Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:18])=[C:7]([C:13]([O:15]CC)=[O:14])[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[C:26]=2[OH:33])=[CH:21][CH:20]=1.[OH-].[Li+]>C1COCC1.O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:18])=[C:7]([C:13]([OH:15])=[O:14])[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[C:26]=2[OH:33])=[CH:23][CH:24]=1
Reactant: CCOC(=O)c1c(O)c2cc(-c3ccc(-c4cccc(OC)c4O)cc3)c(Cl)cc2[nH]c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(-c2ccc(-c3cc4c(O)c(C(=O)O)c(=O)[nH]c4cc3Cl)cc2)c1O
Temperature: 50 °C
Reaction time: 24 h
Yield: 17.7 %

Procedure:
To a suspension of ethyl 7-chloro-4-hydroxy-6-[2′-hydroxy-3′-(methyloxy)-4-biphenylyl]-2-oxo-1,2-dihydro-3-quinolinecarboxylate (Example 28) (150 mg, 0.322 mmol) in THF (4 mL) and water (2 mL) was added lithium hydroxide (100 mg, 2.4 mmol). The reaction mixture was stirred 48 h at 50° C. and 24 h at room temperature before being cooled down. The mixture was then evaporated, acidified with 1N HCl, filtered and dried. The resulting solid was triturated in hot acetonitrile, filtered and dried to give the title compound 7-chloro-4-hydroxy-6-[2′-hydroxy-3′-(methyloxy)-4-biphenylyl]-2-oxo-1,2-dihydro-3-quinolinecarboxylic acid (25 mg, 0.057 mmol, 17.7% yield) as cream solid. LCMS: (M−H)+=436; Rt=2.89 min. HRMS: calculated for C23H15ClNO6 (M−H)+: 436.0588. found: 436.0560.
Reaction SMILES: NC1SC2C[C@@H](N)CCC=2N=1.[CH2:12]([NH:15][C@H:16]1[CH2:25][CH2:24][C:19]2[N:20]=[C:21]([NH2:23])[S:22][C:18]=2[CH2:17]1)[CH2:13][CH3:14].NC1SC2CC(NCCC)CCC=2N=1>>[CH2:12]([NH:15][C@@H:16]1[CH2:25][CH2:24][C:19]2[N:20]=[C:21]([NH2:23])[S:22][C:18]=2[CH2:17]1)[CH2:13][CH3:14]
Reactant: CCCN[C@H]1CCc2nc(N)sc2C1
Agent: CCCNC1CCc2nc(N)sc2C1
Agent: Nc1nc2c(s1)C[C@@H](N)CC2
Product: CCCN[C@@H]1CCc2nc(N)sc2C1
Reaction time: 0.1 h

Procedure:
The products of purification processes were then analyzed by HPLC for chemical and chiral purity. FIG. 3A shows an exemplary HPLC trace starting material. In FIG. 4A, a large (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine peak can be observed at about 6 minutes and a much smaller (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine peak can be seen at about 9 minutes. The area of these peaks provides an estimated composition for the mixture which is shown in the table below the trace, and shows the mixture as containing about 90.2% (6R) and 8.8% (6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine. FIG. 3B shows an exemplary trace of the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole product following purification. In FIG. 3B, a large (6R)2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole peak is observed at about 6 minutes, and no (6S)2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole peak is observed. It is additionally of note that several other minor peaks are also reduced or eliminated in the product trace, and the table below the trace indicates that (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine makes up 99.9% of the product solution which is within the limits of analytical detectability. Results for each exemplary reaction are provided in Table 3:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]=[C:24]1[NH:29][C:28]2[CH:30]=[C:31]([CH:34]=O)[CH:32]=[CH:33][C:27]=2[S:26][CH2:25]1.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.CO>[CH3:21][O:20][C:17]1[CH:18]=[C:19]2[C:14]([N:13]=[CH:12][C:11](=[O:22])[N:10]2[CH2:9][CH2:8][N:5]2[CH2:4][CH2:3][CH:2]([NH:1][CH2:34][C:31]3[CH:32]=[CH:33][C:27]4[S:26][CH2:25][C:24](=[O:23])[NH:29][C:28]=4[CH:30]=3)[CH2:7][CH2:6]2)=[CH:15][CH:16]=1
Reactant: O=Cc1ccc2c(c1)NC(=O)CS2
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4ccc5c(c4)NC(=O)CS5)CC3)c2c1
Reaction time: 4 h
Yield: 18.9 %

