Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:3]=12.[CH:18]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19]1.C(N(CC)CC)C>C(O)C>[CH:18]1([NH:23][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]3[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:3]=23)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1Cl
Reactant: NC1CCCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1cnc2c(cnn2CC)c1NC1CCCC1
Temperature: 80 °C
Yield: 121.7 %

Procedure:
Intermediate 1 (0.051 g) and cyclopentyl amine (0.019 g) were suspended in ethanol (2 ml) and triethylamine (0.14 ml) was added. The mixture was stirred under nitrogen and heated at 80° C. for 16 h. After cooling to room temperature, ethanol was removed by evaporation under a stream of nitrogen and the residue partitioned between DCM and water. The organic layer was loaded directly onto an SPE cartridge (silica, 5 g) and eluted sequentially with; (i) DCM, (ii) DCM:Et2O (2:1), (iii) DCM:Et2O (1:1), (iv) Et2O, (v) EtOAc and (vi) MeOH. Fractions containing desired material were combined and concentrated in vacuo to afford Intermediate 2 (0.074 g). LCMS showed MH+303; TRET=3.45 min
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH2:9][C:10](=[O:17])[CH2:11][C:12](=[O:16])[CH2:13][CH2:14][CH3:15])[CH:6]=[CH:7][CH:8]=1.CO[CH:22](OC)[N:23]([CH3:25])[CH3:24].Cl.CN>CO>[C:12]([C:11]1[C:10](=[O:17])[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:18])([F:19])[F:1])[CH:4]=2)=[CH:24][N:23]([CH3:25])[CH:22]=1)(=[O:16])[CH2:13][CH2:14][CH3:15]
Reactant: CCCC(=O)CC(=O)Cc1cccc(C(F)(F)F)c1
Reactant: COC(OC)N(C)C
Agent: CN
Agent: Cl
Solvent: CO
Product: CCCC(=O)c1cn(C)cc(-c2cccc(C(F)(F)F)c2)c1=O

Procedure:
A mixture of 1.6 g. of 1-(3-trifluoromethylphenyl)-2,4-heptanedione and 50 ml. of N,N-dimethylformamide dimethyl acetal was stirred for 3 hours at reflux temperature, and then at ambient temperature overnight. The mixture was evaporated under vacuum to obtain 2.3 g. of a thick dark oil, which was dissolved in 25 ml. of methanol. Five g. of methylamine hydrochloride was added, and the mixture was stirred under reflux for 2 hours and then at ambient temperature overnight. The mixture was then evaporated under vacuum, and the residue was partitioned between diethyl ether and water. The organic layer was dried over magnesium sulfate and evaporated under vacuum to obtain a thick brown oil, which was chromatographed on a 300 g. silica gel column with 2:3 ethyl acetate:dichloromethane. The product-containing fractions were combined, and the product crystallized from the solvent on standing. The product was collected and triturated under hexane to obtain 0.19 g. of the desired product, m.p. 93°-94°. Nmr analysis in DMSOd6 showed peaks at δ7.6-8.3 (m, 6H, aromatic); 3.9 (s, 3H, N--CH3); 3.0-3.2 (t, 2H, COCH2); 1.3-1.9 (m, 2H, CH2CH3); 0.8-1.1 (t, 3H, CH2CH3).
Reaction SMILES: [CH:1]([S:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:22][CH2:23][N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34].C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CC(=O)CC>[CH:1]([S:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:22][CH2:23][N:24]2[C:25](=[O:34])[C:26]3[C:27](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]2=[O:29])[CH2:17][CH2:16]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: c1ccc(C(SC2CCNCC2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCN1CCC(SC(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C

Procedure:
The mixture of 4-benzhydrylsulfanyl-piperidine (12 mg, 0.0423 mmol, 1.0 eq.), N-(2-bromoethyl)phthalimide (11 mg, 0.0423 mmol, 1.0 eq.), K2CO3 (9 mg, 0.0635 mmol, 1.5 eq.), and NaI (9 mg, 0.0600 mmol, 1.4 eq.) in 2-butanone (5 ml) was refluxed for 2-3 hours. The mixture was then cooled to room temperature. The solvent was removed and the resulted residue was dissolved in CHCl3 (25 ml). The solution was washed with water (3×5 ml), then dried over anhydrous Na2SO4. After removed all solvent, the crude product 2-[2-(4-benzhydrylsulfanyl-piperidin-1-yl)-ethyl]-isoindole-1,3-dione was yielded (15 mg).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[O:18][C:19]([CH3:22])=[N:20][N:21]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CCOC(C)=O.[Pd]>[CH3:22][C:19]1[O:18][C:17]([CH:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)=[N:21][N:20]=1
Reactant: Cc1nnc(C2CCN(C(=O)OCc3ccccc3)CC2)o1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1nnc(C2CCNCC2)o1
Yield: 100.4 %

