Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=O.ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.[ClH:33].Cl.[S:35]1[CH:39]=[C:38]([CH2:40][C@@H:41]([C:43]([N:45]2[CH2:52][CH2:51][CH2:50][C@H:46]2[C:47]([NH2:49])=[O:48])=[O:44])[NH2:42])[N:37]=[CH:36]1.C(N(CC)CC)C>CN(C)C=O>[ClH:33].[ClH:33].[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:42][C@H:41]([C:43]([N:45]1[CH2:52][CH2:51][CH2:50][C@H:46]1[C:47]([NH2:49])=[O:48])=[O:44])[CH2:40][C:38]1[N:37]=[CH:36][S:35][CH:39]=1)=[O:9]
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)Cc1cscn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1cscn1)NC(=O)[C@@H]1CCC(=O)N1
Reaction time: 2 h

Procedure:
L-Pyroglutamic acid (1.76 g, 13.64 mmol) and N-hydroxysuccinimide (1.73 g, 15 mmol) were dissolved in N,N-dimethylformamide (50 ml). To this solution was added the solution of DCC (3.09 g, 15 mmol) in N,N-dimethylformamide (10 ml) under ice-cooling and the resulting mixture was stirred for 2 h at, the same temperature. 3-(4-thiazolyl)-L-alanyl-L-prolineamide dihydrochloride (4) (6.67 g, 15 mmol) and triethylamine (4.6 ml. 33 mmol) were added successively to the solution and the reaction mixture was stirred overnight. After the precipitation which appeared was filtered off, to the filtrate was added sodium hydrogencarbonate aq. to adjust pH 8. The reaction mixture was subjected to gel filtration column chromatography (MCI gel CHP-20P, 200 ml, aq. MeOH) to give the compound (I-1) (2.54 g, 49%).
Reaction SMILES: C([C:5]1N=C(N2CCC(F)(F)C2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])N=2)[N:10]=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][C:39]([F:42])([F:41])[C:38]([F:44])([F:43])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].Cl.ClCC1N(C)C(C)=NN=1>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][C:39]([F:41])([F:42])[C:38]([F:43])([F:44])[CH2:37]2)[C:30]2[C:31](=[N:33][N:34]([CH2:8][C:9]3[N:10]([CH3:5])[C:14]([CH3:15])=[N:12][N:11]=3)[N:35]=2)[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: CC(C)(C)c1nc(N2CC(F)(F)C(F)(F)C2)c2nn[nH]c2n1
Agent: Cc1nnc(CCl)n1C
Agent: Cl
Product: Cc1nnc(Cn2nc3nc(C(C)(C)C)nc(N4CC(F)(F)C(F)(F)C4)c3n2)n1C

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-Butyl-7-(3,3,4,4-tetrafluoro-pyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(chloromethyl)-4,5-dimethyl-4H-1,2,4-triazole hydrochloride and isolated as white solid. MS (m/e): 428.3 (MH+).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[C:13](/[CH:15]=[C:16](\[O:21][CH3:22])/[C:17]([O:19]C)=[O:18])[CH:12]=[CH:11][C:10]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]([CH3:38])[C:30]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:31])[CH:24]=1)[CH3:4].O.Cl>O1CCCC1.CO>[CH2:3]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[C:13](/[CH:15]=[C:16](\[O:21][CH3:22])/[C:17]([OH:19])=[O:18])[CH:12]=[CH:11][C:10]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]([CH3:38])[C:30]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:31])[CH:24]=1)[CH3:4]
Reactant: CCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OC)C(=O)OC)cc2OCCOCC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OC)C(=O)O)cc2OCCOCC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
17 mg (4.2 mmol) of sodium hydroxide are added to a solution of 211 mg (0.42 mmol) of methyl (Z)-3-[2-(2-ethoxyethoxy)-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]-2-methoxyacrylate in 5 mL of tetrahydrofuran and 0.5 mL of methanol. The reaction mixture is stirred overnight at room temperature. After addition of 10 mL of water and acidification to pH 3 with 1 N hydrochloric acid, the reaction medium is extracted with ethyl acetate. The organic phases are combined, dried over sodium sulfate and evaporated, and the residue obtained is then purified by chromatography on a column of silica eluted with a 98/2 dichloromethane/methanol mixture. 160 mg (74%) of (Z)-3-[2-(2-ethoxyethoxy)-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]-2-methoxyacrylic acid are obtained in the form of white crystals. (m.p.=78.2° C.).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[NH:16][C:15]([CH3:22])=[CH:14]2>CC(O)=O>[Br:8][C:14]1[C:13]2[C:18](=[CH:19][CH:20]=[C:11]([O:10][CH3:9])[CH:12]=2)[C:17](=[O:21])[NH:16][C:15]=1[CH3:22]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2c(=O)[nH]c(C)cc2c1
Solvent: CC(=O)O
Product: COc1ccc2c(=O)[nH]c(C)c(Br)c2c1
Reaction time: 1 h
Yield: 99.1 %

