Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1([C:13]2[CH:18]=[CH:17][C:16]([Sn](CCCC)(CCCC)CCCC)=[CH:15][CH:14]=2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)(=[O:3])[CH3:2].Br[C:33]1[N:34]=[C:35]([N:43]2[CH2:48][CH2:47][N:46]([CH2:49][CH3:50])[CH2:45][CH2:44]2)[C:36]2[C:41]([CH:42]=1)=[CH:40][CH:39]=[CH:38][CH:37]=2>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C.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>[CH2:49]([N:46]1[CH2:45][CH2:44][N:43]([C:35]2[C:36]3[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:42]=[C:33]([C:16]3[CH:15]=[CH:14][C:13]([C:7]4([CH2:6][CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH2:8][CH2:9][O:10][CH2:11][CH2:12]4)=[CH:18][CH:17]=3)[N:34]=2)[CH2:48][CH2:47]1)[CH3:50]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C2(CCOC(C)=O)CCOCC2)cc1
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: CCN1CCN(c2nc(-c3ccc(C4(CCOC(C)=O)CCOCC4)cc3)cc3ccccc23)CC1
Yield: 90.2 %

Procedure:
4-(2-Acetoxyethyl)-4-(4-tributylstannylphenyl)tetrahydropyran (2.20 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (0.83 g) were heated under reflux overnight in the presence of tetrakistriphenylphosphinepalladium(0) (0.12 g) in xylene in nitrogen atmosphere. After cooling, the reaction solution was diluted with ethyl acetate and filtered. The filtrate was extracted with 2N hydrochloric acid, and the resulting aqueous layer was washed with ethyl acetate, adjusted to pH 10 with a 8N aqueous solution of sodium hydroxide, and then extracted with ethyl acetate. The extract was washed with a 10% sodium carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, to give a mixture (1.14 g) of 1-(4-ethylpiperazin-1-yl)-3-{4-[4-(2-acetoxyethyl)tetrahydropyran-4-yl]phenyl}isoquinoline as a brown viscous oil and the starting material.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:13])[NH:5][C:6](=[O:12])[NH:7]2.[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)(O)[O-].[Na+]>COCCOC.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>[C:14]1([C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[C:4](=[O:13])[NH:5][C:6](=[O:12])[NH:7]3)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1ccccc1
Reactant: O=c1[nH]c(=O)c2c(Br)cccc2[nH]1
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
Product: O=c1[nH]c(=O)c2c(-c3ccccc3)cccc2[nH]1

Procedure:
See J. Med. Chem., 50(7):1675 (2007), 76759-011. To a mixture of 5-bromoquinazoline-2,4(1H,3H)-dione (900 mg, 3.73 mmol) and Pd(Ph3P)4 (216 mg, 0.187 mmol) in DME (90 mL) was added phenylboronic acid (683 mg, 5.60 mmol) followed by a solution of sodium bicarbonate (941 mg, 11.2 mmol) in water (30 mL) and the reaction heated at reflux for 40 h. At the conclusion of this period, the organic solvent was removed under reduced pressure. The resulting mixture was filtered and the solid washed with water. The solid was concentrated under reduced pressure from MeOH/DCM to remove the water to yield 5-phenylquinazoline-2,4(1H,3H)-dione as an off-white solid. The 5-phenylquinazoline-2,4(1H,3H)-dione (9.64 g, 40.4 mmol) was added to POCl3 (75 mL, 810 mmol) followed by PhN(CH3)2 (10.3 mL, 81.0 mmol). Upon completion of addition, the reaction mixture was heated to reflux (105° C.) where it was stirred for 2 hours. After this time, the reaction mixture was allowed to cool to ambient temperature. Once at the prescribed temperature, the reaction mixture was concentrated under reduced pressure, diluted with DCM and then quenched by the addition of cold 1M K3PO4 solution. The organic layer was separated and the aqueous layer was extracted twice with DCM. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to yield a residue. The residue was purified by ISCO chromatography (330 g column) using hexanes/EtOAc (0-25% over 20 min, flow rate 100 mL/min) to give 2,4-dichloro-5-phenylquinazoline (7.11 g, 63.9% yield) as a yellow solid. 1H NMR (400 MHz, chloroform-d) ppm 8.04 (1H, m) 7.96 (1H, m) 7.59 (1H, dd, J=7.28, 1.25 Hz) 7.45 (3H, dd, J=5.02, 1.76 Hz) 7.32 (2H, m).
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:8]=[C:9]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:10]([O:24][CH3:25])=[C:11]([NH:13][C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([OH:22])[CH:16]=2)[CH:12]=1)([CH3:6])([CH3:5])[CH3:4].[H][H].[Cl:33][C:34]1[CH:39]=[C:38](I)[CH:37]=[CH:36][N:35]=1>CN(C)C=O>[C:3]([C:7]1[CH:8]=[C:9]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:10]([O:24][CH3:25])=[C:11]([NH:13][C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([O:22][C:38]3[CH:37]=[CH:36][N:35]=[C:34]([Cl:33])[CH:39]=3)[CH:16]=2)[CH:12]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: Clc1cc(I)ccn1
Reactant: [H][H]
Reactant: COc1c(NC(=O)c2ccc(C)c(O)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c(NC(=O)c2ccc(C)c(Oc3ccnc(Cl)c3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 110 °C
Reaction time: 8 h

