Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:2]CC.[CH2:11]([O:13][C:14]1[CH:28]=[CH:27][C:17]([CH2:18][C:19]2[S:23][C:22]([C:24](Cl)=[O:25])=[CH:21][CH:20]=2)=[CH:16][CH:15]=1)[CH3:12]>>[CH2:9]([O:8][P:1]([C:24]([C:22]1[S:23][C:19]([CH2:18][C:17]2[CH:16]=[CH:15][C:14]([O:13][CH2:11][CH3:12])=[CH:28][CH:27]=2)=[CH:20][CH:21]=1)=[O:25])(=[O:2])[O:5][CH2:6][CH3:7])[CH3:10]
Reactant: CCOP(OCC)OCC
Reactant: CCOc1ccc(Cc2ccc(C(=O)Cl)s2)cc1
Product: CCOc1ccc(Cc2ccc(C(=O)P(=O)(OCC)OCC)s2)cc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
Triethyl phosphite (1.3 mL) was added to 5-(4-ethoxybenzyl)thiophen-2-carbonylchloride (1.10 g), and the mixture was stirred for 22 hr at room temperature. After evaporation, the residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=2/1) to give the title compound (0.54 g) as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:27])[NH:4][C:5]([CH:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)[CH3:9])=[N:6][CH:7]=1.I[CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[C:3]([O:27][CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)=[N:4][C:5]([CH:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)[CH3:9])=[N:6][CH:7]=1
Reactant: IC1CCCC1
Reactant: COc1ccc(S(=O)(=O)N2CCN(C(C)c3ncc(Br)c(=O)[nH]3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N2CCN(C(C)c3ncc(Br)c(OC4CCCC4)n3)CC2)cc1
Temperature: 90 °C

Procedure:
To a solution of 5-Bromo-2-{1-[4-(4-methoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl}-3H-pyrimidin-4-one(100 mg, 0.22 mmol) in 2 ml DMF was added iodo-cyclopentane (85.7 mg, 0.22 mmol) and potassium carbonate (152.0 mg, 1.1 mmol). This reaction was heated to 90° C. for 18 hours. After cooling down to room temperature, the K2CO3 was filtrated. Purification was accomplished by HPLC (Gilson-215, 0.035% TFA in acetonitrile and 0.05% water as mobile phase). The product was collected and dried under reduced pressure to give 5-bromo-4-cyclopentyloxy-2-{1-[4-(4-methoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl}-pyrimidine. (Yield 11.5 mg, 9.9%). 1H NMR (400 MHz, CDCl3): δ 1.30 (d, J=6.82 Hz, 3H), 1.64-1.51 (m, 2H), 1.82-1.67 (m, 4H), 1.96-1.82 (m, 2H), 2.65-2.52 (m, 4H), 3.00-2.85 (m, 4H), 3.67 (q, J=6.82 Hz, 1H), 3.78 (s, 3H), 5.41 (m, 1H), 6.90 (d, J=9.09, 2H), 7.59 (d, J=9.09, 2H), 8.39 (s, 1H). MS m/z calc. 525.2 found (ESI); 526.2 (M+1)+. Retention time 2.91 minutes.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[CH2:7]1[O:16][C:10]2([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[O:9][CH2:8]1.N1C=CC=CC=1>ClCCl>[CH2:7]1[O:16][C:10]2([CH2:15][CH2:14][N:13]([C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[CH2:12][CH2:11]2)[O:9][CH2:8]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: CCCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC(=O)N1CCC2(CC1)OCCO2
Temperature: 20 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
Butyryl chloride (0.53 g, 5 mmol) in dry dichloromethane (5 ml) was added dropwise with stirring to 4-piperidone ethylene ketal (0.72g, 5 mmol) and pyridine (0.5 ml) in dry dichloromethane (10 ml). The solution was stirred at 20° C. overnight then washed successively with dilute HCl, saturated sodium bicarbonate solution and water and dried (sodium sulphate). Evaporation of the solvent gave the product as a clear syrup (0.66 g). MS (+EI) 213 (M+), 1H NMR (CDCl3) 3.98 (4H, s), 3.70 (2H, t), 3.53 (2H, t), 2.33 (2H, t), 1.61-1.83 (6H, m), 0.97 (3H, t).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:15])[C:6]=1[NH:7][NH:8][C:9]([O:11][CH2:12][CH2:13][Cl:14])=[O:10].[CH3:16][O:17][CH2:18][C:19](Cl)=[O:20].Cl>C1(C)C=CC=CC=1>[CH3:16][O:17][CH2:18][C:19]([N:7]([C:6]1[C:5]([CH3:15])=[CH:4][S:3][C:2]=1[CH3:1])[NH:8][C:9]([O:11][CH2:12][CH2:13][Cl:14])=[O:10])=[O:20]
Reactant: COCC(=O)Cl
Reactant: Cc1csc(C)c1NNC(=O)OCCCl
Agent: Cl
Solvent: Cc1ccccc1
Product: COCC(=O)N(NC(=O)OCCCl)c1c(C)csc1C
Temperature: 25 °C