Procedure:
NBS (6.9 g, 40 mmol) is added in one portion to ice-cold suspension of 6-methoxy-3-methyl-2H-isoquinolin-1-one (6.7 g, 35 mmol) in AcOH (100 ml). The ice bath is removed, and after 1 h, the mixture is concentrated in vacuo. The residue is diluted with water (40 ml) and basified with 10N—NaOH to pH 12. The resulting white solid is filtered and dried to give 9.3 g of 4-bromo-6-methoxy-3-methyl-2H-isoquinolin-1-one. 1H NMR (CDCl3) 8.10 (d, 1H), 7.14 (s, 1H), 7.08 (d, 1H), 3.89 (s, 3H), 2.37 (s, 3H).
Reaction SMILES: CO[C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:27])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]([F:26])([F:25])[F:24])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:4].[CH2:28]([NH2:33])[CH2:29][CH2:30][CH2:31][CH3:32].[C-]#N.[Na+]>>[CH2:28]([NH:33][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:11][CH2:12][N:13]([C:16](=[O:27])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]([F:26])([F:25])[F:24])[CH2:14][CH2:15]2)=[N:7][CH:6]=1)=[O:4])[CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCN
Reactant: COC(=O)c1cnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)s1
Agent: [C-]#N
Agent: [Na+]
Product: CCCCCNC(=O)c1cnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]thiazole-5-carboxylic acid methyl ester (0.317 g, 0.79 mmol), amylamine (2.0 mL) and NaCN (0.078 g, 1.59 mmol) was stirred at room temperature overnight. The title compound was obtained as a white powder after purification by column chromatography (0.207 g, 8.5% in 2 steps). m.p. 92-94° C. 1H NMR (300 MHz, CDCl3) δ 7.72 (d, J=7.5 Hz, 1H), 7.63-7.51 (m, 2H), 7.39 (s, 1H), 7.33 (d, J=7.5 Hz, 1H), 7.14-7.05 (m, 1H), 4.05-3.82 (m, 2H), 3.65-3.51 (m, 2H), 3.42-3.29 (m, 6H), 1.60-1.46 (m, 2H), 1.33-1.24 (m, 4H), 0.87 (t, J=4.2 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 170.1, 167.5, 161.2, 146.6, 134.2, 132.3, 129.5, 127.2, 126.8, 125.4, 121.7, 112.5, 48.1, 48.0, 40.8, 39.2, 29.4, 29.1, 22.3, 14.0. MS (ES+) m/z 455.0 (M+1).
Reaction SMILES: [CH2:1]=[O:2].[Cl:3][C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[CH2:6][N:7]1[C:11]([CH3:12])=[C:10]([CH3:13])[N:9]=[CH:8]1>C(O)(=O)C>[Cl:3][C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[CH2:6][N:7]1[C:11]([CH3:12])=[C:10]([CH3:13])[N:9]=[C:8]1[CH2:1][OH:2]
Reactant: C=O
Reactant: Cc1ncn(Cc2ccccc2Cl)c1C
Solvent: CC(=O)O
Product: Cc1nc(CO)n(Cc2ccccc2Cl)c1C
Temperature: 127.5 °C
Yield: 79 %

