Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:9]1[CH2:13][C@@H:12]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([Cl:24])=[N:18][C:19]=3Cl)[C@H:11](O)[C@@H:10]1O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(C(C)C)C(C)C.[C:43]1([CH:49]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH2:50][NH2:51])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C1COCC1>[Cl:24][C:17]1[N:16]=[C:15]2[C:20]([N:21]=[CH:22][N:14]2[C@@H:12]2[CH2:13][C@H:9]([N:8]([C:27]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28])[C:1]([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2])[CH:10]=[CH:11]2)=[C:19]([NH:51][CH2:50][CH:49]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[N:18]=1
Reactant: NCC(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H]1C=C[C@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)C1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
(1S,2R,3S,5R)-3-(di-Boc-amino)-5-(2,6-dichloro-purin-9-yl)-cyclopentane-1,2-diol (13.0 g, 27.66 mmol) is dissolved in THF (250 mL) under an atmosphere of argon. DIPEA (4.28 g, 33.19 mmol) is added followed by 2,2-diphenylethylamine (6.0 g, 30.43 mmol) and the reaction mixture is stirred at 50° C. The reaction is shown to be complete by LCMS after 18 hours. The solvent is removed in vacuo and the reaction mixture is partitioned between dichloromethane (250 mL) and 0.1 M HCl (250 mL). The organic layer is washed with water (200 mL) and brine (200 mL), dried over MgSO4, filtered and the solvent is removed in vacuo to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:14])[N:9]([CH2:11][O:12][CH3:13])[N:10]=[C:4]2[C:3]=1I.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:14])[N:9]([CH2:11][O:12][CH3:13])[N:10]=[C:4]2[C:3]=1[C:20]1[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COCn1nc2c(I)c(Br)ccn2c1=O
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COCn1nc2c(-c3ccc(Cl)cc3)c(Br)ccn2c1=O
Temperature: 20 °C
Yield: 94.9 %

Procedure:
To a degassed mixture of 7-bromo-8-iodo-2-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (3.0 g, 7.8 mmol), 4-chlorophenylboronic acid (1.32 g, 8.6 mmol) and K2CO3 (2.16 g, 15.6 mmol) in 1,4-dioxane (42 mL) and H2O (14 mL) under argon at 20° C. was added Pd(PPh3)4 (450 mg, 0.39 mmol). The reaction mixture was refluxed for 40 h under argon and then cooled to 20° C. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (3×50 mL). The combined organic extract was washed with saturated aqueous NaHCO3 solution (50 mL), then brine (50 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was successively triturated with hexanes and Et2O and dried under high vacuum to obtain the title compound as a light yellow solid (2.7 g, 7.4 mmol) in 85% purity along with bis-4-chlorophenyl coupled by-product. The crude product was used without further purification. MS: [M+H]+=368.0.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].Cl[CH2:6][C:7]1[N:8]=[N:9][CH:10]=[CH:11][CH:12]=1>>[N:9]1[CH:10]=[CH:11][CH:12]=[C:7]([CH2:6][NH:3][CH2:2][CH2:1][NH2:4])[N:8]=1
Reactant: NCCN
Reactant: ClCc1cccnn1
Product: NCCNCc1cccnn1

Procedure:
Reacting ethylenediamine with 3-chloromethylpyridazine by the procedure of Example 34 gives N-(3-pyridazinylmethyl)ethylenediamine. This intermediate is reacted with S-methylisothiouronium sulphate by the procedure of Example 1 to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][N:10]1[C:14]([CH3:15])=[C:13]([C:16](O)=[O:17])[C:12](=[O:19])[N:11]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C.O.CCOC(C)=O>[OH:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:16]([C:13]2[C:12](=[O:19])[N:11]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:10]([CH3:9])[C:14]=2[CH3:15])=[O:17])=[N:7][CH:6]=1
Reactant: Nc1ccc(O)cn1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2ccc(O)cn2)c(=O)n(-c2ccccc2)n1C
Temperature: 60 °C
Reaction time: 4 h
Yield: 69.9 %

