Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[C:6]([O:32][CH3:33])=[C:7]([CH:21]=[C:22]([N:24]2[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:25]2=[O:31])[CH:23]=1)/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13](NS(C)(=O)=O)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[F:34]C1C=CC(CP(=O)(OCC)OCC)=CC=1>>[C:1]([C:5]1[CH:23]=[C:22]([N:24]2[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:25]2=[O:31])[CH:21]=[C:7](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([F:34])=[CH:12][CH:11]=2)[C:6]=1[O:32][CH3:33])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOP(=O)(Cc1ccc(F)cc1)OCC
Reactant: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2)cc(N2CCC(=O)NC2=O)cc1C(C)(C)C
Product: COc1c(/C=C/c2ccc(F)cc2)cc(N2CCC(=O)NC2=O)cc1C(C)(C)C

Procedure:
The title compound was prepared according the procedures described in Example 1, Part H and Example 1, Part I using the product obtained in Example 1, Part G (50 mg, 0.164 mmol) and diethyl 4-fluorobenzylphosphonate (40.5 mg, 0.164 mmol). The title compound was obtained as a solid (30 mg, 46%). 1H NMR (300 MHz, DMSO-d6): δ ppm 1.37 (s, 9H), 2.72 (t, J=6.6 Hz, 2H), 3.76 (s, 3H), 3.79 (t, =6.6 Hz, 2H), 7.21 (m, 4H), 7.30 (d, J=16.3 Hz, 1H), 7.53 (d, J=2.6 Hz, 1H), 7.73 (m, 2H), 10.35 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[C:3]=1[S:23][CH3:24].ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)(Cl)Cl.ClCCl>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]([F:21])([F:20])[F:22])[C:3]=1[S:23]([CH3:24])=[O:33]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1c(C(F)(F)F)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CS(=O)c1c(C(F)(F)F)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reaction time: 6 h

Procedure:
A stirred solution of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-methylthio-3-trifluoromethylpyrazole (1.0 g) in chloroform (40 ml) was treated with m-chloroperbenzoic acid (0.42 g), portionwise at room temperature. After stirring for 6 hours, the solution was diluted with dichloromethane and washed in turn with solidum sulphite solution, sodium hydroxide solution, and water. The solution was dried over anhydrous magnesium sulphate, and evaporated in vacuo to give a yellow oil. Purification by chromatography on silica (Merck, 230°-400 mesh, 0.7 kg cm-2) eluting with dichloromethane-ethylacetate (4:1) gave 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-methylsulphinyl-3-trifluoromethylpyrazole in the form of a white solid, m.p. 142°-145° C. with decomposition.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH:9]=[O:10])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[Si:12]([O:19][CH2:20][CH:21]([O:32][NH2:33])[CH2:22][CH2:23][P:24](=[O:31])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].C(N(CC)CC)C>O1CCOCC1>[Si:12]([O:19][CH2:20][CH:21]([O:32][NH:33][C:6]1[N:5]=[CH:4][N:3]=[C:2]([Cl:1])[C:7]=1[NH:8][CH:9]=[O:10])[CH2:22][CH2:23][P:24]([O:28][CH2:29][CH3:30])([O:25][CH2:26][CH3:27])=[O:31])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CCOP(=O)(CCC(CO[Si](C)(C)C(C)(C)C)ON)OCC
Reactant: O=CNc1c(Cl)ncnc1Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCOP(=O)(CCC(CO[Si](C)(C)C(C)(C)C)ONc1ncnc(Cl)c1NC=O)OCC
Temperature: 90 °C
Yield: 28.8 %