Procedure:
To a solution of 10 ml of glacial acetic acid and 10 ml of 37% formaldehyde is added 2.67 g (0.012 mol) of 1-(2′-chlorobenzyl)-4,5-dimethylimidazole. The mixture is stirred and heated in a sealed tube at 125-130° C. (oil bath temperature) overnight. After cooling, the solvent is evaporated in vacuo. The residue is subjected to chromatography on silica gel using dichloromethane-methanol (10:1) as eluent to give 2.39 g (79%) of 1-(2′-chlorobenzyl)-4,5-dimethyl-2-hydroxymethylimidazole as colorless powder. MS m/z (M++1) 251; 1H-NMR 400 MHz(δ, CDCl3): 1.94 (3H, s), 2.11 (3H, s), 4.53 (2H, s), 5.26 (2H, s), 6.42 (1H, dd, J=8, 1.2 Hz), 7.14(1H, td, J=8, 1.2Hz), 7.21 (1H, td, J=7.4, 1.6 Hz), 7.39 (1H, dd, J=8, 1.2 Hz) ppm.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.C(N(C(C)C)C(C)C)C.[CH2:21]([O:23][C:24]([C:26]1[C:27]([OH:33])=[N:28][C:29]([NH2:32])=[N:30][CH:31]=1)=[O:25])[CH3:22]>O1CCOCC1>[CH2:21]([O:23][C:24]([C:26]1[C:27]([OH:33])=[N:28][C:29]2[N:30]([CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=3)[N:32]=2)[CH:31]=1)=[O:25])[CH3:22]
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: CCOC(=O)c1cnc(N)nc1O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cn2cc(-c3ccc(F)cc3)nc2nc1O
Yield: 4 %

Procedure:
2-Bromo-1-(4-fluoro-phenyl)ethanone (200.1 mg, 0.922 mmol), ethyl-diisopropylamine (160.6 μl, 0.922 mmol) and 2-amino-4-hydroxy-pyrimidine-5-carboxylic acid ethyl ester (168.9 mg, 0.922 mmol) were heated under reflux in 50 ml dioxane for 8.5 hours. The mixture was evaporated. Ethyl acetate and water were added, the organic layer was separated, washed with water, dried and evaporated. The crude product was purified by preparative HPLC (RP18, acetonitrile/water 0.1% TFA) to yield 11 mg (4%) of the desired product. MS (mass spectrum): M+H+=302.11.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([C@@]1(O)[C@@H](CO)O[C@@](C(=O)C)([N:19]2[C:29]3[N:28]=[C:26]([NH2:27])[NH:25][C:23](=[O:24])[C:22]=3[N:21]=[CH:20]2)[C@]1(C(=O)C)O)(=O)C.Cl>C(#N)C>[CH2:1]([N:21]1[C:22]2[C:23](=[O:24])[NH:25][C:26]([NH2:27])=[N:28][C:29]=2[N:19]=[CH:20]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)[C@@]1(O)[C@@](O)(C(C)=O)[C@@H](CO)O[C@@]1(C(C)=O)n1cnc2c(=O)[nH]c(N)nc21
Reactant: BrCc1ccccc1
Agent: Cl
Solvent: CC#N
Product: Nc1nc2ncn(Cc3ccccc3)c2c(=O)[nH]1
Reaction time: 0.83 h
Yield: 85.8 %

Procedure:
Four milliliters of acetonitrile and 0.59 ml (2.7 equivalents) of benzyl bromide were added to 0.755 g (1.84 mmols) of triacetylguanosine, and the mixture was reacted at 50° C. for 16 hours. Subsequently, 2.5 ml (16.1 equivalents) of conc. hydrochloric acid were added thereto. The reaction was conducted at 50° C. for 50 minutes, and the temperature was then returned to room temperature. Then, the solid was precipitated. Fifteen milliliters of methanol were added thereto, and the slurry was stirred for 1 hour, and then filtered. The crystals were washed twice with 5 ml of methanol, and dried at 50° C. under reduced pressure for 2 hours to give 0.496 g of 7-benzylguanine crystals in a yield of 85.8%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[C:6]([CH2:8][CH2:9][C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[N:14][CH:15]=2)[CH:7]=1.[Cl:32][C:33]1[N:38]=[C:37](Cl)[C:36]([Cl:40])=[CH:35][N:34]=1>>[C:28]([O:27][C:25]([NH:24][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:35]2[C:36]([Cl:40])=[CH:37][N:38]=[C:33]([Cl:32])[N:34]=2)=[CH:7][C:6]=1[CH2:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[N:14][CH:15]=1)=[O:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CC(C)(C)OC(=O)Nc1cncc(CCc2cc(N)ccc2NC(=O)OC(C)(C)C)c1
Product: CC(C)(C)OC(=O)Nc1cncc(CCc2cc(Nc3nc(Cl)ncc3Cl)ccc2NC(=O)OC(C)(C)C)c1
Yield: 43 %

Procedure:
This compound was prepared according to the procedure of Example B19 step E, using tert-butyl [5-(2-{5-amino-2-[(tert-butoxycarbonyl)amino]phenyl}ethyl)pyridin-3-yl]carbamate and 2,4,5-trichloropyrimidine as the starting materials in 43% yield. LCMS calculated for C27H33Cl2N6O4(M+H)+: m/z=575.1, 577.1.
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[CH:26]=[CH:25][C:24]2[C:19](=[N: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[CH:26]=[CH:25][C:24]2[C:19](=[N:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1CN
Reactant: Clc1ccc2cccnc2n1
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1CNc1ccc2cccnc2n1
Yield: 70.8 %