Procedure:
To 3.0 mL of methanol solution containing 0.20 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one, 0.13 g of 3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carbaldehyde, 38 μL of acetic acid and 83 mg of sodium cyanoborohydride were added at room temperature and stirred at the same temperature for 4 hours. To the mixture, chloroform and aqueous saturated sodium hydrogen carbonate solution was added to be adjusted to pH 9.5, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=20 3], to give 60 mg of 6-(((1-(2-(7-methoxy-2-oxoquinoxaline-1-(2H)-yl)ethyl)piperidin-4-yl)amino)methyl)-2H-1,4-benzothiazine-3(4H)-one a pale yellow solid.
Reaction SMILES: [CH2:1]([C:4]1[C:13]([OH:14])=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(C)=O.C(OCC)C>[CH2:1]([C:4]1[C:13]([O:14][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)[CH:2]=[CH2:3]
Reactant: BrCc1ccccc1
Reactant: C=CCc1ccc2cccnc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: C=CCc1ccc2cccnc2c1OCc1ccccc1
Temperature: 25 °C
Yield: 72 %

Procedure:
To a stirring solution of 7-allylquinolin-8-ol (14.56 mmol, 1 eq.) in acetone (50 mL) in a round bottom flask equipped with a reflux condenser was added potassium carbonate (151.94 mmol, 10.44 eq.) followed by benzyl bromide (17.47 mmol, 1.2 eq.) and the resulting solution was stirred and heated to reflux for 20 h. Additional potassium carbonate (151.94 mmol, 10.44 eq.) was added followed by additional benzyl bromide (29.12 mmol, 2 eq.) and the resulting mixture was heated at reflux and stirred 2 h. The reaction mixture was then cooled to room temperature and diluted with 50 mL of diethyl ether. The resulting suspension was filtered and the filtrate concentrated to a yellow oil that was purified by column chromatography using 10% acetone/dichloromethane to give the product as a pale yellow oil (10.48 mmol, 72%). MS (ESI) m/z 276.2; HRMS: calcd for C19H17NO+H+, 276.13829; found (ESI-FTMS, [M+H]1+), 276.13828.
Reaction SMILES: [CH3:1][CH:2]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].ClS(O)(=O)=O.Cl.C[O-].[Na+]>C(Cl)(Cl)Cl>[CH3:1][CH:2]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH:8][OH:9]
Reactant: CCCCCC(C)CCCCCCO
Agent: C[O-]
Agent: Cl
Agent: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: CCCCCC(C)CCCCC=CO
Temperature: 27.5 °C