Procedure:
A mixture of 4,6-dichloro-5-formamidopyrimidine (0.73 g, 3.8 mmol), diethyl [4-(t-butyldimethylsilyloxy)-3-(aminooxy)butyl]phosphonate (1.35 g, 3.8 mmol) and triethylamine (0.78 ml, 5.7 mmol) in dioxan (20 ml) was heated at 90° C. for 3 hours. After cooling to ambient temperature, the mixture was filtered and the filtrate evaporated. The residue was chromatographed on silica gel using dichloromethane-methanol (98:2) as eluant to yield the title compound as a oil (0.56 g, 29). IR: υmax (film) 3180, 2940, 2870, 1690, 1635, 1250, 1030, 970, 830, 780 cm-1. 1H NMR: δH (CDCl3) 0.05 (6H, s, SiMe2), 0.9 (9H, s, SiBut), 1.3 (6H, t, J=7Hz, (OCH2CH3 )2), 1.6-2.3 (4H, m, CH2CH2P), 3.6-4.3 (7H, m, OCH2CH+(OCH2CH3)2), 7.3-10.05 (4H, broad, --NHCHO+--NHO+H-2).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.BrCCBr.[Mg].[CH3:18][C:19]1[S:23][C:22]([CH:24]=[O:25])=[CH:21][CH:20]=1>O.C1COCC1>[O:9]1[CH2:10][CH2:11][O:12][CH:8]1[C:4]1[CH:3]=[C:2]([CH:24]([C:22]2[S:23][C:19]([CH3:18])=[CH:20][CH:21]=2)[OH:25])[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1ccc(C=O)s1
Reactant: Brc1cccc(C2OCCO2)c1
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C(O)c2cccc(C3OCCO3)c2)s1
Temperature: 0 °C
Yield: 50.2 %

Procedure:
To a solution of THF (20 mL), 2-(3-bromophenyl)-1,3-dioxolane (2.7 g) and 1,2-dibromoethane (150 mg) was added magnesium (270 mg), which was heated to reflux for 10 minutes. The reaction mixture was cooled to 0° C., and a solution of 5-methyl-2-thiophencarbaldehyde (1.0 g) and THF (5 mL) was added thereto under stirring. The reaction solution was returned to room temperature and stirred for 10 minutes. Water was added to the reaction solution, which was then extracted with ethyl acetate. The solvent was evaporated from the organic layer under a reduced pressure, and the residue was purified by silica gel chromatography (heptane:ethyl acetate=2:1) to obtain the titled compound (1.1 g).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[CH:9][C:10]=2[O:12][CH3:13])[N:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:18]=[C:19]([S:29]([NH:32][CH3:33])(=[O:31])=[O:30])[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][C:25]([F:28])([F:27])[F:26]>CC(O)C>[ClH:1].[CH3:13][O:12][C:10]1[CH:9]=[C:8]([O:14][CH3:15])[CH:7]=[C:6]2[C:11]=1[C:2]([NH:16][C:17]1[CH:18]=[C:19]([S:29]([NH:32][CH3:33])(=[O:30])=[O:31])[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][C:25]([F:27])([F:26])[F:28])=[N:3][CH:4]=[N:5]2
Reactant: COc1cc(OC)c2c(Cl)ncnc2c1
Reactant: CNS(=O)(=O)c1ccc(OCC(F)(F)F)c(N)c1
Solvent: CC(C)O
Product: CNS(=O)(=O)c1ccc(OCC(F)(F)F)c(Nc2ncnc3cc(OC)cc(OC)c23)c1
Product: Cl
Temperature: 25 °C
Yield: 76.5 %

