Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([N:18]([CH2:26][C:27]#[N:28])[C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]1[OH:25])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:11]([N:18]([CH2:26][C:27]#[N:28])[C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C:20]1=[O:25])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: N#CCN(Cc1ccccc1)[C@@H]1CCCC[C@H]1O
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CCN(Cc1ccccc1)[C@@H]1CCCCC1=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To oxalyl chloride (1,842 ml, 3.68 mmol) in CH2Cl2 (12.300 ml) at −78° C. was added DMSO (0.523 ml, 7.37 mmol). The reaction mixture was stirred for 10 min and then {benzyl[(1R,2R)-2-hydroxycyclohexyl]amino}acetonitrile (2-1) (300 mg, 1.228 mmol) in 2 ml of CH2Cl2 was added. The reaction mixture was stirred at −78° C. for 1 hr before triethylamine (2.054 ml, 14.73 mmol) was added. The reaction mixture was stirred at −78° C. for 30 min and then warm gradually to 0° C. After another 30 min the reaction was quenched by H2O. The reaction mixture was diluted with aqueous potassium carbonate (saturated, 20 mL) and extracted with dichloromethane (3×30 mL). The combined organic fractions were washed with brine (saturated, 30 mL), dried, filtered. The organic phase was concentrated and the residue was diluted with dry THF, filtered with 0.25 uM filter and concentrated to give the title compound. LRMS m/z (M+H) Calcd:243.1. found: 243.3.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]4[N:30]=[C:31]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[C:32]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:39]1([C:31]2[C:32]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[C:20]3[N:19]=[C:18]([C:15]4[CH:16]=[CH:17][C:12]([C:8]5([NH2:7])[CH2:9][CH2:10][CH2:11]5)=[CH:13][CH:14]=4)[C:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:22][N:21]3[N:30]=2)[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(-c5ccccc5)c(-c5ccccc5)nn4cc3-c3ccccc3)cc2)CCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1(c2ccc(-c3nc4c(-c5ccccc5)c(-c5ccccc5)nn4cc3-c3ccccc3)cc2)CCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the solution of 9-5 (60 mg, 0.1 mmol) in 1 mL of DCM was added TFA (1 mL) and the mixture was stirred at room temperature for 3 h. The mixture was concentrated by evaporation and the residue was purified by prep.HPLC to give the product 9-6.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)[CH:9]=2)[CH:5]=[CH:4][N:3]=1.Cl.[CH3:23][O:24][CH:25]([CH3:28])[CH2:26][NH2:27].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[F:21][C:17]1[CH:16]=[C:15]([NH:14][C:10]2[CH:9]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:27][CH2:26][CH:25]([O:24][CH3:23])[CH3:28])[N:7]=3)[CH:13]=[CH:12][N:11]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: COC(C)CN
Reactant: Fc1cccc(Nc2cc(-c3ccnc(Cl)n3)ccn2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(C)CNc1nccc(-c2ccnc(Nc3cccc(F)c3)c2)n1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(2-chloro-4-pyrimidinyl)-N-(3-fluorophenyl)-2-pyridinamine (i.e., the product of Step C) (55 mg, 0.18 mmol) in toluene (3.0 mL) was added 2-methoxy-1-aminopropane hydrochloride (125 mg, 1.0 mmol) and potassium carbonate (200 mg, 1.5 mmol). The mixture was stirred at 100° C. for 2 h and then allowed to cool to room temperature. The mixture was partitioned with water and ethyl acetate and the water layer was decanted. The organic layer was washed with brine and passed through a Celite® containing drying tube. The solvent was evaporated, and the resulting residue was chromatographed using 5% to 60% ethyl acetate in hexanes as eluant to give an oil which solidified upon standing. This solid was suspended in hexanes, filtered and washed with hexanes to give 25 mg of the title compound as a yellow solid, m.p. 103-105° C.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[CH:8][C:6]=2[N:7]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[CH3:17][O:16][C:9]1[C:10]([O:14][CH3:15])=[C:11]([O:12][CH3:13])[C:5]2[S:4][C:3]([CH2:2][N:18]3[CH2:23][CH2:22][N:21]([CH2:2][C:3]4[S:4][C:5]5[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[CH:8][C:6]=5[N:7]=4)[CH2:20][CH2:19]3)=[N:7][C:6]=2[CH:8]=1
Reactant: C1CNCCN1
Reactant: COc1cc2nc(CCl)sc2c(OC)c1OC
Product: COc1cc2nc(CN3CCN(Cc4nc5cc(OC)c(OC)c(OC)c5s4)CC3)sc2c(OC)c1OC