Procedure:
Into a dried 1L 3 neck round bottom flask fitted with a nitrogen inlet, dropping funnel, thermometer, mechanical stirring and nitrogen outlet is added chloroform (300 ml) and 7-methyldodecanol (100 g, 0.5 mol). Chlorosulfonic acid (60 g, 0.509 mol) is slowly added to the stirred mixture while maintaining 25-30° C. temperature with a ice bath. Once HCl evolution has stopped (1 hr.) slowly add sodium methoxide (25% in methanol) while keeping temperature at 25-30° C. until an aliquot at 5% concentration in water maintains a pH of 10.5. To the mixture is added hot ethanol (55° C., 2L). The mixture is vacuum filtered immediately. The filtrate is concentrated to a slurry on a rotary evaporator, cooled and then poured into 2L of ethyl ether. The mixture is chilled to 5° C., at which point crystallization occurs, and vacuum filtered. The crystals are dried in a vacuum oven at 50C for 3 hrs. to obtain a white solid (119 g, 92% active by cat SO3 titration).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[Cl:27][C:28]1[CH:29]=[C:30]([CH:34]([CH2:37][CH2:38][C:39]([F:42])([F:41])[F:40])[CH2:35]O)[CH:31]=[CH:32][CH:33]=1>ClCCl>[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]([CH2:35][I:25])[CH2:37][CH2:38][C:39]([F:42])([F:41])[F:40])[CH:29]=1
Reactant: OCC(CCC(F)(F)F)c1cccc(Cl)c1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)CCC(CI)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of triphenylphosphine (1.56 g, 6.0 mmol) and imidazole (0.41 g, 6.0 mmol) in dichloromethane (16 ml) under an argon atmosphere was added slowly iodine (1.51 g, 6.0 mmol) and 2-(3-chloro-phenyl)-5,5,5-trifluoro-pentan-1-ol (1.26 g, 5.0 mmol). The mixture was stirred for 2 hours at room temperature, then dichloromethane (50 ml) was added and mixture was extracted with saturated sodium thiosulfate solution (50 ml) and hydrochloric acid (1N, 25 ml). The organic layer was dried over MgSO4 and evaporated. The residue was suspended in ether and filtered to remove insoluble triphenylphosphine oxide. The ether was evaporated and the residue was purified by column chromatography (SiO2, heptane/EtOAc=9:1) to yield a light yellow liquid, (1.73 g, 96%); (EI): 235.0 ((M−I)+.).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](O)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4](C(=O)C2C=CC=CC=2)[CH2:3]1.[O:23]([CH2:30]CN1CCC(O)(C2C=CC=CC=2)C(C(=O)C2C=CC=CC=2)C1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[O:23]([CH2:30][CH2:1][N:2]1[CH2:7][CH2:6][C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CN1CCC(O)(c2ccccc2)C(C(=O)c2ccccc2)C1
Reactant: O=C(c1ccccc1)C1CN(CCOc2ccccc2)CCC1(O)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: c1ccc(OCCN2CCC(c3ccccc3)(c3ccccc3)CC2)cc1

Procedure:
When proceeding as described in Example 2 but replacing the corresponding 1-methyl-3-benzoyl-4-hydroxy-4-phenylpiperidine by 1 -(2-phenoxyethyl)-3-benzoyl-4-hydroxy-4-phenylpiperidine and reacting 20 g. thereof with benzene in the presence of anhydrous aluminum chloride, 13 g. of 1-(2-phenoxyethyl)-4,4-diphenylpiperidine are obtained. Its boiling point is 145° C./0.01 mm. Hg. The compound yields a fumaric acid salt melting at 199.5° C.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][C:4](O)=[O:5].C(Cl)(=O)C(Cl)=O.C(OC([N:22]1[C:26]2[N:27]=[CH:28][N:29]=[C:30]([N:31]3[CH2:38][C:35]4([CH2:37][CH2:36]4)[N:34]([S:39](=[O:43])(=[O:42])[NH:40][CH3:41])[CH2:33][CH2:32]3)[C:25]=2[CH:24]=[CH:23]1)=O)(C)(C)C.CCN(CC)CC>C(Cl)Cl.O.CN(C=O)C>[F:1][C:2]([F:8])([F:7])[CH2:3][C:4]([N:40]([CH3:41])[S:39]([N:34]1[C:35]2([CH2:37][CH2:36]2)[CH2:38][N:31]([C:30]2[C:25]3[CH:24]=[CH:23][NH:22][C:26]=3[N:27]=[CH:28][N:29]=2)[CH2:32][CH2:33]1)(=[O:42])=[O:43])=[O:5]
Reactant: O=C(O)CC(F)(F)F
Reactant: CNS(=O)(=O)N1CCN(c2ncnc3c2ccn3C(=O)OC(C)(C)C)CC12CC2
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C(=O)CC(F)(F)F)S(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3,3,3-trifluoropropanoic acid (0.24 mmol) was dissolved in dry DCM (0.5 mL) in a 4 mL vial, added oxalyl chloride (0.24 mmol) and a catalytic amount of DMF. Stirred at rt for 1 h and added to a mixture of intermediate 4 (0.05 mmol) and Et3N (0.47 mmol) in dry DCM (0.5 mL). Stirred at rt for 16 h. Reaction mixture filtered through a syringe filter, added TFA (1 mL) and stirred at rt for 15 min. Reaction mixture added H2O (5 mL) and extracted with DCM (3×5 mL). The organic phase was dried (Na2SO4), filtered, concentrated in vacuo and redissolved in DMSO (1 mL). The pure compound was obtained by standard preparative HPLC purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[Cl:13][C:14]1[CH:22]=[C:21]2[C:17]([C:18](=[O:24])[C:19](=[O:23])[NH:20]2)=[CH:16][CH:15]=1>O1CCCC1>[Cl:13][C:14]1[CH:22]=[C:21]2[C:17]([C:18]([C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=3)([OH:24])[C:19](=[O:23])[NH:20]2)=[CH:16][CH:15]=1
Reactant: COc1cc(OC)cc([Mg]Br)c1
Reactant: O=C1Nc2cc(Cl)ccc2C1=O
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C2(O)C(=O)Nc3cc(Cl)ccc32)c1
Temperature: -25 °C
Reaction time: 2 h