Procedure:
A mixture of 4-chloro-5,7-bis(methyloxy)quinazoline (75 mg, 0.334 mmol, prepared according to J. Med. Chem. (2006) 49 6465) and 3-amino-N-methyl-4-[(2,2,2-trifluoroethyl)oxy]benzenesulfonamide (95 mg, 0.334 mmol) in i-PrOH (2 mL) was subjected to microwave irradiation (100° C., 1 bar) for 30 minutes before being cooled to room temperature. The solid was collected by filtration, washed with i-PrOH, and dried under vacuum to give 3-{[5,7-bis(methyloxy)-4-quinazolinyl]amino}-N-methyl-4-[(2,2,2-trifluoroethyl)oxy]benzenesulfonamide hydrochloride (130 mg, 76%) as a yellow soid.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CCN(CC)CC.[NH:20]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C@H:21]([C:26](OC1C(F)=C(F)C(F)=C(F)C=1F)=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24]>CN(C=O)C>[NH:20]([C:40]([O:42][C:43]([CH3:45])([CH3:44])[CH3:46])=[O:41])[C@H:21]([C:26]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)Oc1c(F)c(F)c(F)c(F)c1F
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
H-Phe-OH (1.49 g, 9 mmol) fine powder was suspended in DMF (20 ml). After cooling at 0°, Et3N (1.26 ml, 9 mmol) was added, followed by Boc-Leu-pentafluorophenylester, i.e., Boc-Leu-OPfp (3.93 g, 9.9 mmol). It was stirred for 1 hr at 0° C and for 2.5 hr at room temperature. After filtration the solvent was evaporated and the residue was treated with H2O. The separated oil was extracted with EtOAc. The organic phase was washed with 10% citric acid, H2O, dried (Na2SO4) and evaporated to a smaller volume. Addition of petroleum ether and standing overnight in the refrigerator provided the product (XVI) which was recrystallized from EtOAc-petroleum ether to fine crystals, yield 2.3 g (67.6%); mp 104°-106° C; [α]D25 -3.40° (c 1, EtOH). Anal. Calcd for C20H30N2O5 (378.476): C, 63.47; H, 7.99; N, 7.40. Found: C, 63.46; H, 8.18; N, 7.49.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([O:23][CH3:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[S:44]1[CH:48]=[CH:47][N:46]=[C:45]1[C@@H:49]([NH2:51])[CH3:50]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:36]([NH:51][C@H:49]([C:45]2[S:44][CH:48]=[CH:47][N:46]=2)[CH3:50])=[O:42])=[C:18]([O:23][CH3:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc(Oc2ccnc3cc(OC)c(OC)cc23)ccc1N
Reactant: C[C@H](N)c1nccs1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc(Oc2ccnc3cc(OC)c(OC)cc23)ccc1NC(=O)N[C@@H](C)c1nccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methoxyaniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of (1S)-1-(1,3-thiazol-2-yl)-1-ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (33 mg, yield 75%).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[F:25][C:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[CH:28][C:27]=1[NH:41][C:42]1[O:43][C:44]2[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=2[N:46]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@H:12]3[CH2:17][CH2:16][C@@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=[C:2]([C:30]3[CH:29]=[CH:28][C:27]([NH:41][C:42]4[O:43][C:44]5[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=5[N:46]=4)=[C:26]([F:25])[CH:31]=3)[C:10]=12
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: CC1(C)OB(c2ccc(Nc3nc4ccccc4o3)c(F)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6ccccc6o5)c(F)c4)c4c(N)ncnc43)CC2)CC1
Temperature: 83 °C
Reaction time: 19 h
Yield: 25 %

