Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][OH:23])[C:6](=[O:24])[N:5]([CH2:25][CH3:26])[C:4]=2[N:3]=1.[CH3:27][C:28]1[CH:29]=[C:30]([OH:34])[CH:31]=[N:32][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:10]2[C:9]3[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][OH:23])[C:6](=[O:24])[N:5]([CH2:25][CH3:26])[C:4]=3[N:3]=[C:2]2[O:34][C:30]2[CH:31]=[N:32][CH:33]=[C:28]([CH3:27])[CH:29]=2)=[CH:13][CH:14]=1
Reactant: Cc1cncc(O)c1
Reactant: CCn1c(=O)n(CCCO)c(=O)c2c1nc(Cl)n2Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(=O)n(CCCO)c(=O)c2c1nc(Oc1cncc(C)c1)n2Cc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 21.3 %

Procedure:
To a solution of 8-chloro-7-(4-chlorobenzyl)-3-ethyl-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione (30 mg, 0.08 mmol, intermediate 78) in DMF (2 mL) was added 5-methylpyridin-3-ol (12.36 mg, 0.12 mmol), followed by potassium carbonate (15.66 mg, 0.11 mmol). The reaction was stirred at 80° C. for 3 h. The reaction was cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, and concentrated to give a crude product, which was purified by preparative HPLC to give 7-(4-chlorobenzyl)-3-ethyl-1-(3-hydroxypropyl)-8-((5-methylpyridin-3-yl)oxy)-1H-purine-2,6(3H,7H)-dione (8 mg, 22.5%) as white solid. 1H-NMR (CD3OD) δ 8.35-8.42(d, 2H), 7.68(s, 1H), 7.38-7.48(m, 4H), 5.52(s, 2H), 4.01-4.14(m, 4H), 3.61-3.64(m, 2H), 2.43(s, 3H), 1.87-1.90(m, 2H), 1.22-1.26(m, 3H). LCMS retention time 2.511 min; LCMS MH+ 470.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([NH:12][C:13]2[CH:21]=[CH:20][CH:19]=[C:15]([C:16]([OH:18])=O)[C:14]=2[C:22]([OH:24])=O)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].Cl.[NH2:26][CH:27]1[CH2:33][CH2:32][C:31](=[O:34])[NH:30][C:28]1=[O:29]>N1C=CC=CC=1>[O:29]=[C:28]1[CH:27]([N:26]2[C:22](=[O:24])[C:14]3[C:15](=[CH:19][CH:20]=[CH:21][C:13]=3[NH:12][C:6]3[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)[C:16]2=[O:18])[CH2:33][CH2:32][C:31](=[O:34])[NH:30]1
Reactant: CCOc1cc(Nc2cccc(C(=O)O)c2C(=O)O)ccc1OC
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: c1ccncc1
Product: CCOc1cc(Nc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)ccc1OC
Yield: 67 %

Procedure:
A mixture of 3-(3-ethoxy-4-methoxyphenylamino)phthalic acid (0.85 g, 2.6 mmol) and rac-α-aminoglutarimide hydrochloride (0.43 g, 2.6 mmol) in pyridine (10 mL) was heated to reflux for 16 hours. The mixture was cooled and evaporated under vacuum. The residue was dissolved in ethyl acetate (150 mL), washed with dilute aqueous HCl (2×100 mL) and water (2×100 mL), and evaporated. The residue was chromatographed in 95:5 methylene chloride-methanol, eluting 0.72 g of the product, in 67% yield: mp 162-164° C.; 1H NMR (CDCl3) δ 1.46 (t, J=7.0 Hz, 3H), 2.11-2.18 (m, 1H), 2.72-2.94 (m, 3H), 3.89 (s, 3H), 4.06 (q, J=7.0 Hz, 3H), 4.96 (dd, J=12.0 Hz, J=5.0 Hz, 1H), 6.76-6.89 (m, 3H), 7.14-7.19 (m, 2H), 7.43 (t, J=7.8 Hz, 1H), 7.86 (s, 1H), 8.43 (s, 1H); 13C NMR (CDCl3) δ 14.7, 22.8, 31.4, 49.0, 56.2, 64.5, 109.9, 110.8, 112.1, 113.1, 116.4, 118.5, 131.7, 132.4, 135.9, 145.2, 147.4, 149.1, 167.5, 168.4, 169.4, 171.1; Anal. calcd for C22H21N3O6: C, 62.41; H, 5.00; N, 9.92. Found: C, 62.16; H, 4.89; N, 9.72.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH:7]=[N:8]O)([O-])=O.B(O)(O)O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH2:7][NH2:8]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc(C=NO)c1
Agent: [Pd]
Agent: OB(O)O
Solvent: CCO
Product: NCc1cccc(N)c1
Reaction time: 8 h
Yield: 81.9 %