Procedure:
A suspension of 100 mg (0.33 mmol) of 4-(5-methyl-[1,3,4]oxadiazol-2-yl)-piperidine-1-carboxylic acid benzyl ester in 5 ml EtOAc and 10 mg Pd/C 10% was hydrogenated (1 atm) for 1 h. The reaction was filtered (Celite) and evaporated to give 55.4 mg (99%) of the title compound as white solid. MS: 167.9 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:13]=[C:12]([OH:14])[NH:11][N:10]=1.[OH-].[Na+].Cl[CH:18]([F:20])[F:19]>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:13]=[C:12]([O:14][CH:18]([F:20])[F:19])[NH:11][N:10]=1
Reactant: Oc1cc(-c2ccc(Cl)cc2Cl)n[nH]1
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: FC(F)Oc1cc(-c2ccc(Cl)cc2Cl)n[nH]1
Reaction time: 6 h
Yield: 47.3 %

Procedure:
237 g of 3-(2,4-dichlorophenyl)-5-hydroxy-1H-pyrazol from Example 3.1 were initially charged in 2160 ml of dioxane. A solution of 84 g of sodium hydroxide in 250 ml of water was added, and the mixture was heated at reflux. With stirring, 620 g (7.17 mol, 6.9 eq.) of gaseous chlorodifluoromethane were introduced, and, during the addition, the pH was monitored continuously and when it approached the neutral range (pH 9) increased to pH 12 by addition of additional NaOH solution. After 6 h, the mixture was allowed to cool, 1.7 l of water were added and the mixture was extracted three times with in each case 500 ml of MTBE. The combined organic phases were washed with in each case 1500 ml of water and saturated sodium chloride solution, dried over Na2SO4, filtered and concentrated. The residue was suspended in 500 ml of cyclohexane and heated to reflux, and undissolved particles were filtered off. The residue was once more extracted with 200 ml of boiling cyclohexane. The combined filtrates were concentrated to obtain the title compound. This gave 136.7 g of 3-(2,4-dichlorophenyl)-5-difluoromethoxy-1H-pyrazole as a solid. (Yield 47.3%).
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[C:10]=1[NH2:11].[C:18]([NH:23][NH:24][C:25](Cl)=[O:26])([O:20][CH2:21][CH3:22])=[O:19]>C(OCC)(=O)C.C1(C)C=CC=CC=1>[F:8][C:9]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[C:10]=1[NH:11][C:25](=[O:26])[NH:24][NH:23][C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)NNC(=O)Cl
Reactant: Nc1c(F)cc(F)cc1F
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)NNC(=O)Nc1c(F)cc(F)cc1F

Procedure:
A toluene solution of 2,4,6-trifluoroaniline is reacted with 2-carbethoxyhydrazinecarbonyl chloride as described above in Example 1b, mp 177°-178° (ethyl acetate/toluene).
Reaction SMILES: Br[C:2]1[C:3](=[O:11])[NH:4][C:5](=[O:10])[NH:6][C:7]=1[CH2:8][CH3:9].[F-].[K+].[CH2:14]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:8]([C:7]1[NH:6][C:5](=[O:10])[NH:4][C:3](=[O:11])[C:2]=1[N:24]1[CH2:25][CH2:26][N:21]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:22][CH2:23]1)[CH3:9]
Reactant: CCc1[nH]c(=O)[nH]c(=O)c1Br
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: [F-]
Agent: [K+]
Product: CCc1[nH]c(=O)[nH]c(=O)c1N1CCN(Cc2ccccc2)CC1
Temperature: 140 °C