Procedure:
545 mg sodium hydride (60% in mineral oil) are added to 2.77 g N-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-3-hydroxy-4-methyl-benzamide in 15 ml N,N-dimethylformamide under an argon atmosphere and while cooling with an ice bath, and the reaction mixture is stirred at ambient temperature until no further hydrogen development can be detected. Then 1.63 g 2-chloro-4-iodopyridine are added, and the reaction mixture is stirred overnight at 110° C. After cooling to ambient temperature the solvent is distilled off using the rotary evaporator. The flask residue is taken up in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried on magnesium sulphate and evaporated down. The flask residue is chromatographed through a silica gel column with petroleum ether/ethyl acetate (80:20→30:70) as eluant. The product is stirred with diethyl ether, suction filtered and dried.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[C:12](Cl)(=[O:22])/[CH:13]=[CH:14]/[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(O)(=O)/C=C/CCCCCCC.S(Cl)(Cl)=O>O1CCCC1>[C:12]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:22])/[CH:13]=[CH:14]/[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: C1CCNC1
Reactant: CCCCCCC/C=C/C(=O)Cl
Agent: CCCCCCC/C=C/C(=O)O
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCCCCCC/C=C/C(=O)N1CCCC1
Yield: 62.7 %

Procedure:
A tetrahydrofuran solution (20 mL) of pyrrolidine (0.71 g, 0.01 mol) containing pyridine (0.79 g, 0.01 mol) was added to a tetrahydrofuran solution (20 mL) of (E)-2-decenoic acid chloride (1.9 g, 0.01 mol), synthesized using (E)-2-decenoic acid and thionyl chloride, and the mixture was heated under refluxing in a warm water bath for 3 hours. After distilling off excess tetrahydrofuran, water was added to a liquid reaction mixture, and the liquid mixture was extracted with ethyl acetate, and washed with water, and ethyl acetate was distilled off. The residue was purified with silica gel column chromatography (developing solvent:hexane:ethyl acetate=1:3), to give an intended compound (1.4 g) in the form of a colorless oily substance.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:17]([O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=O)[CH:18]([CH3:20])[CH3:19].C(OCC)(=O)C>O1CCCC1.O>[CH2:17]([O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1/[CH:24]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)COc1ccccc1C=O
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C/c1ccccc1OCC(C)C
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
0.92 g of 60% sodium hydride was suspended in 30 mL of tetrahydrofuran, to which 5.0 mL of ethyl diethylphosphonoacetate was added dropwise over 5 minutes at room temperature, and this mixture was stirred for 30 minutes at 40° C. Then, after 3.40 g of 2-isobutoxybenzaldehyde dissolved in 20 mL of tetrahydrofuran was added to the mixture dropwise over 20 minutes at room temperature, this mixture was stirred for one hour at the same temperature. The reaction mixture was added to a mixture of ethyl acetate and water, and the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=9:1] to yield 4.30 g of ethyl (E)-3-(2-isobutoxyphenyl)-2-propenoate as light yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[N:36]=C(C)O[N:33]=3)=[CH:28][CH:27]=2)[C:13]2[NH:14][C:15](=[O:24])[N:16]([C:18]3[N:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].O.[C:39]([OH:42])(=[O:41])[CH3:40]>CO.[Fe]>[C:39]([OH:42])(=[O:41])[CH3:40].[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]([NH2:36])=[NH:33])=[CH:30][CH:31]=2)[C:13]2[NH:14][C:15](=[O:24])[N:16]([C:18]3[N:19]=[CH:20][CH:21]=[CH:22][N:23]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)ccc1OC
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CCOc1cc(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)ccc1OC
Temperature: 60 °C
Reaction time: 14 h