Procedure:
16.6 g (0.1 mol) of m-nitrobenzaldoxime obtained in Example 2, 0.3 g of a 5% Pd-C catalyst, 6.2 g (0.1 mol) of boric acid and 50 ml of ethanol were charged into a hermetically sealed glass container and stirred vigorously while charging hydrogen. Reaction was effected at temperatures of 20° to 25° C. for 8 hours. After reaction, the resulting mixture was filtered to remove the catalyst and was subject to the same post-treatment as in Example 1. 10 g of m-aminobenzylamine of 99.9% in purity was obtained (yield 82%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([F:10])[CH:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][SH:20])=[CH:15][CH:14]=1.C1(C)C=CC=CC=1.CCN(C(C)C)C(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.O>[F:10][C:4]1[CH:3]=[C:2]([S:20][CH2:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=1
Reactant: COc1ccc(CS)cc1
Reactant: COc1cc(F)cc(Br)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CSc2cc(F)cc(OC)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To a mixture of 1-bromo-3-fluoro-5-methoxybenzene (5 g), (4-methoxyphenyl)methanethiol (3.76 g), and toluene (100 mL) were added Pd2(dba)3 (0.447 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.564 g) and DIPEA (8.52 mL). The mixture was stirred at room temperature overnight. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (6.20 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[N:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][NH:15][C:17]1[N:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1ncc2ccccc2n1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1CN
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1CNc1ncc2ccccc2n1
Yield: 55.2 %

Procedure:
The title compound (0.6 g) was prepared from (S)-2-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (0.68 g) and 2-chloroquinazoline (0.53 g) according to the method of D30.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[C:30]([Br:32])[CH:31]=1)[NH:28][C:27](=[O:33])[CH2:26]2>>[Br:32][C:30]1[CH:31]=[C:23]([F:22])[CH:24]=[C:25]2[C:29]=1[NH:28][C:27](=[O:33])[C:26]2=[CH:20][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: O=C1Cc2cc(F)cc(Br)c2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Product: Cc1c(C=C2C(=O)Nc3c(Br)cc(F)cc32)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Yield: 89.5 %