Procedure:
2-Chloromethyl-5,6,7-trimethoxybenzothiazole (365 mg) and piperazine (58 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)=[O:11])[CH2:6][C@@H:5]1[CH3:25])([CH3:3])[CH3:2].[ClH:26]>>[ClH:26].[ClH:26].[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([CH:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)=[O:11])[CH2:6][C@@H:5]1[CH3:25])([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)C[C@@H]1C
Agent: Cl
Product: CC(C)N1CCN(C(=O)C2CCNCC2)C[C@@H]1C

Procedure:
(S)-1-Isopropyl-4-[1-(tert-butoxycarbonyl)-piperidine-4-carbonyl]-2-methyl-piperazine (D28)(3.8 g) was treated with HCl as described in Description 8 step 4 to give the title dihydrochloride (D29) as a white solid (2.5 g). LCMS electrospray (+ve) 254 (MH+).
Reaction SMILES: [O:1]([CH2:9][CH3:10])S(C(F)(F)F)(=O)=O.[C:11]1([C:17](C2C=CC=CC=2)(C2C=CC=CC=2)[N:18]2[CH:22]=[C:21](C(=O)C)[N:20]=[C:19]2[CH3:26])C=CC=CC=1>C(Cl)Cl>[CH2:17]([N:18]1[C:22]([C:9](=[O:1])[CH3:10])=[CH:21][N:20]=[C:19]1[CH3:26])[CH3:11]
Reactant: CC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(C)n1
Reactant: CCOS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CCn1c(C(C)=O)cnc1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.2 %

Procedure:
Ethyl triflate (11 ml, 83.2 mmol) was added dropwise over 15 minutes to a solution of 1-(triphenylmethyl)-2-methyl-4-acetylimidazole (Method 34; 23.4 g, 64 mmol) in DCM (300 ml) and the mixture stirred for 5 hours at ambient temperature. The solution was diluted with DCM (100 ml) and extracted with 1M aqueous citric acid solution (5×75 ml). The aqueous extracts were combined, basified with solid sodium hydrogen carbonate and the extracted with DCM (5×75 ml). The organic extracts were combined, dried and evaporated to give the title compound (8.59 g, 88%) as a pale yellow oil. NMR 1.32 (t, 3H), 2.41 (s, 6H), 4.29 (q, 2H), 7.68 (s, 1H); m/z 153.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:11]([OH:13])[CH3:12].[OH-].[K+]>>[CH2:11]([O:13][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1)[CH3:12]
Reactant: Clc1ncnc2[nH]ccc12
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Product: CCOc1ncnc2[nH]ccc12
Temperature: 120 °C
Yield: 66.9 %

Procedure:
4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (9, 300 mg, 1.95 mmol) is combined with 3.00 mL of ethanol (10, 51.4 mmol), then potassium hydroxide (0.226 g, 4.03 mmol) is added. The reaction is heated at 120° C. for 3 hours in a microwave, then extracted with ethyl acetate and aqueous saturated ammonium chloride. The organic layer is washed with brine, dried with magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is recrystallized from methanol to provide the desired compound (11, 213 mg). MS (ESI) [M+H+]+=164.9.
Reaction SMILES: [CH3:1][NH:2][C:3]([C@@H:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]1[C:14](=[O:29])[C@@H:15]([NH:18]C(OCC1C=CC=CC=1)=O)[CH2:16][CH3:17])=[O:4].C(O)(=O)C(O)=O>CO.[Pd]>[CH3:1][NH:2][C:3]([C@@H:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]1[C:14](=[O:29])[C@@H:15]([NH2:18])[CH2:16][CH3:17])=[O:4]
Reactant: CC[C@H](NC(=O)OCc1ccccc1)C(=O)N1c2ccccc2C[C@H]1C(=O)NC
Agent: [Pd]
Agent: O=C(O)C(=O)O
Solvent: CO
Product: CC[C@H](N)C(=O)N1c2ccccc2C[C@H]1C(=O)NC
Reaction time: 3 h