Procedure:
A solution of 3,5-dimethoxyphenyl magnesium bromide in tetrahydrofuran (1.0 M, 6.9 mmol) (Aldrich) was added dropwise with magnetic stirring to a suspension of 6-chloroisatin (0.5 g, 2.76 mmol) in tetrahydrofuran (14 mL) under argon with cooling in a −25° C. bath at such a rate that reaction temperature was kept below −10° C. Cooling bath was then removed and mixture was allowed to warm to room temperature. After stirring for an additional 2 hours, 15% aqueous ammonium chloride solution and water were added and mixture extracted with ethyl acetate. Ethyl acetate layers were then washed with water, brine, combined, dried (Na2SO4), filtered and concentrated. Residue was stirred in dichloromethane at room temperature for 15 minutes and filtered to give crude rac-6-chloro-3-(3,5-dimethoxy-phenyl)-3-hydroxy-1,3-dihydro-indol-2-one as an off-white powder. This was used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[N:29](CC3C=CC(OC)=CC=3)[N:28]=[CH:27][CH:26]=2)[N:4]=1)[CH3:2]>C(O)(C(F)(F)F)=O.[SiH](CC)(CC)CC>[NH:28]1[CH:27]=[CH:26][C:25]([CH2:24][N:5]2[C:6]3[C:11](=[C:10]([NH:12][C:13]([C:15]4[N:19]5[CH:20]=[CH:21][CH:22]=[CH:23][C:18]5=[N:17][CH:16]=4)=[O:14])[CH:9]=[CH:8][CH:7]=3)[C:3]([CH2:1][CH3:2])=[N:4]2)=[N:29]1
Reactant: CCc1nn(Cc2ccnn2Cc2ccc(OC)cc2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCc1nn(Cc2cc[nH]n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Temperature: 80 °C
Reaction time: 2 h
Yield: 64.6 %

Procedure:
To N-(3-ethyl-1-((1-(4-methoxybenzyl)-1H-pyrazol-5-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (400 mg, 0.791 mmol) was added in TFA (4 mL) and Et3SiH (2 mL). The mixture was heated at 80° C. for 3 hours, and then at 100° C. for an additional 2 hours. The reaction mixture was concentrated under reduced pressure to a residue. Purification by silica gel chromatography (EtOAc/hexanes 1:2) provided the product (197 mg).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([O:12][CH3:13])[CH:5]=1)=[O:3].[BH4-].[Na+].[Cl-].[NH4+]>CO>[CH3:13][O:12][C:6]1[CH:5]=[C:4]([CH:2]([OH:3])[CH3:1])[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=1
Reactant: COc1cc(OC)cc(C(C)=O)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: COc1cc(OC)cc(C(C)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 111.8 %

