Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:22])[C:5]2=[C:6]([CH2:8][C@H:9]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[Br:21])[NH:10]/[C:11]/2=[N:12]\[OH:13])[N:7]=1.[CH3:23][O:24][C:25]1[N:30]=[C:29](B2OCCN(C3C=CC=CC=3)CCO2)[CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+]>CC(N(C)C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[N:3]=[C:4]([CH3:22])[C:5]2=[C:6]([CH2:8][C@H:9]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[Br:21])[NH:10]/[C:11]/2=[N:12]\[OH:13])[N:7]=1.[NH2:1][C:2]1[N:3]=[C:4]([CH3:22])[C:5]2=[C:6]([CH2:8][C@H:9]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[C:29]3[CH:28]=[CH:27][CH:26]=[C:25]([O:24][CH3:23])[N:30]=3)[NH:10]/[C:11]/2=[N:12]\[OH:13])[N:7]=1
Reactant: COc1cccc(B2OCCN(c3ccccc3)CCO2)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cc1nc(N)nc2c1/C(=N/O)N[C@@H](c1ccc(F)cc1Br)C2
Solvent: CC(=O)N(C)C
Product: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3/C(=N/O)N2)n1
Temperature: 85 °C

Procedure:
(R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one oxime (Compound 86c) was prepared as described in Example 85 above. A mixture of 86c (36.5 mg, 0.1 mmol and 2-(6-methoxypyridin-2-yl)-6-phenyl-1,3,6,2-dioxazaborocane (86f, 149 mg, 0.5 mmol), Pd(dppf)2Cl2 (8.12 mg, 0.01 mmol), and 2N Na2CO3 (0.25 mL, 0.5 mmol) in DMA (3 mL) was degassed with N2 and heated at 85° C. overnight. The reaction mixture was cooled to ambient temperature, diluted with ethyl acetate and filtered through Celite. The filtrate was concentrated to afford brown oil which was purified by preparative HPLC to afford (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one oxime (86 g or 61), 13.2 mg, 33%) as white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.78 (s, 3H) 3.14-3.31 (m, 1H) 3.43-3.46 (m, 1H) 3.89 (s, 3H) 5.08 (d, J=7.58 Hz, 1H) 6.78 (d, J=8.34 Hz, 1H) 7.05 (d, J=7.07 Hz, 2H) 7.18 (d, J=8.84, 2H) 7.70 (t, J=7.71, 1H). MS (ES) [M+H] calculated for C20H20FN6O2, 395.16. found 395.20.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH:11]=[C:12]([CH2:15][OH:16])O[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=1>Cl>[CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH:11]=[C:12]([CH2:15][OH:16])[N:24]([C:20]2[CH:19]=[C:18]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:23]=[CH:22][CH:21]=2)[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2ccccc2)c1
Reactant: O=c1cc(CO)occ1OCc1ccccc1
Agent: Cl
Product: O=c1cc(CO)n(-c2cccc(-c3ccccc3)c2)cc1OCc1ccccc1

Procedure:
To a suspension of 5-(benzyloxy)-2-(hydroxymethyl)-4H-pyran-4-one (92.9 g, 0.40 mol) in dilute aq hydrochloric acid (0.5 N, 800 mL) was added biphenyl-3-amine (74.4 g, 0.44 mol). The resulting mixture was heated under refluxed for 16 h. Concentration of the solvent gave a residue which was purified by silica gel chromatography (EtOAc:MeOH/20:1) to afford 5-(benzyloxy)-1-(biphenyl-3-yl)-2-(hydroxymethyl)pyridin-4(1H)-one as pale solid MS (ESI) (M+H)+384.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:30])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[NH:11][C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH2:28][CH3:29])=[N:9]2)=[CH:4][CH:3]=1.[C:31](Cl)([Cl:33])=[O:32]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH3:30])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:31]([Cl:33])=[O:32])[C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH2:28][CH3:29])=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: CCOc1ccccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Solvent: CCN(CC)CC
Product: CCOc1ccccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was reacted with phosgene in the presence of triethylamine to give the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:18])=[C:4]([N+:15]([O-])=O)[C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].O>C(O)C>[Br:1][C:2]1[C:3]([NH2:18])=[C:4]([NH2:15])[C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: CN1CCN(c2ncc(Br)c(N)c2[N+](=O)[O-])CC1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN1CCN(c2ncc(Br)c(N)c2N)CC1
Yield: 81.8 %

