Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[N:10]1[C:11]2[C:2](=[O:1])[CH2:3][CH2:4][CH2:5][C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: OC1CCCc2cccnc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=C1CCCc2cccnc21
Reaction time: 18 h
Yield: 81.8 %

Procedure:
To a stirred solution of 8-hydroxy-5,6,7,8-tetrahydroquinoline (13.96 g, 93.6 mmol) in dry CH2Cl2 (400 mL) was added activated manganese dioxide (85% purity, 82.22 g, 804 mmol). The resulting heterogeneous mixture was stirred 18 h, at which point the black slurry was filtered through a cake of celite and washed with CH2Cl2 (3×50 mL). The combined washings were concentrated to afford 11.27 g (82%) of the title compound as a pale yellow solid, which was used in subsequent reactions without further purification. 1H NMR (CDCl3) δ 2.17–2.25 (m, 2H), 2.82 (t, 2H, J=7 Hz), 3.04 (t, 2H, J=6 Hz), 7.37 (dd, 1H, J=9, 6 Hz), 7.66 (dd, 1H, J=9, 1 Hz), 8.71 (dd, 1H, J=6, 1 Hz); 13C NMR (CDCl3) δ 22.2, 28.6, 39.2, 126.6, 137.3, 140.5, 147.6, 148.6, 196.5. ES-MS m/z 148 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:3]=1.[Cl:24]N1C(=O)CCC1=O>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10]([Cl:24])=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: N#Cc1c(OCCc2ccccn2)nc(N)nc1-c1ccco1
Solvent: CN(C)C=O
Product: N#Cc1c(OCCc2ccccn2)nc(N)nc1-c1ccc(Cl)o1

Procedure:
From 2-amino-4-furan-2-yl-6-(2-pyridin-2-yl-ethoxy)-pyrimidine-5-carbonitrile and N-chlorosuccinimide in DMF. ES-MS m/e (%): 344 (M{37C }+H+, 30), 342 (M{35Cl}+H+, 100).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][CH:12]=1.[CH2:13]([NH2:17])[CH:14]([CH3:16])[CH3:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:13]([N:17]1[C:9](=[O:10])[C:4]2=[CH:3][C:2]([CH3:1])=[CH:12][CH:11]=[C:5]2[C:6]1=[O:8])[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)CN
Reactant: Cc1ccc2c(c1)C(=O)OC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)C(=O)N(CC(C)C)C2=O
Temperature: 140 °C

Procedure:
N-Isobutyl-4-methylphthalimide is prepared as described in Example 2, starting with 6.0 g of 4-methylphthalic anhydride, 3.7 cm3 of isobutylamine and a catalytic amount of para-toluenesulphonic acid in 60 cm3 of toluene. The reaction mixture is heated at a temperature in the region of 140° C. for three hours and is then cooled to a temperature in the region of 20° C. The reaction mixture is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is taken up in 50 cm3 of saturated aqueous sodium bicarbonate solution, and the mixture is then extracted twice with 75 cm3 of dichloromethane. The organic extracts are combined, dried over sodium sulphate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 30° C., giving 6.7 g of N-isobutyl-4-methylphthalimide in the form of a white solid melting at 102° C.
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH:25]1[CH2:31][CH2:30][CH2:29][C@H:26]1[CH2:27][OH:28]>>[OH:28][CH2:27][C@@H:26]1[CH2:29][CH2:30][CH2:31][N:25]1[C:3]([C:4]1[CH:5]=[N:6][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])=[CH:8][CH:9]=1)=[O:24]
Reactant: OC[C@@H]1CCCN1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N2CCC[C@H]2CO)cn1
Yield: 84 %

Procedure:
As described for example 220, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (120 mg, 0.37 mmol) was converted, using L-prolinol instead of 3-amino-1-propanol, to the title compound (122 mg, 84%) which was obtained as a colourless oil. MS: m/e=394.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[C:8]([CH:9]3[C:14]=1[CH2:13][CH2:12][NH:11][CH2:10]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH2:15]([NH:19][C:20](=[O:23])[CH:21]=[CH2:22])[CH2:16][CH2:17][CH3:18].Cl>>[CH2:15]([NH:19][C:20](=[O:23])[CH2:21][CH2:22][N:11]1[CH2:12][CH2:13][C:14]2=[C:2]([CH3:1])[C:3]3[C:8]([CH:9]2[CH2:10]1)=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH2:16][CH2:17][CH3:18]
Reactant: CC1=C2CCNCC2c2ccccc21
Reactant: C=CC(=O)NCCCC
Agent: Cl
Product: CCCCNC(=O)CCN1CCC2=C(C)c3ccccc3C2C1