Procedure:
A solution of 24.85 g (0.1 mol) of 2-chloroethyl 2-(2,4-dimethylthien-3-yl)-hydrazinecarboxylate in 150 ml dry toluene is treated with 10.85 g (0.1 mol) methoxyacetylchloride, and the mixture is heated to 80° for 2 hours, vigorous HCl-formation starting at approx. 50° C. The mixture is cooled to room temperature, washed subsequently with water, 10% aqueous NaHCO3 -solution and water, dried over MgSO4 and evaporated in vacuo to yield the compound 2-chloroethyl 2-(methoxyacetyl)-2-(2,4-dimethylthien-3-yl)hydrazinecarboxylate, which may be directly reacted with NaOCH3 (see Step β).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.[F:11][C:12]1[CH:13]=[C:14]([CH2:19][CH2:20][NH2:21])[CH:15]=[CH:16][C:17]=1[F:18].C(=O)(O)[O-].[Na+].O>CCO>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH3:10])[N:3]=[C:2]([NH:21][CH2:20][CH2:19][C:14]2[CH:15]=[CH:16][C:17]([F:18])=[C:12]([F:11])[CH:13]=2)[CH:7]=1
Reactant: NCCc1ccc(F)c(F)c1
Reactant: COc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1nc(Cl)cc(NCCc2ccc(F)c(F)c2)n1
Yield: 93.9 %

Procedure:
A solution of 4,6-dichloro-2-methoxypyrimidine (0.7 g), 2-(3,4-difluoro-phenyl)-ethylamine (0.66 g) and sodiumbicarbonate (0.88 g) in EtOH (25 mL) is heated at 80° C. for three hours, poured into water (400 mL) and the solid is filtered and air dried to afford (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(3,4-difluoro-phenyl)-ethyl]-amine (1.1 g). MS: 312 (M+H); 1H NMR (300 MHz, CDCl3) □6.9-7 (3H, m); 6.05 (1H, s); 3.95 (3H, s); 3.6-3.7 (2H, m); 2.95 (2H, t).
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:23]=[CH:24][CH:25]=2)[C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[O:11])=[CH:4][CH:3]=1.[S-:28][C:29]#[N:30].[K+].BrBr>>[NH2:30][C:29]1[S:28][C:3]2[CH:4]=[C:5]([O:6][C:7]3[CH:8]=[C:9]([CH:23]=[CH:24][CH:25]=3)[C:10]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=3)=[O:11])[CH:26]=[CH:27][C:2]=2[N:1]=1
Reactant: N#C[S-]
Reactant: Nc1ccc(Oc2cccc(C(=O)Nc3cccc(C(F)(F)F)c3)c2)cc1
Agent: BrBr
Agent: [K+]
Product: Nc1nc2ccc(Oc3cccc(C(=O)Nc4cccc(C(F)(F)F)c4)c3)cc2s1
Yield: 79.3 %

