Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].Br[C:16]1[S:17][CH:18]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[N:20]=1>>[CH3:24][O:23][C:21]([C:19]1[N:20]=[C:16]([C:2]#[C:1][C:3]2[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:5][O:6][C:7]=2[CH3:8])[S:17][CH:18]=1)=[O:22]
Reactant: C#Cc1c(-c2ccccc2)noc1C
Reactant: COC(=O)c1csc(Br)n1
Product: COC(=O)c1csc(C#Cc2c(-c3ccccc3)noc2C)n1
Yield: 70 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using methyl 2-bromothiazole-4-carboxylate instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 113 mg, 70%) which was obtained as a light yellow solid. MS: m/e=325.2 [M+H]+.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[F:6][C:7]1([F:21])[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[C:15]([C:16]3[CH:20]=[CH:19][NH:18][N:17]=3)[C:9]=2[O:8]1.C(Cl)[Cl:23]>OS(O)(=O)=O>[Cl:23][C:20]1[C:16]([C:15]2[C:9]3[O:8][C:7]([F:6])([F:21])[O:11][C:10]=3[CH:12]=[CH:13][C:14]=2[N+:1]([O-:4])=[O:2])=[N:17][NH:18][CH:19]=1
Reactant: O=[N+]([O-])[O-]
Reactant: FC1(F)Oc2cccc(-c3cc[nH]n3)c2O1
Reactant: ClCCl
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1ccc2c(c1-c1n[nH]cc1Cl)OC(F)(F)O2
Temperature: 0 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
6.3 g (0.063 mol) of KNO3 are added, in small portions and at 0° C., to 12.8 g of 1-(acetyl),4-chloro, 3-(2,2-difluorobenzo-1,3-dioxol-4-yl)pyrazole dissolved in 21 ml of H2SO4 (96%) and 140 ml of CH2Cl2. The reaction mixture is stirred for 3 h at 0° C. and then poured poured onto 300 cm3 of ice. The precipitate is recovered by filtration, washed with water and then heptane and dried. We obtain 8.05 g of 4-chloro-3-(2,2-difluoro-5-nitrobenzo-1,3-dioxol-4-yl)pyrazole melting at 180° C. (yield 63%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=O)=[CH:7][CH:8]=1.[C:11]([C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)([OH:13])=[O:12].CC1C=CC(S(O)(=O)=O)=CC=1>ClC1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[N:23][S:20]([C:17]2[CH:16]=[CH:15][C:14]([C:11]([OH:13])=[O:12])=[CH:19][CH:18]=2)(=[O:21])=[O:22])=[CH:5][CH:4]=1
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: COc1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1
Product: COc1ccc(C=NS(=O)(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
In a similar manner to Example 2, 1.28 g (9 mmol) of anisaldehyde, 1.89 g (9 mmol) of 4-carboxybenzenesulfonamide and 20 mg of TsOH in 150 mL of chlorobenzene and under nitrogen were heated for 4.5 hours to yield 2.86 g (96%) of SULF-8 as a white powder: IR (Nujol) 3300-2700 (br), 1693, 1601, 1584, 1155 cm-1 ; 1H NMR (DMSO-d6, TMS ext std)δ 8.91 (s, 1), 8.4-7.7 (m, 8), 3.92 (s, 3).
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][O:9][CH2:10][CH3:11])[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[N:3]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(O)(=O)/C=C/C(O)=O>>[CH2:10]([O:9][CH2:8][CH2:7][N:6]1[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[N:3]=[C:2]1[N:20]1[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]1)[CH3:11]
Reactant: CCOCCn1c(Cl)nc2ccccc21
Reactant: CN1CCNCC1
Agent: O=C(O)/C=C/C(=O)O
Product: CCOCCn1c(N2CCN(C)CC2)nc2ccccc21

Procedure:
In the same manner as described in Example 1 using 2-chloro-1-[2-(ethoxy)ethyl]benzimidazole (100.0 g), N-methylpiperazine (90.0 g) and fumaric acid (83.0 g), there are obtained crude crystals, which are recrystallized from ethanol to give 1-[2-(ethoxy)ethyl]-2-(4-methyl-1-piperazinyl)benzimidazole.3/2 fumarate (148.0 g) as colorless plates, m.p. 167.5°-168.5° C.