Procedure:
To a solution of cis-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.150 g, 0.340 mmol) in ethylene glycol dimethyl ether (3 mL) and water (1.5 mL) under nitrogen was added N2-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzoxazol-2-amine (0.151 g, 0.425 mmol), tetrakis(triphenylphosphine)palladium (0) (0.020 mg, 0.017 mmol), and sodium carbonate monohydrate (0.105 mg, 0.850 mmol). The solution was stirred at 83° C. for 19 h. The resulting yellow mixture was concentrated in vacuo to give a yellow oil. Purification by preparative RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 20 min at 21 mL/min using a 8 m Hypersil HS C18, 250×21 mm column, tr=5.7-8.1 min.) afforded cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-1,3-benzoxazol-2-amine as an off-white solid (0.046 g, 25%): 1H NMR (DMSO-d6, 400 MHz) δ 10.65 (s, 1H), 8.49 (m, 1H), 8.25 (s, 1H), 7.53 (d, 2H), 7.48 (d, 2H), 7.26 (t, 1H), 7.20 (t, 1H), 4.80 (m, 1H), 3.51-2.50 (m, 11H), 2.33-2.32 (m, 4H), 2.09-2.06 (m, 2H), 1.80-1.40 (m, 3H); RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 250×4.6 mm column) tr=6.95 min., 99%; m/z 542 (MH+).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2N=1)(C)(C)C.Cl.ClCC1N(C)N=NC=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[N:35]([CH3:30])[N:34]=[N:33][CH:31]=3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: Cl
Agent: Cn1nncc1CCl
Product: Cn1nncc1Cn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)-1-methyl-1H-1,2,3-triazole hydrochloride and isolated as light yellow solid. MS (m/e): 378.3 (MH+).
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][C:3]=1[C:16]#[N:17].[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[C:22]([CH3:27])[CH:21]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][C:3]([C:16]#[N:17])=[C:2]2[NH:24][C:23]1[CH:25]=[CH:26][C:20]([O:19][CH3:18])=[CH:21][C:22]=1[CH3:27]
Reactant: COc1ccc(N)c(C)c1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1ccc(Nc2c(C#N)cnc3cc(OC)c(OC)cc23)c(C)c1

Procedure:
A reaction mixture of 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 164.6 mg (1.2 mmol) of 4-methoxy-2-methyl-aniline and 115.6 mg (1 mmol) of pyridine hydrochloride in 10 mL of 2-ethoxyethanol was refluxed under N2 for 3 hr. After removal of the solvent, the residue was diluted with water and neutralized to pH 7-8 with diluted sodium carbonate solution. The precipitate was filtered and washed with water and ether. After drying in vacuo. this yielded 250.2 mg (71.7%) of the product as a off red solid, m.p.>131° C. (dec.), mass (electrospray, m/e): M+H 349.9.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].ClC(Cl)(O[C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.[CH2:36]([N:43]1[CH2:47][CH2:46][C@H:45]([NH2:48])[CH2:44]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)(Cl)Cl>[CH2:36]([N:43]1[CH2:47][CH2:46][C@H:45]([NH:48][C:28]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([O:9][C:10]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]=[CH:12][N:11]=3)=[CH:8][C:2]=2[Cl:1])=[O:34])[CH2:44]1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: N[C@H]1CCN(Cc2ccccc2)C1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc(NC(=O)N[C@H]4CCN(Cc5ccccc5)C4)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
Chloroform (15 ml) and triethylamine (3 ml) were added to 2-chloro-4-[ (6,7-dimethoxy-4-quinazolinyl)oxy]aniline (200 mg) to prepare a solution. Triphosgene (198 mg) was added to the solution, and the mixture was stirred at room temperature for 30 min. (3S)-(+)-1-Benzyl-3-aminopyrrolidine (80 mg) was then added thereto, and the mixture was stirred at room temperature overnight. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The extract was washed with saturated brine and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/acetone for development. Diethyl ether was added to the purification product, and the precipitated crystal was collected by filtration and was washed to give the title compound (204 mg, yield 63%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:26]3[CH2:31][CH2:30][C@@H:29]([N:32]4[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]4)[CH2:28][CH2:27]3)[N:9]=[C:10]([C:11]3[CH:25]=[CH:24][C:14]([O:15][C:16]4[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=4)=[CH:13][CH:12]=3)[C:3]=12.[OH-].[Na+].OO.C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:46]>O1CCOCC1.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:26]3[CH2:31][CH2:30][C@@H:29]([N:32]4[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]4)[CH2:28][CH2:27]3)[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:15][C:16]4[CH:17]=[CH:18][C:19]([C:20]([NH2:21])=[O:46])=[CH:22][CH:23]=4)=[CH:24][CH:25]=3)[C:3]=12
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Oc5ccc(C#N)cc5)cc4)c4c(N)ncnc43)CC2)CC1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Oc5ccc(C(N)=O)cc5)cc4)c4c(N)ncnc43)CC2)CC1

