Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[C:18]1[CH:26]=O)[CH:15]=[CH2:16]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:26][C:18]1[N:17]([CH2:14][CH:15]=[CH2:16])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: C=CCn1c(C=O)nc2ccccc21
Solvent: ClCCl
Product: C=CCn1c(CNCCCCNC(=O)OC(C)(C)C)nc2ccccc21
Yield: 30 %

Procedure:
Using General Procedure B: Reaction of (4-amino-butyl)-carbamic acid tert-butyl ester in CH2Cl2 and 1-allyl-1H-benzimidazole-2-carbaldehyde gave {4-[(1-allyl-1H-benzoimidazol-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester as a colorless oil (0.10 g, 30%). 1H NMR (CDCl3) δ 1.43 (s, 9H), 1.54 (s, 4H), 2.71 (m, 2H), 3.11 (m, 2H), 4.04 (s, 2H), 4.87 (d, 2H, J=5.3 Hz), 5.02 (d, 1H, J=17.1 Hz), 5.19 (d, 1H, J=11.0 Hz), 5.98 (m, 1H), 7.30 (m, 3H), 7.73 (m, 1H)
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[CH:20]([OH:28])[CH2:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20](=[O:28])[CH2:21][CH:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1c(C(O)CC2CCOCC2)cc2cc(F)cnc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C(CC1CCOCC1)c1cc2cc(F)cnc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
To a solution of 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-pyran-4-yl)-ethanol (1.23 g, 3.04 mmol) in dichloromethane (100 ml) was added Dess-Martin periodinane (3.87 g, 9.12 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 1 h and then quenched with a saturated aqueous sodium bicarbonate solution (60 mL). The mixture was extracted with ethyl acetate (150 mL), washed with a saturated aqueous sodium bicarbonate solution (3×30 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. The residue was purified by flash column chromatography (silica gel from QingDao, 200-300 mesh, 33% ethyl acetate/hexanes) to afford 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-pyran-4-yl)-ethanone (1.1 g, 90%) as a light yellow solid: LC/MS m/e calcd for C20H19FN2O4S [M+H]+ 403.45, observed 403.2.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1.[Br:14][C:15]1[CH:16]=C([Li])[CH:18]=[CH:19][CH:20]=1>>[Br:14][C:15]1[CH:16]=[C:11]([CH:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH:2]([F:13])[F:1])[CH:5]=2)[OH:12])[CH:18]=[CH:19][CH:20]=1
Reactant: CC(=O)c1cccc(OC(F)F)c1
Reactant: [Li]c1cccc(Br)c1
Product: OC(c1cccc(Br)c1)c1cccc(OC(F)F)c1

Procedure:
In an analogous reaction sequence to that described for Building Block C, the reaction of 1-(3-difluoromethoxy-phenyl)-ethanone with 3-bromophenyllithium yielded the (3-bromo-phenyl)-(3-difluoromethoxy-phenyl)-methanol which was used as crude material in the following elimination reaction with a catalytic amount of p-toluenesulfonic acid to yield the 1-bromo-3-[1-(3-difluoromethoxy-phenyl)-vinyl]-benzene (yield: 68% of theory) as a light yellow oil. TLC: Rf: 0.66 (silica gel; heptane:ethyl acetate=4:1, UV, 254 nm).
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([NH:11]N=C2CCCNC2=O)[CH:3]=1.O.[CH:21]([OH:23])=O>>[F:1][C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[C:5]2[C:2]3[CH2:3][CH2:4][NH:11][C:21](=[O:23])[C:10]=3[NH:11][C:4]=2[CH:3]=1
Reactant: O=CO
Reactant: O=C1NCCCC1=NNc1cc(F)c2c(c1)CCO2
Solvent: O
Product: O=C1NCCc2c1[nH]c1cc(F)c3c(c21)CCO3
Yield: 57 %