Procedure:
Using 3-(4-aminophenoxy)-N-[3-(trifluoromethyl)phenyl]benzamide (2.45 g, 6.58 mmol), potassium thiocyanate (1.94 g, 20.0 mmol) and bromine (1.20 g, 7.50 mmol), and in the same manner as in Example A25(v), the title compound (2.24 g, 79%) was obtained as a pale-yellow powder.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][N:5]=[C:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:3]=1.[H][H]>[Pd].CO>[CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][N:5]=[C:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:3]=1
Reactant: [H][H]
Reactant: Cc1cc(-c2cccnc2)ncc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Cc1cc(-c2cccnc2)ncc1N
Yield: 82.1 %

Procedure:
A mixture of 4-methyl-5-nitro-2,3′-bipyridine (215 g, 1 mol), Pd/C (10 g, 10%) and MeOH (1000 mL) was stirred at room temperature for 16 h under 10 atm of hydrogen. After reaction, the mixture was filtered. The filtrate was evaporated at reduced pressure to afford 4-methyl-2,3′-bipyridin-5-amine as a yellow solid (152 g, 82%)
Reaction SMILES: CCN(CC)CC.[O:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10](=[O:18])[CH2:9]1.[CH:19]([C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1)=O>CC(OC(C)=O)=O>[O:18]=[C:10]1[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:8][CH:9]1[CH2:19][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1
Reactant: O=C1COc2ccccc2N1
Reactant: COC(=O)c1ccc(C=O)cc1
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CC2Oc3ccccc3NC2=O)cc1
Yield: 13.2 %

Procedure:
Et3N (3.18 ml, 22.8 mmol) was added to a stirring solution of 2-H-1,4-benzoxazin-3-(4H)one (2.50 g, 16.8 mmol) and methyl 4-formylbenzoate (4.59 g, 27.5 mmol) in Ac2O (20 ml). The reaction mixture was refluxed 16 h. After this mixture was cooled for 3 days, the solid was filtered and rinsed with ethyl acetate to afford the title compound 266 (657 mg, 13%) as a yellow solid. LRMS: 295.1 (Calc.). 296.0 (found).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[CH2:34]([N:41]1[CH2:46][CH2:45][O:44][CH:43]([CH2:47]Cl)[CH2:42]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CN(C)C=O>C(OCC)(=O)C>[CH2:34]([N:41]1[CH2:46][CH2:45][O:44][CH:43]([CH2:47][N:8]2[C:9](=[O:26])[C:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:14][CH:13]=3)=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:6]=[C:7]2[CH3:27])[CH2:42]1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: ClCC1CN(Cc2ccccc2)CCO1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(CC2CN(Cc3ccccc3)CCO2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.25 g), potassium carbonate (0.96 g), 4-benzyl-2-(chloromethyl)morpholine (0.87 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless viscous substance (0.62 g, 34%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][CH2:28][O:29][C:22]=3[CH:21]=2)[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][CH2:28][O:29][C:22]=4[CH:21]=3)[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccc4c(c3)OCCO4)c2c1C
Product: Cc1sc2nc(-n3cccn3)nc(NCc3ccc4c(c3)OCCO4)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-5,6-dimethyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5,6-dimethyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1.C(O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH2:13][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])[CH:3]=1
Reactant: COC(=O)c1cc(Cl)c(Cl)c(Cl)n1
Reactant: OCc1ccccc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: O=C(OCc1ccccc1)c1cc(Cl)c(Cl)c(Cl)n1
Temperature: 100 °C
Reaction time: 4 h
Yield: 97.9 %