Reaction SMILES: [NH2:1][CH:2]1[C:34](=[O:35])[N:4]2[C:5]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[S:19])=[C:6]([C:9]3[S:10][C:11]4[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=4[N:13]=3)[CH2:7][S:8][C@H:3]12.[C:36]([NH:55][C:56]1[S:57][CH:58]=[C:59](/[C:61](=[N:65]/[O:66][C:67]([C:80]2[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=2)([C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=2)[C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)/[C:62](O)=[O:63])[N:60]=1)([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>C(Cl)Cl>[C:36]([NH:55][C:56]1[S:57][CH:58]=[C:59](/[C:61](=[N:65]/[O:66][C:67]([C:80]2[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=2)([C:74]2[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=2)[C:68]2[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=2)/[C:62]([NH:1][CH:2]2[C:34](=[O:35])[N:4]3[C:5]([C:18]([O:20][CH:21]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[S:19])=[C:6]([C:9]4[S:10][C:11]5[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=5[N:13]=4)[CH2:7][S:8][C@H:3]23)=[O:63])[N:60]=1)([C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: O=C(O)/C(=N\OC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(c3nc4ccccc4s3)CS[C@H]12
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(c3nc4ccccc4s3)CS[C@H]12)/C(=N\OC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 71.3 %

Procedure:
350 mg of diphenylmethyl 7-amino-3-(benzothiazol-2-yl)thio-3-cephem-4-carboxylate as synthesized in the same manner as in Example 1 (b) above were dissolved in ml of methylene chloride, and to the solution obtained were added 531 mg of (Z)-2-(2-tritylaminothiazol-4-yl)-trityloxyiminoacetic acid, 0.21 ml of pyridine and 74 μl of phosphorus oxychloride. Next, the acylation reaction and the post-treatment of the reaction solution were carried out in the same way as in Example 1 (b), and the resultant residue was then purified by a column chromatography on 35 g of silica gel (as developed with mixed solvents of toluene and ethyl acetate, 10:1) to obtain 566 mg of the titled compound (yield, 73%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][NH:6][N:5]=1)[CH3:2].[CH2:16]([O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN(C)C=O.[H-].[Na+]>O>[CH2:16]([O:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:28][N:6]2[CH:7]=[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4]([O:3][CH2:1][CH3:2])=[N:5]2)=[CH:30][CH:31]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3ccccc3)cc2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
To a mixture of ethyl 3-[3-ethoxy-1H-pyrazol-4-yl]propionate (1.50 g), 4-benzyloxybenzyl chloride (1.81 g), and N,N-dimethylformamide (30 ml), sodium hydride (60%, oily, 0.35 g) was added at 0° C., and then the mixture was stirred at room temperature for one hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[1-(4-benzyloxybenzyl)-3-ethoxy-1H-pyrazol-4-yl]propionate (2.76 g, yield: 96%) was obtained as a colorless oily substance from the faction eluted with ethyl acetate-hexane (1:4, volume ratio).
Reaction SMILES: O[CH2:2][C:3]#[N:4].[CH:5]([NH:8][CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:7])[CH3:6]>O.C(O)C>[CH:9]1([N:8]([CH2:2][C:3]#[N:4])[CH:5]([CH3:7])[CH3:6])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: N#CCO
Reactant: CC(C)NC1CCCC1
Solvent: CCO
Solvent: O
Product: CC(C)N(CC#N)C1CCCC1

Procedure:
Hydroxyacetonitrile (82 ml of a 70% w/w solution in water, 0.1 mol) was added to a solution of N-isopropylcyclopentanamine (11.43 g, 0.09 mol) (Preparation 23) in ethanol (60 ml). The reaction mixture was heated under reflux for 3 hours, allowed to cool and the solvent removed under reduced pressure. The residue was purified by chromatography on silica gel eluting with dichloromethane:methanol (98:2, by volume) to give the title compound (14.1 g) as a clear oil.