Procedure:
2.15 g (5.44 mmol) of the compound obtained in step d) are dissolved in 200 ml of methanol and 0.85 g of activated 10% palladium-on-charcoal (wet) is added. The reaction mixture is hydrogenated at 60 psi for 3 hours. The solution is filtered and 1.3 equivalents (0.64 g) of oxalic acid (7.07 mmol) are added and the solution is then concentrated under vacuum. Ethanol is added, followed by ether (1:50 ratio) and a crystallized product is obtained. After filtration and washing with diethyl ether, the solid is dried under vacuum for 24 hours over P2O5 at 35° C. The desired product is obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:19]([F:22])([F:21])[F:20])=[N:4][N:5]([CH3:18])[C:6]=1[C:7]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:8]=1[O:16][CH3:17].O.O.Cl[Sn]Cl>CCO>[Br:1][C:2]1[C:3]([C:19]([F:22])([F:20])[F:21])=[N:4][N:5]([CH3:18])[C:6]=1[C:7]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:8]=1[O:16][CH3:17]
Reactant: COc1ccc([N+](=O)[O-])cc1-c1c(Br)c(C(F)(F)F)nn1C
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: COc1ccc(N)cc1-c1c(Br)c(C(F)(F)F)nn1C
Yield: 85 %

Procedure:
To a stirred solution of 4-bromo-5-(2-methoxy-5-nitro-phenyl)-1-methyl-3-trifluoromethyl-1H-pyrazole (0.08 g, 0.20 mmol) in EtOH (0.7 mL) was added SnCl2.2H2O (0.18 g, 0.80 mmol, 4.0 eq.) and the mixture was stirred at reflux for 2 hours followed by the removal of EtOH under vacuum. The resulting solid was dissolved in EtOAc and 1N NaOH was added until the pH was adjusted to 6. The mixture was stirred overnight and filtered through celite. The aqueous phase was extracted with EtOAc (3×50 mL). The combined organic phase was dried over anhydrous MgSO4, filtered and evaporated to give 3-(4-bromo-2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.06 g, 0.17 mmol, 99% yield after two steps) as a white solid: LCMS m/z (%)=350 (M+H79Br, 95), 352 (M+H81Br, 100). 1H NMR (400 MHz, CDCl3) δ: 6.78 (dd, J=14.0, 6.0 Hz, 1H), 6.76 (dd, J=8.0, 4.0 Hz, 1H), 6.54 (d, J=4.0 Hz, 1H), 3.67 (s, 3H), 3.66 (s, 3H) 3.36 (broad s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]=[C:7]([CH:9]3[CH2:12][C:11](=C)[CH2:10]3)[S:8][C:4]=2[CH:3]=1.I([O-])(=O)(=O)=[O:17].[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[Br:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]=[C:7]([CH:9]3[CH2:12][C:11](=[O:17])[CH2:10]3)[S:8][C:4]=2[CH:3]=1
Reactant: C=C1CC(c2nc3ccc(Br)cc3s2)C1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CC(c2nc3ccc(Br)cc3s2)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 75.6 %