Procedure:
To a suspension of 6-aminopyridin-3-ol (330 mg, 3 mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (710 mg, 306 mmol) in DMF (10 mL) was added EDCI (690 mg, 3.6 mmol) and HOAT (80 mg, 0.6 mmol). The reaction was stirred at 60° C. for 4 hours, then cooled to rt and diluted with water (100 mL) and EtOAc (2 mL). The mixture was cooled to 0° C. and stirred overnight. The resulted solid was collected through filtration to give title compound as a light brown solid (680 mg, 70%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][CH:6]([O:9][CH2:10][CH3:11])[CH2:7]Br)[CH3:4].Cl[CH2:13]Cl.[CH2:15]1[CH2:19]O[CH2:17][CH2:16]1>>[CH2:3]([O:5][CH:6]([O:9][CH2:10][CH3:11])[CH2:7][CH:15]1[CH:19]=[CH:13][CH:17]=[CH:16]1)[CH3:4]
Reactant: CCOC(CBr)OCC
Reactant: ClCCl
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: CCOC(CC1C=CC=C1)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (2.00 g, 60% wt. dispersion in mineral oil, 50.0 mmol) was washed with 40 mL hexanes. Hexanes were decanted and THF (35 mL) was added to the sodium hydride. A solution of 10 mL of freshly cracked cyclopentadiene in 10 mL of THF was slowly added dropwise, releasing heat and gas. This sodium cyclopentadienyl solution was added dropwise to a solution of bromoacetaldehyde diethylacetal (7.8 mL, 9.90 g, 50.0 mmol) in 45 mL THF to give a brown solution and light precipitate. After stirring overnight at 25° C., the mixture was filtered over Celite to remove sodium bromide, and solvent was removed from the filtrate in vacuo to give to a brown oil. To this was added 50 mL of dichloromethane and the mixture was again filtered through Celite. Solvent was removed in vacuo leaving a brown oil. 1H NMR data suggests a 1:1 mixture of 1,2- and 1,3-isomers. 1H NMR (CDCl3, 600 MHz): δ 6.50 (m, 1H), 6.43 (m, 1H), 6.40 (m, 1H), 6.29 (m, 1H), 6.27 (m, 1H), 6.14 (m, 1H), 4.66 (t, 1H), 4.61 (t, 1H), 3.67 (m, 4H), 3.51 (m, 4H), 2.96 (m, 2H), 2.75 (d, 1H), 2.72 (d, 1H) 1.21 (t, 12H). 13C{1H} NMR (CDCl3, 150.8 MHz): 144.16 (s), 142.05 (s), 135.01 (s), 133.47 (s), 132.30 (s), 131.54 (s), 128.68 (s), 128.51 (s), 102.72 (s), 102.52 (s), 61.26 (s), 61.08 (s), 44.07 (s), 41.33 (s), 35.24 (s), 34.62 (s), 15.30 (s).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([O:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][N:19]=2)[CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([C:14]([NH2:16])=O)=[CH:10]2)[CH3:3].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1.[C:50]([O:55][CH2:56][CH3:57])(=[O:54])[C:51]#[C:52][CH3:53].C(P(CCCC)CCCC)CCC>O1CCCC1>[CH3:3][CH:2]([O:4][C:5]1[CH:6]=[C:7]([O:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][N:19]=2)[CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([C:14]1[S:37][CH:52]([CH2:51][C:50]([O:55][CH2:56][CH3:57])=[O:54])[CH2:53][N:16]=1)=[CH:10]2)[CH3:1]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cn2)cc2cc(C(N)=O)[nH]c12
Reactant: CC#CC(=O)OCC
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cn4)cc(OC(C)C)c3[nH]2)S1
Temperature: 65 °C
Reaction time: 1 h
Yield: 44.4 %