Procedure:
The title compound was prepared under the same conditions as described in Example 13 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-fluoro-7-bromo-1,3-dihydro-indol-2-one as starting materials to give 2-(7-bromo-5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-morpholin-4-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (73 mg, 89.5%) as an orange solid.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:18]=[CH:17][N:16]=[C:15]3[CH2:19][N:20]([CH3:22])[CH3:21])=[CH:10][C:9]=2[F:23])[C:3]1=[O:24].[Cl:25][C:26]1[S:30][C:29]([CH:31]=[CH:32][S:33](Cl)(=[O:35])=[O:34])=[CH:28][CH:27]=1>C(Cl)Cl>[Cl:25][C:26]1[S:30][C:29]([CH:31]=[CH:32][S:33]([NH:1][N:2]2[CH2:7][CH2:6][CH2:5][N:4]([C:8]3[CH:13]=[CH:12][C:11]([N:14]4[CH:18]=[CH:17][N:16]=[C:15]4[CH2:19][N:20]([CH3:21])[CH3:22])=[CH:10][C:9]=3[F:23])[C:3]2=[O:24])(=[O:35])=[O:34])=[CH:28][CH:27]=1
Reactant: O=S(=O)(Cl)C=Cc1ccc(Cl)s1
Reactant: CN(C)Cc1nccn1-c1ccc(N2CCCN(N)C2=O)c(F)c1
Solvent: ClCCl
Product: CN(C)Cc1nccn1-c1ccc(N2CCCN(NS(=O)(=O)C=Cc3ccc(Cl)s3)C2=O)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
18.6 mg (0.046 mmol) of the diHCl salt of 1-amino-3-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)-2-fluorophenyl)-tetrahydropyrimidin-2(1H)-one prepared as above, were dissolved in 3 mL of anhydrous CH2Cl2. To this solution placed under N2 atmosphere were added 50 μL of TEA followed by 11.2 mg (0.046 mmol) of 2-(5-chlorothiophen-2-yl)ethenesulfonyl chloride. The mixture was stirred at room temperature overnight. An additional 3 mL of CH2Cl2 were added, and the mixture was washed twice with 2 mL of saturated NaHCO3 solution. The organic phase was dried and concentrated to yield 17.2 mg of a brown oil. A pure compound was obtained after purification by preparative HPLC. 1H NMR (500 MHz, MeOD) δ 7.53 (t, 1H), 7.49 (s, 1H) 7.41 (d, J=10.4 Hz, 1H), 7.29 (s, 1H), 7.27 (d, J=8.2 Hz, 1H), 6.93(d, J=3.8 Hz, 1H), 6.86 (d, J=3.8 Hz, 1H), 5.1 (m, 1H), 4.45 (q, 2H), 3.5 (m, 2H), 3.14 (m, 1H), 2.86 (s, 6H), 2.0 (m, 2H), ppm. LC-MS (ESI) 556.8 [M+NH4+, tR=4.645 min (Shimadzu Phenomenex S5 ODS 4.6×50 mm Luna flow rate 2.5 ml/mn; detection at 220 nM; Gradient elution 0% to 100% B over 8 min; (A=10% MeOH, 90% H2O, 0.2% H3PO4& B=90% MeOH, 10% H2O, 0.2% H3PO4). HRMS (ESI) m/z calcd for C22H25ClFN6O3S2 [M+H]+ 539.1102. found 539.1105
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:8][O:9][C:10]([C:12]1[CH:13]=[C:14]([CH3:35])[C:15]2[O:21][C:20]3[C:22]([Cl:31])=[CH:23][C:24]([NH:26][C:27](=[O:30])[CH2:28]Cl)=[CH:25][C:19]=3[CH2:18][S:17](=[O:33])(=[O:32])[C:16]=2[CH:34]=1)=[O:11]>CN(C=O)C>[CH3:8][O:9][C:10]([C:12]1[CH:13]=[C:14]([CH3:35])[C:15]2[O:21][C:20]3[C:22]([Cl:31])=[CH:23][C:24]([NH:26][C:27](=[O:30])[CH2:28][NH:7][CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:25][C:19]=3[CH2:18][S:17](=[O:33])(=[O:32])[C:16]=2[CH:34]=1)=[O:11]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC(=O)CCl)cc(Cl)c1O2
Reactant: NC1CCCCC1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC(=O)CNC3CCCCC3)cc(Cl)c1O2
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Cyclohexyl amine (0.3 ml, 2.7 mmol) was added to a solution of Example 133 (0.4 g, 0.9 mmol) in DMF (10 mL). The reaction mixture was stirred at 80° C. for 3 h, concentrated, treated with water and the solid that precipitated was filtered, washed with water and purified using flash chromatography (silica gel, 2% methanol/chloroform) to obtain the title compound. Yield: 0.365 g (80%); 1H NMR (CDCl3): δ 1.21 (q, 2H, CH2), 1.25 (q, 2H, CH2), 1.63 (bs, 2H, CH2), 1.73 (bs, 2H, CH2), 1.88 (bs, 2H, CH2), 2.44 (m, 1H, CH), 2.77 (s, 3H, CH3), 3.4 (s, 2H, CH2), 3.9 (s, 3H, OCH3), 4.7 (s, 2H, CH2), 7.57 (d, 1H, Ar), 7.83 (d, 1H, Ar), 8.1 (s, 1H, Ar), 8.4 (s, 1H, Ar), 9.72 (s, 1H, NH); MS m/e (ES+) 507 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]2[C:7]=1[C:8](=[O:33])[N:9]([C@@H:16]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH2:31][CH3:32])[CH:23]=1)[CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:10]2)=[O:4].[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>CC#N>[Cl:15][C:12]1[CH:13]=[CH:14][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:38]2[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]2)=[C:7]2[C:11]=1[CH2:10][N:9]([C@@H:16]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH2:31][CH3:32])[CH:23]=1)[CH2:17][S:18]([CH3:21])(=[O:19])=[O:20])[C:8]2=[O:33]
Reactant: CN1CCNCC1
Reactant: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3c(Cl)ccc(NC(=O)CCl)c3C2=O)ccc1OC
Solvent: CC#N
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3c(Cl)ccc(NC(=O)CN4CCN(C)CC4)c3C2=O)ccc1OC
Temperature: 70 °C
Yield: 25.2 %