Procedure:
1,3,4,9b-Tetrahydro-5-methyl-2H-indeno[1,2-c]pyridine and N-n-butyl acrylamide are reacted in accordance with the process described in Example 6. Reaction period 14 hours. M.P. of the hydrochloride of the title compound 193°-194° from ethanol (decomp.).
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH3:15])=[C:9]([O:16][CH2:17][CH3:18])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:34](=[O:35])[C:33]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]2[C:31]1=[O:40])(OCC)=O.Cl>CCOCC.C(#N)C.O>[CH2:17]([O:16][C:9]1[CH:8]=[C:7]([CH:2]([N:1]2[C:34](=[O:35])[C:33]3=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]3[C:31]2=[O:40])[CH2:3][C:4]([OH:6])=[O:5])[CH:12]=[CH:11][C:10]=1[O:13][CH2:14][CH3:15])[CH3:18]
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: CCOc1ccc(C(N)CC(=O)O)cc1OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOCC
Product: CCOc1ccc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)cc1OCC
Reaction time: 1 h
Yield: 124.3 %

Procedure:
To a stirred solution of 3-amino-3-(3,4-diethoxyphenyl)propionic acid (1.03 g, 4.07 mmol) and sodium carbonate (0.453 g, 4.27 mmol) in a 1/1 mixture of 150 mL of acetonitrile/water (heated to 45° C. to dissolve) was added N-carbethoxyphthalimide (0.89 g, 4.07 mmol). The reaction mixture was stirred 1 hour, then partially concentrated in vacuo to remove the acetonitrile to afford a pale yellow solution. The stirred solution was acidified to pH 0-1 with 4 N hydrochloric acid to form a gum. The mixture was stirred overnight. The gum had not solidified and 1 mL of ether was added to mixture. The gum solidified on stirring and the slurry was filtered and the solid dried to afford 1.94 g (94%) of 3-(3,4-diethoxyphenyl)-3-phthalimidopropionic acid as a yellow solid: 1H NMR (DMSO-d6, 250 MHz) 12.41 (br s, 1H, COOH), 8.10-7.75 (m, 4H, Ar), 7.15-6.85 (m, 3H, Ar), 5.62 (overlapping dd, 1H), 4.20-3.90 (m, 4H, 2OCH2), 3.51 (dd, 1H, J=16.5, 9 Hz), 3.25 (dd, 1H, J=16.5, 7 Hz), 1.5-0.9 (m, 6H, 2 CH3) 13C NM (DMSO-d6) 1717, 167.6, 147.9, 147.8, 134.6, 131.3, 131.0, 123.1, 119.4, 113.2, 112.7, 63.8, 63.7, 50.0, 36.0, 14.6, 14.6; Anal. Calcd for C21H21NO6 : Theory C, 65.79; H, 5.52; N, 3.65. Found: C, 65.54; H, 5.55; N, 3.62.
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.O>C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.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>[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Reactant: Cc1ccccc1B(O)O
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: Cc1ccccc1
Solvent: CCO
Product: Cc1ccccc1-c1cccc2c1OCCN(C(=O)OC(C)(C)C)C2
Yield: 87.7 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.605 mmol), a solution of 2-methylphenylboronic acid (124 mg, 0.912 mmol) in ethanol (0.7 ml), 2N aqueous sodium carbonate solution (2.5 ml), and tetrakis(triphenylphosphine)palladium(0) (84.0 mg, 0.0730 mmol) in toluene (5 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (180 mg, 87.8%) as an oil.
Reaction SMILES: [CH:1]1[C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[S:15]([NH:18][C@H:19]([C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH3:35])[CH2:31][CH:30]1[C:36]([O:38]CC)=[O:37])=[O:28])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:26])[NH2:25])(=[O:17])=[O:16].[OH-].[Na+]>CO>[CH:1]1[C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[S:15]([NH:18][C@H:19]([C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH3:35])[CH2:31][CH:30]1[C:36]([OH:38])=[O:37])=[O:28])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:25])[NH2:26])(=[O:16])=[O:17]
Reactant: CCOC(=O)C1CC(C)CCN1C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2c(c1)Sc1ccccc1O2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1CCN(C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c2ccc3c(c2)Sc2ccccc2O3)C(C(=O)O)C1
Reaction time: 10 h
Yield: 30 %