Procedure:
A mixture of 7-(1-methylethoxy)-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole-2-carboxamide (2.0 g), Lawesson's reagent (2.27 g) and tetrahydrofuran (70 mL) was stirred at 65° C. for 1 h. The mixture was concentrated in vacuo. Toluene and diisopropyl ether were added to the residue to give crystals. The crystals were collected by filtration and washed with toluene-diisopropyl ether to give yellow crystals. A mixture of the crystals, ethyl 2-butynoate (1.44 g), tributylphosphine (1.03 g) and tetrahydrofuran (100 mL) was stirred at 70° C. for 2 h, and then concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:hexane=1:4 to 2:1, volume ratio) to give the title compound (1.18 g, 45%) as a yellow amorphous solid. MS 518 (MH+).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[S:5][CH:6]=[C:7]([CH3:11])[C:8]=1[CH:9]=[O:10].C(O)C>O>[CH3:3][C:4]1[S:5][CH:6]=[C:7]([CH3:11])[C:8]=1[CH2:9][OH:10]
Reactant: Cc1csc(C)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1csc(C)c1CO
Reaction time: 0.25 h

Procedure:
0.68 G. (18 mmol) of sodium borohydride was added in three portions to a solution of 10.88 g. (72 mmol) of 2,4-dimethylthiophene-3-carboxaldehyde in 120 ml. of ethanol. After 15 min., the reaction mixture was poured into water, extracted with ether, dried and the solvent evaporated. The resulting residue was recrystallized from hexane to yield 2,4-dimethyl-3-hydroxymethylthiophene, m.p. 80° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[C:12]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[N:13][NH:14][CH:15]=2)C=CC=CC=1.BrCCCC.N1C=CC=C(C2C(O)=CN(COCC[Si](C)(C)C)N=2)C=1>CCOCC.C(OCC)(=O)C>[CH2:9]([O:10][C:11]1[C:12]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:13][NH:14][CH:15]=1)[CH2:8][CH2:7][CH3:1]
Reactant: c1ccc(CCCOc2c[nH]nc2-c2cccnc2)cc1
Agent: C[Si](C)(C)CCOCn1cc(O)c(-c2cccnc2)n1
Solvent: CCCCBr
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCCCOc1c[nH]nc1-c1cccnc1
Yield: 30 %

Procedure:
Compound 32C was prepared following the procedure as described for the synthesis of compound 32A (see Scheme 5) using 1-bromo-butane as the alkyl halogenide and 3-pyridin-3-yl-1-(2-trimethylsilanyl-1-ethoxymethyl)-1H-pyrazol-4-ol (30). Work-up and flash chromatography (ethyl acetate/diethyl ether 1/1) afforded compound 31C. Yield 30% (oil). 1H-NMR (major isomer is given, 400 MHz, CDCl3): δ 8.9 (d, J=2 Hz, 1H), 8.6 (dd, J=5 Hz, 2 Hz, 1H), 8.05 (dt, J=8 Hz, 2 Hz, 1H), 7.42 (s, 1H), 7.41-7.37 (m, 1H), 5.37 (s, 2H), 3.98 (t, J=7 Hz, 2H), 3.74-3.68 (m, 2H), 1.74-1.66 (m, 2H), 1.49-1.39 (m, 2H), 0.92 (t, J=7 Hz, 3H), 0.02 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[C:8]([Cl:10])[CH:9]=1)[CH:6]=[O:7].[C:12]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C.CCOC(C)=O>[Cl:10][C:8]1[CH:9]=[C:2]([Cl:1])[CH:3]=[C:4]([O:11][CH3:12])[C:5]=1[CH:6]=[O:7]
Reactant: O=Cc1c(O)cc(Cl)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(Cl)cc(Cl)c1C=O
Temperature: 50 °C

Procedure:
To a solution of 4,6-dichlorosalicylaldehyde (2.69 mmol) in 5 mL DMF was added K2CO3 (5.39 mmol) followed by iodomethane (2.96 mmol). The reaction mixture was heated to 50° C. for 3.5 h. At RT, the mixture was diluted with EtOAc and washed 3 times with water and then with brine. The combined organic layers were dried over MgSO4 and concentrated in vacuo to give the desired product as beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:19][C:20]2[CH:21]=[CH:22][C:23]3[O:27][N:26]=[C:25]([CH3:28])[C:24]=3[CH:29]=2)[C:9]2[C:10]([C:16]([OH:18])=O)=[N:11][N:12]([CH3:15])[C:13]=2[CH3:14])=[CH:4][CH:3]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:9]3[C:10](=[N:11][N:12]([CH3:15])[C:13]=3[CH3:14])[C:16](=[O:18])[N:19]2[C:20]2[CH:21]=[CH:22][C:23]3[O:27][N:26]=[C:25]([CH3:28])[C:24]=3[CH:29]=2)=[CH:4][CH:3]=1
Reactant: Cc1noc2ccc(NC(c3ccc(Cl)cc3)c3c(C(=O)O)nn(C)c3C)cc12
Solvent: ClCCl
Solvent: CO
Product: Cc1noc2ccc(N3C(=O)c4nn(C)c(C)c4C3c3ccc(Cl)cc3)cc12