Procedure:
To a solution of 3,5-dimethoxyacetophenone (1 g; 5.5 mmol) in methanol (30 mL) is added sodium borohydride (315 mg; 8.3 mmol) in four portions over one hour. The reaction is stirred at room temperature overnight, neutralized with saturated ammonium chloride, and extracted with ethyl acetate. The organics are separated, washed with water, and dried over magnesium sulfate. The solvent is removed to give 1.12 grams of 1-(3,5-dimethoxyphenyl)-ethanol.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]2[N:9]([CH:10]=1)[C:8]1[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=1[S:6]2)[CH3:2].P(Cl)(Cl)(Cl)=O.[OH-].[NH4+].CN(C)[CH:24]=[O:25]>>[CH:24]([C:10]1[N:9]2[C:5]([S:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=32)=[N:4][C:3]=1[CH2:1][CH3:2])=[O:25]
Reactant: CN(C)C=O
Reactant: CCc1cn2c(n1)sc1ccccc12
Agent: [NH4+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1nc2sc3ccccc3n2c1C=O
Temperature: 50 °C

Procedure:
Subsequently, 4.3 g of 2-ethylimidazo[2,1-b]-benzothiazole was added to a solution prepared from 11 g of phosphorus oxychloride and 20 ml of dimethylformamide followed by heating at 50° C. for 2.5 hours. The reaction mixture was poured onto ice water. After neutralizing with ammonium hydroxide, the precipitated crystals were filtered to give 3.88 g of 3-formyl-2-ethylimidazo[2,1-b]benzothiazole.
Reaction SMILES: C(OC1C=[CH:13][C:12]([NH:15][C:16]2[N:21]=CN=[C:18]([O:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:42])[CH2:31][C:32](NC4C=CC(F)=CC=4)=O)=[CH:25][C:24]=3[F:43])[CH:17]=2)=CC=1)C1C=CC=CC=1.CCO[C:47]([CH3:49])=O.C([O-])(O)=O.[Na+]>ClCCCl>[NH2:21][C:16]1[CH:17]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:42])[C:31]3[CH:32]=[CH:12][N:15]=[C:16]([NH:21][C:47]4[CH:49]=[CH:25][C:24]([F:43])=[CH:23][CH:28]=4)[CH:17]=3)=[CH:25][C:24]=2[F:43])[CH:13]=[CH:12][N:15]=1
Reactant: O=C(CC(=O)Nc1ccc(Oc2cc(Nc3ccc(OCc4ccccc4)cc3)ncn2)c(F)c1)Nc1ccc(F)cc1
Reactant: CCOC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: Nc1cc(Oc2ccc(NC(=O)c3ccnc(Nc4ccc(F)cc4)c3)cc2F)ccn1
Reaction time: 8 h
Yield: 6.3 %

Procedure:
A solution of 4-(4-amino-2-fluorophenoxy)pyridine-2-amine (Compound B of Example 24, 450 mg, 2.1 mmol) in 1,2-dichloroethane (10 mL) was added slowly to a solution of acylchloride obtained above in 1,2-dichloroethane (10 mL) at ice bath temperature with stirring. The reaction mixture was allowed to stand at rt overnight. To the reaction mixture were added EtOAc (150 mL) and saturated aq. NaHCO3 solution (50 mL). The EtOAc layer was separated, dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative HPLC to obtain the title compound (69 mg, 6.3%) as a yellow solid (bis-TFA salt). 1H NMR (DMSO-d6) δ 10.90 (s, 1H), 9.32 (s, 1H), 8.27 (d, 1H, J=5.5 Hz), 7.92-7.07 (m, 11H), 6.68 (dd, 1H, J=7.1, 2.2 Hz), 6.10 (d, 1H, J=2.2 Hz); MS (ESI+) m/z 217.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[CH:18])[CH:12]=1>C1COCC1.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.[Cu]I>[Br:10][C:11]1[CH:12]=[C:13]([C:17]#[C:18][C:6]2[C:5]([F:9])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: C#Cc1cccc(Br)c1
Reactant: Fc1cnc(Cl)nc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: Fc1cnc(Cl)nc1C#Cc1cccc(Br)c1
Yield: 80.2 %