Procedure:
A solution of 3.5 g of ethyl 1-[N2 -(2-phenoxathiinylsulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylate in 15 ml of methanol and 10 ml of 2N-NaOH solution was warmed to 30° C and held at that temperature for 10 hours. At the end of this period, the reaction mixture was concentrated and chromatographed on 200 ml of Daiaion® SK 102 ion exchange resin (200-300 mesh, H+ form, manufactured by Mitsubishi Chemical Industries Limited) packed in water, washed with ethanol-water (1:4) and eluted with ethanol-water-NH4OH (10:9:1). The main fraction was evaporated to dryness and washed with ether to give 1.0 g of 1-[N2 -(2-phenoxathiinylsulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylic acid as an amorphous solid. I.R. (KBr): 3400, 1625, 1460, 1165 cm-1.
Reaction SMILES: [CH2:1]([N:6]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:9](=O)[C:7]1=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:19][CH:20]([CH3:26])[CH2:21][C:22]([NH:24][NH2:25])=[O:23]>>[CH3:18][O:17][C:14]1[CH:15]=[C:16]2[C:11](/[C:9](=[N:25]/[NH:24][C:22](=[O:23])[CH2:21][CH:20]([CH3:26])[CH3:19])/[C:7](=[O:8])[N:6]2[CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:12][CH:13]=1
Reactant: CCCCCN1C(=O)C(=O)c2ccc(OC)cc21
Reactant: CC(C)CC(=O)NN
Product: CCCCCN1C(=O)/C(=N\NC(=O)CC(C)C)c2ccc(OC)cc21

Procedure:
The title compound was prepared as a yellow solid, using 1-pentyl-6-methoxy-isatin obtained in Example 39(A) and 3-methylbutanohydrazide according to the synthetic method E. NMR (CDCl3): δ 0.92 (t, 3H), 1.05 (d, 6H), 1.36 to 1.39 (m, 4H), 1.69-1.75 (m, 2H), 2.30 (m, 2H), 2.72 (d, 1H), 3.72 (t, 2H), 3.89 (s, 3H), 6.44 (d, 1H), 6.64 (dd, 1H), 7.54 and 7.77 (d for isomers, 1H), 12.41 and 13.03 (br s for isomers, 1H).
Reaction SMILES: O[C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH2:8][O:9][CH3:10])[CH:3]=1.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH2:8][O:9][CH3:10])[CH:3]=1
Reactant: COCc1cc(O)ncn1
Reactant: O=P(Cl)(Cl)Cl
Product: COCc1cc(Cl)ncn1