Procedure:
The title compound (0.28 g) was prepared from (S)-2-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (0.35 g) and 2-chloro-1,8-naphthyridine (0.19 g) according to the method of D30.
Reaction SMILES: C(NC1C=CC(C2C=C3C(=CC=2)C(=O)N([C@@H](C(C)C)C(O)=O)C3)=CC=1)(=O)C1C=CC=CC=1.[C:33]([C:37]1[CH:69]=[CH:68][C:40]([C:41]([NH:43][C:44]2[CH:49]=[CH:48][C:47]([C:50]3[CH:51]=[C:52]4[C:56](=[CH:57][CH:58]=3)[C:55](=[O:59])[N:54]([C@@H:60]([CH:65]([CH3:67])[CH3:66])[C:61]([O:63]C)=[O:62])[CH2:53]4)=[CH:46][CH:45]=2)=[O:42])=[CH:39][CH:38]=1)([CH3:36])([CH3:35])[CH3:34]>>[C:33]([C:37]1[CH:69]=[CH:68][C:40]([C:41]([NH:43][C:44]2[CH:45]=[CH:46][C:47]([C:50]3[CH:51]=[C:52]4[C:56](=[CH:57][CH:58]=3)[C:55](=[O:59])[N:54]([C@@H:60]([CH:65]([CH3:66])[CH3:67])[C:61]([OH:63])=[O:62])[CH2:53]4)=[CH:48][CH:49]=2)=[O:42])=[CH:39][CH:38]=1)([CH3:35])([CH3:34])[CH3:36]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)cc3)ccc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=O)c4ccccc4)cc3)ccc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)cc3)ccc2C1=O
Yield: 76 %

Procedure:
The compound of example 323 was prepared analogous to compound of example 305 by hydrolysis of compound of example 322.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Br[CH:17]([CH3:21])[C:18](=O)[CH3:19]>>[CH3:21][C:17]1[N:1]=[C:2]2[C:7]([O:8][CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:6][CH:5]=[N:4][N:3]2[C:18]=1[CH3:19]
Reactant: Nc1nnccc1OCc1ccccc1
Reactant: CC(=O)C(C)Br
Product: Cc1nc2c(OCc3ccccc3)ccnn2c1C

Procedure:
Similarly, condensation of the 3-amino-4-phenylmethoxypyridazine with 3-bromo-2-butanone gives the 2,3-dimethyl-8-phenylmethoxyimidazo[1,2-b]pyridazine as shown in the following reaction Scheme IV: ##STR16##
Reaction SMILES: [Cl:1][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])[NH:7][C:6](=[O:20])[NH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:27][Si:28]([CH3:35])([CH3:34])[CH2:29][CH2:30][O:31][CH2:32]Cl>CN(C=O)C>[Cl:1][C:2]1[N:10]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[C:9]2[C:8](=[O:19])[NH:7][C:6](=[O:20])[N:5]([CH2:32][O:31][CH2:30][CH2:29][Si:28]([CH3:35])([CH3:34])[CH3:27])[C:4]=2[N:3]=1
Reactant: O=c1[nH]c(=O)c2c(nc(Cl)n2Cc2ccc(Cl)cc2)[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(=O)[nH]c(=O)c2c1nc(Cl)n2Cc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 39.1 %

Procedure:
To a solution of 8-chloro-7-(4-chlorobenzyl)-1H-purine-2,6(3H,7H)-dione (450 mg, 1.45 mmol) in DMF (20 mL) was added potassium carbonate (0.4 g, 2.90 mmol), followed by 2-(trimethylsilyl)ethoxymethyl chloride (0.7 mL, 3.96 mmol) at 0° C. The resulting mixture was stirred at 60° C. for 16 h. The mixture was partitioned between ethyl acetate and water. The combined organic phase was washed with brine, dried over sodium sulfate, and concentrated to give crude product. This material was purified by silica gel chromatography eluting with petroleum/ethyl acetate (3:1 to 1:1) to give 8-chloro-7-(4-chlorobenzyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (250 mg, 39.2% yield) as yellow oil. LCMS retention time 1.886; LCMS MH+-28 413.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:24])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)[C:11]([CH3:23])([CH3:22])[CH2:10]2)=[O:4].[CH3:25][N:26]([CH3:36])[C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C(OCC)(=O)C.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>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:24])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:16]=[C:17]([C:30]3[CH:31]=[CH:32][C:27]([N:26]([CH3:36])[CH3:25])=[CH:28][CH:29]=3)[CH:18]=[CH:19][CH:20]=1)[C:11]([CH3:23])([CH3:22])[CH2:10]2)=[O:4]
Reactant: CN(C)c1ccc(B(O)O)cc1
Reactant: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(Br)c1)C(C)(C)C2
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: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(-c3ccc(N(C)C)cc3)c1)C(C)(C)C2
Yield: 89.8 %