Procedure:
A mixture of 57.0 g (0.260 mole) of 5-bromo-6-ethyl-2,4(1H,3H)pyrimidinedione and 26.6 g (0.286 mole) of anhydrous potassium fluoride in 176 ml (1 mole) of 1-benzylpiperazine was heated under reflux at 140° C. for four hours and cooled. The reaction mixture was poured into 1000 ml of ice water. The solid was collected and washed with water. Recrystallization from N,N dimethylformamide and drying in vacuo at 59° C. for 16 hours gave the product as an off-white solid; mp 255°-256° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[CH2:12][CH2:11][CH2:10]2)(=O)=O.[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[Sn](CCCC)(CCCC)CCCC.[Cl-].[Li+].[Cl-].[F-].[NH4+]>CN(C)C=O.[Ag]=O.C(OCC)(=O)C>[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[CH2:12][CH2:11][CH2:10]2
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(F)cc1F
Reactant: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Agent: O=[Ag]
Agent: [Cl-]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1CCCc2cc(-c3ccc(F)cc3F)ccc21
Temperature: 120 °C
Reaction time: 1 h
Yield: 53.5 %

Procedure:
1.00 g (3.40 mmol) of 3,4-dihydro-6-trifluoromethylsulfonyloxy-1(2H) -naphthalenone was dissolved in 10 ml of N,N-dimethylformamide in an argon atmosphere, and 2.05 g (5.10 mmol) of 2,4-difluorophenyltributyltin, 0.43 g (11.0 mmol) of lithium chloride, 0.12 g (0.17 mmol) of bistriphenylphosphinepalladium chloride and 0.04 g (0.17 mmol) of silver oxide were added to the solution. The mixture was stirred at 120° C. for 1 hour. The reaction product was cooled to room temperature. Ethyl acetate and a 2M-ammonium fluoride aqueous solution were added thereto, followed by stirring the mixture at room temperature overnight. The precipitate was filtered through Celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica-gel column chromatography (eluent: a mixture of 3% ethyl acetate and hexane) to obtain 0.47 g of the above-mentioned compound (yield 54%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([NH2:11])=[C:4]([OH:12])[CH:3]=1.[C:13](Cl)(=O)[CH3:14].C(N(CC)CC)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[O:12][C:13]([CH3:14])=[N:11][C:5]2=[C:6]([C:7]([OH:9])=[O:8])[CH:10]=1
Reactant: Nc1c(O)cc(Br)cc1C(=O)O
Reactant: CC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: Cc1nc2c(C(=O)O)cc(Br)cc2o1
Temperature: 25 °C

Procedure:
To a solution of 5-bromo-3-hydroxyanthranilic acid (prepared as described in Eur. J. Med. Chem., 1999, 34, 729) (400 mg) in xylene (30 mL), were added acetyl chloride (135 μL), triethylamine (265 μL) and pyridinium p-toluenesulfonate (130 mg), and the mixture was heated at reflux for 8 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed sequentially with water and brine, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified on silica gel column chromatography to obtain the titled compound (471 mg).
Reaction SMILES: N[C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9](=[O:11])[CH2:10][C:4]=2[CH:3]=1.N([O-])=O.[Na+].[C-]#N.[K+].[C:25]([Cu])#[N:26]>Cl.O.CCOC(C)=O>[C:25]([C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9](=[O:11])[CH2:10][C:4]=2[CH:3]=1)#[N:26]
Reactant: Nc1ccc2c(c1)CC(=O)c1ccccc1S2
Reactant: N#C[Cu]
Agent: Cl
Agent: O=N[O-]
Agent: [C-]#N
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc2c(c1)CC(=O)c1ccccc1S2
Temperature: 50 °C