Procedure:
A 250 mL round bottom flask was charged with 5-bromo-2-(4-methylpiperazin-1-yl)-3-nitropyridin-4-amine (1.5 g, 4.7 mmol), Na2S2O4 (2.0 g, 11 mmol), water (10 mL) and ethanol (20 mL). The mixture was heated at reflux for 0.5 h. Work-up: the solvent was evaporated. The residue was re-suspended in triethylamine (15 mL) and ethyl acetate (300 mL), and then filtered. The filtrate was concentrated in vacuo, to afford 1.1 g (80%) of the product as a pale-red solid. MS m/z: 286 (M+H+).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:13]([C:16]1[S:17][C:18](B(O)O)=[CH:19][CH:20]=1)([OH:15])=[O:14].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.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>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([C:18]3[S:17][C:16]([C:13]([OH:15])=[O:14])=[CH:20][CH:19]=3)[S:3][C:4]=2[CH:10]=1
Reactant: O=C(O)c1ccc(B(O)O)s1
Reactant: COc1ccc2nc(Br)sc2c1
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: CN(C)C=O
Solvent: O
Product: COc1ccc2nc(-c3ccc(C(=O)O)s3)sc2c1
Temperature: 120 °C
Reaction time: 2 h
Yield: 37.8 %

Procedure:
2-Bromo-6-methoxy-benzothiazole (1.22 g, 5.00 mmol), 2-carboxythiophene-5-boronic acid (860 mg, 5.00 mmol), sodium carbonate (2.65 g, 25.00 mmol) and tetrakis(triphenylphosphine)palladium (300 mg, 0.25 mmol) were dissolved in a mixture of 80 mL N,N-dimethylformamide and 80 mL water. The mixture was stirred at 120° C. under argon for 2 h. The reaction mixture was evaporated and the residue was partitioned between 100 mL of water and 100 mL of dichloromethane. A considerable amount of white solid precipitated between the layers and was filtered off and triturated with diethyl ether, affording the title compound (550 mg, 1.89 mmol, 38%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]=1/[CH:17]=[CH:18]/[CH:19](O)[CH2:20][CH:21]([OH:27])[CH2:22][C:23]([O:25]C)=[O:24].[OH-].[Na+].C(O)C.Cl>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:3]=1/[CH:17]=[CH:18]/[CH:19]1[O:25][C:23](=[O:24])[CH2:22][CH:21]([OH:27])[CH2:20]1
Reactant: COC(=O)CC(O)CC(O)/C=C/c1c(Cl)cc(Cl)cc1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C1CC(O)CC(/C=C/c2c(Cl)cc(Cl)cc2OCc2ccccc2)O1
Yield: 103.5 %