Procedure:
To a mixture of 2-(3-bromo-phenyl)-6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (680 mg, 1.67 mmol), 4-dimethylaminophenylboronic acid (358 mg, 1.3 mmol) and tetrakis(triphenylphosphine)palladium(0) (193 mg, 0.17 mmol) in dioxane (5.0 mL) was added 2 M sodium carbonate solution in water (1.7 mL). The resulting mixture was subjected to microwave irradiation for 2 h at 110° C. The mixture was diluted with ethyl acetate (200 mL), washed with saturated aqueous sodium bicarbonate solution (50 mL×2), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (10% ethyl acetate/hexanes) afforded 6-chloro-2-(4′-dimethylamino-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (524 mg, 70.0%) as a white solid: LC/MS m/e calcd for C27H29ClN2O2 (M+H)+: 450.01, observed: 449.1.
Reaction SMILES: [OH:1][CH:2]=[C:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:4]([O:6][CH3:7])=[O:5].[C:22](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.O>CN(C=O)C>[CH3:22][O:1]/[CH:2]=[C:3](\[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)/[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(=CO)c1ccccc1OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: O
Solvent: CN(C)C=O
Product: CO/C=C(/C(=O)OC)c1ccccc1OCc1ccccc1
Yield: 17 %

Procedure:
The crude methyl 3-hydroxy-2-(2'-benzyloxyphenyl)propenoate was dissolved in dry DMF (100 ml) and potassium carbonate (29.0 g) was added in one portion. Dimethyl sulphate (16.00 g) in dry DMF (10 ml) was then added dropwise with stirring. After ninety minutes, water (300 ml) was added and the solution was extracted with ether (2×300 ml). After washing with water (3×150 ml) and brine, the extracts were dried and concentrated under reduced pressure, and the resulting yellow oil solidified on trituation with ether/petrol. Recrystallization from dry methanol afforded E-methyl 3-methoxy-2-(2'-benzyloxyphenyl)propenoate as a white, crystalline solid (5.44 g, 17% yield from methyl 2-bemnzyloxyphenylacetate), M.P. 76°-77° C.; infrared maxima (nujol mull): 1710, 1640 cm-1 ; 1H nmr (CDCl3, 90 MHz): delta 3.63 (3H, s), 3.75 (3H, s), 5.05 (2H, s), 6.80-7.40 (9H, m), 7.50 (1H, s) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([N+:10]([O-])=O)[CH:4]=1>C(O)C.[C].[Pd]>[NH2:10][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[OH:9]
Reactant: COc1ccc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(O)c(N)c1
Yield: 93 %

