Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:42])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:28][CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:27])([F:26])[F:25])[CH:18]=2)[CH:6]=1.[OH-].[Na+]>CO>[C:36]1([CH:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:28][N:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:25])([F:26])[F:27])[CH:18]=2)[CH2:14][CH2:13][CH2:12][O:11][C:7]2[CH:6]=[C:5]([CH2:4][C:3]([OH:42])=[O:2])[CH:10]=[CH:9][CH:8]=2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: COC(=O)Cc1cccc(OCCCN(Cc2cccc(OC(F)(F)F)c2)CC(c2ccccc2)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1cccc(OCCCN(Cc2cccc(OC(F)(F)F)c2)CC(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
A solution of (3-{3-[(2,2-Diphenyl-ethyl)-(3-trifluoromethoxy-benzyl)-amino]-propoxy}-phenyl)-acetic acid methyl ester (4c). (0.58 g, 0.001 mol) in methanol (7.5 mL) was treated with 2N NaOH (5.0 ml) and the mixture stirred overnight at ambient temperature. After concentration to dryness, the residue was dissolved in EtOAc (25 mL) and water was added (10 mL), the solution acidified to pH 3 with concentrated hydrochloric acid, then extracted into EtOAc (3×20 mL). The combined organic extracts were dried over Na2SO4, and then concentrated in vacuo to provide the carboxylic acid as waxy oil (5c) 0.5 g in 89% yield. 1H NMR (CD3OD) δ 7.22 (m, 12H), 7.05 (d, 1H), 7.01 (d, 1H), 6.98 (s, 1H), 6.63 (d, 1H), 6.61 (s, 1H), 6.57 (d, 1H), 4.22 (t, 1H), 3.61 (s, 2H), 3.58 (t, 2H), 3.54 (s, 2H), 3.11 (d, 2H), 2.63 (t, 2H), 1.79 (t, 2H); 13C NMR (CD3OD) δ 175.7, 160.4, 150.4, 145.0, 143.9, 137.3, 130.6, 130.5, 130.2, 129.5, 129.2, 128.6, 127.3, 122.4, 120.9, 120.3, 116.5, 114.1, 66.3, 60.9, 59.6, 58.3, 51.6, 51.1, 42.2, 27.9. Anal. Calcd for C33H32F3NO4: C, 70.32; H, 5.72; N, 2.49; F, 10.11. Found: C, 70.05; H, 5.93; N, 2.58; F, 9.84.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:20]2[CH:29]=[CH:28][C:23]([C:24]([NH:26][NH2:27])=[O:25])=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.[C:30](O)(C(F)(F)F)=O>C(OC(OCC)OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[N:11][C:10]=2[C:20]2[CH:21]=[CH:22][C:23]([C:24]([NH:26][NH2:27])=[O:25])=[CH:28][CH:29]=2)=[CH:4][CH:3]=1.[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[N:11][C:10]=2[C:20]2[CH:21]=[CH:22][C:23]([C:24]3[O:25][CH:30]=[N:27][N:26]=3)=[CH:28][CH:29]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)C(F)(F)F
Agent: NNC(=O)c1ccc(-c2nc(-c3ccccc3)oc2Sc2ccc(Cl)cc2)cc1
Solvent: CCOC(OCC)OCC
Product: Clc1ccc(Sc2oc(-c3ccccc3)nc2-c2ccc(-c3nnco3)cc2)cc1
Temperature: 130 °C