Procedure:
To a solution of 70 mg of 5-{(3-ethoxy-4-methoxyphenyl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[1,2,4]triazol-3-one in 3 ml of a methanol:water:acetic acid=1:1:1 mixed solvent there was added 70 mg of iron powder, and the mixture was stirred at 60° C. for 14 hours under a nitrogen atmosphere. After filtering the reaction mixture, it was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid), to give 41 mg of the title compound.
Reaction SMILES: [C:1]([O:4]CC)(=[O:3])C.[C:7]([O-])(O)=O.[Na+:11].[CH3:12][O:13][C:14]([O:17][CH3:18])([CH3:16])[CH3:15]>>[CH3:15][C:14]1([CH3:16])[O:17][C:18]([CH3:7])([C:1]([O-:4])=[O:3])[CH2:12][O:13]1.[Na+:11]
Reactant: COC(C)(C)OC
Reactant: O=C([O-])O
Reactant: CCOC(C)=O
Agent: [Na+]
Product: CC1(C)OCC(C)(C(=O)[O-])O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92 %

Procedure:
In a 250 ml flask, equipped with a magnetic stirrer, 1.8 g of the diol (6C, R=menthyl) from the Step 2 of Example 4 (fast moving diastereomer) was dissolved in 50 ml of 2,2-dimethoxypropane at room temperature. Then, 100 mg of paratoluenesulfonic acid monohydrate was added, and the resulting mixture was stirred at room temperature for 18 hours. Then, 100 ml of ethyl acetate and 100 ml of saturated aqueous NaHCO3 were added. The aqueous phase was extracted with 100 ml of ethyl acetate. The combined organic layers were washed with 100 ml of brine, dried (Na2SO4) and concentrated at reduced pressure. The crude product was purified by column chromatography (Merck60 SiO2; eluens=ethyl acetate/heptane=1/4) to give the acetonide (8, R=menthyl) (1.855 g; 92%) as a colourless oil. 1H-NMR and 13C-NMR confirmed the structure
Reaction SMILES: FC(F)(F)[C:3]([O-:5])=[O:4].[CH:8]1([C@H:14]2[C:47](=[O:48])[N:46]3[CH2:49][C@@H:43]([CH2:44][C@H:45]3[C:50](=[O:67])[NH:51][C@:52]3([C:57](=[O:66])[NH:58][S:59]([C:62]4([CH3:65])[CH2:64][CH2:63]4)(=[O:61])=[O:60])[CH2:54][C@H:53]3[CH:55]=[CH2:56])[O:42][C:26]3=[N:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:33]=4[C:34]([O:35][CH:36]4[CH2:41][CH2:40][NH2+:39][CH2:38][CH2:37]4)=[C:25]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]3[CH2:68][C@H:18]3[O:17][C:16](=[O:69])[NH:15]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.Br[CH2:71][CH2:72][F:73]>>[CH:3]([O-:5])=[O:4].[CH:8]1([C@H:14]2[C:47](=[O:48])[N:46]3[CH2:49][C@@H:43]([CH2:44][C@H:45]3[C:50](=[O:67])[NH:51][C@:52]3([C:57](=[O:66])[NH:58][S:59]([C:62]4([CH3:65])[CH2:63][CH2:64]4)(=[O:61])=[O:60])[CH2:54][C@H:53]3[CH:55]=[CH2:56])[O:42][C:26]3=[N:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:33]=4[C:34]([O:35][CH:36]4[CH2:37][CH2:38][NH+:39]([CH2:71][CH2:72][F:73])[CH2:40][CH2:41]4)=[C:25]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]3[CH2:68][C@H:18]3[O:17][C:16](=[O:69])[NH:15]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCCC1)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1OC1CC[NH2+]CC1)O2)C(=O)NS(=O)(=O)C1(C)CC1
Reactant: O=C([O-])C(F)(F)F
Reactant: FCCBr
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCCC1)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1OC1CC[NH+](CCF)CC1)O2)C(=O)NS(=O)(=O)C1(C)CC1
Product: O=C[O-]

