and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off, the residue was suspended in ethyl acetate and diluted with hexane, and the precipitated crystals were filtered out and blow-dried to obtain the title compound (414.4 mg, 0.842 mmol, 99.6%) as white crystals.