Procedure:
A solution of methyl (E)-7-(2,4-dichloro-6-phenylmethoxyphenyl)-3,5-dihydroxy-6-heptenoate (34.8 g, 81.8 mmole), 1N sodium hydroxide (82 ml, 82 mmole) and ethanol (200 ml) was stirred at 25° C. for 15 min. The reaction solution was acidified with 6N hydrochloric acid, diluted with water (400 ml) and extracted with ether (3×200 ml). The combined organic extracts were washed with brine (3×100 ml), dried over magnesium sulfate and filtered. The filtrate was evaporated in vacuo, leaving the title compound as an orange oil (33.3 g, 99%): pmr (CDCl3) δ2.47 (2H, d), 4.30 (2H, br m), 4.98 (2H, s), 7.30 (5H, s).
Reaction SMILES: [CH:1]1([CH2:4][C:5]([OH:7])=O)[CH2:3][CH2:2]1.C(N(CC)CC)C.CC(C)(C)C(Cl)=O.[CH2:22]([C@H:29]1[CH2:33][O:32][C:31](=[O:34])[NH:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Cl-].[Li+]>O1CCCC1>[CH2:22]([C@H:29]1[CH2:33][O:32][C:31](=[O:34])[N:30]1[C:5](=[O:7])[CH2:4][CH:1]1[CH2:2][CH2:3]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(O)CC1CC1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CC1CC1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -40 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
A cooled (−40° C.) solution of cyclopropylacetic acid (5.13 g, 51.250 mmol) in anhydrous tetrahydrofuran (150 mL) was subsequently treated with triethylamine (21.4 mL, 153.75 mmol) and trimethylacetyl chloride (6.9 mL, 56.375 mmol). After stirring at −40° C. for 1 h, the mixture was treated with (S)-4-benzyl-oxazolidin-2-one (9.99 g, 56.375 mmol) and lithium chloride (2.39 g, 56.375 mmol). The mixture was allowed to slowly warm to room temperature and after stirring at room temperature for 22 h, the reaction was partitioned between dichloromethane and half-saturated ammonium chloride. The aqueous layer was extracted with dichloromethane. The organics were combined, filtered through a phase separator and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 100 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 9:1 to afford the title compound (11.63 g, 87%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 0.19-0.32 (m, 2H), 0.56-0.69 (m, 2H), 1.10-1.24 (m, 1H), 2.76-2.87 (m, 2H), 2.96 (dd, J=16.9, 6.9 Hz, 1H), 3.34 (dd, J=13.2, 3.3 Hz, 1H), 4.15-4.29 (m, 2H), 4.66-4.77 (m, 1H), 7.20-7.40 (m, 5H). LCMS (m/z) 282.1 [M+Na], Tr=2.78 min.
Reaction SMILES: [CH2:1]([O:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH:31]=1)[CH2:27]O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].S(Cl)([Cl:57])=O.CN(C=O)C>C(Cl)(Cl)Cl>[CH2:1]([O:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH:31]=1)[CH2:27][Cl:57])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCCCCCCCCCCCCCOc1cc(CO)cc(OCCCCCCCCCCCCCCCCCCCCCC)c1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCCCCCOc1cc(CCl)cc(OCCCCCCCCCCCCCCCCCCCCCC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
3,5-Di(docosyloxy)benzyl alcohol (500 mg, 0.66 mmol) was dissolved in chloroform (5 ml), thionyl chloride (71 μl, 0.99 mmol) and DMF (10 μl, 0.13 mmol) were added dropwise, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated, and the residue was precipitated with acetonitrile to give 3,5-di(docosyloxy)benzylchloride (505 mg, 0.65 mmol, 99%).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][C:3]1=[O:29].Cl.[NH2:31][OH:32].C(=O)([O-])O.[Na+]>C(O)C.O.C(OCC)(=O)C>[OH:32]/[N:31]=[C:8](/[C:6]1[CH:5]=[CH:4][C:3](=[O:29])[N:2]([CH3:1])[CH:7]=1)\[CH2:9][C@@H:10]([C:18]1[CH:19]=[CH:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: Cc1ccccc1[C@H](CC(=O)c1ccc(=O)n(C)c1)c1ccc(S(C)(=O)=O)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccccc1[C@@H](C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(S(C)(=O)=O)cc1
Temperature: 120 °C
Yield: 97.1 %

Procedure:
To a microwave vial was added (R)-1-methyl-5-(3-(4-(methylsulfonyl)phenyl)-3-o-tolylpropanoyl)pyridin-2(1H)-one (168 mg, 410 μmol), hydroxylamine hydrochloride (85.5 mg, 1.23 mmol) and sodium hydrogencarbonate (103 mg, 1.23 mmol) in ethanol (3 mL) and water (0.2 mL). The vial was capped and heated at 120° C. for 15 min. The reaction mixture was diluted with ethyl acetate and poured onto water. The organic layer was washed with brine, dried over magnesium sulfate and evaporated to afforded the title compound (169 mg, 97%) as a mixture of the E and Z isomers (ratio ca. 85:15). Light yellow foam, MS (ESI+): m/z=425.2 [M+H]+.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[CH:15]=[C:14]([O:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([O:35]C)=[O:34])=[CH:29][CH:28]=3)=[CH:23][CH:22]=1)[CH:13]=[CH:12]2)(=[O:3])[CH3:2].CO.O.[OH-].[Na+]>C1COCC1>[C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[CH:15]=[C:14]([O:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([OH:35])=[O:34])=[CH:29][CH:28]=3)=[CH:23][CH:22]=1)[CH:13]=[CH:12]2)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(-c2ccc(OCCOc3ccc4cccc(CCNC(C)=O)c4c3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)NCCc1cccc2ccc(OCCOc3ccc(-c4ccc(C(=O)O)cc4)cc3)cc12
Temperature: 25 °C
Reaction time: 10 h

Procedure:
In a 100 ml round-bottomed flask, 19 mmol of the compound obtained in Example 1 are suspended in 25 ml of THF, and then 15 ml of methanol, 15 ml of water and 38 mmol of sodium hydroxide are added. The reaction mixture is maintained at ambient temperature with stirring for 10 hours. The solution is subsequently concentrated, poured into water and then acidified with 12M HCl. The precipitate obtained is filtered off, washed with water and recrystallised to yield the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13](/[CH:16]=[N:17]/[C:18]3[CH:19]=[CH:20][C:21]4[C:26](=[O:27])[O:25][C:24]([CH3:29])([CH3:28])[O:23][C:22]=4[CH:30]=3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]3[CH:19]=[CH:20][C:21]4[C:26](=[O:27])[O:25][C:24]([CH3:28])([CH3:29])[O:23][C:22]=4[CH:30]=3)=[CH:12][CH:11]=2)=[CH:6][CH:7]=1
Reactant: CC1(C)OC(=O)c2ccc(/N=C/c3ccc(C#Cc4ccc(Cl)cc4)cc3)cc2O1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC1(C)OC(=O)c2ccc(NCc3ccc(C#Cc4ccc(Cl)cc4)cc3)cc2O1
Temperature: 50 °C
Yield: 78.4 %