Procedure:
The title compound was prepared in analogy to the procedure described in Example 1 using 4-((4-chlorophenyl)(3-methylbenzo[d]isoxazol-5-ylamino)methyl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (Step 33.5). tR: 4.70 min (HPLC 1); tR: 1.03 min (LC-MS 2); ESI-MS: 393 [M+H]+ (LC-MS 2); Rf=0.50 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.08 (s, 3H) 2.44-2.57 (m, 3H) 3.85 (s, 3H) 6.52 (s, 1H) 7.29 (s, 4H) 7.63 (d, J=9.0 Hz, 1H) 7.73 (dd, J=9.0, 2.0 Hz, 1H) 8.01 (d, J=1.6 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9](O)=[N:8][C:6]=2[N:7]=1.ClCCl.S(Cl)(Cl)=O>CN(C)C=O>[CH2:4]([NH:3][C:9]1[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:11][C:5]2[CH:4]=[N:3][C:2]([NH2:1])=[N:7][C:6]=2[N:8]=1)[CH2:5][CH2:11][CH3:10]
Reactant: Nc1ncc2cc(-c3ccccc3)c(O)nc2n1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCCNc1nc2nc(N)ncc2cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 44.4 %

Procedure:
To a mixture of 23.8 g of 2-amino-6-phenyl-pyrido-[2,3-d]pyrimidin-7-ol prepared above in Example 8, 250 mL of dichloromethane, and 77.5 mL of dimethylformamide was added dropwise with cooling 36 mL of thionyl chloride keeping the temperature below 15° C. Following complete addition, the suspension was heated to reflux with stirring for 5 hours. The solvents were removed in vacuo maintaining the temperature below 60° C. The resulting solid was added with cooling to 250 mL of n-butylamine and the suspension refluxed for 6 hours with stirring. The reaction mixture was allowed to cool to room temperature, filtered, and the volatile components of the filtrate removed on a rotary evaporator in vacuo. The viscous oil was partitioned between diethyl ether and water, the layers were separated, and the ethereal layer was washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and evaporated. The residue was partitioned between diethyl ether and dilute 1N HCl. The aqueous layer was washed three times with diethylether and made alkaline to pH 12 by addition of sodium hydroxide. The solid product was collected by filtration and dried in vacuo to afford 6.5 g of the title compound N7 -butyl-6-phenyl-pyrido[2,3-d]pyrimidine-2,7-diamine, mp 174°-181° C. dec.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][N:15]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])[CH2:14][CH:13]([C:25](O)=[O:26])[CH2:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O[N:29]=[C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=1)[NH2:31]>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:12][CH:13]([C:25]3[O:26][N:31]=[C:30]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:39])([F:40])[F:41])[CH:33]=4)[N:29]=3)[CH2:14][N:15]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])[CH2:16]2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: NC(=NO)c1cccc(C(F)(F)F)c1
Reactant: CS(=O)(=O)c1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Product: CS(=O)(=O)c1ccc(C2CC(c3nc(-c4cccc(C(F)(F)F)c4)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
60 mg (0.15 mmol) of the compound from Example 198A and 46 mg (0.23 mmol) of N′-hydroxy-3-(trifluoromethyl)benzenecarboximidamide were reacted according to the General Method 2. Yield: 61 mg (69% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:22][C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[N:28]([C:32]([O-:34])=[O:33])[N:27]=[CH:26]4)=[N:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=3)=[N:10]2)=[CH:5][C:4]=1[O:35][CH2:36][CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>CO.[Pd]>[NH2:19][C:15]1[CH:14]=[C:13]([C:9]2[N:8]=[C:7]([NH:22][C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[N:28]([C:32]([O:34][C:6]([CH3:11])([CH3:7])[CH3:5])=[O:33])[N:27]=[CH:26]4)[C:6]3[C:11](=[CH:12][C:3]([O:2][CH3:1])=[C:4]([O:35][CH2:36][CH2:37][CH2:38][N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)[CH:5]=3)[N:10]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: COc1cc2nc(-c3cccc([N+](=O)[O-])c3)nc(Nc3ccc4c(cnn4C(=O)[O-])c3)c2cc1OCCCN1CCOCC1
Agent: [Pd]
Solvent: CO
Product: COc1cc2nc(-c3cccc(N)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OCCCN1CCOCC1
Reaction time: 0.33 h