Procedure:
4-{5-[(4-chlorophenyl)thio]-2-phenyl-1,3-oxazol-4-yl}benzohydrazide from Step C (33 mg, 0.077 mmol) was dissolved in 5 mL triethylorthoformate. A catalytic amount of TFA was added and the reaction was heated at 130° C. for 2 h. The volatiles were removed and the residue was purified by reverse phase HPLC to afford 12 mg (36% over 4 steps) of the title compound 2-(4-{5-[(4-chlorophenyl)thio]-2-phenyl-1,3oxazol-4-yl}phenyl)-1,3,4-oxadiazole. LCMS: m/z 432.1 (M+H)+. 1H NMR (500 MHz, CDCl3: δ 8.55 (1H, s), 8.40 (2H, d), 8.19 (4H, br), 7.55 (3H, br), 7.30 (4H, br).
Reaction SMILES: C[O-].[K+].[F:4][C:5]1[C:6]([O:34][C:35]2[N:39]([CH3:40])[N:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=2)=[N:7][C:8]([O:23][C:24]2[N:28]([CH3:29])[N:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[C:9]([F:22])[C:10]=1[O:11][C:12]1N(C)N=C(C(F)(F)F)C=1.O>CO>[CH3:40][N:39]1[C:35]([O:34][C:6]2[C:5]([F:4])=[C:10]([O:11][CH3:12])[C:9]([F:22])=[C:8]([O:23][C:24]3[N:28]([CH3:29])[N:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=3)[N:7]=2)=[CH:36][C:37]([C:41]([F:44])([F:42])[F:43])=[N:38]1
Reactant: Cn1nc(C(F)(F)F)cc1Oc1nc(Oc2cc(C(F)(F)F)nn2C)c(F)c(Oc2cc(C(F)(F)F)nn2C)c1F
Agent: C[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1c(F)c(Oc2cc(C(F)(F)F)nn2C)nc(Oc2cc(C(F)(F)F)nn2C)c1F
Reaction time: 0.5 h
Yield: 75 %

Procedure:
A 25% solution of potassium methylate in dry methanol (4.4 ml, 15 mmol) is added to a solution of 3,5-difluoro-2,4,6-tris (1-methyl-3-trifluoromethylpyrazol-5-yloxy)pyridine (9.1 g, 15 mmol; see (a) above) in dry methanol (50 ml). After 30 min at ambient temperature the reaction is stopped by adding 2 ml of water. The solvent is removed under reduced pressure and pentane/ethyl acetate (1/1 by volume) is added to the residue. After filtration through a bed of silica gel the filtrate is washed with a 2 N sodium hydroxide solution. After drying and filtration of the organic layer, the solvents are removed and the residue is washed with diisopropyl ether. One obtains colorless crystals (5.3 g 75% yield), m.p. 83° C.
Reaction SMILES: [CH3:1][C:2]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[CH:13][N:12]=1)([NH:4]C(=O)C(F)(F)F)[CH3:3].[OH-].[Na+]>CO.C(OCC)(=O)C>[NH2:4][C:2]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[CH:13][N:12]=1)([CH3:3])[CH3:1]
Reactant: CC(C)(NC(=O)C(F)(F)F)c1ncc2sccn12
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(N)c1ncc2sccn12
Temperature: 50 °C
Reaction time: 10 h
Yield: 0.1 %

Procedure:
To the solution of 1 g (3.6 mole) of 5-[1-methyl-1-[(trifluoroacetyl)amino]-ethyl]imidazo[5,1-b]thiazole in 3 ml of methanol was added 0.72 g (0.018 mole) of sodium hydroxide, and the mixture was stirred at 50° C. for 10 hours. The reaction mixture was concentrated, and the residue thus obtained was dissolved in 100 ml of ethyl acetate and washed twice with 100 ml of a saturated aqueous potassium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated to dryness to give 0.74 g of crude 5-(1-amino-1-methylethyl)imidazo[5,1-b]thiazole. The mixture of 0.74 g of the crude product, 3 ml of formic acid and 1.5 ml of acetic anhydride was stirred in the absence of solvents for 3 hours and treated in the same manner as in Preparation 15 (c) to give 0.63 g of the title compound. Yield 83%. NMR (CDCl3) δ: 1.74 (6H, s), 6.95 (1H, s), 7.11 (1H, d, J=4.8 Hz), 7.71 (1H, d, J=4.8 Hz), 8.01 (1H, s).
Reaction SMILES: CN(S(F)(F)[F:5])C.O[C:9]1([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25][C:24]3=[O:33])=[CH:19][C:18]=2[F:34])[CH:14]=[CH:13][S:12](=[O:16])(=[O:15])[CH2:11][CH2:10]1>C(Cl)Cl.C(OCC)(=O)C>[F:34][C:18]1[CH:19]=[C:20]([N:23]2[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25][C:24]2=[O:33])[CH:21]=[CH:22][C:17]=1[C:9]1([F:5])[CH:14]=[CH:13][S:12](=[O:16])(=[O:15])[CH2:11][CH2:10]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3(O)C=CS(=O)(=O)CC3)c(F)c2)C(=O)O1
Reactant: CN(C)S(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(C3(F)C=CS(=O)(=O)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C