Procedure:
Diazotized compound 9 (500 mg, 1.89 mmol) was solved in 8.25 mL formic acid (90%) and the solution was heated at reflux for 1 h. The reaction was allowed to cool and 10 mL of water were added. The resulting mixture was extracted with ethyl acetate. The organic layer was concentrated to obtain the desired compound 10 (270 mg, yield 57%).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:5]([CH:22]2[CH2:24][CH2:23]2)[C:6]2[C:12]([C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[O:14])=[C:11]([F:21])[CH:10]=[CH:9][C:7]=2[N:8]=1)[CH3:3].[NH2:25][C:26]1[C:31]([C:32]#[N:33])=[C:30](Cl)[N:29]=[CH:28][N:27]=1.CCN(C(C)C)C(C)C>CC(O)C.CO>[NH2:25][C:26]1[C:31]([C:32]#[N:33])=[C:30]([NH:1][C@H:2]([C:4]2[N:5]([CH:22]3[CH2:23][CH2:24]3)[C:6]3[C:12]([C:13]([N:15]4[CH2:16][CH2:17][O:18][CH2:19][CH2:20]4)=[O:14])=[C:11]([F:21])[CH:10]=[CH:9][C:7]=3[N:8]=2)[CH3:3])[N:29]=[CH:28][N:27]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: C[C@H](N)c1nc2ccc(F)c(C(=O)N3CCOCC3)c2n1C1CC1
Solvent: CO
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(C(=O)N3CCOCC3)c2n1C1CC1
Temperature: 90 °C
Yield: 41.6 %

Procedure:
A mixture of [2-((S)-1-aminoethyl)-3-cyclopropyl-5-fluoro-3H-benzoimidazol-4-yl]-morpholin-4-yl-methanone (106 mg, 0.32 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (54 mg, 0.35 mmol) and DIPEA (170 μL, 0.98 mmol) in IPA (1 mL) was heated at 90° C. in a sealed vial for 17 h. After cooling to RT, the reaction mixture was diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% MeOH in EtOAc) followed by trituration with EtOAc to afford 401 as a white solid (60 mg, 31%). LCMS (Method K): RT 2.81 min [M+H]+ 451.06. 1H NMR (CDCl3, 400 MHz): δ 8.18 (1H, s), 7.71-7.65 (1H, m), 7.05-6.97 (1H, m), 6.47-6.40 (0.7H, m), 6.15-6.05 (0.3H, m), 5.98-5.88 (1H, m), 5.38-5.31 (2H, m), 4.22-4.14 (1H, m), 3.93-3.72 (4H, m), 3.69-3.52 (2H, m), 3.44-3.33 (2H, m), 1.73 (1H, d, J=6.78 Hz), 1.65 (2H, d, J=6.76 Hz), 1.43-1.24 (2H, m), 1.11-0.93 (1H, m), 0.86-0.69 (1H, m)
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[N:8]=[CH:9][CH:10]=[CH:11][C:5]=2[CH2:4][N:3]1[CH:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1.[ClH:25]>O1CCOCC1>[ClH:25].[ClH:25].[NH:15]1[CH2:14][CH2:13][CH:12]([N:3]2[CH2:4][C:5]3[CH:11]=[CH:10][CH:9]=[N:8][C:6]=3[NH:7][C:2]2=[O:1])[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2Cc3cccnc3NC2=O)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C1Nc2ncccc2CN1C1CCNCC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 62 %

