Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][N:9]2[C:30](=[O:31])[N:12]3[CH:13]=[CH:14][C:15]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)=[C:16]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)[C:11]3=[N:10]2)=[CH:6][CH:5]=[C:4]([C:32]([F:35])([F:34])[F:33])[N:3]=1.[CH2:36]([Zn]CC)[CH3:37].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CCOC(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].C1COCC1>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([C:15]2[CH:14]=[CH:13][N:12]3[C:30](=[O:31])[N:9]([CH2:8][C:7]4[C:2]([CH2:36][CH3:37])=[N:3][C:4]([C:32]([F:34])([F:35])[F:33])=[CH:5][CH:6]=4)[N:10]=[C:11]3[C:16]=2[C:17]2[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=2)=[CH:28][CH:27]=1
Reactant: O=c1n(Cc2ccc(C(F)(F)F)nc2Cl)nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn12
Reactant: CC[Zn]CC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Temperature: 25 °C
Yield: 50.2 %

Procedure:
A mixture of 2-((2-chloro-6-(trifluoromethyl)pyridin-3-yl)methyl)-7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (22 mg, 0.043 mmol), anhydrous THF (0.5 mL), diethylzinc (1.1 M solution in toluene, 0.059 mL, 0.065 mmol), solid K2CO3 (18 mg, 0.129 mmol) and Pd(dppf)Cl2.CH2Cl2 (7 mg, 0.0086 mmol) in a sealed tube was stirred at 80° C. for 16 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with water, then saturated aqueous NaCl, dried over Na2SO4 and concentrated under reduced pressure. Two products were purified using preparative reverse phase HPLC (Phenomenex Luna 5 μm C-18 21.2×100 mm column eluted with a linear gradient of 50% to 80% B over 10 min (A=0.1% trifluoroacetic acid, 90% water, 10% methanol and B=0.1% trifluoroacetic acid, 90% methanol, 10% water) with flow rate at 20 mL/min and UV detection at 220 nm). HPLC fractions were concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with saturated aqueous NaHCO3 once, water twice, then saturated aqueous NaCl, dried over Na2SO4 and evaporated. The residue was dissolved in acetonitrile, frozen and lyophilized to afford 7-(4-chlorophenyl)-2-((2-ethyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (11 mg) and the title compound (7 mg) as a yellow powder. Title compound: HPLC/MS: retention time=3.20 min, [M+H]+=504.3.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[C:7]([NH:14][C:15]2[C:24]3[C:19](=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)[CH:6]=1)([O-:4])=[O:3].ClC1C2C(=C(C(F)(F)F)C=CC=2)N=CC=1.NC1C=C([N+]([O-])=O)C=CC=1C(O)=O.S(Cl)(Cl)=O.[NH2:61][CH:62]1[CH2:67][CH2:66][N:65]([CH3:68])[CH2:64][CH2:63]1>>[CH3:68][N:65]1[CH2:66][CH2:67][CH:62]([NH:61][C:9](=[O:10])[C:8]2[CH:12]=[CH:13][C:5]([N+:2]([O-:4])=[O:3])=[CH:6][C:7]=2[NH:14][C:15]2[C:24]3[C:19](=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)[CH2:63][CH2:64]1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1Nc1ccnc2c(C(F)(F)F)cccc12
Reactant: CN1CCC(N)CC1
Agent: Cl
Agent: FC(F)(F)c1cccc2c(Cl)ccnc12
Agent: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Solvent: O=S(Cl)Cl
Product: CN1CCC(NC(=O)c2ccc([N+](=O)[O-])cc2Nc2ccnc3c(C(F)(F)F)cccc23)CC1

Procedure:
4-Nitro-2-(8-trifluoromethyl-4-quinolylamino)benzoyl chloride hydrochloride prepared by the reaction of 4-chloro-8-trifluoromethylquinoline with 2-amino-4-nitrobenzoic acid and treatment of the reaction product with thionyl chloride, is reacted with 4-amino-1-methylpiperidine to afford the title compound.