Procedure:
The product from Step 1, Example 236 was reacted with 1-bromo-2-fluoro ethane as described for the synthesis of Example 237 to give Example 272. LRMS m/z 921.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([CH3:39])([CH3:38])[C:3]([N:5]1[CH2:10][CH2:9][C:8]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)([CH2:11][CH2:12][N:13]2[CH:18]3[CH2:19][CH2:20][CH:14]2[CH2:15][CH:16]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH3:30])[CH2:17]3)[CH2:7][CH2:6]1)=[O:4].[Cl:40][CH:41]([Cl:45])[C:42](Cl)=[O:43].CCN(C(C)C)C(C)C>>[Cl:40][CH:41]([Cl:45])[C:42]([NH:1][C:2]([CH3:39])([CH3:38])[C:3]([N:5]1[CH2:10][CH2:9][C:8]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)([CH2:11][CH2:12][N:13]2[CH:18]3[CH2:19][CH2:20][CH:14]2[CH2:15][CH:16]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH3:30])[CH2:17]3)[CH2:7][CH2:6]1)=[O:4])=[O:43]
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)C(C)(C)N)CC1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)C(C)(C)NC(=O)C(Cl)Cl)CC1
Yield: 48.4 %

Procedure:
2,2-Dichloro-N-[2-(4-(3-fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidin-1-yl)-1,1-dimethyl-2-oxo-ethyl]-acetamide was obtained from treating 2-(4-(3-Fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidin-1-yl)-1,1-dimethyl-2-oxo-ethyl]-carbamic acid tert-butyl ester (0.610 g, 0.97 mmol) with HCl as outlined in the procedure for example 890 to form 2-Amino-1-(4-(3-fluoro-phenyl)-4-{2[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidin-1-yl)-2-methyl-propan-1-one (0.510 g, 99%). 2-Amino-1-(4-(3-fluoro-phenyl)-4-{2[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidin-1-yl)-2-methyl-propan-1-one (0.050 g, 0.09 mmol), Dichloro-acetyl chloride (0.013 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in example 890 to give the title compound, 2,2-Dichloro-N-[2-(4-(3-fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidin-1-yl)-1,1-dimethyl-2-oxo-ethyl]-acetamide (0.028 g, 48%) as an oil. ES-LCMS m/z 642 (M+1).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:38]2[N:47]=[CH:46][C:45]3[C:40](=[C:41]([F:52])[CH:42]=[C:43]([C:48]([CH3:51])([CH3:50])[CH3:49])[CH:44]=3)[C:39]2=[O:53])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][N:28]([CH:31]4[CH2:34][O:33][CH2:32]4)[CH2:27][C@@H:26]3[CH3:35])=[CH:21][N:20]=2)[C:15](=[O:36])[N:14]([CH3:37])[N:13]=1)(=O)C.[OH-].[Li+]>C1COCC1.C(O)(C)C.O>[C:48]([C:43]1[CH:44]=[C:45]2[C:40](=[C:41]([F:52])[CH:42]=1)[C:39](=[O:53])[N:38]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([N:25]5[CH2:30][CH2:29][N:28]([CH:31]6[CH2:34][O:33][CH2:32]6)[CH2:27][C@@H:26]5[CH3:35])=[CH:21][N:20]=4)[C:15](=[O:36])[N:14]([CH3:37])[N:13]=3)[CH:10]=[CH:9][N:8]=1)[N:47]=[CH:46]2)([CH3:50])([CH3:49])[CH3:51]
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C5COC5)C[C@@H]4C)cn3)c(=O)n(C)n2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)nn(C)c2=O)nc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
A mixture of 117d (110 mg, 0.15 mmol) and lithium hydroxide (65 mg, 1.5 mmol) in THF/i-propanol (5/3 mL) and water (2 mL) was stirred at 30° C. for 1 h. The mixture was evaporated under reduced pressure and the residue was extracted with ethyl acetate (2×20 mL). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 117 (100 mg, 95%) as a yellow solid. MS-ESI: [M+H]+ 682.4. 1H NMR (500 MHz, CDCl3) δ 8.73 (d, J=5.0 Hz, 1H), 8.60 (s, 1H), 8.33 (d, J=2.5 Hz, 1H), 8.24 (s, 1H), 8.07 (s, 1H), 7.65 (d, J=5.0 Hz, 1H), 7.56-7.51 (m, 2H), 7.34 (s, 1H), 6.96 (d, J=9.0 Hz, 1H), 4.73-4.55 (m, 5H), 3.92 (m, 4H), 3.73-3.74 (m, 1H), 3.55-3.53 (m, 1H), 3.16-3.15 (m, 2H), 2.64-2.39 (m, 4H), 1.44 (s, 9H), 1.09-1.07 (m, 3H).
Reaction SMILES: C(O)(=O)C.Cl[CH2:6][C:7]([C:9]1[CH:10]=[C:11]([OH:16])[C:12](=[CH:14][CH:15]=1)[OH:13])=[O:8]>O.C(O)C.[Zn]>[C:7]([C:9]1[CH:10]=[C:11]([OH:16])[C:12](=[CH:14][CH:15]=1)[OH:13])(=[O:8])[CH3:6]
Reactant: O=C(CCl)c1ccc(O)c(O)c1
Agent: [Zn]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(=O)c1ccc(O)c(O)c1
Reaction time: 2 h