Procedure:
To a solution of (1S)-2-chloro-N-{7-chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide (250 mg, 0.48 mmol) in CH3CN (10 ml) was added 1-methylpiperazine (0.21 ml, 1.9 mmol). The mixture was heated at 70° C. for 2 hrs. The reaction mixture was concentrated on rota-vap and extracted with water (50 ml) and EtOAc (50 ml). The organic layer was washed with water (50 ml), brine (25 ml), dried over Na2SO4 and concentrated. The resulted oil was purified by chromatography to give (1S)-N-{7-chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-2-(4-methyl-piperazin-1-yl)-acetamide as a white solid (70 mg, 25% yield): mp, 205–207° C.; 1H NMR (CDCl3) δ 1.47 (t, J=7.0 Hz, 3H, OCH2CH3), 2.36 (s, 3H, CH3), 2.64 (broad, 8H, CH2 on piperazine ring), 2.99 (S, 3H, NCH3), 3.21 (d, J=2 Hz, 2H, CH2NCO), 3.73 (dd, J=5, 15 Hz, 1H, CHHSO2), 3.88 (s, 3H, OCH3), 4.05–4.20 (m, 4H, CHHSO2+CNHH+OCH2CH3), 4.39 (d, J=15 Hz, 1H, CHHN), 5.74–5.80 (m, 1H, NCH), 6.86–6.98 (m, 3H, Ar), 7.40 (d, J=8 Hz, 1H, Ar), 8.55 (d, J=8 Hz, 1H, Ar), 11.45 (s, 1H, NHCO); 13C NMR (CDCl3) δ 14.73, 41.37, 46.11, 46.81, 51.57, 53.46, 54.81, 55.76, 55.98, 62.18, 64.62, 111.61, 112.42, 119.46, 119.77, 119.87, 122.32, 129.20, 132.95, 135.98, 139.21, 148.93, 149.87, 168.50, 170.01. Anal Calcd for C27H35ClN4O6S: C, 56.00; H, 6.09; N, 9.67. Found: C, 55.82; H, 5.79; N, 9.42.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[S:24][CH:25]=[CH:26][C:27]=3[O:28][CH2:29][CH3:30])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:33][O:34][CH2:35][CH2:36][N:37]([CH2:47][CH2:48][O:49][CH3:50])[C:38](=[O:46])[CH2:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:43]3[CH2:44][CH2:45][N:40]([CH2:39][C:38]([N:37]([CH2:47][CH2:48][O:49][CH3:50])[CH2:36][CH2:35][O:34][CH3:33])=[O:46])[CH2:41][CH2:42]3)=[O:21])[C:10]([C:23]3[S:24][CH:25]=[CH:26][C:27]=3[O:28][CH2:29][CH3:30])=[N:9]2)=[CH:6][CH:7]=1
Reactant: COCCN(CCOC)C(=O)CN1CCNCC1
Reactant: CCOc1ccsc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1ccsc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(CCOC)CCOC)CC1