Procedure:
50 g of 6-hydroxy-4-methoxymethylpyrimidine were heated in 375 ml of phosphorus oxychloride until a clear solution had been produced. The excess phosphorus oxychloride was removed by distillation in vacuo, and the residue was poured into ice-water. Extraction with dichloromethane and drying over sodium sulfate were followed by concentration of the solution in vacuo. 58 g of 6-chloro-4-methoxymethylpyrimidine were obtained as an oil which was used without further purification in the next stage.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH2:9][CH3:10])=[CH:6][C:5]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[NH:13][C:12]2=[O:22])=[C:4]([F:23])[CH:3]=1.CI.[C:26](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[C:7]([O:8][CH2:9][CH3:10])=[CH:6][C:5]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:26])[C:12]2=[O:22])=[C:4]([F:23])[CH:3]=1
Reactant: CCOc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
3-(4-Bromo-5-ethoxy-2-fluorophenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (2.38 g), methyl iodide (1.06 g) and potassium carbonate (1.04 g) were suspended in DMF (12 ml), and the mixture was stirred at room temperature for about 8 hours. After the reaction, DMF was distilled off under reduced pressure, extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. Then, ethyl acetate was distilled off, and the resulting residue was crystallized from a mixed solvent of ethyl acetate and n-hexane (1:5 v/v) to obtain the objective 3-(4-bromo-5-ethoxy-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2,4( 1H,3H)-pyrimidinedione (2.08 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[C:10]([C:15](=O)[CH3:16])[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[SH:25].C(O)(=O)C>CN(C)C=O.CCOCC.C(OC(C)C)(C)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:15]([CH3:16])[NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[S:25]2)=[CH:5][CH:4]=1
Reactant: Nc1ccccc1S
Reactant: COC(=O)C(=Cc1ccc(OC)cc1)C(C)=O
Solvent: CN(C)C=O
Solvent: CC(C)OC(C)C
Solvent: CC(=O)O
Product: COC(=O)C1=C(C)Nc2ccccc2SC1c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-[(4-methoxyphenyl)methylene]-3-oxobutanoic acid, methyl ester (1.17 g., 5 mmole) in dimethylformamide (5 ml.) is treated with 2-aminothiophenol (695 mg., 5 mmole) and the resulting yellow solution is allowed to stir at room temperature for one hour. It is then treated with acetic acid (0.3 ml., about 5 mmoles) and the reaction is allowed to warm up to 65°. Stirring is continued at this temperature for 24 hours. After cooling to room temperature, the reaction is diluted with ether and washed with water (5×20 ml.), sodium bicarbonate, and brine, and is then dried over anhydrous magnesium sulfate. Evaporation provides a yellow foam which is dissolved in isopropyl ether and allowed to sit under refrigeration for several days. A light yellow crystalline product forms (410 mg.). Recrystallization from isopropyl ether gives an analytically pure sample of 2,5-dihydro-2-(4-methoxyphenyl)-4-methyl-1,5-benzothiazepine-3-carboxylic acid, methyl ester; m.p. 107°-109.5°. TLC (silica gel; ethyl acetate:hexane, 50:50) Rf =0.50.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[CH2:17](Br)[CH:18]=[CH2:19].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:19]([O:16][C:12]1[C:9]2[C:10]([CH3:11])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[O:7][C:8]=2[CH:15]=[CH:14][CH:13]=1)[CH:18]=[CH2:17]
Reactant: C=CCBr
Reactant: CCOC(=O)c1oc2cccc(O)c2c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cccc2oc(C(=O)OCC)c(C)c12
Yield: 92.2 %

