Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:20][OH:21])[CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1.C(OC([N:29]1[C:37]2[N:32]([C:33](=[O:39])[N:34]=[C:35](Cl)[CH:36]=2)[CH2:31][C@@H:30]1[CH3:40])=O)(C)(C)C>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=1)[CH2:20][O:21][C:35]1[CH:36]=[C:37]2[NH:29][C@@H:30]([CH3:40])[CH2:31][N:32]2[C:33](=[O:39])[N:34]=1
Reactant: OCc1cc(F)c(Oc2ccnc(C(F)(F)F)c2)c(F)c1
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C(=O)OC(C)(C)C
Product: C[C@H]1Cn2c(cc(OCc3cc(F)c(Oc4ccnc(C(F)(F)F)c4)c(F)c3)nc2=O)N1

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol and (S)-tert-butyl-7-chloro-2-methyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]([CH2:11][C:12]2[CH:13]=[C:14]([C:18]3[CH:22]=[C:21]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:20][C:19]=3[S:27]([NH:30]C(C)(C)C)(=[O:29])=[O:28])[CH:15]=[CH:16][CH:17]=2)[CH:8]=[CH:9][N:10]=1.B(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+].Cl[C:46]([O:48][CH2:49][CH2:50][CH2:51][CH3:52])=[O:47]>C(Cl)Cl.O>[CH2:49]([O:48][C:46]([NH:30][S:27]([C:19]1[S:20][C:21]([CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:22][C:18]=1[C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH2:11][N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH:13]=1)(=[O:29])=[O:28])=[O:47])[CH2:50][CH2:51][CH3:52]
Reactant: CCCCOC(=O)Cl
Reactant: CC(C)Cc1cc(-c2cccc(Cn3ccnc3-c3cccs3)c2)c(S(=O)(=O)NC(C)(C)C)s1
Agent: ClB(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCCCOC(=O)NS(=O)(=O)c1sc(CC(C)C)cc1-c1cccc(Cn2ccnc2-c2cccs2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To a solution of 3-[3-(2-thiophen-2-yl-imidazol-1-ylmethyl)phenyl]-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (42 mg, 0.082 mmol; see step (a)) in CH2Cl2 (1 mL) was added BCl3 (0.3 mL, 1.0 M in hexane) and the reaction mixture was stirred for 1 h at ambient temperature. The reaction mixture was concentrated in vacuo. Water (5 mL) was added to the residue and this was then extracted with EtOAc. The combined organic phase was washed with water and brine, dried (over anhydrous MgSO4) and concentrated in vacuo. To the crude product dissolved in CH2Cl2 (5 mL) was added Na2CO3 (39.0 mg, 0.377 mmol), water (2 mL) and butyl chloroformate (15.6 μL, 0.0123 mmol), and the reaction mixture was stirred for 9 h at ambient temperature. The reaction mixture was diluted with CH2Cl2 (30 mL) and washed with citric acid (10% aq), brine and water, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue purified by LCMS (20-100% CH3CN in water) to give the title compound as a white solid in 55% yield, over two steps, (25 mg, 0.045 mmol).
Reaction SMILES: [C:1](=O)([O:43]C1C=CC([N+]([O-])=O)=CC=1)[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@H:10]([NH:31][C:32]([O:34][C@@H:35]2[C@H:42]3[C@H:38]([O:39][CH2:40][CH2:41]3)[O:37][CH2:36]2)=[O:33])[C@H:11]([OH:30])[CH2:12][N:13]([S:18]([C:21]2[CH:29]=[CH:28][C:24]3[O:25][CH2:26][O:27][C:23]=3[CH:22]=2)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:5][CH:4]=1.[N:54]1([CH2:59][CH2:60][NH2:61])[CH:58]=[CH:57][N:56]=[CH:55]1>O1CCOCC1.C(OCC)(=O)C>[O:25]1[C:24]2[CH:28]=[CH:29][C:21]([S:18]([N:13]([CH2:14][CH:15]([CH3:16])[CH3:17])[CH2:12][C@@H:11]([OH:30])[C@@H:10]([NH:31][C:32](=[O:33])[O:34][C@@H:35]3[C@H:42]4[C@H:38]([O:39][CH2:40][CH2:41]4)[O:37][CH2:36]3)[CH2:9][C:6]3[CH:5]=[CH:4][C:3]([O:2][C:1]([NH:61][CH2:60][CH2:59][N:54]4[CH:58]=[CH:57][N:56]=[CH:55]4)=[O:43])=[CH:8][CH:7]=3)(=[O:20])=[O:19])=[CH:22][C:23]=2[O:27][CH2:26]1
Reactant: NCCn1ccnc1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OC(=O)NCCn2ccnc2)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.9 %