Procedure:
The product of Example 1B (931 mg, 3.33 mmole) and osmium tetraoxide (28 mg, cat.) were dissolved in 30 ml THF and 15 ml water. The solution was cooled to 0° C. Sodium periodate (1.5 g, 7.0 mmole) was added in small portions. The mixture was stirred at room temperature overnight. The solution was quenched with water, and extracted three times with dichloromethane. The combined organics were dried over sodium sulfate and concentrated to give the crude product, which was purified by chromatography (20% hexane in dichloromethane) to give the title compound (710 mg, 76%). 1H NMR (500 MHz, CDCl3) δ ppm 8.00 (d, J=1.87 Hz, 1H), 7.84 (d, J=8.74 Hz, 1H), 7.59 (dd, J=8.73, 1.87 Hz, 1H), 3.96-4.10 (m, 1H), 3.54-3.76 (m, 4H). MS: (M+H)+=281/283
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][C:20]([CH3:23])([OH:22])[CH3:21])[CH2:15][CH2:14]1)=[O:12])=[CH:5]2.[C:24](OC(=O)C)(=[O:26])[CH3:25].O>O1CCOCC1.C1COCC1>[OH:22][C:20]([CH3:23])([CH3:21])[CH2:19][CH:16]1[CH2:17][CH2:18][N:13]([C:11]([C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([NH:1][C:24](=[O:26])[CH3:25])=[CH:10][CH:9]=3)=[O:12])[CH2:14][CH2:15]1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(O)CC1CCN(C(=O)c2cc3cc(N)ccc3[nH]2)CC1
Solvent: C1COCCO1
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc2[nH]c(C(=O)N3CCC(CC(C)(C)O)CC3)cc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 105 mg of 1-{1-[(5-amino-1H-indol-2-yl)carbonyl]piperidin-4-yl}-2-methylpropan-2-ol in 2 mL of dioxane and 2 mL of THF was added 32 μL of acetic anhydride, followed by stirring at room temperature for 2 hours. Water was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography [chloroform:methanol=1:0-10:1], and then solidified using ethyl acetate-hexane to obtain 110 mg of N-(2-{[4-(2-hydroxy-2-methylpropyl)piperidin-1-yl]carbonyl}-1H-indol-5-yl) acetamide as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]1[CH2:6][C@@H:5]1[CH:7]1[CH2:12][CH2:11][N:10](C(OCC2C=CC=CC=2)=O)[CH2:9][CH2:8]1.[H][H]>CCOC(C)=O.CO.[Pd]>[NH:10]1[CH2:11][CH2:12][CH:7]([C@H:5]2[CH2:6][C@H:4]2[CH2:3][CH2:2][OH:1])[CH2:8][CH2:9]1
Reactant: O=C(OCc1ccccc1)N1CCC([C@H]2C[C@H]2CCO)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: OCC[C@@H]1C[C@@H]1C1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzyl 4-((1R,2S)-2-(2-hydroxyethyl)cyclopropyl)piperidine-1-carboxylate (10 g, 33 mmol) was dissolved in 100 mL of EtOAc/MeOH (1:1 v/v), to which was added 1 g of 5% Pd/C and apply hydrogen balloon. After stirring at rt for 1 h, the reaction mixture was filtered through Celite to give the product that was used in the next step without further purification. Rf was 0 @ 50% EtOAc in hexanes (blue spot on CAM stain).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[C:10]#[C:11][CH:12](OC(=O)C)[CH3:13].C(Cl)Cl.C1(C)C=CC(S(O)(=O)=[O:28])=CC=1>O>[C:10]([C:3]1[C:4]([CH3:9])([CH3:8])[CH2:5][CH:6]=[CH:7][C:2]=1[CH3:1])(=[O:28])/[CH:11]=[CH:12]/[CH3:13]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(=O)OC(C)C#CC1=C(C)C=CCC1(C)C
Solvent: O
Solvent: ClCCl
Product: C/C=C/C(=O)C1=C(C)C=CCC1(C)C
Yield: 60 %

Procedure:
In a 100 ml. three-necked flask fitted with a mechanical stirrer and a Dean-Stark water separator provided with a reflux condenser, a solution of 5 g. of 2,6,6-trimethyl-1-(3-acetoxy-but-1-ynyl)cyclohexa-1,3-diene in 70 ml. of methylene chloride is refluxed while stirring. Then 0.2 g. of p-toluenesulfonic acid is added and the reaction mixture is refluxed for an additional 4 to 5 hours. The reaction mixture is cooled and poured into 70 ml. of water. The organic layer is separated, subsequently washed with 10% sodium bicarbonate solution and water, and finally dried over sodium sulfate. Concentration yields 5 g. of a residue which gives on distillation 2.5 g. or 60% yield of 1-crotonoyl-2,6,6-trimethylcyclohexa-1,3-diene, b.p. 75°-80° C./0.1 mm., nD20 1.5150.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[N:5]=[CH:4][N:3]=1.[C:14](O)(=O)[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1>P(Cl)(Cl)(Cl)=O>[CH2:10]([N:9]([CH2:12][CH3:13])[C:6]1[N:5]=[CH:4][N:3]=[C:2]2[C:7]=1[NH:8][C:14]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)=[N:1]2)[CH3:11]
Reactant: CCN(CC)c1ncnc(N)c1N
Reactant: O=C(O)c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCN(CC)c1ncnc2nc(-c3ccncc3)[nH]c12
Yield: 45.9 %