Reaction SMILES: N[C:2]1[C:3]([O:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])=[N:4][C:5]([O:8][C:9]2[CH:14]=[C:13]([N:15]3[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]([CH3:26])[C:16]3=[O:27])[C:12]([F:28])=[CH:11][C:10]=2[Cl:29])=[CH:6][CH:7]=1.COCCOC.ClCCl.N(OC(C)(C)C)=O>CCCCC>[Cl:29][C:10]1[CH:11]=[C:12]([F:28])[C:13]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]([CH3:26])[C:16]2=[O:27])=[CH:14][C:9]=1[O:8][C:5]1[CH:6]=[CH:7][CH:2]=[C:3]([O:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[N:4]=1
Reactant: COC(=O)COc1nc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2Cl)ccc1N
Agent: CC(C)(C)ON=O
Solvent: ClCCl
Solvent: COCCOC
Solvent: CCCCC
Product: COC(=O)COc1cccc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2Cl)n1
Reaction time: 0.17 h
Yield: 58.7 %

Procedure:
0.72 g of boron trifluoride diethyl ether complex was added to a mixture of 1.28 g of 3-amino-6-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxypyridine, 3 ml of 1,2-dimethoxyethane and 1 ml of dichloromethane dropwise at −7° C. The mixture was stirred for 10 minutes at the same temperature, then, to the reaction solution was added 0.31 g of t-butyl nitrite dropwise at −5° C. or lower. The mixture was stirred for 1 hour at the same temperature, then, into the mixture was poured n-pentane. The solvent was removed by decantation. 7 ml of ethanol, and 1.2 g of zinc (dust) was added to the residue, and it was stirred at reflux temperature for 1.5 hour. The reaction solution was filtrated through Celite, and the solvent was distilled off, then, the resulted residue was subjected to silica gel chromatography to obtain 0.73 g of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-6-(methoxycarbonyl)methoxypyridine [present compound 2-45].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([S:17]([CH2:20][CH3:21])(=O)=[O:18])[O:9]2)=[CH:4][C:3]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH3:31])=[CH:25][CH:24]=1.ClC1C=CC([C@H]2[C@H](O)[C@@H](O)[C@H](O)[C@@H](SCC)O2)=CC=1CC1C=CC(OCC)=CC=1.OO>CC(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([S:17]([CH2:20][CH3:21])=[O:18])[O:9]2)=[CH:4][C:3]=1[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH3:31])=[CH:27][CH:28]=1
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](S(=O)(=O)CC)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Agent: CCOc1ccc(Cc2cc([C@@H]3O[C@H](SCC)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Agent: OO
Solvent: CC(=O)O
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](S(=O)CC)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Preparation of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-ethanesulfonyl-tetrahydro-pyran-3,4,5-triol and (2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-ethanesulfonyl-tetrahydro-pyran-3,4,5-triol. To a solution of compound from step A (10 mg, 0.023 mmol) in AcOH (0.5 ml) was added H2O2 (35 wt % solution in H2O, 3 mg, 0.092 mmol, 9 μl). The mixture was stirred at ambient temperature for 2 hours before being concentrated under vacuum. Purification of the mixture by silica gel chromatography (5% MeOH/CH2Cl2) afforded (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-ethanesulfinyl-tetrahydro-pyran-3,4,5-triol (as a mixture of diastereomers at sulfur) (2 mg, 19%) and (2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-ethanesulfonyl-tetrahydro-pyran-3,4,5-triol (5 mg, 46%) both as white solids.