Procedure:
(N,N-Dimethylamino)sulfur trifluoride (2.5 μL, 0.019 mmol) is added to a cooled (−78° C.) solution of the product of Example 12 (6.0 mg, 0.014 mmol) in DCM (0.75 mL). The solution is warmed slowly to room temperature over 4 hours and diluted with ethyl acetate. The organic solution is extracted with satd NaHCO3, H2O, brine and dried (Na2SO4). The crude product is purified by preparative TLC (7% MeOH-DCM) to provide the title compound as a mixture of diastereomers.
Reaction SMILES: C([O:3][C:4]([CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]3([CH:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)OCC[O:16]3)[CH:13]=2)[N:8]([CH2:25][CH3:26])[C:7]1=[O:27])=O)C.[NH2:28][C:29]1[CH:30]=[C:31]([CH:41]=[CH:42][CH:43]=1)[C:32]([NH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:33]>>[C:35]1([NH:34][C:32]([C:31]2[CH:30]=[C:29]([NH:28][C:4]([CH:6]3[C:14]4[C:9](=[CH:10][CH:11]=[C:12]([C:15]([CH:20]5[CH2:21][CH2:22][CH2:23][CH2:24]5)=[O:16])[CH:13]=4)[N:8]([CH2:25][CH3:26])[C:7]3=[O:27])=[O:3])[CH:43]=[CH:42][CH:41]=2)=[O:33])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Nc1cccc(C(=O)Nc2ccccc2)c1
Reactant: CCOC(=O)C1C(=O)N(CC)c2ccc(C3(C4CCCC4)OCCO3)cc21
Product: CCN1C(=O)C(C(=O)Nc2cccc(C(=O)Nc3ccccc3)c2)c2cc(C(=O)C3CCCC3)ccc21

Procedure:
Prepared as in Example 1 from 5-(2-cyclopentyl-[1,3]dioxolan-2-yl)-1-ethyl-2-oxo-2,3-dihydro-1H-indole-3-carboxylic acid ethyl ester and 3-amino-N-phenyl-benzamide. Purified by flash-chromatography (hexanes/acetone, 1:1) followed by trituration in ethyl acetate. mp 208-213° C.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[N:8][C:9](Cl)=[CH:10][CH:11]=2)[N:6]([C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)[C:5]1=[O:23])[CH:2]=[CH2:3].[NH3:24]>>[CH2:1]([N:4]1[C:12]2[C:7](=[N:8][C:9]([NH2:24])=[CH:10][CH:11]=2)[N:6]([C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)[C:5]1=[O:23])[CH:2]=[CH2:3]
Reactant: N
Reactant: C=CCn1c(=O)n(-c2ccc3c(c2)OCO3)c2nc(Cl)ccc21
Product: C=CCn1c(=O)n(-c2ccc3c(c2)OCO3)c2nc(N)ccc21