Procedure:
400 ml of a mixture of 1:8 v/v glacial acetic acid in water was added in two portions to a stirred mixture of 35 g of 4-(chloroacetyl)catechol in 300 ml of ethanol. At 10-minute intervals, four 10 g portions of 90% zinc dust were added, the mixture being held below about 45° C. The mixture then was stirred for 2 hours at 30°-40° C. and allowed to stand over a weekend. The liquid phase was decanted and stripped to a quarter of its volume under reduced pressure. The residue was extracted with ether. The ether extract was washed with sodium bicarbonate solution. The solvent was evaporated. The solid residue was recrystallized from toluene to give 4-acetylcatechol (1A), mp: 118°-119° C.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[N:10][N:11]=[C:12]3[C:17]2[CH:18]=[N:19][CH:20]=[C:21]([CH:27]=2)[C:22]([O:24]CC)=[O:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-]>CCO.C1COCC1.O>[C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[N:10][N:11]=[C:12]3[C:17]2[CH:18]=[N:19][CH:20]=[C:21]([CH:27]=2)[C:22]([OH:24])=[O:23])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cncc(-c2nnc(NCc3ccccn3)c3c(-c4ccccc4)cccc23)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: O=C(O)c1cncc(-c2nnc(NCc3ccccn3)c3c(-c4ccccc4)cccc23)c1
Reaction time: 16 h
Yield: 13.3 %