Procedure:
To a solution of 4-{(2S,3R)-2-({[(3R,3aS,6aR)-Hexahydrofuro [2,3-b]furan-3-yloxy]carbonyl}amino)-4-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-3-hydroxybutyl}phenyl 4-nitrophenyl carbonate (50 mg, 0.07 mmol) in 1,4-dioxane (1 mL) was added 2-(1H-imidazol-1-yl)ethanamine (50 mg, 0.45 mmol, Synthetic Communications 1991, 21, 535-544) and the mixture was stirred at ambient temperature for 30 min. The mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate/water (4×), dried (sodium sulfate), evaporated and purified by chromatography (silica gel, dichloromethane/2M ethanolic ammonia, 93:7) to provide the title compound as a white solid (25 mg). 1H NMR (DMSO-d6): δ 0.78 (3H, d), 0.82 (3H, d), 1.2 (1H, dd), 1.4 (1H, quintuplet), 1.9-2.0 (1H, m), 2.4 (1H, t), 2.55-2.80 (3H, m), 2.9-3.0 (2H, m), 3.3-3.4 (3H, m), 3.5-3.6 (4H, m), 3.7 (1H, t), 3.8 (1H, dd), 4.03-4.07 (2H, m), 4.8 (1H, dt), 0.505 (1H, d), 5.5 (1H, d), 6.18 (2H, s), 6.87 (1H, s), 6.9 (2H, d), 7.05 (1H, d), 7.15 (1H, s), 7.2 (2H, d), 7.23 (1H, s), 7.25-7.30 (2H, m), 7.6 (1H, s), 7.8 (1H, t); MS: 730 (MH+)
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[C@@H:10]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[Cl:56][C:57]1[CH:67]=[CH:66][C:60]([O:61][CH:62]2[CH2:65][NH:64][CH2:63]2)=[CH:59][CH:58]=1>ClCCl>[CH2:1]([O:8][C:9](=[O:23])[C@@H:10]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C:12]([N:64]1[CH2:65][CH:62]([O:61][C:60]2[CH:59]=[CH:58][C:57]([Cl:56])=[CH:67][CH:66]=2)[CH2:63]1)=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)C(=O)OCc1ccccc1
Reactant: Clc1ccc(OC2CNC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CC(Oc2ccc(Cl)cc2)C1)C(=O)OCc1ccccc1
Reaction time: 3 h