Procedure:
Heat a mixture of 2.5 g. of the imidazopyridin product of Step D and 25 ml. of liquid ammonia in a bomb at 150° C. for 3 hours. Remove the excess ammonia and crystallize the residue from dimethyl formide-water.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[CH:12]=[C:11]([NH:13][C:14]3[C:19](=[O:20])[NH:18][C:17]([C:21]([NH2:23])=[O:22])=[C:16]([CH3:24])[N:15]=3)[CH:10]=[CH:9][N:8]=2)=[O:5])[CH2:3][CH2:2]1.[C:25]1(=O)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>C(#N)C.[Fe](Cl)(Cl)Cl>[CH3:24][C:16]1[N:15]=[C:14]([NH:13][C:11]2[CH:10]=[CH:9][N:8]=[C:7]([NH:6][C:4]([CH:1]3[CH2:2][CH2:3]3)=[O:5])[CH:12]=2)[C:19](=[O:20])[N:18]2[C:25]3([CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[NH:23][C:21](=[O:22])[C:17]=12
Reactant: Cc1nc(Nc2ccnc(NC(=O)C3CC3)c2)c(=O)[nH]c1C(N)=O
Reactant: O=C1CCCCC1
Agent: Cl[Fe](Cl)Cl
Solvent: CC#N
Product: Cc1nc(Nc2ccnc(NC(=O)C3CC3)c2)c(=O)n2c1C(=O)NC21CCCCC1
Temperature: 80 °C
Yield: 13.4 %

Procedure:
5-((2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methyl-6-oxo-1,6-dihydropyrazine-2-carboxamide (8, 600 mg, 1.83 mmol) and cyclohexanone (538 mg, 5.48 mmol) were charged in acetonitrile in a 20 mL microwave vial. Iron(III) chloride (889 mg, 1.83 mmol) was added and heated the reaction mixture at 80° C. for 16 h. On completion of the reaction, solvent was removed under vacuum and purified the compound by silica gel (200-400 mesh) column chromatography eluting with 5% methanol in dichloromethane. Appropriate column fractions were concentrated under reduced pressure to afford N-(4-((8′-methyl-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyrazin]-6′-yl)amino)pyridin-2-yl)cyclopropanecarboxamide (10, 100 mg, crude) as light brown crude solid which was directly forwarded to next step. MS (ESI) m/z 409.43 [M+1]+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:12]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH2:22][CH2:23][OH:24])[CH:19]=4)[N:14]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=4)[C:13]=3[C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:9]=[CH:10][CH:11]=2)[CH2:3][CH2:2]1.[H-].[Na+].[CH2:41](I)[CH3:42]>CN(C)C=O>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:12]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH2:22][CH2:23][O:24][CH2:41][CH3:42])[CH:19]=4)[N:14]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=4)[C:13]=3[C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:9]=[CH:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(-c2cccc(OCC3CC3)c2)c2cc(OCCO)ccc2n1Cc1cccc(OC)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCCOc1ccc2c(c1)c(-c1cccc(OCC3CC3)c1)c(C(=O)OCC)n2Cc1cccc(OC)c1
Temperature: 0 °C
Yield: 49.6 %