Reaction SMILES: [NH2:1][C:2]1([C:6]2[S:7][C:8]([C:11]3[CH:12]=[C:13]([NH:18][C:19]4[N:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][N:20]=4)[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[CH:9][N:10]=2)[CH2:5][O:4][CH2:3]1.CCN(CC)CC.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl.C(OCC)(=O)C>[CH3:17][C:15]1[CH:16]=[C:11]([C:8]2[S:7][C:6]([C:2]3([NH:1][S:37]([CH3:36])(=[O:39])=[O:38])[CH2:3][O:4][CH2:5]3)=[N:10][CH:9]=2)[CH:12]=[C:13]([NH:18][C:19]2[N:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][N:20]=2)[CH:14]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(N)COC3)s2)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(NS(C)(=O)=O)COC3)s2)c1
Temperature: 25 °C
Reaction time: 1.58 h
Yield: 47.5 %

Procedure:
To a solution of N-{3-[2-(3-aminooxetan-3-yl)-1,3-thiazol-5-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine (200 mg, 0.491 mmol) and Et3N (82 μL, 0.589 mmol) in dichloromethane (3.9 mL), methanesulfonyl chloride (57 μL, 0.736 mmol) was added. The reaction mixture was stirred at room temperature for 95 minutes. The mixture was then diluted with ethyl acetate, washed with saturated NaHCO3, followed by brine, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography on silica (10-100% ethyl acetate in hexanes) and lyophilized to afford N-{3-[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]oxetan-3-yl}methanesulfonamide (113 mg, 0.233 mmol, 47.4% yield) as a white powder. MS ESI: [M+H]+ m/z 486.0. 1H NMR (500 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.83 (m, 2H), 8.11 (s, 1H), 7.99 (s, 1H), 7.50 (s, 1H), 7.29 (m, 1H), 7.21 (s, 1H), 4.91 (dd, J=6.6, 16.1, 4H), 2.98 (s, 3H), 2.33 (s, 3H). rhSYK activity=+++
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46]O)[CH:41]=5)[C:36]([F:39])=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[I:50]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][I:50])[CH:41]=5)[C:36]([F:39])=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CO)c3)c2)c1
Reactant: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CI)c3)c2)c1
Temperature: 25 °C
Reaction time: 28 h

Procedure:
To a solution of N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-yl]methyl}-N′-{[6-fluoro-3′-(hydroxymethyl)-3-biphenylyl]methyl}-1,3-benzenedicarboxamide (0.0997 g, 0.15 mmol) in DCM (1.0 mL) was added iodine (0.0381 g, 0.15 mmol), and PS-PPh3 (0.0818 g, 0.18 mmol). This mixture was stirred at room temperature for 28 h, filtered and concentrated to afford N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-{[6-fluoro-3′-(iodomethyl)-3-biphenylyl]methyl}-1,3-benzenedicarboxamide which was carried on to the next step of the reaction directly.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:16]=[C:15]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([OH:22])=[O:21])[O:14][N:13]=2)=[CH:8][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:33][C:34](=[O:36])[CH3:35]>>[O:36]=[C:34]([CH3:35])[CH2:33][O:21][C:20](=[O:22])[C:19]1[CH:23]=[CH:24][CH:25]=[C:17]([C:15]2[O:14][N:13]=[C:12]([C:9]3[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:11][CH:10]=3)[CH:16]=2)[CH:18]=1
Reactant: CC(=O)CCl
Reactant: COCCOc1ccc(-c2cc(-c3cccc(C(=O)O)c3)on2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COCCOc1ccc(-c2cc(-c3cccc(C(=O)OCC(C)=O)c3)on2)cc1
Temperature: 55 °C
Reaction time: 48 h

Procedure:
In a 25 ml round flask, 150 mg (0.44 mmol) of 3-{3-[4-(2-methoxy-ethoxy)-phenyl]-isoxazol-5-yl}-benzoic acid are dissolved. Then, 122 mg (0.88 mmol, 4 eq.) of K2CO3 and 49 mg (0.53 mmol, 1.2 eq.) of 1-chloro-propan-2-one are added and the suspension heated to 55° C. under nitrogen. After 48 h, the reaction is cooled to room temperature and the solvent evaporated. Chromatographic purification (10 g SiO2; eluent: hexane/ethyl acetate 1:0 to 4:6) yields the title compound as a white solid. Mass spectrum: m/z (M+H)+: 396.0