Procedure:
To an oven-dried flask under N2 was added 2,4-dichloro-5-fluoropyrimidine (1.66 g, 10 mmol), anhydrous, degassed THF (100 mL), dichlorobis(triphenyl-phosphine)palladium(II) (180 mg, 0.26 mmol), copper(I) iodide (29 mg, 0.15 mmol), and TEA (2.02 g, 20 mmol). After heating the reaction at 60° C. for 30 min, 1-bromo-3-ethynylbenzene (0.9 g, 5.0 mmol) was added dropwise as a solution in THF (25 mL) and the resulting mixture was allowed to heat overnight. The crude reaction mixture was adsorbed to silica gel and purified by column chromatography (2-10% EtOAc in hexanes) to afford the desired product (1.25 g, 78%) as an off white solid. ESIMS (M+H)+=311.
Reaction SMILES: [CH3:1][N:2]([O:11][CH3:12])[C:3]([C:5]1[O:6][C:7](Br)=[CH:8][CH:9]=1)=[O:4].B([O-])([O-])O[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C(CCO)=CC=CC=1.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>[CH3:1][N:2]([O:11][CH3:12])[C:3]([C:5]1[O:6][C:7]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:8][CH:9]=1)=[O:4]
Reactant: Cc1ccc(OB([O-])[O-])cc1
Reactant: CON(C)C(=O)c1ccc(Br)o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccccc1CCO
Agent: O=C([O-])[O-]
Solvent: O
Product: CON(C)C(=O)c1ccc(-c2ccc(C)cc2)o1
Temperature: 25 °C
Yield: 91.3 %

Procedure:
Under argon atmosphere, a solution of N-methyl-N-methoxy-5-bromofuran-2-carboxamide (2.77 g), 4-methylphenyl borate (1.93 g) and potassium carbonate (3.27 g) in toluene-ethanol-water (110-11-11 ml) was stirred at room temperature for 1 hour. To the reaction mixture was added tetrakistriphenylphosphinepalladium (0.41 g), and the mixture was refluxed for 20 hours and cooled to room temperature. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/hexane=1:5→1:2→1:1) to give N-methyl-N-methoxy-5-(4-methylphenyl)furan-2-carboxamide (2.65 g) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].[CH3:36][N:37]([CH3:48])[CH2:38][CH2:39][CH2:40][N:41]([CH3:47])[CH2:42][CH2:43][CH2:44][NH:45][CH3:46].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:45]([CH2:44][CH2:43][CH2:42][N:41]([CH2:40][CH2:39][CH2:38][N:37]([CH3:36])[CH3:48])[CH3:47])[CH3:46])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35]
Reactant: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Reactant: CNCCCN(C)CCCN(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(N(C)CCCN(C)CCCN(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 56.2 %

Procedure:
To a solution of 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide (20 mg, 0.04 mmol) in CH2Cl2 (1 mL) were added N-[3-(dimethylamino)propyl]N,N′-dimethyl-1,3-propanediamine (0.004 mL, 0.02 mmol) and triethylamine (0.05 mL, 0.36 mmol). The resultant solution was stirred at room temperature over night. The reaction mixture was concentrated. Separation via a HPLC followed by treatment with t-amino SPE cartridge then provided the title compound as a white solid (7 mg, 29%). LC-MS m/z 609 (M+H)+; 1H-NMR (MeOD) δ 1.29 (d, 6H), 1.95 (m, 4H), 2.33 (s, 3H), 2.75 (s, 3H), 2.78 (s, 3H), 2.92 (s, 3H), 3.17 (m, 6H), 3.50 (m, 2H), 4.15 (s, 2H), 4.23 (m, 1H), 7.19 (m, 2H), 7.48 (d, 1H), 7.55 (m, 1H), 7.71 (s, 1H), 7.86 (d, 1H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[O:21]=[S:17]1(=[O:20])[CH2:16][CH2:15][CH:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH2:19][CH2:18]1
Reactant: O=S1(=O)CCC(N2CCN(Cc3ccccc3)CC2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=S1(=O)CCC(N2CCNCC2)CC1

Procedure:
A suspension of 0.57 g (1.85 mmol) 1-benzyl-4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-piperazine and 300 mg 10% Pd/C in 30 mL MeOH was hydrogenated at 50° C. and 50 psi hydrogen pressure for 10 h. The catalyst was removed by suction filtering and the filtrate was concentrated by evaporation i. vac. The product was reacted further without purification.