Procedure:
A suspension of tert-butyl 4-(2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)piperidine-1-carboxylate (220 mg, 0.66 mmol) in 4N hydrogen chloride in 1,4-dioxane (5.0 mL) was stirred at room temperature for 45 minutes. Mixture was concentrated in vacuo. Crystallization from ethanol and ethyl acetate afforded the title compound as white solid in 62% yield. (M+H)+=233.2.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N([O-])=O.[Na+].[BrH:19]>O>[Br:19][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Br
Reactant: Nc1ccc(N2CCC(O)CC2)cc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: OC1CCN(c2ccc(Br)cc2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of 1-(4-aminophenyl)piperidin-4-ol (3.7 g, 319 mmol) in 60 mL of HBr 48%, a solution of NaNO2 (1.38 g, 20 mmol) in 15 mL of water was slowly added at 0° C. The mixture was stirred for 30 minutes and added to a solution of CuBr (1.57 g, 11 mmol) in 50 mL of HBr 48%. The resulting mixture was stirred and refluxed for 2 hours. The suspension thus obtained was partitioned between 2N NaOH and ethyl acetate. The organic layer was washed with aqueous NaCl, dried over Na2SO4 and concentrated to afford crude compound as grey solid 4.6 g. MS (m/z): 256 (M)+
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]=2[N+:18]([O-])=O)=[CH:4][CH:3]=1.[NH4+].[Cl-]>CO.C1COCC1.[Zn]>[NH2:18][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:8]=1[NH:7][CH2:6][C:5]1[CH:21]=[CH:22][C:2]([Br:1])=[CH:3][CH:4]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1ccc(NCc2ccc(Br)cc2)c([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NCc2ccc(Br)cc2)c(N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 4-(4-bromobenzylamino)-3-nitrobenzoate (1 g, 2.73 mmol) in methanol (10 mL) and THF (15 mL) was added sat. NH4Cl aqueous solution (15 mL), then zinc powder (2.11 g, 27.3 mmol) was added in one portion. The mixture was stirred at RT for 1 hr. Then the solid was filtered and the filtrate was concentrated. The residue was washed with water (20 mL) and EtOAc (30 mL×3), the combined organic layers were concentrated to the titled compound which was used to the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:10]([N:12]1[CH2:16][CH:15]([OH:17])[CH2:14][CH:13]1[C:18]([NH:20][C:21]1([C:26]([OH:28])=[O:27])[CH2:23][CH:22]1[CH2:24][CH3:25])=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC([O-])(C)C.[K+].Cl[C:40]1[C:49]2[C:44](=[CH:45][C:46]([O:50][CH3:51])=[CH:47][CH:48]=2)[N:43]=[N:42][CH:41]=1>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([NH:8][CH:9]([C:29]([CH3:31])([CH3:30])[CH3:32])[C:10]([N:12]1[CH2:16][CH:15]([O:17][C:40]2[C:49]3[C:44](=[CH:45][C:46]([O:50][CH3:51])=[CH:47][CH:48]=3)[N:43]=[N:42][CH:41]=2)[CH2:14][CH:13]1[C:18]([NH:20][C:21]1([C:26]([OH:28])=[O:27])[CH2:23][CH:22]1[CH2:24][CH3:25])=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCC1CC1(NC(=O)C1CC(O)CN1C(=O)C(NC(=O)OC(C)(C)C)C(C)(C)C)C(=O)O
Reactant: COc1ccc2c(Cl)cnnc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC1CC1(NC(=O)C1CC(Oc2cnnc3cc(OC)ccc23)CN1C(=O)C(NC(=O)OC(C)(C)C)C(C)(C)C)C(=O)O
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 57 %

Procedure:
To 1-{[1-(2-tert-butoxycarbonylamino-3,3-dimethyl-butyryl)-4-hydroxy-pyrrolidine-2-carbonyl]-amino}-2-ethyl-cyclopropanecarboxylic acid (210 mmg, 0.46 mmol) at 0° C. (external temperature, ice bath) was added KOt-Bu (1 m in THF, 2.3 mL, 2.3 mmol, 5 equiv.) and 4-chloro-7-methoxy-cinnoline (95 mg, 0.49 mmol, 1.06 equiv.) in THF (3 mL). The reaction was stirred at 0° C. for 2.5 h and diluted with EtOAc. The solution was washed with aqueous HCl (1M), resulting a precipitation of the crude product. The organic layer was dried over Na2SO4 and combined with the precipitate. The crude product was purified by column chromatography (0→15% MeOH/CH2Cl2) to provide 1-{[1-(2-tert-butoxycarbonylamino-3,3-dimethyl-butyryl)-4-(7-methoxy-cinnolin-4-yloxy)-pyrrolidine-2-carbonyl]-amino}-2-ethyl-cyclopropanecarboxylic acid (161 mg, 57%).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[NH:11][C:10](=O)[CH:9]=[C:8]([CH3:13])[N:7]=1)[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:16])=O.[OH-].[Na+]>O>[CH2:1]([NH:5][C:6]1[N:11]=[C:10]([Cl:16])[CH:9]=[C:8]([CH3:13])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1nc(C)cc(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCNc1nc(C)cc(Cl)n1
Yield: 88 %