Procedure:
2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 34) was reacted with N,N-bis-(2-methoxy-ethyl)-2-piperazin-1-yl-acetamide dihydrochloride to give 2-(4-[(4S,5R)-4,5-bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N,N-bis-(2-methoxy-ethyl)-acetamide in an analogous manner as described in example 1. LR-MS: 702.3 [(M+H)+]
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][C@@H:12]([CH3:16])[CH2:13][O:14][CH3:15])[CH:10]=1)[C:5]([OH:7])=[O:6].F[C:18]1[CH:19]=[CH:20][C:21]2[S:27](=[O:29])(=[O:28])[N:26]([CH3:30])[CH2:25][CH2:24][O:23][C:22]=2[CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:30][N:26]1[CH2:25][CH2:24][O:23][C:22]2[CH:31]=[C:18]([O:1][C:2]3[CH:3]=[C:4]([CH:8]=[C:9]([O:11][C@@H:12]([CH3:16])[CH2:13][O:14][CH3:15])[CH:10]=3)[C:5]([OH:7])=[O:6])[CH:19]=[CH:20][C:21]=2[S:27]1(=[O:29])=[O:28]
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)O)c1
Reactant: CN1CCOc2cc(F)ccc2S1(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC[C@H](C)Oc1cc(Oc2ccc3c(c2)OCCN(C)S3(=O)=O)cc(C(=O)O)c1
Temperature: 120 °C
Reaction time: 28 h
Yield: 57.1 %

Procedure:
A mixture of 3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzoic acid (0.2 g, 0.88 mmol), 7-fluoro-2-methyl-3,4-dihydro-2H-5,1,2-benzoxathiazepine 1,1-dioxide (205 mg, 0.88 mmol) and potassium carbonate (244 mg, 1.77 mmol) in acetonitrile (5 mL) was stirred in a microwave reactor at 120° C. for 28 hours. The solvent was removed in vacuo and water (50 mL) and ethyl acetate (50 mL) added. The ethyl acetate layer was separated and discarded and the aqueous layer acidified and extracted into ethyl acetate (2×50 mL). The combined organics were washed with brine, dried (MgSO4), filtered and the solvent removed in vacuo to give the desired compound as a brown oil (0.22 g) which was used in the following steps without further purification. m/z 436 (M−H)−
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1[S:7][CH:6]=[C:5]([OH:8])[CH:4]=1.Cl[C:12]1[N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:15]=[N:14][N:13]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:17]1([N:16]2[C:12]([O:8][C:5]3[CH:4]=[C:3]([C:2]([F:10])([F:9])[F:1])[S:7][CH:6]=3)=[N:13][N:14]=[N:15]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Oc1csc(C(F)(F)F)c1
Reactant: Clc1nnnn1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: FC(F)(F)c1cc(Oc2nnnn2-c2ccccc2)cs1
Yield: 67.3 %

Procedure:
A solution of 5-trifluoromethyl-thiophen-3-ol (2.0 g, 11.9 mmol) in dry acetone (480 mL) containing 5-chloro-1-phenyl-1H-tetrazole (2.1 g, 11.9 mmol) and K2CO3 (3.3 g, 23.8 mmol) is maintained at reflux with careful exclusion of moisture overnight. The acetone is removed under reduced pressure and the residue is partitioned between CH2Cl2 (500 mL) and H2O (50 mL). The organic extracts are washed with brine, then dried (Na2SO4), filtered and concentrated. The crude product is chromatographed on silica gel, eluting with EtOAc:Hex (1:80) to afford the title compound (2.5 g, 68%) as a white solid.
Reaction SMILES: [H-].[Na+].[C:3]([O:22][CH2:23][CH:24]([CH2:26][OH:27])[OH:25])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]>CN(C)C=O>[CH2:29]([O:27][CH2:26][CH:24]([CH2:23][O:22][C:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[O:25][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH3:29])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: OCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCOCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 12 h
Yield: 68.3 %