Procedure:
To a mixture of 5-(7-methoxy-6-(3-morpholinopropoxy)-2-(3-nitrophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.215 g) in MeOH (60 mL) was added Pd/C (0.21 g) and NH4CO2 (0.21 g). The mixture was heated at 60° C. for 40 mins, upon which an additional portion of NH4CO2 (0.095 g) was added, heating was continued for a further 20 minutes. The mixture was filtered to remove the Pd/C and the filtrate was concentrated under reduced pressure. The residue was taken up in CH2Cl2 (300 mL) wand was washed with water and brine. The mixture was dried (Na2SO4) and the volatiles removed in vacuo. The material was combined with an identical experiment using 0.2 g and the residue was subjected to preparative TLC (SiO2, CH2Cl2: MeOH 9:1) to give the desired product tert-butyl 5-(2-(3-aminophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-ylamino)-1H-indazole-1-carboxylate. HPLC retention time 4.67 mins.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:8]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:9]=3[S:10][CH:11]=2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:29]([O:33][CH3:34])(=[O:32])[CH:30]=[CH2:31]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:8]2[C:7]([O:6][C:5]3[CH:18]=[CH:19][C:2](/[CH:31]=[CH:30]/[C:29]([O:33][CH3:34])=[O:32])=[CH:3][CH:4]=3)=[CH:11][S:10][C:9]=2[CH:12]=1
Reactant: C=CC(=O)OC
Reactant: COc1ccc2c(Oc3ccc(Br)cc3)csc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc(Oc2csc3cc(OC)ccc23)cc1
Temperature: 120 °C
Yield: 63.8 %

Procedure:
To a solution of 3-(4-bromophenoxy)-6-methoxybenzo[b]thiophene (125 g, 373 mmol) and Pd(PPh3)2Cl2 (13.09 g, 18.64 mmol) in DMF (2500 mL) and diisopropyl ethylamine (326 mL, 1864 mmol) at room temperature was added (subsurface) methyl acrylate (845 mL, 9322 mmol) over 3-4 hours. As the addition started, the reaction was heated at 120° C. for 13 hours. Methyl acrylate (150 mL, 1654.8 mmol) was added (subsurface). The reaction was heated at 120° C. for 1 hour. The mixture was cooled to RT. Excess methyl acrylate and diisopropyl ethylamine were remove in vacuo. The resulting mixture was filtered through celite pad and the cake was washed with EtOAc (2000 mL). The resulting mixture was washed with water (2×), dried with anhydrous Na2SO4 and concentrated in vacuo. The crude material was purified by column chromatography (SiO2, 5% to 500/(EtOAc/Heptane) to afford (E)-methyl 3-(4-((6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (81 g, 238 mmol, 64% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm=1.46 (s, 3 H), 3.73 (s, 3 H), 6.28 (d, J=16.17 Hz, 1 H), 6.59 (s, 1 H), 6.90 (dd, J=8.59, 2.02 Hz, 1 H), 7.00 (d, J=8.59 Hz, 2 H), 7.21 (d, J=2.02 Hz, 1 H), 7.37-7.48 (m, 3 H), 7.59 (d, J=16.17 Hz, 1 H), LC/MS (m/z. MH+): 341.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:21](N1C=CN=C1)([N:23]1C=CN=C1)=O.CN>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:23][CH3:21])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(F)cc2)nc2cccnc21
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)Cn1c(-c2ccc(F)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.9 %