Procedure:
2-Butylamino-6-methylpyrimidin-4-one (8.4 g, 0.046M) was treated with phosphorus oxychloride (5 ml). A vigorous reaction ensued. When this had subsided, the resultant mixture was heated at 90° C. for 30 minutes. This gave an orange coloured syrup which was cooled and added to water to decompose the excess phosphorus oxychloride. The aqueous solution was adjusted to pH 7 using 2M sodium hydroxide solution. The resultant white precipitate was extracted with methylene chloride. The extracts were dried (MgSO4) and the solvent evaporated to give 2-butylamino-4-chloro-6-methylpyrimidine (8.1 g) as a solid, m.p. 35°-36° C., in 88% yield.
Reaction SMILES: [CH:1](=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Cl:9][C:10]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:11]=1[CH:12]=O.[OH-].[Na+].C(O)(=O)C>CO>[CH2:3]([C:2](=[CH:12][C:11]1[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:10]=1[Cl:9])[CH:1]=[O:8])[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCC=O
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CCCCCC(C=O)=Cc1ccc(Cl)cc1Cl
Reaction time: 1 h
Yield: 61.3 %

Procedure:
342 g of heptanal were added dropwise to a solution of 525 g of 2,4-dichlorobenzaldehyde and 12 g of NaOH in 1.5 l of methanol in the course of 6 hours. The mixture was allowed to continue reacting for 1 hour, then acidified with glacial acetic acid, and concentrated after a further 15 hours. The residue was taken up in CH2Cl2 /H2O, and the organic phase was washed with water, dried over Na2SO4 and concentrated. Distillation of the residue gave 498 g of (I) of boiling point 152°-160° C./0.2 mbar.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:28]=[CH:27][C:17]([O:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[C:16]([N+:29]([O-])=O)[CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H][H]>[C].[Pd].C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:28]=[CH:27][C:17]([O:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])=[C:16]([NH2:29])[CH:15]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)COc1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1N
Yield: 66 %

Procedure:
360 mg of 10% palladium-carbon were added to 15 ml of ethyl acetate solution of 3.61 g of t-butyl 4-[2-(4-chlorobenzenesulfonamido)ethyl]-2-nitrophenoxyacetate and stirred at one atmospheric pressure in the presence of hydrogen gas. The reaction mixture was filtered and concentrated under reduced pressure. The resulting residue was subjected to silica-gel column chromatography, whereupon 2.23 g (yield 66%) of t-butyl 4-[2-(4-chlorobenzenesulfonamido)ethyl]-2-aminophenoxyacetate were obtained from the fraction as eluted with hexane/ethyl acetate (2/1, v/v) as a yellow oily substance.
Reaction SMILES: ClC(OCC(C)C)=O.CN1CCOCC1.[N:16]1([CH2:22][C:23]#[C:24][C:25]([OH:27])=O)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.[Br:28][C:29]1[CH:30]=[C:31]([NH:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[C:43]([NH2:46])[CH:44]=3)[N:39]=[CH:38][N:37]=2)[CH:32]=[CH:33][CH:34]=1>O1CCCC1.N1C=CC=CC=1>[Br:28][C:29]1[CH:30]=[C:31]([NH:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[C:43]([NH:46][C:25](=[O:27])[C:24]#[C:23][CH2:22][N:16]4[CH2:17][CH2:18][O:19][CH2:20][CH2:21]4)[CH:44]=3)[N:39]=[CH:38][N:37]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reactant: O=C(O)C#CCN1CCOCC1
Agent: CC(C)COC(=O)Cl
Solvent: c1ccncc1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: O=C(C#CCN1CCOCC1)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 32.4 %