Procedure:
To a suspension of 2-amino-10-oxo-dibenzo[b,f]thiepine (1 g, 4.40 mmol) in 2N HCl (7.00 mL) at 0° C., was slowly added a solution of NaNO2 l (0.316 g, 4.60 mmol) in water (4.00 mL). A CuCN solution was prepared by heating KCN (1.30 g, 20.0 mmol) in water (5.0 mL) and adding CuSO4.5H2O (1.09 g, 4.40 mmol) solution in water (4.0 mL). Once cooled to room temperature the CuCN solution was slowly added to the diazonium salt mixture and heated to 50° C. for 1 hour. The reaction mixture was diluted with EtOAc and filtered through celite pad. The filtrate was washed with brine, dried (MgSO4) and concentrated to give an oil. The crude material was chromatographed (5%EtOAc/Hexane); yield 0.16 g (15%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24]>ClCCl>[CH2:23]([N:25]([CH2:26][CH3:27])[C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([F:11])=[C:2]([F:1])[CH:3]=1)[CH3:24]
Reactant: O=C(O)c1ccc(F)c(F)c1
Reactant: CCNCC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1ccc(F)c(F)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A flask is charged with 3,4-difluorobenzoic acid (2.40 g, 14.88 mmol) and dichloromethane (50 mL) is added. Upon complete dissolution, the mixture is cooled to 0° C. and DMF (0.022 g, 0.298 mmol) and oxalyl chloride (3.85 g, 29.75 mmol) are added. The cooling bath is removed. After 2 h, the mixture is concentrated, taken up in dichloromethane (50 mL) and diethylamine (5.50 g, 74.38 mmol) is added. After 30 min, dichloromethane (500 mL) is added and the mixture is washed with 1M aqueous HCl, saturated aqueous sodium bicarbonate and brine. The organic phase is dried over magnesium sulfate and concentrated in vacuo to afford N,N-diethyl-3,4-difluorobenzamide as a brown oil, which is redissolved in anhydrous THF (60 mL). A 2 neck-flask is charged with paraformaldehyde (2.40 g, 76.22 mmol) and connected via a small length of tubing to another two-neck flask fitted with a pipette using an appropriate adapter. The second flask is charged with THF (60 mL) and cooled to −78° C. The paraformaldehyde is cracked with a heatgun and bubbled into the cold THF through the pipette. A clear solution is formed. To the solution of N,N-diethyl-3,4-difluorobenzamide in THF, is added TMEDA (2.98 g, 25.41 mmol) and the flask is cooled to −78° C. sec-BuLi (1.4M in cyclohexane, 18.1 mL, 25.4 mmol) is added and after 30 min, the cold solution of formaldehyde is added via cannula. After 2 h, the cooling bath is removed. Upon reaching room temperature, the reaction is quenched with 1M aqueous sodium bisulfate. After dilution with ethyl acetate, the organic phase is washed with saturated aqueous sodium bicarbonate and brine. The organic phase is dried over magnesium sulfate and concentrated in vacuo. The residue is purified by silica gel flash chromatography (ethyl acetate-heptane, 3:7 to 2:3 to 1:1) to yield N,N-diethyl-3,4-difluoro-2-hydroxymethyl-benzamide as an orange oil; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.12 (t, J=7.1 Hz, 3 H), 1.28 (t, J=7.1 Hz, 3 H), 3.26 (q, J=7.1 Hz, 2 H), 3.58 (q, J=7.1 Hz, 2H), 4.62 (br. s., 2 H), 7.00 (ddd, J=8.4, 4.6, 1.6 Hz, 1 H), 7.09-7.19 (m, 1 H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[NH:25][C:12]2=[N:13][CH:14]=[C:15]([C:17]([NH:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[O:18])[CH:16]=[C:11]2[N:10]=1)(C)(C)C.Cl>O1CCOCC1>[NH2:7][CH2:8][C:9]1[NH:25][C:12]2=[N:13][CH:14]=[C:15]([C:17]([NH:19][CH2:20][C:21]([F:24])([F:22])[F:23])=[O:18])[CH:16]=[C:11]2[N:10]=1
Reactant: CC(C)(C)OC(=O)NCc1nc2cc(C(=O)NCC(F)(F)F)cnc2[nH]1
Agent: Cl
Solvent: C1COCCO1
Product: NCc1nc2cc(C(=O)NCC(F)(F)F)cnc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-butyl[(6-{[(2,2,2-trifluoroethyl)amino]carbonyl}-3H-imidazo[4,5-b]pyridin-2-yl)methyl]carbamate (0.657 g, 1.76 mmol) was treated with 4N HCl in dioxane (30 ml). The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure and co-evaporated with EtOAc twice to give title compound. This crude product was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7](/[N:8]=N/C2C=CC(C)=CC=2)=[C:6]([Cl:17])[N:5]=[C:4]([S:18][CH2:19][CH2:20][CH3:21])[N:3]=1>[Pt].C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([Cl:17])[N:5]=[C:4]([S:18][CH2:19][CH2:20][CH3:21])[N:3]=1
Reactant: CCCSc1nc(Cl)c(/N=N/c2ccc(C)cc2)c(Cl)n1
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CCCSc1nc(Cl)c(N)c(Cl)n1
Temperature: 20 °C
Yield: 90.8 %