Procedure:
A mixture obtained by grinding homogeneously 5 g of 4,5-diamino-6-diethylaminopyrimidine and 3.4 g of isonicotinic acid in a mortar is added to 110 ml of phosphorus oxychloride under stirring, and refluxed with heating for 3 hours. The reaction solution is concentrated and 180 ml of water is added to the residual oil. The resulting solution is neutralized with an ammonia solution and the precipitated crystals are filtered and washed with water. Recrystallization from ethanol gives 3.4 g of 6-diethylamino-8-(4-pyridyl)purine, melting at 260°-262° C.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:9][N:10]1[C:18]2[C:13](=[CH:14][C:15](B(O)O)=[CH:16][CH:17]=2)[CH:12]=[N:11]1.C([O-])([O-])=O.[K+].[K+]>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>[Cl:8][C:6]1[CH:7]=[C:2]([C:15]2[CH:14]=[C:13]3[C:18](=[CH:17][CH:16]=2)[N:10]([CH3:9])[N:11]=[CH:12]3)[N:3]=[N:4][CH:5]=1
Reactant: Cn1ncc2cc(B(O)O)ccc21
Reactant: Clc1cnnc(Cl)c1
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: [K+]
Product: Cn1ncc2cc(-c3cc(Cl)cnn3)ccc21
Temperature: 95 °C

Procedure:
3,5-dichloropyridazine (200 mg, 1.34 mmol), 1-methyl-1H-indazole-5-boronic acid (260 mg, 1.48 mmol), K2CO3 (556.6 mg, 4.03 mmol), and tetrakis(triphenylphosphine)palladium(0) (233, 0.20 mmol) were taken in a microwave vial, and the vial was vacuum pumped and flushed with argon three times. To this mixture was added degassed 1,4-dioxane (10 mL) and degassed water (2.5 mL). The reaction mixture was heated at 95° C. for 2 h then cooled to room temperature. The reaction mixture was filtered through Celite (ethyl acetate eluent) and concentrated. Purification by flash column chromatography on silica gel (hexanes/ethyl acetate eluent) provided the product. LCMS-ESI+: calc'd for C14H10ClN4: 245.1 (M+H+); Found: 245.2 (M+H+). 1H NMR (400 MHz, Chloroform-d) δ 9.15 (d, J=2.2 Hz, 1H), 8.44 (s, 1H), 8.21 (dd, J=8.8, 1.5 Hz, 1H), 8.11 (s, 1H), 7.97 (s, 1H), 7.56 (d, J=8.8 Hz, 1H), 4.14 (s, 3H).
Reaction SMILES: N1C=CC=CC=1.[C:7]([CH:15]([OH:29])[C@H:16]1[O:20][C@@H:19]([N:21]2[CH:28]=[CH:27][C:25](=O)[NH:24][C:22]2=[O:23])[CH2:18][CH2:17]1)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:31]>O>[C:7]([CH:15]([OH:29])[C@H:16]1[O:20][C@@H:19]([N:21]2[CH:28]=[CH:27][C:25](=[S:31])[NH:24][C:22]2=[O:23])[CH2:18][CH2:17]1)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C(c1ccccc1)C(O)[C@@H]1CC[C@H](n2ccc(=O)[nH]c2=O)O1
Solvent: c1ccncc1
Solvent: O
Product: O=C(c1ccccc1)C(O)[C@@H]1CC[C@H](n2ccc(=S)[nH]c2=O)O1
Yield: 157.8 %