Procedure:
A mixture of methyl 4,5,6-trichloropicolinate (25 g, 0.10 moles (mol)) and benzyl alcohol (100 g, 0.2 mol) in a 250 mL three-neck round bottom flask was heated under nitrogen at 100° C. Titanium isopropoxide (0.6 g, 0.02 mol) was added. After 4 h at 100° C., the nearly colorless solution was cooled and transferred to a 250 mL round bottom single neck flask. Excess benzyl alcohol was removed under vacuum to give a nearly white solid (31 g, 94%): mp 125-126.5° C.; 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H, pyridine H), 7.42 (m, 2H, phenyl), 7.31 (m, 3H, phenyl), 5.40 (s, 2H, CH2Ph); 13C{1H} NMR (101 MHz, CDCl3) δ 162.0 (CO2R), 150.4, 145.0, 144.9, 134.7, 133.1, 128.3 (phenyl CH), 125.4 (pyridine CH), 67.88 (CH2Ph).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:17][CH:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[C:11]([CH3:19])([CH3:18])[CH2:10]2)[C:5]([F:20])=[CH:4][N:3]=1.[CH3:21][C:22]1([CH3:37])[O:27][C:26]2[C:28](F)=[CH:29][C:30]([NH2:32])=[CH:31][C:25]=2[N:24]2[N:34]=[N:35][N:36]=[C:23]12.Cl>CC(O)C.O1CCOCC1>[CH3:21][C:22]1([CH3:37])[O:27][C:26]2[CH:28]=[CH:29][C:30]([NH:32][C:2]3[N:7]=[C:6]([NH:8][CH:9]4[CH2:17][CH:16]5[N:12]([CH2:13][CH2:14][CH2:15]5)[C:11]([CH3:19])([CH3:18])[CH2:10]4)[C:5]([F:20])=[CH:4][N:3]=3)=[CH:31][C:25]=2[N:24]2[N:34]=[N:35][N:36]=[C:23]12
Reactant: CC1(C)Oc2c(F)cc(N)cc2-n2nnnc21
Reactant: CC1(C)CC(Nc2nc(Cl)ncc2F)CC2CCCN21
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CC1(C)Oc2ccc(Nc3ncc(F)c(NC4CC5CCCN5C(C)(C)C4)n3)cc2-n2nnnc21
Temperature: 100 °C
Yield: 83.4 %

Procedure:
A solution of (R/S,S/R)—N-(2-chloro-5-fluoropyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amine (D1) (0.1 g, 0.3 mmol, single diastereomer) in 3 ml of iPrOH, 4,4-dimethyl-6-fluoro-4H-benzo[b]tetrazolo[1,5-d][1,4]oxazin-8-amine (0.093 g, 0.4 mmol) and 4N HCl in dioxane (0.1 ml) were added. The reaction mixture was heated to 100° C. in a sealed vial for 12 hours. LCMS analysis of the crude reaction mixture indicated the completion of the reaction. The crude product was purified by column chromatography to give 0.12 g (Yield=72%) of the product as a mixture of two enantiomers.
Reaction SMILES: [CH:1]1([CH2:7][C:8]2([OH:25])[CH2:13][CH2:12][N:11]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:28]N(C)P(N(C)C)(N(C)C)=O.CI>C1COCC1.OS([O-])(=O)=O.[Na+]>[CH:1]1([CH2:7][C:8]2([O:25][CH3:28])[CH2:13][CH2:12][N:11]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)c1ccc(N2CCC(O)(CC3CCCCC3)CC2)cc1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(N2CCC(CC3CCCCC3)(OC)CC2)cc1
Temperature: 50 °C

Procedure:
A solution of EXAMPLE 1F (380 mg) in THF (5 mL) was treated with NaH (96 mg, 60% dispersion in mineral oil), heated to 50° C. for 2 hours, and treated with hexamethylphosphoramide (1 mL) followed by MeI (1 mL). The reaction mixture was refluxed overnight, cooled to 0° C., and diluted with saturated aqueous NaHSO4 solution (10 mL). The resulting two-phase mixture was separated, the aqueous phase was extracted twice with ether, and the combined organic layers washed with water and brine. After drying over MgSO4, the mixture was concentrated in vacuo and purified by silica gel chromatography eluting with 15% ethyl acetate in hexanes.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]2)([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1.C([Li])(C)(C)C.CCCCC.[C:39](=[O:41])=[O:40].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[C:25]([O:24][C:22]([N:18]1[CH2:19][CH2:20][CH2:21][C@@H:16]([C@@:8]([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[C:39]([OH:41])=[O:40])([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH2:17]1)=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: O=C=O
Reactant: COCCCC[C@@](O)(c1cccc(Br)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: COCCCC[C@@](O)(c1cccc(C(=O)O)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 59 %