Procedure:
20 g of 4-methoxy-2-nitrophenol was suspended in 350 ml of ethanol. Thereto was added 550 mg of 5% palladium-carbon. The mixture was subjected to hydrogenation at 20°-30° C. at atmospheric pressure. After the completion of the reaction, the catalyst was removed by filtration and then the solvent was removed by distillation under reduced pressure. The resulting crystal was recrystallized from isopropyl alcohol to obtain 15.3 g (yield: 93%) of 2-amino-4-methoxyphenol.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1.[O-:23][S:24]([O-:26])=[O:25].[Na+:27].[Na+].O>CCO>[Na+:27].[CH2:16]([O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][S:24]([O-:26])(=[O:25])=[O:23])=[CH:10][CH:11]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=S([O-])[O-]
Reactant: BrCCCCCCCc1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=S(=O)([O-])CCCCCCCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
A stirred mixture of 10.1 (0.9 g, 2.50 mmol) and anhydrous Na2SO3 (0.423 g, 3.36 mmol) in EtOH (20 mL)/H2O (10 ml) was heated under reflux (6 h) or microwaved using a CEM-discover system (ram time: 2 min, hold time: 5 min, temperature: 150° C., pressure: 250 psi, power: 250 W). The reaction mixture was cooled to room temperature and the solvent evaporated under reduced pressure. The residue obtained was scrupulously dried under high vacuum and the crude product (10.1, pale yellow solid) was used in the next step without further purification.
Reaction SMILES: CO[C:3]([C:5]1([CH2:15][CH:16]=O)[CH2:10][CH2:9][CH:8]([C:11]([O:13][CH3:14])=[O:12])[CH2:7][CH2:6]1)=[O:4].[CH3:18][CH:19]1[CH2:23][CH2:22][CH2:21][N:20]1[CH:24]1[CH2:28][CH2:27][C@H:26]([C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)[CH2:25]1>>[CH3:14][O:13][C:11]([CH:8]1[CH2:7][CH2:6][C:5]2([C:3](=[O:4])[N:35]([C:32]3[CH:33]=[CH:34][C:29]([CH:26]4[CH2:27][CH2:28][CH:24]([N:20]5[CH2:21][CH2:22][CH2:23][CH:19]5[CH3:18])[CH2:25]4)=[CH:30][CH:31]=3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=[O:12]
Reactant: COC(=O)C1CCC(CC=O)(C(=O)OC)CC1
Reactant: CC1CCCN1C1CC[C@H](c2ccc(N)cc2)C1
Product: COC(=O)C1CCC2(CC1)CCN(c1ccc(C3CCC(N4CCCC4C)C3)cc1)C2=O

Procedure:
The title compound was synthesized in the manner essentially the same as the Example 1 by condensing 1-(2-oxo-ethyl)-cyclohexane-1,4-dicarboxylic acid dimethyl ester (Intermediate 5) with 4-[(S)-3-(2-methyl-pyrrolidin-1-yl)-cyclopentyl]-phenylamine (Intermediate 15), and subsequently cyclization.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:20]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[CH2:21][C:22]([NH:24][CH:25]3[CH2:28][CH2:27][CH2:26]3)=[O:23])([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH3:35][N:36]([CH3:40])[C:37](Cl)=[O:38].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH3:35][N:36]([CH3:40])[C:37]([N:32]1[CH2:31][CH2:30][CH:29]([N:20]([C:6]2([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C:5]3[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=3)[NH:8][C:7]2=[O:11])[CH2:21][C:22](=[O:23])[NH:24][CH:25]2[CH2:26][CH2:27][CH2:28]2)[CH2:34][CH2:33]1)=[O:38]
Reactant: O=C(CN(C1CCNCC1)C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21)NC1CCC1
Reactant: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CN(C)C(=O)N1CCC(N(CC(=O)NC2CCC2)C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)CC1
Reaction time: 1 h
Yield: 22.7 %

Procedure:
At room temperature, rac-2-{[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidin-4-yl-amino}-N-cyclobutyl-acetamide (77 mg, 0.154 mmol) and dimethylcarbamyl chloride (14 mg, 0.185 mmol) and K2CO3 were mixed in about 2 ml CH2Cl2. After stirred for about 1 h, the solution was concentrated and the crude product was purified by chromatography to obtain 20 mg solid rac-4-{[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-cyclobutylcarbamoylmethyl-amino}-piperidine-1-carboxylic acid dimethylamide.
Reaction SMILES: O=C1CCCN1C1C=C(C=C(N2CCCC2=O)C=1)C(O)=O.[C@@H:22]([O:26][C:27]1[CH:28]=[C:29]([CH:34]=[C:35]([N:37]2[CH2:41][CH2:40][CH2:39][C:38]2=[O:42])[CH:36]=1)[C:30]([O:32]C)=[O:31])([CH2:24][CH3:25])[CH3:23]>>[C@@H:22]([O:26][C:27]1[CH:28]=[C:29]([CH:34]=[C:35]([N:37]2[CH2:41][CH2:40][CH2:39][C:38]2=[O:42])[CH:36]=1)[C:30]([OH:32])=[O:31])([CH2:24][CH3:25])[CH3:23]
Reactant: CC[C@H](C)Oc1cc(C(=O)OC)cc(N2CCCC2=O)c1
Agent: O=C(O)c1cc(N2CCCC2=O)cc(N2CCCC2=O)c1
Product: CC[C@H](C)Oc1cc(C(=O)O)cc(N2CCCC2=O)c1

Procedure:
Prepared in an analogous manner to D8 from methyl 3-((S)-sec-butyloxy)-5-(2-oxopyrrolidin-1-yl)benzoate (D44).