Procedure:
A mixture of ethyl-4-hydroxy-3-methylbenzofuran-2-carboxylate (11.0 g, 50 mmol), allyl bromide (4.8 ml, 55 mmol) and potassium carbonate (55 mmol) was refluxed in acetone (300 ml) for 4 hours. The resulting mixture was cooled, filtered and concentrated. The residue was chromatographed (silica gel, eluted with 5% ethyl acetate in hexane) to give 12 g of the title compound, m.p. 64°-65° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH3:13])[CH2:10][C@H:9]1[C:14]1[NH:15][CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:56]=[CH:55][C:34]5[NH:35][C:36]([C@@H:38]6[CH2:42][C@H:41]([CH3:43])[CH2:40][N:39]6[C:44](=[O:54])[C@@H:45]([NH:49][C:50]([O:52][CH3:53])=[O:51])[CH:46]([CH3:48])[CH3:47])=[N:37][C:33]=5[CH:32]=4)=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[N:18]=1)=O)(C)(C)C.[ClH:57].O1CCOCC1>>[ClH:57].[CH3:53][O:52][C:50](=[O:51])[NH:49][C@H:45]([C:44]([N:39]1[CH2:40][C@@H:41]([CH3:43])[CH2:42][C@H:38]1[C:36]1[NH:35][C:34]2[CH:55]=[CH:56][C:31]([C:28]3[CH:29]=[CH:30][C:25]([C:22]4[CH:23]=[CH:24][C:19]([C:17]5[N:18]=[C:14]([C@@H:9]6[CH2:10][C@H:11]([CH3:13])[CH2:12][NH:8]6)[NH:15][CH:16]=5)=[CH:20][CH:21]=4)=[CH:26][CH:27]=3)=[CH:32][C:33]=2[N:37]=1)=[O:54])[CH:46]([CH3:48])[CH3:47]
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc2cc(-c3ccc(-c4ccc(-c5c[nH]c([C@@H]6C[C@H](C)CN6C(=O)OC(C)(C)C)n5)cc4)cc3)ccc2[nH]1)C(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc2cc(-c3ccc(-c4ccc(-c5c[nH]c([C@@H]6C[C@H](C)CN6)n5)cc4)cc3)ccc2[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(2S,4S)-2-[4-(4′-{2-[(2S,4S)-1-((S)-2-Methoxycarbonylamino-3-methyl-butyryl)-4-methyl-pyrrolidin-2-yl]-1H-benzoimidazol-5-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (75 mg, 0.0987 mmol) is stirred with 4M HCl in dioxane (4 mL, 16 mmol). The reaction mixture is stirred at room temperature for 0.5 hour and concentrated to dryness. The product {(S)-2-methyl-1-[(2S,4S)-4-methyl-2-(5-{4′-[2-((2S,4S)-4-methyl-pyrrolidin-2-yl)-1H-imidazol-4-yl]-biphenyl-4-yl}-1H-benzoimidazol-2-yl)-pyrrolidine-1-carbonyl]-propyl}-carbamic acid methyl ester hydrochloride is used as such in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH:9]=O)=[C:6]([NH:11][O:12][CH2:13][CH2:14][O:15][CH2:16][P:17]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])=[O:18])[N:5]=[CH:4][N:3]=1>C(OC(OCC)OCC)(=O)C>[Cl:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]2[C:7]=1[N:8]=[CH:9][N:11]2[O:12][CH2:13][CH2:14][O:15][CH2:16][P:17]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOP(=O)(COCCONc1ncnc(Cl)c1NC=O)OCC
Agent: CCOC(OCC)OC(C)=O
Product: CCOP(=O)(COCCOn1cnc2c(Cl)ncnc21)OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.6 %

Procedure:
A solution of 4-chloro-6-[2-(diethoxyphosphorylmethoxy)ethoxyamino]-5-formamidopyrimidine (2.4 g, 6.3 mmol) in diethoxymethyl acetate (10 ml) was heated at 120° C. for 45 minutes. After cooling to ambient temperature, the solvent was removed under reduced pressure. The residue was dissolved in methanol (15 ml) and 0.880 ammonia (1 ml). After 15 minutes, the reaction mixture was evaporated to dryness and the residue chromatographed on silica gel (eluted with dichloromethane: methanol, 98:2) to give the title compound as an oil (2.15 g, 94%). IR: νmax (film) 3100, 3070, 2995, 1600, 1570, 1440, 1395, 1335, 1250, 1220, 1170, 1030, 930, 640 cm-1. 1H NMR: δH [(CD3)2SO] 1.23 (6H,t,J=7Hz, (OCH2CH3)2), 3.88 (2H, d, J=8Hz, OCH2P), 3.89 (2H,m, CH2OCH2P), 4.0-4.1 (4H,m, (OCH2CH3)2), 4.61 (2H,m, N--OCH2), 8.82 (1H,s,H-8), 8.97 (1H,s,H-2). Found: C,38.38; H,5.10; N,15.14%. C12H18N4O5PCl. 0.5H2O requires: C,38.56; H,5.12; N,14.99%. Found: m/z 364.0703. C12H18N4O5PCl requires: m/z 364.0701.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH:15][C@H:16]([C:20]([O:22][CH3:23])=[O:21])[CH2:17][S:18][CH3:19])=[O:14])=O)(C)(C)C>Cl.O1CCOCC1>[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH:15][C@H:16]([C:20]([O:22][CH3:23])=[O:21])[CH2:17][S:18][CH3:19])=[O:14]
Reactant: COC(=O)[C@H](CSC)NC(=O)CCCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@H](CSC)NC(=O)CCCCN
Reaction time: 2 h