Procedure:
Isobutyl chloroformate (0.343 g, 2.5 mmol) and N-methylmorpholine (0.322 g, 3.18 mmol) were added to an ice cold solution of 0.540 g (3.18 mmol) of 4-morpholin-4-yl-but-2-ynoic acid in 50 mL of tetrahydrofuran under nitrogen. After stirring for 30 min, a solution of 0.500 g of N-(3-bromophenyl)-4,6-quinazolindiamine in 10 mL of pyridine was added and the mixture was stirred at 0° C. for 2 hr. The reaction was then quenched with ice water, poured into saturated sodium bicarbonate, and the product was extracted with ethyl acetate. Chromatography of the extract on silica gel, eluting with methanol/ethyl acetate (15:85), gave 0.240 g of 4-morpholin-4-yl-but-2-ynoic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide: mass spectrum (m/e): M+H 466.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:11](=[O:13])[NH:10][C:9](=[O:14])[N:8]([CH3:15])[C:7]=2[N:6]=[C:5]1Cl)[CH:2]=[CH2:3].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:5]2[N:4]([CH2:1][CH:2]=[CH2:3])[C:12]3[C:11](=[O:13])[NH:10][C:9](=[O:14])[N:8]([CH3:15])[C:7]=3[N:6]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2C
Product: C=CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)[nH]c(=O)n2C
Temperature: 25 °C
Yield: 85.7 %

Procedure:
7-Allyl-8-chloro-3-methyl-3,7-dihydropurine-2,6-dione (420 mg) and 1-piperazine carboxylic acid tert-butyl ester (975 mg) were stirred at 150° C. for 50 minutes. After cooling to room temperature, the resulting reaction mixture was purified by silica gel column chromatography to obtain 584 mg of the title compound from a fraction eluted with ethyl acetate.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:17]1[CH2:18][CH2:19][N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([C:28]3[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=3)[N:3]=2)[CH2:15][CH2:16]1
Reactant: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 40.5 %

Procedure:
A mixture of 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine (1.40 g, 4.90 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.62 g, 11.9 mmol) and tetrakis(triphenylphosphine) palladium (0) (282 mg, 0.240 mmol) in 2M sodium carbonate aqueous solution (10 mL, 20 mmol) and 40 mL of DME was stirred at 80° C. for 2 hr. The reaction mixture was diluted with 300 mL of ethyl acetate and washed with water. The organic layer was concentrated and purified by flash chromatography (ISCO, 120 g silica gel column, eluting with 0-100% EtOAc/Hexane) to give 4-(4,6-dimorpholino-1,3,5-triazin-2-yl)aniline (0.68 g, 40% yield). HPLC: Rt=2.09 min; MS 343 [M+H].
Reaction SMILES: [CH2:1]([CH:3]([CH:6]1[C:13]2[C:12]([C:14]3[CH:15]=[N:16][C:17]([O:20]C)=[CH:18][CH:19]=3)=[N:11][NH:10][C:9]=2[C:8](=[O:22])[N:7]1[C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:33]=[CH:32][O:31][N:30]=2)=[CH:25][CH:24]=1)[CH2:4][CH3:5])[CH3:2].[I-].[Na+].Cl[Si](C)(C)C.O>C(#N)C.C(OCC)(=O)C>[CH2:1]([CH:3]([CH:6]1[C:13]2[C:12]([C:14]3[CH:19]=[CH:18][C:17](=[O:20])[NH:16][CH:15]=3)=[N:11][NH:10][C:9]=2[C:8](=[O:22])[N:7]1[C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:33]=[CH:32][O:31][N:30]=2)=[CH:27][CH:28]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)C1c2c(-c3ccc(OC)nc3)n[nH]c2C(=O)N1c1ccc(-c2ccon2)cc1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CCC(CC)C1c2c(-c3ccc(=O)[nH]c3)n[nH]c2C(=O)N1c1ccc(-c2ccon2)cc1
Reaction time: 1 h
Yield: 63.6 %