Procedure:
A solution of (S)-2-tert-butoxycarbonylamino-succinic acid 1-benzyl ester (5.0 g, 13.99 mmol) in dichloromethane (50 ml) is treated with diisopropylethylamine (7.51 ml, 41.97 mmol) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium tetrafluoroborate (4.49 g, 13.99 mmol). To the reaction mixture is added 3-(4-chloro-phenoxy)-azetidine hydrochloride (3.06 g, 13.99 mmol) and stirring continued for 3 hours. The dichloromethane is evaporated and residue partitioned between ethylacetate and saturated NaHCO3 solution. The ethylacetate phase is washed with 1M HCl solution and brine, dried over MgSO4 and evaporated. The crude product is purified by flash silica chromatography (elution with 1:1 ethylacetate/hexane) to afford (S)-2-tert-butoxycarbonylamino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]4-oxo-butyric acid benzyl ester. [M-BOC] 389.0.
Reaction SMILES: [CH:1]1([CH2:6][O:7][C:8]2[C:9]([NH2:21])=[N:10][CH:11]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:22](N1C=CN=C1)([N:24]1C=CN=C1)=[S:23].[NH4+].[OH-].O>C1COCC1>[CH:1]1([CH2:6][O:7][C:8]2[C:9]([NH:21][C:22]([NH2:24])=[S:23])=[N:10][CH:11]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1ncc(Oc2ccccc2)cc1OCC1CCCC1
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NC(=S)Nc1ncc(Oc2ccccc2)cc1OCC1CCCC1
Reaction time: 22 h
Yield: 70 %

Procedure:
3-Cyclopentylmethoxy-5-phenoxy-pyridine-2-ylamine (0.97 mmol) is dissolved in THF (10 ml) and 1,1′-thiocarbonyldiimidazole (4 eq.) is added. The reaction solution is stirred 22 hours. 32% NH4OH (20 eq.) is added and stirred 2 hours at room temperature. Water (250 ml) is added and extracted with dichloromethane. The combined organic layers are washed with brine and dried over MgSO4. The solvent is removed in vacuo. (3-Cyclopentylmethoxy-5-phenoxy-pyridine-2-yl)-thiourea is obtained as yellow solid in a yield of 70%. HPLC (method C): 2.24 min; LC-MS (method A): 2.372 min, 344.15 (MH+).
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C@@H:16]([CH2:17][O:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][C@@H:14]([N:27]2[CH:35]=[N:34][C:33]3[C:28]2=[N:29][CH:30]=[N:31][C:32]=3[NH2:36])[C@H:13]([OH:37])[CH2:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(#N)C.[C:41]1([O:47][C:48](Cl)=[S:49])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.CO>[C:1]([O:9][CH2:10][C@@H:11]1[C@@H:16]([CH2:17][O:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][C@@H:14]([N:27]2[CH:35]=[N:34][C:33]3[C:28]2=[N:29][CH:30]=[N:31][C:32]=3[NH2:36])[C@H:13]([O:37][C:48]([O:47][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[S:49])[CH2:12]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: S=C(Cl)Oc1ccccc1
Reactant: Nc1ncnc2c1ncn2[C@@H]1C[C@H](COC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)C[C@H]1O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: Nc1ncnc2c1ncn2[C@@H]1C[C@H](COC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)C[C@H]1OC(=S)Oc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 57 %

Procedure:
In an atmosphere of argon gas, 9-[(1R,2R,4S,5S)-4,5-bis(benzoyloxymethyl)-2-hydroxycyclohexyl]-adenine (151 mg, 0.3 mmole) was dissolved into acetonitrile (5 ml), to which were then added 4-dimethylaminopyridine (75.1 mg, 0.62 mmole) and phenyloxythiocarbonyl chloride (57 μl, 0.33 mmole). After stirring the resulting mixture at room temperature for 24 hours. 0.1M aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was subjected to extraction with ethyl acetate. The extract solution was washed with water and then with saturated aqueous solution of sodium chloride and dried on anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride:methanol=50:1, v/v) to obtain 9-[(1R,2R,4S,5S)-4,5-bis(benzoyloxymethyl)-2-(phenoxythiocarbonyloxy)cyclohexyl]-adenine (109 mg, Yield 56.8%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[N:7]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][Si](C(C)(C)C)(C)C)=[CH:22][CH:21]=1)[C:8]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][N:16]=2)[N:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl.C1COCC1>[C:1]([O:5][C:6](=[O:34])[N:7]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[C:8]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][N:16]=2)[N:11]=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(O[Si](C)(C)C(C)(C)C)cc1)c1ncnc2nccnc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CCc1ccc(O)cc1)c1ncnc2nccnc12
Reaction time: 18 h