Procedure:
A mixture of 7-[((E)-{4-[(4-chlorophenyl)ethynyl]phenyl}methylidene)amino]-2,2-dimethyl-4H-1,3-benzodioxin-4-one (1.65 g, 3.97 mmol), sodium triacetoxyborohydride (2.52 g, 11.9 mmol) and acetic acid (0.34 mL, 5.95 mmol) in anhydrous DCE (100 mL) was heated at 50° C. for 3 h. Then the reaction mixture was diluted with H2O (100 mL) and a saturated aqueous solution of NaHCO3 (100 mL) and extracted with DCM (3×200 mL). The combined organic layers were dried over MgSO4 and the solvents were removed under reduced pressure. Precipitation by addition of pentane and filtration gave 1.30 g of the titled compound as a pale yellow powder (77%). M− (ESI): 415.9. HPLC, Rt: 5.05 min (Purity: 98.0%).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([C:25]4[O:26][C:27]([CH:30]5OCC[O:31]5)=[CH:28][CH:29]=4)=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>Cl.O1CCCC1>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([C:25]4[O:26][C:27]([CH:30]=[O:31])=[CH:28][CH:29]=4)=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Oc2ccc(Nc3ccnc4cc(-c5ccc(C6OCCO6)o5)ccc34)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2ccc3c(Nc4ccc(Oc5ccccc5)cc4)ccnc3c2)o1
Yield: 95 %

Procedure:
(4-Phenoxyphenyl)-(7-(5-(1,3-dioxolan-2-yl)furan-2-yl)-quinolin-4-yl)amine (1.4 g) was treated with 1M aqueous hydrochloric acid-tetrahydrofuran (60 ml, 1:1) in accordance with procedure C. Addition of 1M aqueous sodium hydroxide solution to pH 10 followed by extraction with ethyl acetate, drying (magnesium sulfate) and concentration to dryness afforded a yellow solid (1.2 g); δH [2H6] DMSO 9.70 (1H, s), 9.10 (1H, s), 8.51 (2H, m), 8.35 (1H, s), 8.02 (1H, d), 7.73 (1H, d), 7.57 (1H, d), 7.42 (4H, m), 7.22-7.04 (5H, m), 6.88 (1H, d); m/z 407 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][C@H:35]1[CH3:47])(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([N:34]3[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][C@H:35]3[CH3:47])(=[O:33])=[O:32])=[CH:7][C:2]=2[F:1])=[CH:18][N:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1S(=O)(=O)c1ccccc1Br
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1S(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)nc2)c(F)c1

Procedure:
The title compound was prepared using methods analogous to those described in Example 376 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and (R)-tert-butyl 4-((2-bromophenyl)sulfonyl)-3-methypiperazine-1-carboxylate. MS (ESI): mass calcd. for C26H30FN5O4S, 527.20; m/z found, 528.2 [M+H]+.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[CH:7][N:6]=1)(=O)=O.[Cl:26][C:27]1[CH:28]=[C:29]([OH:33])[CH:30]=[N:31][CH:32]=1>>[Cl:26][C:27]1[CH:28]=[C:29]([O:33][C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[Cl:18])[C:8]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[CH:7][N:6]=2)[CH:30]=[N:31][CH:32]=1
Reactant: Oc1cncc(Cl)c1
Reactant: CS(=O)(=O)c1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Product: Clc1ccc(-c2cnc(Oc3cncc(Cl)c3)nc2-c2ccc(Cl)cc2Cl)cc1

Procedure:
2-Methylsulfonyl-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine from Reference Example 3 was reacted with 5-chloro-3-hydroxypyridine according to the procedure described in Example 74 to afford 2-(5-chloro-3-pyridyloxy)-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine: HPLC/MS: m/e=462 (M++1); Rt=4.40 min; 1H-NMR 400 MHz (CDCl3): δ 7.05. (d, J=9 Hz, 2H), 7.21 (d, J=10 Hz, 1H), 7.25-7.31 (m, 3H), 7.41 (s, 1H), 7.75 (s, 1H), 8.50 (s, 1H), 8.55 (s, 1H), 8.62 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:12]O>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: CO
Reactant: O=C(O)Cc1ccccc1Cl
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccccc1Cl
Yield: 97.5 %