Procedure:
Into 50 ml of pyridine were dissolved 3.16 g of 5'-benzoyl-2',3'-dideoxy-uridine and 0.22 g of distilled water. Then, after added 2.67 g of phosphorus pentasulfide at room temperature under stirring, the mixture was refluxed for 3 hours. After the completion of reaction, the solids deposited by allowing to cool were collected by filtration, which were washed with small amount of pyridine. The pyridine filtrate obtained was concentrated to dryness and the residue was extracted with chloroform to separate 3.15 g of 5'-benzoyl-2',3'-dideoxy-4-thio-uridine(yield: 95%).
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=1)[NH2:25].C(=O)([O-])O.[Na+]>C(O)(C)C>[Cl:21][C:22]1[CH:23]=[C:24]([NH:25][C:2]2[C:3]3[N:10]([CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:26]=[CH:27][C:28]=1[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=1
Reactant: CC(C)(C)OC(=O)NCCn1ccc2ncnc(Cl)c21
Reactant: Nc1ccc(Oc2cccc(Cl)c2)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(Cl)c4)c(Cl)c3)c21
Temperature: 80 °C
Reaction time: 15 h
Yield: 81.9 %

Procedure:
A mixture of tert-butyl 2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethylcarbamate (1.19 g), 3-chloro-4-(3-chlorophenoxy)aniline (1.22 g) and isopropyl alcohol (12.0 mL) was stirred at 80° C. for 15 hrs. Under ice-cooling, aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer washed with brine, and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (eluent:hexane/ethyl acetate=50/50→100/0), and washed with diisopropyl ether-hexane to give the title compound (1.69 g) as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:16][CH2:17][N:18]([C:25](=[O:26])[C:24]3[CH:28]=[CH:29][CH:30]=[C:22]([F:21])[CH:23]=3)[CH2:19][CH2:20]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCNCC1
Reactant: O=C(Cl)c1cccc(F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2cccc(F)c2)CC1
Reaction time: 2 h
Yield: 110 %

Procedure:
1-(5-Chloro-8-piperazin-1-ylquinolin-7-yl)ethanone (0.030 g, 0.10 mmol, from Example 47, Step 1) was combined with 3-fluorobenzoyl chloride (0.019 mL, 0.16 mmol) and triethylamine (0.043 mL, 0.31 mmol) in methylene chloride (1.0 mL) at room temperature and stirred for 2 hours. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give the desired product (45.3 mg). LCMS calculated for C22H20ClFN3O2 (M+H)+: m/z=412.1; Found: 412.1.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[CH:3]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)CO>C(O)(C)C.[Cu]I>[I:8][C:4]1[CH:3]=[C:2]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:7]=[CH:6][CH:5]=1
Reactant: C1COCCN1
Reactant: Ic1cccc(I)c1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: Ic1cccc(N2CCOCC2)c1
Temperature: 80 °C
Yield: 40.9 %

Procedure:
To a solution of 1,3-diiodobenzene (5.05 g, 15.3 mmol) in isopropanol (16 mL) under nitrogen was added morpholine (1.33 g, 1.33 mL, 15.3 mmol), potassium phosphate (6.50 g, 30.6 mmol), ethylene glycol (1.90 g, 1.70 mL, 30.6 mmol) and copper (I) iodide (146 mg, 0.765 mmol). The mixture was heated at 80° C. for 15 h, and then cooled to room temperature. The solids were removed by filtration and the solution was concentrated. The residue was purified by silica gel column chromatograghy eluted with EtOAc:hexanes (5 to 25% EtOAc) to give 4-(3-iodo-phenyl)-morpholine (1.81 g, 41%) as a colorless oil. MS (ES+): m/z=290.0; 1H NMR (CDCl3, 500 MHz): δ 3.15 (t, 4H), 3.85 (t, 4H), 6.87 (dd, 1H), 6.96-7.00 (m, 1H), 7.20 (d, 1H), 7.22-7.25 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:30])[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:30])[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)[N:24]=2)=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(-c2ccnc(Cl)n2)cc1
Product: CN1CCN(c2nccc(-c3ccc(C(=O)Nc4ccccc4NC(=O)OC(C)(C)C)cc3)n2)CC1
Yield: 70.2 %

Procedure:
Using an analogous procedure to that described in Method 41, the N-(2-t-butoxycarbonylaminophenyl)-4-(2-chloropyrimidin-4-yl)benzamide (Method 52, 59 mg, 0.14 mmol) was reacted with 1-methylpiperazine (77 mg, 0.69 mmol) and residue purified by flash chromatography eluting with methanol/dichloromethane (0-20%) to give the title compound (48 mg, 71%); Mass Spectrum: M+H+ 489.