Procedure:
To a solution of (R)-tert-butyl 3-((S)-1-(3-bromophenyl)-1-hydroxy-5-methoxy-pentyl)piperidine-1-carboxylate (279.1 mg, 0.61 mmol) in THF (5 mL) at −70° C. was added t-butyllithium in pentane (1.7 M, 0.71 mL, 1.22 mmol) dropwise. When the addition was complete dried carbon dioxide was bubbled through the reaction system for 10 min, and completion of reaction was confirmed by LC-MS. The solution was warmed to rt, and sat'd aq Na2CO3 solution (5 mL) was added. The organic layer was separated, and washed once with 1 N NaOH (2 mL). The combined aqueous solutions were acidified with 1 N aq HCl and extracted with EtOAc (5×5 mL). The organic layer was dried over Na2SO4, and concentrated under vacuum to give 3-((S)-1-((R)-1-(tert-butoxycarbonyl)piperidin-3-yl)-1-hydroxy-5-methoxy-pentyl)benzoic acid (152.4 mg, 59%) as a white solid. MS m/z 422 (M+H+).
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([OH:24])=[C:14]([C:19]([O:21]CC)=O)[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1>>[CH2:1]([S:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([OH:24])=[C:14]([C:19]([NH:31][CH2:30][C:29]3[CH:32]=[CH:33][C:26]([Cl:25])=[CH:27][CH:28]=3)=[O:21])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2cc(SCc3ccccc3)ccc2c1O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2cc(SCc3ccccc3)ccc2c1O
Yield: 92.4 %

Procedure:
A mixture of 4.07 g of ethyl 7-(benzylsulfanyl)-4-hydroxy-3-quinolinecarboxylate from Preparation No. 29 and 8.5 g of 4-chlorobenzylamine is heated at 165° C. for 18 h, then cooled and partitioned between 1 N HCl and chloroform-methanol. The organic phase is dried (MgSO4) and concentrated under reduced pressure, and the residue flash chromatographed on silica using 2-5% methanol in dichloromethane to provide 4.82 g of the title compound.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[N:11]1([CH2:17][CH2:18][NH2:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(N(CC)CC)C>C(O)C>[N:11]1([CH2:17][CH2:18][NH:19][C:2]2[S:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Clc1nc2ccccc2s1
Reactant: NCCN1CCCCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: c1ccc2sc(NCCN3CCCCC3)nc2c1

Procedure:
2-Chlorobenzothiazole (10 mmol), 10 mmol of 2-piperidinoethanamine, and 30 mmol of triethylamine in 50 ml of dry ethanol were refluxed for 6 hours. The product was crystallized with hydrochloric acid in 2-propanol and recrystallized in methanol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH3:11])=[CH:4][CH:3]=1.C([Li])(C)(C)C.I[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20][CH:19]=1>C1COCC1.CCOCC.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>[CH2:8]([C:5]1[CH:6]=[CH:7][C:2]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20][CH:19]=2)=[CH:3][CH:4]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCc1ccc(Br)cc1
Reactant: CCOC(=O)CCc1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCc1ccc(-c2ccc(CCC(=O)OCC)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a stirred solution of 3.20 g (15.0 mmol) of 1-bromo-4-butylbenzene (Aldrich Chemical Company #33,576-2) at -78° C. under argon was added, dropwise over 30 min, 18.0 mL (30.6 mmol, 1.7M in pentane) of t-butyllithium solution. The resulting light yellow solution was warmed to 0° C. and stirred for 1 h. To this solution was added 3.4 g (25 mmol) of thrice-fused zinc chloride in 20 mL of THF. The resulting slurry was stirred for 30 min and then a solution of 2.0 g (6.5 mmol) of 4-iodobenzenepropanoic acid, ethyl ester (Example 43, Part B) and 0.4 g (0.35 mmol) of tetrakis(triphenylphosphine)palladium (0) in 5 mL of THF was added. The reaction was stirred for 16 h, diluted with ether and washed once with 10% citric acid. The organic phase was dried (MgSO4) and evaporated. Purification by flash chromatography on silica gel (5×20 cm column) eluted with 1:1 hexanes/dichloromethane gave title compound as a colorless oil, 1.79 g , 91% yield.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:20]O>O.C(OCC)(=O)C>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:20])=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(O)c2ccccc12
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(O)c2ccccc12
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To a solution of 4-hydroxy-1-naphthoic acid (2.18 g) in methanol (15 ml) was added sulfuric acid (1.0 ml), and the mixture was stirred at 70° C. for 3 hours. The solution was diluted with water and ethyl acetate. The organic layer was separated and washed with brine. The extract was dried over magnesium sulfate, filtrated and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with ethyl acetate and hexane to give methyl 4-hydroxy-1-naphthoate (1.64 g) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][C:10]2([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11]2)[CH:3]=1.[F:20][C:21]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[CH:25][C:22]=1[C:23]#[N:24].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[NH2:8][C:6]1[N:7]=[C:2]([C:27]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([F:20])[CH:28]=2)[CH:3]=[C:4]([NH:9][C:10]2([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11]2)[N:5]=1
Reactant: CC1(C)OB(c2ccc(C#N)c(F)c2)OC1(C)C
Reactant: Nc1nc(Cl)cc(NC2(Cc3ccccc3)CC2)n1
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: C1COCCO1
Product: N#Cc1ccc(-c2cc(NC3(Cc4ccccc4)CC3)nc(N)n2)cc1F
Temperature: 110 °C
Yield: 51.5 %