Reaction SMILES: CN.[CH3:3][C:4]([C:9]1[CH:13]=[C:12]([NH:14][C:15](=[O:28])[C:16]([CH3:27])([S:18]([CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH3:17])[O:11][N:10]=1)([CH3:8])[C:5](O)=[O:6].F[P-](F)(F)(F)(F)F.[N:36]1(OC(N(C)C)=[N+](C)C)[C:40]2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[CH3:17][C:16]([S:18]([CH:21]1[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1)(=[O:19])=[O:20])([CH3:27])[C:15]([NH:14][C:12]1[O:11][N:10]=[C:9]([C:4]([CH3:8])([C:5](=[O:6])[NH:36][CH3:40])[CH3:3])[CH:13]=1)=[O:28]
Reactant: CC(C)(C(=O)O)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)C(C)(C)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Temperature: 25 °C
Reaction time: 65 h
Yield: 23 %

Procedure:
2 Methyl amine (2M solution in THF, 0.125 mL, 0.25 mmol) is added to a solution of 2-Methyl-2-{5-[2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionylamino]-isoxazol-3-yl}-propionic acid (50 mg, 0.13 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (57 mg, 0.15 mmol) in DMF (1 mL), followed by the addition of N,N-diisopropylethylamine (0.056 mL, 0.32 mmol). The reaction mixture is stirred at room temperature for 65 h. After this time, more O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (100 mg, 0.26 mmol) and methylamine (2M solution in THF, 0.125 mL, 0.25 mmol) are added to the reaction mixture. The reaction mixture is stirred for 1 hour at room temperature. After this time, the reaction mixture is diluted with water and extracted with ethyl acetate twice. The combined organic extracts are washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by preparative LC-MS affords 12 mg of the title compound. Yield: 23%; m/z 402 [M+H].
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][C:15]=1[CH3:16].O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>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.CO>[CH3:9][C:10]1[CH:11]=[C:12]([C:2]2[CH:3]=[N:4][C:5]([NH2:8])=[N:6][CH:7]=2)[CH:13]=[CH:14][C:15]=1[CH3:16]
Reactant: Cc1ccc(B(O)O)cc1C
Reactant: Nc1ncc(Br)cn1
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: CO
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(-c2cnc(N)nc2)cc1C
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 250-mL 3-necked round bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 5-bromopyrimidin-2-amine (5 g, 28.74 mmol, 1.00 equiv), 3,4-dimethylphenylboronic acid (4.4 g, 29.33 mmol, 1.00 equiv), dioxane (85 mL), methanol (29 mL), sodium carbonate (6.1 g, 57.55 mmol, 2.00 equiv) in water (29 mL), and Pd(PPh3)4 (664 mg, 0.57 mmol, 0.02 equiv). The resulting solution was stirred overnight at 100° C. in an oil bath. The mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane:methanol (50:1). This resulted in 6 g (crude) of 5-(3,4-dimethylphenyl)pyrimidin-2-amine as a yellow solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9])=O.[Cl:13][C:14]1[N:19]=[N:18][C:17]([NH2:20])=[CH:16][CH:15]=1>CCO>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:2]=[C:3]([C:5]3[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=3)[C:8]#[N:9])[N:20]=2)[N:19]=1
Reactant: N#Cc1cccc(C(=O)CBr)c1
Reactant: Nc1ccc(Cl)nn1
Solvent: CCO
Product: N#Cc1cccc(-c2cn3nc(Cl)ccc3n2)c1
Temperature: 25 °C
Yield: 52.8 %

Procedure:
A solution of 3-(2-bromoacetyl)benzonitrile and 6-chloropyridazin-3-amine (1 mmol) in EtOH was heated to reflux overnight. Then the mixture was cooled to r.t., and the precipitate was filtered to give 3-(6-chloroimidazo[1,2-b]pyridazin-2-yl)benzonitrile with a yield of 52.8%.