Procedure:
Cis-4-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzonitrile (0.200 g, 0.000394 mol) was dissolved in dioxane (3 mL), the solution of sodium hydroxide (0.15 g, 0.00197 mol) in water (2 mL) was added followed by the addition of 30% hydrogen peroxide solution in water (5 drops). The reaction mixture was heated at reflux under an atmosphere of nitrogen for 1.5 hours, cooled to ambient temperature and neutralized with 5% solution of citric acid in water. The solvents were removed under reduced pressure and the residue purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile-0.1M ammonium acetate over 25 min, 21 mL/min) to yield cis-4-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzamide (0.120 g, 0.000223 mol) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH3:17])[N:13]=[C:12](Cl)[N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.C(Cl)Cl.[K+].[Br-]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH3:17])[N:13]=[C:12]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)[N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Nc1ccc(O)cc1
Reactant: CNc1nc(Cl)nc(Nc2cc(Cl)cc(Cl)c2)n1
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: CNc1nc(Nc2ccc(O)cc2)nc(Nc2cc(Cl)cc(Cl)c2)n1
Yield: 74 %

Procedure:
The title compound was synthesized from 2-(3,5-dichlorophenylamino)-4-methylamino-6-chloro-1,3,5-triazine and 4-aminophenol using a similar procedure to the one used in 8. Yield: 74%; Tg 83° C., Tc 155° C., Tm 187° C.; FTIR (CH2Cl2/KBr) 3401, 3282, 3180, 3112, 2952, 2918, 2850, 1572, 1514, 1503, 1421, 1400, 1366, 1258, 1227, 1168, 1114, 1080, 1011, 993, 937, 833, 807, 737, 703, 668, 632 cm−1; 1H NMR (300 MHz, DMSO-d6, 298K): δ 9.43 (br s, 0.5H), 9.29 (br s, 0.5H), 9.00 (br s, 0.5H), 8.83 (br s, 0.5H), 7.90 (br d, 2H), 7.43 (br s, 2H), 7.06 (s, 1H), 7.00 (br s, 1H), 6.70 (d, 3J=8.8 Hz, 2H), 2.81 (d, 3J=4.1 Hz, 3H) ppm; 13C NMR (75 MHz, DMSO-d6): δ 165.9, 164.0, 163.6, 152.7, 143.0, 133.6, 131.1, 122.6, 120.0, 117.1, 114.9, 27.2 ppm; HRMS (EI) calcd. for C16H14Cl2N6O (m/e): 376.0606. found: 376.0601.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([C:18]([NH2:20])=[O:19])=[C:11]2[CH2:16][NH:15][CH2:14][CH2:13][N:12]2[CH:17]=1.C(N(CC)CC)C.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1[S:38][C:37]([S:39](Cl)(=[O:41])=[O:40])=[CH:36][CH:35]=1>C(#N)C>[Cl:8][C:9]1[C:10]([C:18]([NH2:20])=[O:19])=[C:11]2[CH2:16][N:15]([S:39]([C:37]3[S:38][C:34]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=4)=[CH:35][CH:36]=3)(=[O:40])=[O:41])[CH2:14][CH2:13][N:12]2[CH:17]=1
Reactant: NC(=O)c1c(Cl)cn2c1CNCC2
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccn2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: NC(=O)c1c(Cl)cn2c1CN(S(=O)(=O)c1ccc(-c3ccccn3)s1)CC2
Temperature: 60 °C
Reaction time: 4 h
Yield: 24.7 %