Procedure:
A mixture of 6-chloro-N4-[1-(phenylmethyl)cyclopropyl]-2,4-pyrimidinediamine (185 mg, 0.67 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (247 mg, 1 mmol), Pd(PPh3)4 (81 mg, 0.07 mmol) and Na2CO3 (178 mg, 1.68 mmol) in 1,4-dioxane (30 mL) and water (10 mL) was stirred and heated at 110° C. for 3.5 hours under nitrogen. Then the mixture was cooled to room temperature and concentrated. The resulting residue was portioned between EtOAc and water. The aqueous was extracted with EtOAc (2×50 mL), and the organics were dried (MgSO4), filtered, concentrated to dryness, and purified by SGC using a petroleum ether to 4:1 petroleum ether/EtOAc to 1:1 petroleum ether/EtOAc as eluent to afford the title compound (124 mg) as a brown oil solid. LC-MS (ES) m/z=360 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[C:5]3[N:6]([CH:20]=[CH:21][N:22]=3)[CH:7]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)[CH:9]=2)[CH2:3][CH2:2]1.[I:23]Cl>>[CH:1]1([C:4]2[C:5]3[N:6]([C:20]([I:23])=[CH:21][N:22]=3)[CH:7]=[C:8]([C:10]3[CH:11]=[CH:12][C:13]([C:16]([F:18])([F:17])[F:19])=[CH:14][CH:15]=3)[CH:9]=2)[CH2:2][CH2:3]1
Reactant: FC(F)(F)c1ccc(-c2cc(C3CC3)c3nccn3c2)cc1
Reactant: ClI
Product: FC(F)(F)c1ccc(-c2cc(C3CC3)c3ncc(I)n3c2)cc1
Yield: 99 %

Procedure:
Prepared from 8-cyclopropyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.25 step 4) (2.2 g, 7 mmol) and iodine monochloride as described in example C.20 step 3. Obtained the title compound as a grey solid (3.1 g, 99%). MS (ISP) 429.2 [(M+H)+].
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][N:12]=3)[C:8]([C:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=3)=[CH:9]2)=[O:23])=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CN1CC=C(c2c[nH]c3ncccc23)CC1
Product: CN1CC=C(c2cn(C(=O)c3ccc(F)cc3)c3ncccc23)CC1

Procedure:
(10.1 mg, 26%); from 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-7-azaindole (24.8 mg, 0.12 mmol) and 4-fluorobenzoyl chloride (28 μL, 0.24 mmol); HRMS-FAB+ for C20H18N3OF: calculated MH+: 336.15121. Found: 336.15100.