Procedure:
The t-butyl carbamate from Example 7J was taken up in 4N HCl in dioxane and left at r.t. for 2 hours. The solvent was then removed under reduced pressure and the residue was evaporated with acetonitrile twice and pumped under high vacuum. The resulting amine hydrochloride salt was used directly for the coupling.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[CH:29]1([NH2:38])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH2:30]1>>[CH3:28][N:4]1[C:3]([CH2:2][NH:38][CH:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:31][CH2:30]2)=[N:11][C:10]2[C:5]1=[N:6][C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])=[N:8][C:9]=2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: NC1CCc2ccccc21
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CNC3CCc4ccccc43)n(C)c2n1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (25 mg) was reacted with 2,3-dihydro-1H-inden-1-amine via General Procedure E to give 10.6 mg of 271 following reverse phase purification. MS (Q1) 495.2 (M)+
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([C:11]([Cl:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:6])=[O:5].C(OCCCCCC)(=O)[C:15]1[CH:23]=[CH:22]C(C([O-])=O)=[CH:17][CH:16]=1.[K+].S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH2:1]([C:2]1[CH:10]=[C:9]([C:11]([Cl:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:6])=[O:5])[CH2:17][CH2:16][CH2:15][CH2:23][CH3:22]
Reactant: CCCCCCOC(=O)c1ccc(C(=O)[O-])cc1
Reactant: Cc1cc(C(=O)Cl)ccc1C(=O)Cl
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCCCCc1cc(C(=O)Cl)ccc1C(=O)Cl

Procedure:
This compound was prepared by the method described for monomethyl terephthaloyl chloride. Typical reagent levels were as follows: potassium monohexyl terephthalate (18.6 g, 0.64 mole), thionyl chloride (9.21 g, 0.774 mole) and 100 ml of toluene. The product was used without further purification.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1([NH2:21])[CH2:20][CH2:19]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl.O>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH:21][C:18]1([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=2)[CH2:20][CH2:19]1)=[O:7]
Reactant: Cc1ccc(C(=O)O)cc1I
Reactant: NC1(c2ccccn2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC2(c3ccccn3)CC2)cc1I
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Iodo-4-methylbenzoic acid (2.5 g, 9.5 mmol, 1 eq), 1-(pyridin-2-yl)cyclopropanamine (1.41 g, 10.4 mmol, 1.1 eq), EDCI.HCl (2.1 g, 11.4 mmol, 1.2 eq), HOBT (1.5 g, 11.4 mmol, 1.2 eq) and DIPEA (4.9 ml, 28.62 mmol, 3 eq) were dissolved in DCM and the above solution was stirred at room temperature for 18 h. Water was added and product was extracted with DCM. The organic layer was concentrated and the crude product crystallized using dichloromethane and hexane. Yield: 2.3 g (55%). 1HNMR (400 MHz, DMSO-d6): δ 1.26 (m, 2H), 1.53 (m, 2H), 2.43 (s, 3H), 7.13 (m, 1H), 7.29 (d, J=8.00 Hz, 1H), 7.44 (d, 1H), 7.67 (t, J=3.46 Hz, 1H), 7.87 (d, J=3.24 Hz, 1H), 8.38 (s, 1H), 8.44 (d, J=1.10 Hz, 1H), 9.29 (s, 1H).
Reaction SMILES: [CH:1]1[CH:10]=[C:9]2[C:11]([O:13][C:14](=[O:15])[C:7]3=[C:8]2[C:3](=[C:4]([Br:16])[CH:5]=[CH:6]3)[CH:2]=1)=O.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)(=O)C>[Br:16][C:4]1[CH:5]=[CH:6][C:7]2[C:14](=[O:15])[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:11](=[O:13])[C:9]3[C:8]=2[C:3]=1[CH:2]=[CH:1][CH:10]=3
Reactant: Nc1ccccc1
Reactant: O=C1OC(=O)c2ccc(Br)c3cccc1c23
Solvent: CC(=O)O
Product: O=C1c2cccc3c(Br)ccc(c23)C(=O)N1c1ccccc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 4-bromo-1,8-naphthalic anhydride (10 g), aniline (3.54 g) and acetic acid (75 ml) was refluxed with stirring for 10 hrs. The reaction mixture was then cooled to room temperature, whereupon solid separated out. The solid was filtered, washed with water (50 ml) followed by acetic acid (50 ml) and dried at 100° C. for 8 hours (Yield=10.8 gm).