Procedure:
A solution of ethyl 3-[3-(cyclopropylmethoxy)phenyl]-5-(2-hydroxyethoxy)-1-(3-methoxybenzyl)-1-H-indole-2-carboxylate (Example 223, 110 mg, 0.23 mmol) was added to a cooled (0° C.) and stirred suspension of sodium hydride (12 mg, 0.50 mmol) in N,N-dimethylformamide (5 mL). The cold bath was removed and the reaction was stirred for 1 h. Ethyl iodide (80 μL, 156 mg, 1.0 mmol) was added and the reaction was stirred for an additional hour. The reaction was quenched with methanol (1 mL) and then diluted with water (50 mL). The product was extracted with ethyl acetate (3×30 mL) and then the combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. Flash chromatography of the residue over silica gel using 4:1 hexane/ethyl acetate gave 62 mg (50%) of product. The product had: 1H NMR (300 MHz, acetone-D6) δ 7.42 (d, 1 H), 7.29-7.36 (m, 2 H), 7.14 (dd, 1 H), 6.94-7.02 (m, 4 H), 6.63-6.79 (m, 3 H), 5.78 (s, 2 H), 3.99-4.12 (m, 4 H), 3.86 (d, 2 H), 3.64-3.71 (m, 5 H), 3.48 (q, 2 H), 1.24-1.34 (m, 1 H), 1.11 (t, 3 H), 0.98 (t, 3 H), 0.54-0.64 (m, 2 H), 0.32-0.42 (m, 2 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19](=[O:27])(=[O:26])[N:18]=2)=[C:9]1[CH3:28])([CH3:4])([CH3:3])[CH3:2].[CH3:30][Mg+].[Br-]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:29])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2([CH3:30])[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19](=[O:27])(=[O:26])[NH:18]2)=[C:9]1[CH3:28])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Mg+]
Reactant: Cc1c(C2=NS(=O)(=O)c3ccccc32)c2ccccc2n1CC(=O)OC(C)(C)C
Agent: [Br-]
Solvent: Cc1ccccc1
Product: Cc1c(C2(C)NS(=O)(=O)c3ccccc32)c2ccccc2n1CC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
The product of example 3, step b) (1.0 g, 2.44 mmol) was dissolved in 40 mL toluene and cooled to 0° C. Me3AI (1.83 mL of 2 M solution in toluene) was slowly added and the reaction was stirred for 45 minutes at 0° C. MeMgBr (3.5 mL of 1.4 M solution) was added and the reaction was allowed to warn to rt. The reaction was quenched with saturated NH4Cl then partitioned between water and EtOAc. The organic layer was dried over MgSO4 and the crude product was purified by silica gel chromatography (EtOAc/Hex) to give 450 mg of the sub-title compound.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][NH:9][C:8]2=[O:17])(=[O:3])[CH3:2].[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O=S(Cl)Cl.CN(C=O)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][NH:9][C:8]2=[O:17])(=[O:3])[CH3:2].[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:3])[CH3:2]
Reactant: Nc1ccccc1
Agent: COc1cc2nc[nH]c(=O)c2cc1OC(C)=O
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COc1cc2ncnc(Nc3ccccc3)c2cc1OC(C)=O
Temperature: 100 °C
Reaction time: 3 h

Procedure:
6-Acetoxy-7-methoxy-quinazolin-4-one (RO0505111-000) was synthesized according to the literature procedure of Gibson, K. H. et al. Bioorganic & Medicinal Chemistry Letters, 1997, 7(21), 2723–2728. To a solution of 6-acetoxy-7-methoxy-quinazolin-4-one (RO0505111-000) (1.2 g, 5.13 mmol) in SOCl2 (30 mL) Aldrich) was added a few drops of DMF (0.1 mL). The reaction mixture was then heated with stirring at 100° C. for 3 hours. The solvents were evaporated and the residue was dried in vacuo. The residue was dissolved in 2-propanol (30 mL), then aniline (0.47 mL, 5.13 mmol) (Aldrich) was added. The reaction mixture was heated at 110° C. for 3 hours, then cooled to room temperature and filtered. The precipitate was collected and dried in vacuo to give 6-acetoxy-7-methoxy-4-phenylamino-quinazoline as a white solid. (Yield 1.0 g, 63%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[CH3:27][C@H:28]1[C:36]2[C:35]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[N:34][CH:33]=[N:32][C:31]=2[CH2:30][CH2:29]1.[C:43]([O:47][C:48]([NH:50][C:51]([CH3:65])([CH3:64])[CH2:52][CH:53]([C:57]1[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=1)[C:54](O)=[O:55])=[O:49])([CH3:46])([CH3:45])[CH3:44].CCN(C(C)C)C(C)C>C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+].CC(=O)OCC>[Cl:63][C:60]1[CH:59]=[CH:58][C:57]([C@H:53]([C:54]([N:40]2[CH2:41][CH2:42][N:37]([C:35]3[C:36]4[CH:28]([CH3:27])[CH2:29][CH2:30][C:31]=4[N:32]=[CH:33][N:34]=3)[CH2:38][CH2:39]2)=[O:55])[CH2:52][C:51]([NH:50][C:48](=[O:49])[O:47][C:43]([CH3:45])([CH3:44])[CH3:46])([CH3:65])[CH3:64])=[CH:62][CH:61]=1
Reactant: CC(C)(CC(C(=O)O)c1ccc(Cl)cc1)NC(=O)OC(C)(C)C
Reactant: C[C@@H]1CCc2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCc2ncnc(N3CCN(C(=O)[C@H](CC(C)(C)NC(=O)OC(C)(C)C)c4ccc(Cl)cc4)CC3)c21
Reaction time: 16 h
Yield: 94.4 %