Procedure:
{2-[4-(tert-Butyldimethylsilanyloxy)-phenyl]-ethyl}-pteridin-4-yl-carbamic acid tert-butyl ester (680 mg, 1.4 mmol) was dissolved in 5 mL CH2Cl2 and treated with tetrabutylammonium fluoride 3H2O in 10 mL THF. After stirring for 18 h, the solution was washed with H2O, dried (Na2SO4), suction filtered, and concentrated in vacuo to give [2-(4-hydroxyphenyl)-ethyl]-pteridin-4-yl-carbamic acid tert-butyl ester as a tan solid, mp 132-134° C. (dec.); ESIMS m/z ([M+H]+) 368.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([CH2:12][C:13]([OH:15])=[O:14])=[C:7]([CH3:16])[C:6]=1[OH:17])([CH3:4])([CH3:3])[CH3:2].[CH2:18](O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([CH2:12][C:13]([O:15][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH3:18])=[O:14])=[C:7]([CH3:16])[C:6]=1[OH:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C)c1CC(=O)O
Reactant: CCCCCCCCCCCCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOC(=O)Cc1c(C)cc(C(C)(C)C)c(O)c1C

Procedure:
10.68 grams of the compound of Example 5, 11.4 grams of n-octadecanol and 0.8 grams of p-toluene sulfonic acid monohydrate were dispersed in 150 ml of toluene and heated at reflux for seven hours during which the water collected by azeotropic distillation was almost equal to the theory. The reaction mixture was successively washed with water, aqueous saturated sodium bicarbonate solution, and then with water once again until the wash water was neutral. After drying over anhydrous sodium sulfate and filtering free of the drying agent, the clear filtrate was evaporated at reduced pressures to yield the desired product as residue. After successive crystallizations from acetonitrile and n-heptane, the desired compound was isolated as white crystals melting at 57° to 59° C (Compound 1).
Reaction SMILES: [I:1][C:2]1[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=2)=[N:4][NH:5][CH:6]=1.[C:16](=[O:19])([O-])[O-].[Cs+].[Cs+].[Cl-].O>CN(C)C=O>[I:1][C:2]1[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=2)=[N:4][N:5]([CH2:3][C:7]2[CH:12]=[CH:11][C:10]([O:19][CH3:16])=[CH:9][CH:8]=2)[CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cccc(-c2n[nH]cc2I)c1
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2cc(I)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
2 g (6.3 mmol) of 4-iodo-3-(3-nitrophenyl)-1H-pyrazole were dissolved in 20 ml of dry dimethylformamide and 2.46 g (7.5 mmol) of cesium carbonate and 0.85 ml (6.3 mmol) of p-methoxybemzyl chloride were added successively. The reaction mixture was heated at 70° C. under stirring for 5 hours. Water was then added and the product extracted with dichloromethane. The organic phase was dried over sodium sulphate and the solvent evaporated under reduced pressure. 2.4 g (86%) of the title compound crystallized from a mixture diethylether-diisopropylether.
Reaction SMILES: C[N:2]([CH3:19])[C:3]([C:5]1[N:14]([CH:15]2[CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:20]([O:24][C:25]([N:27]1[CH:32]2[CH2:33][CH2:34][CH:28]1[CH2:29][N:30]([C:35]([C:37]1[CH:38]=[N:39][C:40]([NH2:43])=[CH:41][CH:42]=1)=[O:36])[CH2:31]2)=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([O:24][C:25]([N:27]1[CH:28]2[CH2:34][CH2:33][CH:32]1[CH2:31][N:30]([C:35]([C:37]1[CH:38]=[N:39][C:40]([NH:43][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[NH:2][CH3:19])[N:14]([CH:15]5[CH2:16][CH2:17][CH2:18]5)[C:8]=4[N:9]=3)=[CH:41][CH:42]=1)=[O:36])[CH2:29]2)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCC1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)c1ccc(N)nc1)C2
Product: CNC(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5C(=O)OC(C)(C)C)cn3)nc2n1C1CCC1
Yield: 54.2 %