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:46][C:47]1[CH:52]=[C:51]([CH3:53])[N:50]=[C:49]([OH:54])[C:48]=1[CH2:55][NH2:56]>ClCCl.O>[NH2:46][C:47]1[CH:52]=[C:51]([CH3:53])[N:50]=[C:49]([OH:54])[C:48]=1[CH2:55][NH:56][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1
Reactant: Cc1cc(N)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1cc(N)c(CNC(=O)c2ccc(Oc3ccccc3)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
To a solution of 4-phenoxybenzoic acid (196 mg, 0.91 mmol) in dichloromethane (15 mL) were added 1-hydroxybenzotriazole (177 mg, 1.3 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (251 mg, 1.3 mmol) and triethylamine (265 mg, 2.6 mmol). The resulting solution was stirred at room temperature for 30 minutes. Then 4-amino-3-(aminomethyl)-6-methylpyridin-2-ol (200 mg, 1.3 mmol) was added to the solution, and it was stirred at room temperature for 16 hours. Water (20 ml) was added to the mixture. It was extracted with dichloromethane (50 ml). The organic layer was concentrated in vacuo to provide crude product which was purified by silica gel column chromatography with dichloromethane/methanol=10:1 to afford N-((4-amino-2-hydroxy-6-methylpyridin-3-yl)methyl)-4-phenoxybenzamide (180 mg, 57% yield) as a white solid. LRMS (M+H+) m/z: calcd 350.14. found 350. HPLC Purity (214 nm): 97%. 1H NMR (300 MHz, CDCl3): δ 10.71 (d, J=2.4 Hz, 1H), 7.76-7.79 (d, J=8.7 Hz, 2H), 7.32-7.38 (m, 2H), 7.12-7.17 (m, 1H), 6.94-7.02 (m, 4H), 5.64-5.65 (br, 1H), 5.51 (s, 1H), 4.47-4.49 (d, J=6.6 Hz, 2H), 3.48 (s, 2H), 2.16 (s, 3H).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CSC.[N+:12]([C:15]1[CH:34]=[CH:33][C:18]([CH:19]=[N:20][NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)([O-:14])=[O:13]>C(Cl)Cl>[N+:12]([C:15]1[CH:16]=[CH:17][C:18]([C:19]([Cl:1])=[N:20][NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:30])([F:31])[F:32])=[CH:24][CH:23]=2)=[CH:33][CH:34]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc(C=NNc2ccc(OC(F)(F)F)cc2)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: CSC
Product: O=[N+]([O-])c1ccc(C(Cl)=NNc2ccc(OC(F)(F)F)cc2)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a magnetically stirred solution of N-chlorosuccinimide (1.23 g, 9.22 mmoL) in CH2Cl2 (16 mL) at 0° C. was added dimethyl sulfide (1.36 mL, 18.45 mmoL) and the reaction mixture was stirred for 15 min and then cooled to −78° C. To this solution was added 1-(4-nitrobenzylidene)-2-(4-(trifluoromethoxy)-phenyl)hydrazine (2 g, 6.15 mmoL) dissolved in CH2Cl2 (16 mL) and the reaction mixture was stirred at this temperature for 1 h, warmed to room temperature and stirred for 2 h. The solution was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (15 mL) and added to a SiO2 loading cartridge and purified via flash column chromatography (Gradient EtOAc/hexanes). The title compound was isolated as a yellow solid: mp 172-175° C.; 1H NMR (400 MHz, CDCl3) δ 8.29-8.26 (m, 3H), 8.09-8.05 (m, 3H), 7.22 (s, 4H); 19F NMR (376 MHz, CDCl3) δ −58.30; ESIMS m/z 359 ([M+H])+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[OH:14])[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].[CH:15]([O:18][C:19]1[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=1[C:21](OC)=[O:22])([CH3:17])[CH3:16].[H-].[Na+]>O1CCOCC1>[OH:14][C:13]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[C:1]([CH2:2][C:21](=[O:22])[C:20]1[CH:25]=[CH:26][CH:27]=[CH:28][C:19]=1[O:18][CH:15]([CH3:16])[CH3:17])=[O:3]