Procedure:
The Pt/C catalyst (33.3 g, 10% w/w) was added to a reaction vessel that had been purged with nitrogen and maintained under an atmosphere of nitrogen. The solution of 4,6-dichloro-5-[(E)-2-(4-methylphenyl)diazenyl]-2-(propylsulfanyl)pyrimidine (150 g, 430.1 mmol) in ethyl acetate (3000 ml) was added to the reaction vessel containing the catalyst and agitation was initiated. The inner temperature was adjusted to 20° C., the nitrogen atmosphere was evacuated, and the vessel was pressurized with 3 bar of hydrogen (hydrogen pressure of 3 bar was maintained throughout the reaction). The temperature was maintained at 20° C. for about 30 minutes and then it was increased to 40° C. and maintained for 150 minutes. When the reaction was complete (full conversion) the reaction solution was cooled to 20° C. and the catalyst filtered off under a nitrogen atmosphere. The catalyst was washed with ethyl acetate (300 ml) and the filtered wash-solution was combined with the filtered reaction solution. The ethyl acetate solution was concentrated to 5 ml (ethyl acetate)/g (amine) under vacuum at a maximum temperature of 40° C. The resulting solution was extracted twice with aqueous hydrochloric acid (about 3M; 700 ml and 375 ml) until a pH of 1.5-2 was obtained. The concentration of the ethyl acetate layer, under vacuum, yielded about 93 g of the 4,6-dichloro-2-(propylthio)pyrimidin-5-amine as a yellow oil.
Reaction SMILES: [CH:1]([N:4]([CH:25]([CH3:27])[CH3:26])[CH2:5][CH2:6][C:7]([C:17]1[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[C:8]([NH2:10])=[O:9])([CH3:3])[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[CH:25]([N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6][C:7]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[C:8]([NH2:10])=[O:9])([CH3:27])[CH3:26]
Reactant: COc1ccc(C(CCN(C(C)C)C(C)C)(C(N)=O)c2ccccn2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)N(CCC(C(N)=O)(c1ccc(O)cc1)c1ccccn1)C(C)C
Temperature: 25 °C

Procedure:
A solution of 7.32 grams (g) [0.02 moles (mol)] of α-[2-(diisopropylamino)ethyl]-α-(4-methoxyphenyl)-2-pyridineacetamide [Karim, supra] in 250 milliliters (mL) of methylene chloride (CH2Cl2) was cooled to -78° C. while stirring under an inert atmosphere. To this was added dropwise 19.85 g (0.08 mol) of boron tribromide dissolved in 50 mL of CH2Cl2. The resulting brown suspension was allowed to warm to room temperature, then was heated at reflux for 1 hour. It was cooled to -10° C., and excess boron tribromide destroyed by the addition of 150 mL of 10% sodium hydroxide (NaOH) solution. The organic phase was separated and extracted with n-butanol. Evaporation left a residue which was purified by chromatography on silica gel eluting with 60:10:1 (v/v/v) CHCl3 :MeOH:conc. ammonium hydroxide. This gave 4.8 g of the phenol as a pale tan solid. A sample was recrystallized from toluene to give a solid, mp 148°-151° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH3:11])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].Cl[C:13]1[N:18]=[CH:17][C:16]([B:19]([OH:21])[OH:20])=[CH:15][N:14]=1>>[CH3:1][O:2][C:3]([C:5]1([CH3:11])[CH2:6][CH2:7][N:8]([C:13]2[N:18]=[CH:17][C:16]([B:19]([OH:21])[OH:20])=[CH:15][N:14]=2)[CH2:9][CH2:10]1)=[O:4]
Reactant: OB(O)c1cnc(Cl)nc1
Reactant: COC(=O)C1(C)CCNCC1
Product: COC(=O)C1(C)CCN(c2ncc(B(O)O)cn2)CC1

Procedure:
Prepared from 4-methylpiperidine-4-carboxylic acid methyl ester and (2-chloropyrimidin-5-yl)boronic acid according to the method of Intermediate 45.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH:9]=[C:8]2[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1)=[O:4].CCN(C(C)C)C(C)C.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C1COCC1>CCOCC.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH:9]=[C:8]2[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:20][CH:21]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)c(Cc1ccc(N)cc1)cn2C
Reactant: O=C(Cl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: COC(=O)c1ccc2c(c1)c(Cc1ccc(NC(=O)c3ccccc3)cc1)cn2C
Yield: 82.5 %