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][Br:20])=[CH:14][CH:13]=1)C1C=CC=CC=1>CCOC(C)=O.CCO.[Pd]>[Br:20][CH2:19][CH2:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][OH:8])=[CH:13][CH:14]=1
Reactant: BrCCc1ccc(OCCOCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: OCCOc1ccc(CCBr)cc1
Reaction time: 8 h

Procedure:
1-[2-(benzyloxy)ethoxy]-4-(2-bromoethyl)benzene in EtOAc (150 mL) and EtOH (50 mL) was hydrogenated over 10% Pd/C (530 mg) at room temperature and atmospheric pressure for 8 h. The catalyst was removed by filtration over Celite, washed with EtOAc and concentrated in vacuo to give the title compound (3.6 g). LCMS RT=2.82 min.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:16](=[S:31])(OC1C=CC=CN=1)OC1C=CC=CN=1>C(Cl)Cl>[N:15]([C:12]1[CH:11]=[CH:10][C:9]([O:8][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:14][CH:13]=1)=[C:16]=[S:31]
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Reactant: Cc1cccnc1Oc1ccc(N)cc1
Solvent: ClCCl
Product: Cc1cccnc1Oc1ccc(N=C=S)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a round bottomed flask were added 4-(3-methylpyridin-2-yloxy)benzenamine (100 mg, 0.5 mmol), O,O-dipyridin-2-yl carbonothioate (122 mg, 0.52 mmol) and DCM (2 mL). The reaction mixture was stirred at RT for 16 h. The reaction was partitioned between DCM and water, brine. The aqueous layer was extracted with DCM and the combined organics was dried (Na2SO4) and concentrated to give 2-(4-isothiocyanatophenoxy)-3-methylpyridine as tan solid. MS (ESI, pos. ion) m/z: 243.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[N:11]=[C:10]2[S:12][C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])=[N:14][C:9]2=[CH:8][CH:7]=1.[Cl:24][C:25]1[C:33]([C:34]([C:37]#[N:38])([CH3:36])[CH3:35])=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](O)=[O:28].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[Cl:24][C:25]1[C:33]([C:34]([C:37]#[N:38])([CH3:36])[CH3:35])=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([NH:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:4]([O:5][C:6]2[N:11]=[C:10]3[S:12][C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])=[N:14][C:9]3=[CH:8][CH:7]=2)[CH:3]=1)=[O:28]
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)c1
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: c1ccncc1
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)sc4n3)c2)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
A solution of N-[5-(3-aminophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (120 mg, 3.68 μmol), 2-chloro-3-(1-cyano-1-methylethyl)benzoic acid produced in Example C61(v) (87 mg, 386 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (168 mg, 442 μmol) in pyridine (3 mL) was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (15 mL), and the mixture was extracted with ethyl acetate (20 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=40/60→20/80), and fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from tetrahydrofuran and ethanol to give the title compound (60 mg, 31%) as colorless crystals.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([F:31])[CH:30]=1)[C:25](O)=[O:26]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:25](=[O:26])[C:24]2[CH:23]=[C:22]([F:21])[CH:30]=[C:29]([F:31])[CH:28]=2)=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: O=C(O)c1cc(F)cc(F)c1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Agent: Cl
Product: O=C(CNC(=O)c1cc(F)cc(F)c1)NC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 3,5-difluorobenzoic acid.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)=[O:7].[ClH:34].[S:35]1[CH2:40][CH2:39][N:38]([CH2:41][C:42]#[C:43][CH2:44][Cl:45])[CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[ClH:45].[ClH:34].[F:31][C:28]([F:29])([F:30])[C:26]1[CH:25]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:32])[F:33])[CH:27]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:44][C:43]#[C:42][CH2:41][N:38]2[CH2:39][CH2:40][S:35][CH2:36][CH2:37]2)[CH2:10][C@H:9]1[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1ccc2ccccc2c1
Reactant: ClCC#CCN1CCSCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CC#CCN2CCSCC2)C[C@H]1Cc1ccc2ccccc2c1