Procedure:
To a mixture of 4-(1-ethylpropyl)-5-(4-isoxazol-3-ylphenyl)-3-(6-methoxypyridin-3-yl)-4,5-dihydro-1H-pyrrolo[3,4-c]pyrazol-6-one (0.067 g, 0.15 mmol) and sodium iodide (0.067 g, 0.45 mmol) in acetonitrile (3 mL) was added chlorotrimethylsilane (0.058 mL, 0.45 mmol). The mixture was heated under reflux with stirring for 1 h. Water (50 mL) and ethyl acetate (50 mL) were added to the mixture, and the precipitate was collected by filtration and dried to give 4-(1-ethylpropyl)-5-(4-isoxazol-3-ylphenyl)-3-(6-oxo-1,6-dihydropyridin-3-yl)-4,5-dihydro-1H-pyrrolo[3,4-c]pyrazol-6-one (0.041 g, 64%) as slightly yellow crystals.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[N-:18]=[N+:19]=[N-:20].[F:21][C:22]1[N:27]=[CH:26][C:25]([CH:28](O)[CH3:29])=[C:24]([I:31])[CH:23]=1>ClCCl>[N:18]([CH:28]([C:25]1[C:24]([I:31])=[CH:23][C:22]([F:21])=[N:27][CH:26]=1)[CH3:29])=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(O)c1cnc(F)cc1I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Product: CC(N=[N+]=[N-])c1cnc(F)cc1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
Add tetra-N-butylammonium azide to a solution of triphenylphine (11 g, 42 mmol) and 1,4-cyclohexadiene-2,2-dicarbonitrile,4,5-dichloro-3,6-dioxo-(9 g, 40 mmol) in dichloromethane (150 mL) under ice-bath cooling. Then add 1-(6-fluoro-4-iodo-pyridin-3-yl)-ethanol (6.7 g, 25.1 mmol) to the above solution. Stir the mixture at room temperature for 1 hour. Concentrate the mixture in vacuo to about 50 mL. Purify the residue by flash column chromatography (hexane to 20% ethyl acetate in hexane as gradient) to give target product as colorless oil (5.7 g, 78%). MS (ES) m/z 293 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[C:11]([C:12]2[S:13][C:14]([C:23]3[N:27]=[CH:26][N:25](C4CCCCO4)[N:24]=3)=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:16]=2)=[C:5]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][N:4]2[N:3]=1.I[CH2:35][CH2:36][O:37]C(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][C:2]1[C:11]([C:12]2[S:13][C:14]([C:23]3[NH:27][CH:26]=[N:25][N:24]=3)=[C:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:16]=2)=[C:5]2[CH:6]=[C:7]([O:10][CH2:35][CH2:36][OH:37])[CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: Cc1nn2ccc(O)cc2c1-c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Reactant: O=C(OCCI)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn2ccc(OCCO)cc2c1-c1nc(-c2ccccc2)c(-c2nnc[nH]2)s1
Temperature: 60 °C
Reaction time: 4 h
Yield: 80.7 %

Procedure:
A mixture of 2-methyl-3-{4-phenyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}pyrazolo[1,5-a]pyridin-5-ol (73 mg, 0.16 mmol) produced in Example 31-B(i), (2-iodoethyl)benzoate (88 mg, 0.32 mmol), potassium carbonate (44 mg, 0.32 mmol) and N,N-dimethylformamide (3 mL) was stirred at 60° C. for 4 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The collected organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=30/70→100/0). The obtained solution was concentrated under reduced pressure. 1N Hydrochloric acid (2 mL), methanol (2 mL) and tetrahydrofuran (2 mL) were added to the obtained residue, and the mixture was stirred at 60° C. for 1 hr. To the reaction mixture were added methanol (1 mL) and tetrahydrofuran (1 mL), and the mixture was stirred at 60° C. for 2 hr. To the reaction mixture was added 2N aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The collected organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the obtained residue was washed with diisopropyl ether to give the title compound (54 mg, 81%) as a colorless solid.