Procedure:
A solution of 3-(4-amino-phenylmethyl)-1-methyl-1H-indole-5-carboxylic acid methyl ester (62 mg, 0.21 mmol), DIPEA (0.06 mL, 0.32 mmol), benzoyl chloride (0.03 mL, 0.23 mmol) and THF (5 mL) was stirred for 10 hr at room temperature. The solution was then diluted with ether (20 mL) and ethyl acetate (20 mL) and washed with aq. NaHCO3 (50 mL). The organic layer was dried over MgSO4, filtered and concentrated. The remaining residue was subjected to flash chromatography (ethyl acetate/hexane, 2:3) to provide 3-(4-benzoylamino-phenylmethyl)-1-methyl-1H-indole-5-carboxylic acid methyl ester (69 mg, 83% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.P(Cl)(Cl)(Cl)=O.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[C:21]([C:28](O)=O)=[C:22]2[CH2:27][CH2:26][CH2:25][N:23]2[N:24]=1>Cl>[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[C:21]([C:28]2[NH:8][C:7]3[C:2]([N:1]=2)=[N:3][CH:4]=[CH:5][CH:6]=3)=[C:22]2[CH2:27][CH2:26][CH2:25][N:23]2[N:24]=1
Reactant: Nc1cccnc1N
Reactant: O=C(O)c1c(-c2ccccn2)nn2c1CCC2
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc(-c2nn3c(c2-c2nc4ncccc4[nH]2)CCC3)nc1
Reaction time: 0.17 h
Yield: 48.2 %

Procedure:
Add 2,3-diaminopyridine (Fluka; 120 mg, 1.09 mmol) and phosphorous oxychloride (4.4 mL) to 2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylic acid (Preparation 3; 251 mg, 1.09 mmol) and heat the reaction at 106° C. for 3 h. Cool the reaction to 0° C. and add 1N aqueous hydrochloric acid (10 mL) slowly and stir for 10 min. Neutralize the mixture with saturated aqueous sodium bicarbonate and extract with chloroform. Wash the combined organic layers with brine, dry with sodium sulfate, concentrate in vacuo, purify by flash column chromatography, and triturate with hexanes to provide the title compound (159 mg, 48%) as a tan solid. Mp 170-172° C. MS ESI+ m/e 303 (M+1). 1H NMR (CDCl3) δ 8.80 (br, 1H), 8.34 (m, 2H), 7.88 (m, 2H), 7.36 (m, 1H), 7.11 (m, 1H), 4.29 (m, 2H), 3.54 (m, 2H), 2.71 (m, 2H). HPLC: 96.3%, Rt=13.59 min. TLC (SiO2): Rf0.3 (1:3 [80:18:2 chloroform/methanol/concentrated aqueous ammonium hydroxide]/dichloromethane).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][C@H:12]([OH:16])[CH2:13][CH:14]=[CH2:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:18][CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]>O1CCCC1>[CH2:21]([O:20][CH:19]([O:23][CH2:24][CH3:25])[CH2:18][O:16][C@H:12]([CH2:13][CH:14]=[CH2:15])[CH2:11][O:10][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:22]
Reactant: C=CC[C@@H](O)COCc1ccccc1
Reactant: CCOC(CBr)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC[C@H](COCc1ccccc1)OCC(OCC)OCC

Procedure:
This reaction was carried out in two identical experiments. To a 0° C. suspension of sodium hydride (60% in mineral oil, 125 g, 3.12 mol) in tetrahydrofuran (1 L) was added a solution of C1 (200 g, 1.04 mol) in tetrahydrofuran (500 mL). The reaction was stirred for 30 minutes at room temperature, whereupon 2-bromo-1,1-diethoxyethane (528 g, 2.68 mol) was added, and the reaction mixture was heated at reflux for 18 hours. The mixture was carefully quenched with water (2×300 mL) and the combined experiments were concentrated in vacuo. The aqueous residue was partitioned between ethyl acetate (5 L) and water (5 L). The organic layer was washed with saturated aqueous sodium chloride solution (5 L), dried, and concentrated. Purification via silica gel chromatography (Eluent: 20:1 petroleum ether/ethyl acetate) provided the product as a yellow oil. Yield: 300 g, 0.97 mol, 47%. 1H NMR (400 MHz, CDCl3) δ 7.26-7.37 (m, 5H), 5.78-5.90 (m, 1H), 5.01-5.13 (m, 2H), 4.61 (t, J=5.3 Hz, 1H), 4.55 (s, 2H), 3.48-3.74 (m, 9H), 2.30-2.36 (m, 2H), 1.22 (t, J=7.1 Hz, 3H), 1.21 (t, J=7.0 Hz, 3H).