Yield: 67.3 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)piperazine (300 mg), 4-thiomorpholino-2-butynyl chloride hydrochloride (170 mg) and powdered potassium carbonate (210 mg) in dry acetonitrile (3 ml) was refluxed for 7.5 hours in the presence of potassium iodide (20 mg). The reaction mixture was cooled and then filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and methanol (50:1). The obtained product was dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate solution (0.6 ml) to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)-4-(4-thiomorpholino-2-butynyl)piperazine dihydrochloride (300 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[S:19][C:18]([CH:20]=[O:21])=[CH:17][CH:16]=3)[CH:12]=[CH:11][CH:10]=2)[CH:3]=1.O.O1CCC[CH2:24]1>>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[S:19][C:18]([CH:20]([OH:21])[CH3:24])=[CH:17][CH:16]=3)[CH:12]=[CH:11][CH:10]=2)[CH:3]=1
Reactant: C1CCOC1
Reactant: Cc1ccnc(Nc2cccc(-c3ccc(C=O)s3)n2)c1
Solvent: O
Product: Cc1ccnc(Nc2cccc(-c3ccc(C(C)O)s3)n2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
3M-Methylmagnesium bromide ether solution (0.19 ml, 0.57 mmol) was added to a solution of 5-[6-(4-methylpyridin-2-ylamino)pyridin-2-yl]thiophene-2-carboaldehyde (70 mg, 0.24 mmol) in tetrahydrofuran (4 ml) cooled with ice, and after that the mixture was stirred at room temperature for 3 hours in an Ar stream. Water was added to the reaction solution and the solution was extracted with ethyl acetate and the organic layer was washed with a saturated brine and dried over anhydrous magnesium sulfate. Subsequently, the residue obtained by concentration in vacuo was washed with isopropyl ether, dried in vacuo and the title compound (46 mg, 62%) was obtained.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([Cl:17])[C:11]=2[Cl:18])=[N:2]1.Br[CH2:20][C:21]([O:23]CC)=[O:22].C([O-])([O-])=O.[K+].[K+].[OH-].[Na+].[Na]>CN(C)C=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:20][C:21]([OH:23])=[O:22])=[C:12]([Cl:17])[C:11]=2[Cl:18])=[N:2]1
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc(-c2nsc3ccccc23)c(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)COc1ccc(-c2nsc3ccccc23)c(Cl)c1Cl
Reaction time: 0.5 h

Procedure:
The phenol product was warmed at 50° for 30 minutes in 100 ml of dimethylformamide containing 2.90 ml of ethyl bromoacetate and 5.5 g of K2CO3. Twenty mililiters (20 ml) of 20% aqueous NaOH was then added to the mixture and warming was continued an additional 30 minutes with vigorous stirring. The product acid which was in the sodium salt formwas filtered off and washed with water, and then with ether. It was then distributed between 2-butanone and 5% HCl. The organic phase was withdrawn, dried and concentrated under reduced pressure. After recrystallization from acetone/H2O, 8.4 g of a pure product (84% from the methoxy compound), m.p. 224°-226° was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([N:22]=1)[C:18]1[CH:17]=[C:16](Br)[CH:15]=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([O:20][CH3:21])=[CH:9][CH:10]=1.[N:25]1[CH:30]=[C:29](B(O)O)[CH:28]=[N:27][CH:26]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>CCOC(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>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([N:22]=1)[C:6]1[CH:7]=[C:8]([O:20][CH3:21])[CH:9]=[CH:10][C:11]=1[O:12][C:13]1[C:18]2=[CH:17][C:16]([C:29]2[CH:30]=[N:25][CH:26]=[N:27][CH:28]=2)=[CH:15][CH:14]=1
Reactant: OB(O)c1cncnc1
Reactant: COc1ccc2c(c1)C1(N=C(N)N(C)C1=O)c1cc(Br)ccc1O2
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: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)C1(N=C(N)N(C)C1=O)c1cc(-c3cncnc3)ccc1O2
Temperature: 85 °C

Procedure:
A 15 ml resealable vial was charged with 2-amino-2′-bromo-7′-methoxy-1-methylspiro[imidazole-4,9′-xanthen]-5(1H)-one (87 mg, 224 μmol), pyrimidin-5-ylboronic acid (56 mg, 448 μmol) and tetrakis(triphenylphosphine)palladium(0) (26 mg, 22 μmol). DME (1 ml) was added to the mixture, and the vial was capped with argon. Sodium carbonate (2M aq. solution) (336 μl, 672 μmol) was added and the vial was sealed and heated at 85° C. for 16 hr. The heterogeneous mixture was cooled to RT, diluted with 5 ml EtOAc and 2 ml water, then filtered and the solids were washed with water (5 ml). The solids were redissolved in DCM/MeOH and dried with MgSO4, filtered and concentrated in vacuo to afford 2-amino-2′-methoxy-1-methyl-7′-(pyrimidin-5-yl)spiro[imidazole-4,9′-xanthen]-5(1H)-one as brownish solid.