Procedure:
HBTU (0.033 g, 0.086 mmol) was added to a solution of (R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine dihydrochloride (0.025 g, 0.086 mmol), 4-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)-4-methylpentanoic acid (0.029 g, 0.086 mmol), and DIEA (0.045 mL, 0.26 mmol) in DCM (1.2 mL). The reaction was shaken overnight (16 hours), after which it was diluted with 2M Na2CO3 and extracted with DCM. The extracts were dried (Na2SO4), filtered, and concentrated. The crude was flashed on Biotage 12S (ca. 100 mL 3:1 DCM:EA flushed to elute DIEA, then 1:3 DCM:EA eluted prod) to give (R)-tert-butyl 4-(4-chlorophenyl)-2-methyl-5-(4-(5-methyl-6,7-dihydro-5H-cyclopenta[d ]pyrimidin-4-yl)piperazin-1-yl)-5-oxopentan-2-ylcarbamate (0.044 g, 95% yield) as a residue. LCMS (APCI+) [M+H]− 542.2; Rt: 2.94 min.
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[CH:11]=[CH:10][N:9]=[CH:8][C:7]=3[N:6]([CH2:13][C:14]3[N:26]([CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[C:17]4=[N:18][CH:19]=[C:20]([C:22]([O:24]C)=[O:23])[CH:21]=[C:16]4[N:15]=3)[C:5]2=[O:32])[CH2:3][CH2:2]1.[OH-].[Li+].Cl>C1COCC1.O>[CH:1]1([N:4]2[C:12]3[CH:11]=[CH:10][N:9]=[CH:8][C:7]=3[N:6]([CH2:13][C:14]3[N:26]([CH2:27][CH2:28][CH:29]([CH3:30])[CH3:31])[C:17]4=[N:18][CH:19]=[C:20]([C:22]([OH:24])=[O:23])[CH:21]=[C:16]4[N:15]=3)[C:5]2=[O:32])[CH2:3][CH2:2]1
Reactant: COC(=O)c1cnc2c(c1)nc(Cn1c(=O)n(C3CC3)c3ccncc31)n2CCC(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CCn1c(Cn2c(=O)n(C3CC3)c3ccncc32)nc2cc(C(=O)O)cnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound 26 (0.84 g, 1.89 mmol) was dissolved in THF (15 mL) and lithium hydroxide (544 mg, 22.7 mmol) dissolved in water (10 mL) was added. The resulting mixture was stirred at room temperature overnight. The pH of the resulting mixture was adjusted to pH=4 by addition of a 1 M solution of hydrochloric acid. Then the mixture was extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated. The title compound 28 was isolated as a white powder (690 mg, 84%). m/z=421 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[CH2:16][C:17]([OH:19])=O)=[CH:7][CH:6]=[CH:5][N:4]=1.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH2:20]([NH:27][C:17](=[O:19])[CH2:16][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][N:10]1[CH2:9][C:8]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCc1ccccc1
Reactant: COc1ncccc1CN1CCCCC1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1ncccc1CN1CCCCC1CC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.0 g of 2-[1-[(2-Methoxy-3-pyridyl)methyl]-2-piperidyl]acetic acid, 0.41 ml of benzylamine, 950 mg of WSC and 260 mg of HOBt were suspended in DMF, followed by stirring at room temperature for 2 hours. Water was added thereto, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate. The drying agent was filtered off, the solvent was evaporated and the residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:1, subsequently 5:1), to give 500 mg of the title compound as white crystals.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15](Br)[CH:16]=1>COCCOC.C([O-])([O-])=O.[Na+].[Na+]>[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:16]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Brc1cncc(-c2ccccc2)c1
Temperature: 100 °C