Procedure:
Following general N—C coupling procedure 1, 2-Chloro-7-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (200 mg, 0.718 mmol, 1.0 eq) was combined with 3-(6-Amino-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (262 mg, 0.789 mmol, 1.1 eq) to give 3-[6-(7-Cyclobutyl-6-methylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (218 mg, 50% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.51 (s, 9H) 1.62 (br. s., 1H) 1.67 (br. s., 1H) 1.77-2.07 (m, 6H) 2.41-2.58 (m, 2H) 3.17 (s, 6H) 3.19-3.29 (m, 2H) 3.64 (br. s., 1H) 4.28 (br. s., 2H) 4.54 (br. s., 1H) 5.01 (dq, J=8.84, 8.67 Hz, 1H) 6.50 (s, 1H) 7.83 (dd, J=8.84, 2.27 Hz, 1H) 8.42 (d, J=2.02 Hz, 2H) 8.67 (d, J=9.09 Hz, 1H) 8.78 (s, 1H); MS m/z 574.9 (M+H)+.
Reaction SMILES: Cl.ClC1C2NC(=O)C=CC=2CCC1.O.N.O.O.O.[OH:19][CH:20]1[C:29]2[NH:28][C:27](=[O:30])[CH:26]=[CH:25][C:24]=2[CH2:23][CH2:22][CH2:21]1>C(Cl)(Cl)Cl>[O:19]=[C:20]1[C:29]2[NH:28][C:27](=[O:30])[CH:26]=[CH:25][C:24]=2[CH2:23][CH2:22][CH2:21]1
Reactant: O=c1ccc2c([nH]1)C(O)CCC2
Agent: Cl
Agent: N
Agent: O=c1ccc2c([nH]1)C(Cl)CCC2
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C1CCCc2ccc(=O)[nH]c21
Reaction time: 3 h
Yield: 83.2 %

Procedure:
110 g (0.5 mol) of 8-chloro-5,6,7,8-tetrahydro-2-quinolone hydrochloride are heated with 500 ml of water to about 90° C. with agitation, thus obtaining after a short time a transparent solution which is then neutralized with 75 ml of concentrated ammonia. After cooling of the solution, 105 g of 8-hydroxy-5,6,7,8-tetrahydro-2-quinolone trihydrate areisolated having a melting point of 192° C., which correspond to a yield of 85.7% of theory. 105 g (0.48 mol) of trihydrate are heated with 2liters of chloroform while stirring, the hydration water is removed in the form of an azeotropic mixture, and the chloroform phase of the distillate is recycled to the flask. After this operation is complete, 350 g of manganese dioxide (precipitated in an active form) are added to the chloroform solution in portions and in such a manner that the reaction temperature does not exceed 40° C. Intense agitation is continued at this temperature for 3 hours. Subsequently, the batch is separated fromthe manganese dioxide, the chloroform is distilled off, and 65 g of light brown 8-oxo-5,6,7,8-tetrahydro-2-quinolone, corresponding to a yield of 83% of theory, are isolated, which after recrystallization from cyclohexanone has a melting point of 253° C. in a closed vial.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:37])[CH2:16][N:17]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:18]2([CH3:29])[CH2:26][C:25]3[C:20](=[CH:21][C:22]([CH3:28])=[C:23]([CH3:27])[CH:24]=3)[CH2:19]2)=[CH:11][C:10]=1[N+:38]([O-:40])=[O:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:41](OC(=O)C)(=[O:43])[CH3:42]>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:37][C:41](=[O:43])[CH3:42])[CH2:16][N:17]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:18]2([CH3:29])[CH2:26][C:25]3[C:20](=[CH:21][C:22]([CH3:28])=[C:23]([CH3:27])[CH:24]=3)[CH2:19]2)=[CH:11][C:10]=1[N+:38]([O-:40])=[O:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc2c(cc1C)CC(C)(N(Cc1ccccc1)C[C@H](O)c1ccc(OCc3ccccc3)c([N+](=O)[O-])c1)C2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)O[C@@H](CN(Cc1ccccc1)C1(C)Cc2cc(C)c(C)cc2C1)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Reaction time: 18 h