Procedure:
A suspension of 7-chloro-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylic acid amide trifluoroacetic acid salt (156 mg, Reference Example 24) in dry acetonitrile (13 mL) was treated with dry triethylamine (0.28 mL), then with 5-(pyrid-2-yl)thiophene-2-sulfonyl chloride (127 mg). After stirring at 60° C. for 4 hours the reaction mixture was allowed to cool to room temperature and evaporated. The residue was subjected to column chromatography on silica eluting with ethyl acetate to give 7-chloro-2-(5-pyridin-2-ylthiophene-2-sulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylic acid amide (51 mg) as a white solid, m.p. 213–214° C. [Elemental analysis: C, 47.99; H, 3.44; N, 12.97%; Calculated for C17H15ClN4O3S2: C, 48.28; H, 3.58; N, 13.25%].
Reaction SMILES: [C:1]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)O.[C:16](Cl)(=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C(OCC)C>N1C=CC=CC=1.CCCCCC>[Cl:13][C:12]([Cl:15])([Cl:14])[CH2:11][O:10][C:1](=[O:9])[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[C:16](=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: O=C(OCC(Cl)(Cl)Cl)c1ccccc1O
Reactant: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)Cl
Solvent: CCCCCC
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)c1ccccc1C(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Yield: 93 %

Procedure:
--To a solution of 2,2,2-trichloroethyl salicylate (104 g) in dry pyridine (500 ml) at 0°-5° C. and under nitrogen was added (z,z,z)octadeca-6,9,12-trienoyl chloride (137.5 g) dropwise over a period of one hour. The reaction mixture was allowed to stir for twenty hours at room temperature and then the pyridine was removed in vacuo (25° C./0.5 mmHg). The residue was dissolved in diethyl ether (2000 ml) and water (1000 ml) and the resulting two phase system was shaken and acidified slowly to pH1 by addition of 2M hydrochloric acid. The diethyl ether layer was separated and washed with water (4×1000 ml), adding sodium chloride to break any emulsion that formed. After drying the organic layer (Na2SO4), the solvent was removed in vacuo to give an orange/brown oil. This was subjected to MPLC (Column size: 15 cm dia.×40 cm, Column packing: Matrex silica, pore size 60A, particle size 35-70 μm, Solvent: initially hexane, then 15% diethyl ether in hexane, Fraction size: 1000 ml). The requisite fractions were evaporated in vacuo to give 2,2,2-trichloroethyl-2-[(z,z,z) octadeca-6,9,12-trienoyl]benzoate. (189 g, 93% yield) as a pale yellow oil.
Reaction SMILES: CO[C:3]1[CH:31]=CC(CS[C@@H]2CN(C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[C@H](C(O)=O)C2)=C[CH:4]=1.FC(F)(F)C(O)=O.CN([CH2:70][C:71]([NH:73][C@H:74]1[CH2:78]CN[CH2:75]1)=O)C(NC(OCC1C=CC([N+]([O-])=O)=CC=1)=O)=NC(OCC1C=CC([N+]([O-])=O)=CC=1)=O>C(#N)C.O1CCCC1>[CH:3]([N:73]([CH2:71][CH3:70])[CH:74]([CH3:75])[CH3:78])([CH3:31])[CH3:4]
Reactant: CN(CC(=O)N[C@H]1CCNC1)C(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: C1CCOC1
Product: CCN(C(C)C)C(C)C
Temperature: 25 °C

Procedure:
To a solution of (2S,4S)-4-(4-methoxybenzyl)thio-1-(4-nitrobenzyloxycarbonyl)-L-proline (1.05 g) in anhydrous acetonitrile (10 ml), N,N'-carbonyldiimidazole (401 mg) was added, followed by stirring at room temperature. To the reaction mixture, N,N-diisopropylethylamine (392 μl) and a solution of the compound (2.02 g), which had been obtained in (2), in anhydrous tetrahydrofuran (15 ml) were added. The resulting mixture was treated in a similar manner to that described in Referential Example 16-(3), whereby the title compound (1.69 g) was obtained as an amorphous substance.