Procedure:
Phenylboronic acid (0.618 g, 5.065 mmol) is stirred in a mixture of DME (20 ml) and 2M Na2CO3 for 20 minutes. 3,5-dibromopyridine (1.0 g, 4.221 mmol) is added followed by PdCl2(Ph3P)2 (0.296 g, 0.4221 mmol) and the mixture is heated to 100° C. overnight. The DME layer is removed and is diluted with EtOAc, washing with 5M HCl (2×20 ml) then back extracted with EtOAc (70 ml). The acidic aqueous phase is basified with 6M NaOH (50 ml) and extracted with DCM (3×100 ml). The combined organic extracts are dried over MgSO4, filtered and evaporated to an oil which is stirred in iso-hexanes (15 ml) and the resulting solid is removed washing with a further 10 ml of iso-hexanes. Concentration of the organics in vacuo affords the title compound as a white solid MH+[235.74].
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Cl[C:10]1[N:15]=[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]3)=[C:19]([O:29][CH3:30])[CH:18]=2)[CH:13]=[CH:12][CH:11]=1>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]4)=[C:19]([O:29][CH3:30])[CH:18]=3)[N:15]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(Nc2cccc(Cl)n2)ccc1-n1cnc(C)c1
Reactant: Nc1ccc(F)cc1
Product: COc1cc(Nc2cccc(Nc3ccc(F)cc3)n2)ccc1-n1cnc(C)c1

Procedure:
Prepared in analogy to example 62 from 4-fluoroaniline and (6-chloro-pyridin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine. The title compound was obtained as a colorless foam (Yield=17%). MS ISP (m/e): 390.4 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.02 (s, 1H), 8.83 (s, 1H), 7.64 (d, 1H), 7.60-7.50 (m, 2H), 7.45-7.35 (m, 2H), 7.24 (dxd, 1H), 7.15 (d, 1H), 7.07 (t, 1H), 7.02 (s, 1H), 6.24 (qa, 1H), 3.59 (s, 3H), 2.15 (s, 3H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[F:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:12]=1[C:13]([OH:15])=[O:14].O>ClCCl>[F:10][C:11]1[C:12]([C:13]([OH:15])=[O:14])=[C:16]([C:20]([F:21])([F:22])[F:23])[C:17]([N+:1]([O-:4])=[O:2])=[CH:18][CH:19]=1
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1c(F)cccc1C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: O=C(O)c1c(F)ccc([N+](=O)[O-])c1C(F)(F)F
Temperature: 0 °C

Procedure:
1.05 ml (23.3 mmol) of concentrated nitric acid (65%), which also was precooled to 0° C., is instilled in a solution of 17.5 ml of concentrated sulfuric acid and 2.5 g (12.0 mmol) of 2-fluoro-6-trifluoromethyl-benzoic acid, cooled to 0° C. It is allowed to stir for one more hour at 0° C. and then overnight at room temperature. It is then poured in a mixture of ice, water and dichloromethane, the organic phase is separated and the aqueous phase is extracted with dichloromethane. The organic solutions are combined, washed with saturated sodium chloride solution, dried on sodium sulfate and evaporated to dryness in a vacuum. The title compound is obtained in crystalline form.