Procedure:
To 2-chlorophenylacetic acid (1.04 g, 6 mmol) in MeOH (25 mL) was added sulfuric acid (6 drops) and the solution was refluxed for 16 hours. After concentration, the residue was taken up in ethyl acetate and washed with sat'd aq. NaHCO3, H2O and brine. The organic layer was dried over Na2SO4 and concentrated to give methyl (2-chlorophenyl)acetate 6a (1.08 g, 97.5%) as a yellowish oil. GCMS (EI) m/z 184, 186 (M+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:4][N:3]=1.[CH3:19][N:20]1[CH:24]=[CH:23][C:22]([NH2:25])=[N:21]1>O1CCOCC1.Cl[Pd-](P(C1CC2CC1CC2)C1CC2CC1CC2)[C-]1C=CC=C1N(C)C.[CH-]1C=CC=C1.[Fe+2]>[CH3:18][S:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH:25][C:22]3[CH:23]=[CH:24][N:20]([CH3:19])[N:21]=3)=[N:3][CH:4]=2)=[CH:10][CH:11]=1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)c1ccc(Oc2ccc(Br)nc2)cc1
Reactant: Cn1ccc(N)n1
Agent: CN(C)c1ccc[c-]1[Pd-](Cl)P(C1CC2CCC1C2)C1CC2CCC1C2
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: C1COCCO1
Product: Cn1ccc(Nc2ccc(Oc3ccc(S(C)(=O)=O)cc3)cn2)n1
Temperature: 80 °C
Yield: 55 %

Procedure:
2-Bromo-5-(4-methanesulfonyl-phenoxy)-pyridine (0.47 mmol), sodium-tert.-butylate (1.4 eq.), and 1-methyl-1H-pyrazole-3-amine (1.2 eq.) are dissolved in degassed dioxane (2.5 ml) and heated to 80° C. Chloro(di-2-norbornylphosphino)(2-dimethylaminoferrocene-1-yl)palladium (II) (5.9 mg) in degassed dioxane (1 ml) is added and the reaction mixture is heated for 1 hour at 142° C. in the microwave. The reaction is quenched with ethylacetate (30 ml) and filtrated over celite. The solvent of the filtrate is removed in vacuo [5-(4-Methanesulfonyl-phenoxy)-pyridine-2-yl]-(1-methyl-1H-pyrazole-3-yl)-amine (“A27”) is obtained after reversed phase column chromatography (water/acetonitrile+0.1% TFA) as orange powder in a yield of 55%; HPLC (method C): 1.57 min; LC-MS (method A): 0.787 min, 345.15 (M+H+);
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]([C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][C:10]=1[F:18])#[N:8].Br[C:20]1[N:24]2[N:25]=[C:26]([N:29]3[CH2:33][CH2:32][CH2:31][CH:30]3[C:34]3[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=3[F:41])[CH:27]=[CH:28][C:23]2=[N:22][CH:21]=1>O1CCOCC1.O>[F:41][C:35]1[CH:36]=[CH:37][C:38]([F:40])=[CH:39][C:34]=1[CH:30]1[CH2:31][CH2:32][CH2:33][N:29]1[C:26]1[CH:27]=[CH:28][C:23]2[N:24]([C:20]([C:12]3[CH:13]=[CH:14][C:9]([C:7]#[N:8])=[C:10]([F:18])[CH:11]=3)=[CH:21][N:22]=2)[N:25]=1
Reactant: Fc1ccc(F)c(C2CCCN2c2ccc3ncc(Br)n3n2)c1
Reactant: N#Cc1ccc(B(O)O)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2cnc3ccc(N4CCCC4c4cc(F)ccc4F)nn23)cc1F
Temperature: 150 °C

Procedure:
In step 12-1, [Pd(Dppf)2]Cl2 (90 mg, 0.11 mmol), sodium carbonate (0.41 g, 3.9 mmol), and 4-cyano-3-fluorophenylboronic acid (0.36 g, 2.2 mmol) were added to a solution of 3-bromo-6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine (6-6) (0.42 g, 1.1 mmol) in 3 mL of dioxane and 1 mL of DI water. The reaction mixture was heated in a microwave for twenty minutes at 150° C., and the slurry was then cooled to room temperature and filtered through a 0.2 μM nylon fit. The solvent was removed from the mother liquor and the remaining residue was reconstituted in dichloromethane (DCM). This solution was loaded onto a 12 g silica gel column and eluted using a 0-10% methanol in DCM gradient over 30 minutes. The solvent was removed from the desired fractions to yield 4-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-2-fluorobenzonitrile. m/z=420.2 [M+1].