Procedure:
A mixture of 2-(4-fluorophenyl-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.01845 mole) and 1,1'-carbonyldiimidazole (2.99 g, 0.01845 mole) was stirred at room temperature in dry tetrahydrofuran (100 ml) for three hours with a stream of nitrogen bubbling through it. A solution of methylamine in tetrahydrofuran (37 ml of a 3.03 M solution, 0.111 mole) was added and the reaction mixture was stirred at room temperature under nitrogen overnight. The solvents were removed under reduced pressure and the residue was triturated in water (100 ml). The solid was collected by filtration, rinsed twice with water, twice with a 5% potassium hydroxide solution and twice again with water. The solid was dissolved in hot isopropyl alcohol, filtered hot, cooled to room temperature and isopropyl ether was added to the cloud point. The resulting solid was collected by filtration, rinsed with isopropyl ether, and dried under high vacuum at 42° C. overnight to give 2.30 g (44%) of title compound, mp. 215° -217° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:14]([C:15](=O)[NH:16][CH2:17][C:18]([C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=2)=O)[CH2:13][C:10]2([CH2:12][CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+:32]>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH:14]([C:15]2[NH:32][C:18]([C:20]3[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=3)=[CH:17][N:16]=2)[CH2:13][C:10]2([CH2:12][CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N1CC2(CC2)CC1C(=O)NCC(=O)c1ccc(Br)cc1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(Br)cc2)[nH]1
Temperature: 140 °C
Yield: 61.4 %

Procedure:
15 mL Xylenes was added to 6-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-5-aza-spiro[2.4]heptane-5-carboxylic acid tert-butyl ester (424 mg, 0.97 mmol) and ammonium acetate (20 eq., 1.5 g). The mixture was heated in microwave at 140° C. for 60 minutes. The mixture was diluted with EtOAc and washed with sat.NaHCO3 aqueous solution. The organic layer was concentrated down and purified by flash column chromatography (silica gel, 20 to 80% ethyl acetate/hexane) to give 6-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carboxylic acid tert-butyl ester (249 mg, yield 61%). LCMS-ESI−: calc'd for C20H24BrN3O2: 418.33. Found: 418. (M+H+).
Reaction SMILES: C([P:4]([CH2:9][O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15](=[O:31])[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)[O:18]2)=[C:13]([O:32][CH3:33])[CH:12]=1)([CH:6]([CH3:8])[CH3:7])=[O:5])(C)C.[N-]=[N+]=[N-].[Na+].CN(C)C=[O:41].C(OCC)(=O)C>O>[OH:5][P:4]([CH2:9][O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15](=[O:31])[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)[O:18]2)=[C:13]([O:32][CH3:33])[CH:12]=1)([CH:6]([CH3:7])[CH3:8])=[O:41]
Reactant: CN(C)C=O
Reactant: COc1ccc(-c2cc(=O)c3c(OC)cc(OCP(=O)(C(C)C)C(C)C)cc3o2)cc1OC
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cc(=O)c3c(OC)cc(OCP(=O)(O)C(C)C)cc3o2)cc1OC
Temperature: 100 °C
Yield: 33 %

Procedure:
7-{(diisopropylphosphoryl)-methyloxy}-3′,4′,5-trimethoxyflavone (0.5 g, 0.99 mmol, produced in Step 1 of Example 6) and sodium azide (0.5 g, 7.69 mmol) were added dropwise to N,N-dimethylformamide (20 mL) and warmed at 100° C. for 8 hours. The reaction solution was cooled to room temperature, and 50 mL of ethyl acetate and 50 mL of water were added dropwise, followed by separation of the organic layer from the aqueous layer. 10 mL of conc. hydrochloric acid was added dropwise to the aqueous layer which was then extracted with chloroform. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and then evaporated to afford 0.15 g (yield: 33%) of the title compound.