Reaction SMILES: O1CCOCC1.[Cl:7][CH:8]1[C:13](Cl)([NH2:14])[CH:12]=[N:11][CH:10]=[N:9]1.[CH3:16][NH2:17]>O>[Cl:7][C:8]1[N:9]=[CH:10][N:11]=[C:12]([NH:17][CH3:16])[C:13]=1[NH2:14]
Reactant: CN
Reactant: NC1(Cl)C=NC=NC1Cl
Solvent: C1COCCO1
Solvent: O
Product: CNc1ncnc(Cl)c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
A 50 mL 3-necked flask fitted with a thermometer was charged with 1,4-dioxane (20 mL) and 4,5-dichloropyrimdine-5-amine (5.00 g, 30.5 mmol). The reaction mixture was then stirred for 30 minutes at room temperature to ensure complete dissolution of the 4,5-dichloropyrimidine-5-amine, after which a solution of methylamine in water (40% by weight, 120 mmol, 9.3 mL) was added over a period of 30 minutes by means of a pressure-equalized dropping funnel. Upon completion of addition, the dropping funnel was replaced with a reflux condenser. The stirred reaction mixture was then heated to 75° C. over a period of 40 minutes, and the progress was monitored by LCMS. The reaction was complete after 16 hours. The resulting mixture was then cooled to 50° C. and poured into 120 mL of ice and water (approximetely 1:1 by volume), which resulted in the rapid precipitation of a solid. The resulting suspension was then for a period of 2 hours. The precipitated solids were collected by vacuum filtration, washed with ice-cold water (20 mL) and dried on the filter to give 4.76 g (98.4% yield) of 6-chloro-N4-methylpyrimidine-4,5-diamine as a light yellow solid. This material was submitted to the next step without further purification. 1H-NMR (400 MHz, DMSO-d6): δ 7.73 (s, 1H), 6.87 (d, 1H), 4.94 (broad s, 2H), 2.86 (d, 3H). MS (EI) for C5H7ClN4: 159 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=[O:19])[CH:13]=1)[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl.O.C[Si](C)(C)[C:43]([F:46])([F:45])[F:44]>O1CCCC1>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]([OH:19])[C:43]([F:46])([F:45])[F:44])[CH:13]=1)[CH3:2]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CCOC(=O)c1cccnc1Oc1cccc(C=O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cccnc1Oc1cccc(C(O)C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(3-Formyl-phenoxy)-nicotinic acid ethyl ester (2.0 grams, 7.4 mmole) in 0.5 M trimethyl(trifluoromethyl)silane (18 ml) in tetrahydrofuran (20 ml) at 0° C. was added tetrabutyl ammonium fluoride (0.050 g). The mixture was stirred at 0° C. for 1 hour. To the mixture was added 1.0 N hydrochloric acid (10 ml) and stirred at room temperature for 30 minutes. The mixture was poured into 200 ml water and extracted with diethyl ether. The combined extracts were washed with saturated NaHCO3, and water, dried over magnesium sulfate and concentrated to give an oil which was purified via flash chromatography on silica using 60% ethyl acetate/hexane as eluent to give an oil (1.97 g). MW 341.31; MS (m/e) 341 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH2:13][OH:14])[CH:6]=[CH:5]2.C(N(CC)CC)C.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.C([O-])(O)=O.[Na+]>C(OCC)(=O)C.ClCCl>[CH3:32][C:22]1[CH:27]=[CH:26][C:25]([S:28]([O:14][CH2:13][CH2:12][C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=3)[N:8]=2)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCc1ccc2cc(Br)ccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCc2ccc3cc(Br)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 88.6 %

Procedure:
A 500 mL round bottom flask was charged with the product from Example 42B (7.65 g, 0.030 mole), 4-N,N-dimethylaminopyridine (0.36 g, 0.003 mole), dichloromethane (100 mL) and triethylamine (9.3 g, 0.092 mmol). p-Toluenesulfonyl chloride (11.5 g, 0.060 mole) was added in portions, and the solution was stirred at rt for 6 hours. The solution was stripped down to dryness, and the crude product was taken into ethyl acetate (150 mL) and 5% NaHCO3 aq. solution (150 mL). The upper organic was washed with water (150 mL), concentrated, azeotroped with ethyl acetate (250 mL×2) to a volume of ˜50 mL. The slurry was diluted with heptane (50 mL), stirred at room temperature overnight, and then at 5° C. for 8 hours. The precipitate was collected by filtration, rinsed with heptane (20 mL), dried at 50° C. under vacuum overnight to afford 10.80 g of the product as an off-white solid; mp 107-109° C.; MS (ESI): 406, 408 (M+H)+; 1H-NMR (CDCl3) δ 7.92 (1H, m), 7.91 (1H, m), 7.7 (2H, m), 7.58 (2H, m), 7.25 (1H, d, J=8.4 Hz), 7.09 (2H, m), 4.56 (2H, t, J=6.3 Hz), 3.27 (2H, t, J=6.3 Hz), 2.33 (3H, s); 13C-NMR (CDCl3) δ 157.2, 145.9, 144.1, 135.0, 132.5, 132.3, 130.3, 129.2, 129.2, 127.7, 127.4, 122.5, 119.6, 69.2, 38.0, 21.8.