Reactant: COC(=O)c1ccc(O)c(C(C)=O)c1
Reactant: COC(=O)c1ccccc1OC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(O)c(C(=O)CC(=O)c2ccccc2OC(C)C)c1
Reaction time: 4 h
Yield: 63.6 %

Procedure:
A solution consisting of methyl 3-acetyl-4-hydroxy-benzoate (60 g) and methyl 2-isopropoxy-benzoate (120 g) in dioxane (400 ml) was slowly added under stirring at room temperature to a suspension of sodium hydride 50% (45 g) in dioxane (200 ml). The mixture was kept for 4 hours at 80° C, cooled, then diluted with petroleum ether (600 ml), and subsequently, filtered. The collected precipitate was dissolved in water, acidified with acetic acid and extracted with ethylacetate. The organic phase was washed with potassium carbonate 5% and water, then evaporated to dryness and crystallised from ethanol to give (2-hydroxy-5-carbomethoxy-benzoyl)-(2-isopropoxy-benzoyl)-methane (70 g); m.p. 105°-107° C) which was then refluxed for 15 minutes with formic acid 99% (280 ml). After cooling and dilution in water (one liter) and filtration, the collected precipitate was crystallised from acetone to obtain 6-carbomethoxy-2'-isopropoxy-flavone (60 g; m.p. 154°-155° C), which was hydrolysed with a solution of potassium hydroxide 1% (l. 1,020) in ethanol 95% at reflux temperature for 30 minutes. The mixture was cooled, acidified with acetic acid, concentrated under vacuum to obtain a precipitate, which was filtered, washed with ethanol (95%) and water to give, after crystallisation from ethanol, 6-carboxy-2'-isopropoxy-flavone (45 g; m.p. 209°-211° C).
Reaction SMILES: CS([O:5][C@@H:6]([CH3:16])[CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])(=O)=O.CC(C)([O-])C.[K+].CS(C)=O.[Cl:27][C:28]1[CH:29]=[C:30](O)[CH:31]=[N:32][C:33]=1[O:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[N:41]=[CH:40][N:39]=[C:38]2[NH:45][C:46]1[CH:50]=[CH:49][N:48]([CH3:51])[N:47]=1>O>[Si:9]([O:8][CH2:7][C@@H:6]([CH3:16])[O:5][C:30]1[CH:29]=[C:28]([Cl:27])[C:33]([O:34][C:35]2[CH:36]=[C:37]3[C:42](=[CH:43][CH:44]=2)[N:41]=[CH:40][N:39]=[C:38]3[NH:45][C:46]2[CH:50]=[CH:49][N:48]([CH3:51])[N:47]=2)=[N:32][CH:31]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)OS(C)(=O)=O
Reactant: Cn1ccc(Nc2ncnc3ccc(Oc4ncc(O)cc4Cl)cc23)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)Oc1cnc(Oc2ccc3ncnc(Nc4ccn(C)n4)c3c2)c(Cl)c1
Temperature: 100 °C
Reaction time: 24 h
Yield: 33.1 %

Procedure:
(1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl methanesulfonate (79 mg, 0.29 mmol) and potassium tert-butoxide (55 mg, 0.49 mmol) were added to a dimethyl sulfoxide solution (3 ml) of 5-chloro-6-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)pyridin-3-ol (90 mg, 0.24 mmol) obtained in Example 22, then stirred for 24 hours at 100° C. The reaction solution was cooled to room temperature, water was added, and extracted with ethyl acetate. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:2 to 0:1) to obtain 6-{[5-((1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)-3-chloropyridin-2-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)quinazoline-4-amine (43 mg, yield: 33%) as a white solid.