Procedure:
To a solution of ethyl 5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)phthalazin-1-yl)nicotinate (0.120 g, 0.260 mmol) in EtOH (6 mL) and THF (6 mL) was added LiOH (0.0620 g, 2.60 mmol) in water (3 mL) at room temperature. The reaction mixture was stirred at the same temperature for 16 h. Then the reaction mixture was concentrated under reduced pressure and the resulting residue was diluted with water (5 mL). The reaction mixture was extracted with EtOAc and the aqueous layer was separated. The aqueous layer was acidified to pH 5 with citric acid and extracted with EtOAc. The organic extract was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by HPLC (Condition 13 as described in general methods) to afford 5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)phthalazin-1-yl)nicotinic acid (0.0150 g, 13.3%). LCMS (Condition 2): retention time 1.54 min, [M-1]=432.0. HPLC (Condition 25): retention time=5.86 min, purity 95.51%. 1H NMR (400 MHz, DMSO-d6) δ 4.66 (d, J=4.4 Hz, 2 H), 6.25 (dd, J=4.0 Hz, J=4.4 Hz, 1 H), 7.20-7.24 (m, 1 H), 7.28 (d, J=7.6 Hz, 1 H), 7.52-7.59 (m, 5 H), 7.68-7.73 (m, 2 H), 7.82 (dd, J=1.2 Hz, J=8.4 Hz, 1 H), 7.91 (dd, J=7.2 Hz, J=8.4 Hz, 1 H), 8.22-8.25 (m, 1 H), 8.35 (dd, J=1.6 Hz, J=2.0 Hz, 1 H), 8.74 (d, J=2.0 Hz, 1 H), 9.09 (d, J=1.6 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])[C:6]([CH2:12]Cl)=[N:7]2.[N:22]1[C:30]([NH2:31])=[C:29]2[C:25]([N:26]=[CH:27][NH:28]2)=[N:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:31][C:30]1[N:22]=[CH:23][N:24]=[C:25]2[C:29]=1[N:28]=[CH:27][N:26]2[CH2:12][C:6]1[N:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[C:4](=[O:21])[C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[Cl:1])[N:7]=1
Reactant: Nc1ncnc2nc[nH]c12
Reactant: Cc1ccccc1-n1c(CCl)nc2cccc(Cl)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccccc1-n1c(Cn2cnc3c(N)ncnc32)nc2cccc(Cl)c2c1=O
Yield: 38.6 %

Procedure:
Prepared according to Procedure C using 2j (200 mg, 0.626 mmol), adenine (93 mg, 0.689 mmol), K2CO3 (95 mg, 0.689 mmol), and DMF (3 mL). The crude product was chromatographed in MeOH/CH2Cl2 to provide 101 mg of an off-white solid (39%), mp 262.0-266.5° C. 1H NMR (DMSO-d6) δ: 8.08 (s, 1H); 8.07 (s, 1H); 7.70 (t, J=8.0 Hz, 1H); 7.58 (dd, J=0.6, 7.9 Hz, 1H); 7.43-7.57 (m, 4H); 7.36 (dd, J=0.7, 8.0 Hz, 1H); 7.26 (br s, 2H); 5.12 (d, J=18 Hz, 1H); 4.78 (d, J=18 Hz, 1H); 2.20 (s, 3H) 13C NMR (DMSO-d6) ppm: 158.7, 156.2, 152.9, 152.7, 150.0, 149.4, 142.1, 136.1, 135.1, 135.0, 133.2, 131.8, 130.3, 130.1, 128.9, 128.1, 127.2, 118.5, 117.9, 44.9, 17.4. MS (ES): m/z 418.1 (M+). Anal. calcd. for C21H16ClN7O.0.1H2O.0.05KCl: C, 59.57; H, 3.86; Cl, 8.79; N, 23.16. Found: C, 59.65; H, 3.80; Cl, 8.70; N, 22.80.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[C:19]([C:21]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[CH:24]=[C:23]([C:34]([F:37])([F:36])[F:35])[N:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:33][C:30]1[CH:29]=[CH:28][C:27]([C:25]2[CH:24]=[C:23]([C:34]([F:36])([F:37])[F:35])[N:22]=[C:21]([C:19]3[CH:18]=[CH:17][N:16]=[C:15]([C:11]4[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=4)[CH:20]=3)[N:26]=2)=[CH:32][CH:31]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.6 %

Procedure:
To a cooled and stirred solution of 3-{4-[4-(4-fluoro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonic acid tert-butylamide (0.38 g) in dichloromethane (5 ml) was added TFA (5 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N NaHCO3 solution (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by crystallization (ethyl acetate/heptane) yielded the title compound as a white solid (0.25 g, 78%). MS (ISP) 475.0 [(M+H)+]; mp 239.5° C.