Procedure:
1H-nmr (200 MHz, CDCl3), 3.21 (2H, m), 3.65 (2H, m), 3.85 (1H, m), 7.4 (15H, m). ##STR17## Sodium hydride (prewashed with hexane, 60% oil dispersion, 0.79 g, 32.89 mmol) was stirred in dry dimethyl formamide (50 ml) under a stream of nitrogen. 1-trityl glycerol (5.0 g, 14.95 mmol) in dry dimethyl formamide (50 ml) was added carefully. The reaction was stirred at room temperature for 30 minutes before 1-bromohexadecane (9.13 g, 29.90 mmol) was added and the reaction was stirred at room temperature under a nitrogen atmosphere for 12 hours. The reaction mixture was carefully partitioned between dichloromethane (100 ml) and water (100 ml×3). The organic layer was washed successively with saturated NaHCO3 (100 ml) and brine (100 ml), dried over sodium sulphate and evaporated to yield the crude product, which was purified by column chromatography eluting with (40-60) light petroleum: ethyl acetate (230:20). Fractions containing product were evaporated to dryness to give 1,2-dihexadecyl-3-trityl glycerol (8.00 g, 10.21 mmol) 68% yield
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:16][CH2:17][C:18]([N:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])=[O:19])=[N:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][CH:9]=1)([O-])=O>[C].[Pd].C(O)C>[NH2:1][C:4]1[C:5]([NH:16][CH2:17][C:18]([N:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])=[O:19])=[N:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][CH:9]=1
Reactant: CCCN(CCC)C(=O)CNc1nc(-c2ccccc2)ncc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCCN(CCC)C(=O)CNc1nc(-c2ccccc2)ncc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.2 %

Procedure:
A mixture of 2-(5-nitro-2-phenyl-4-pyrimidinylamino)-N,N-dipropylacetamide (1.9 g) obtained in Example 121, ethanol (60 ml) and 10% palladiumcarbon (0.2 g) is stirred at room temperature for three hours under hydrogen atmosphere, and the reaction mixture is filtered. The filtrate is concentrated under reduced pressure, and recrystallized from diethyl ether to give the desired compound (1.5 g), m.p. 120-122° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[C:5](=[O:25])[CH2:6][CH2:7][NH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([Cl:19])=[CH:15][C:16]=2[Cl:18])[NH:11][C:10]=1[C:20]([O:22]CC)=[O:21].[OH-].[Li+].O1CCCC1.O>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[C:5](=[O:25])[CH2:6][CH2:7][NH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([Cl:19])=[CH:15][C:16]=2[Cl:18])[NH:11][C:10]=1[C:20]([OH:22])=[O:21]
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCCC(=O)c1cccc(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CCNc1c(C(=O)O)[nH]c2cc(Cl)cc(Cl)c12)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.8 %

Procedure:
Mix 3-[(m-fluorophenacyl)methylamino]-2-carbethoxy-4,6-dichloroindole (700 mg, 1.7 mmol), lithium hydroxide (210 mg, 5 mmol), tetrahydrofuran (10 mL) and water (10 mL). Stir for 24 hours at room temperature. Dilute with ethyl acetate (40 mL). Acidify while stirring and separate the layers. Dry the organic phase over magnesium sulfate, filter and concentrate in vacuo. Recrystallize the residue (ethyl acetate/hexane) to yield the title compound as a white powder (590 mg, 91%); mp 270°-280° C.
Reaction SMILES: Br[Mg][C:3]1[CH:11]=[CH:10][C:6]2[CH2:7][CH2:8][O:9][C:5]=2[CH:4]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>C1COCC1.CCOCC>[O:9]1[C:5]2[CH:4]=[C:3]([C:12](=[O:14])[CH3:13])[CH:11]=[CH:10][C:6]=2[CH2:7][CH2:8]1
Reactant: Br[Mg]c1ccc2c(c1)OCC2
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)c1ccc2c(c1)OCC2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of bromo(2,3-dihydro-1-benzofuran-6-yl)magnesium (prepared from 6-bromo-2,3-dihydro-benzofuran (2.50 g, 12.56 mmol) and Mg (0.336 g, 13.8 mmol)) in THF (10 mL) was dropwise added to a solution of acetic anhydride (2.40 mL, 25.4 mmol) in Et2O (10 mL) held at −78° C. The reaction mixture was stirred at −78° C. for 1 h before the temperature was allowed to reach −10° C. over a period of 1 h. The reaction mixture was quenched by the addition of NH4Cl (aq, saturated, 20 mL) and the resulting mixture was extracted twice with Et2O (2×10 mL). The organic extracts were pooled, washed with NaOH (aq, 5%, 10 mL) and brine (10 mL), dried over MgSO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC using a gradient of 20-50% MeCN in a 0.1M ammonium acetate buffer as eluent. Freeze-drying of the pure fractions gave the desired product.