Procedure:
To a solution of (R)-1-(4-Benzyloxy-3-nitro-phenyl)-2-[benzyl-(2,5,6-trimethyl-indan-2-yl)-amino]-ethanol in pyridine is added acetic anhydride and the mixture stirred for 18 hours. The reaction mixture is quenched with water and after addition of ethyl acetate washed twice with aqueous KHSO4 solution, twice with aqueous NaHCO3 and once with brine. The product is purified by chromatoghaphy (silica, ethyl acetate/hexane 1:4). ES+ MS m/e 579 (MH+)
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:21][N:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[Sn](CCCC)(CCCC)CCCC>>[CH3:21][N:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:2]1[CH:20]=[CH:19][C:5]([N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccn1C
Product: Cn1cccc1-c1ccc(N(c2ccccc2)c2ccccc2)cc1

Procedure:
As shown in scheme 1, 4-bromo-N,N-diphenylaniline (11) is reacted with 1-methyl-2-(tributylstannyl)-1H-pyrrole by Stille coupling reaction to obtain 4-(1-methyl-1H-pyrrole-2-yl)-N,N-diphenylaniline (12). n-butyl lithium is reacted with 4-(1-methyl-1H-pyrrole-2-yl)-N,N-diphenylaniline (12), and then tributylstannylchloride is added thereto to obtain 4-(1-methyl-5-(tributylstannyl)-1H-pyrrole-2-yl)-N,N-diphenylaniline (13). 4-(1-methyl-5-(tributylstannyl)-1H-pyrrole-2-yl)-N,N-diphenylaniline (13) is reacted with 4-bromobenzaldehyde by Stille coupling reaction to obtain 4-(5-(4-(diphenylamino)phenyl)-1-methyl-1H-pyrrol-2-yl)benzaldehyde (14a). Finally, 4-(5-(4-(diphenylamino)phenyl)-1-methyl-1H-pyrrol-2-yl)benzaldehyde (14a) is reacted with cyanoacetic acid in acetic acid by using ammonium acetate as a catalyst, and (E)-2-cyano-3-[4-(5-(4-(diphenyl-amino)phenyl)-1-methyl-1H-pyrrol-2-yl)]phenyl)acrylic acid (15a) is synthesized.
Reaction SMILES: O[CH:2]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1)=[O:4].OC1C=C(C(=O)C)C=CC=1.O.C(O)C>O.[Zn]>[OH:11][C:7]1[CH:6]=[C:5]([C:3](=[O:4])[CH2:2][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(c1cccc(O)c1)C(O)c1cccc(O)c1
Agent: CC(=O)c1cccc(O)c1
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: O=C(Cc1cccc(O)c1)c1cccc(O)c1
Reaction time: 11 h

Procedure:
2-Hydroxy-1,2-bis(3-hydroxyphenyl)ethanone was reduced by the procedure of M. Pisova and M. Soncek [Coll. Czech, Chem. Comm., 38, 3876 (1973)]. A mixture of 2-hydroxy-1,2-bis(3-hydroxyphenylethanone (18 g.) chromic sulfate hydrate (20.9% Cr; 60 g.), zinc dust (49 g.) and water-ethanol (1:1, 1 liter) was stirred under an atmosphere of nitrogen for 11 hours. The mixture was diluted with water and extracted with three portions of ethyl acetate. The organic solution was washed with saturated brine solution and dried over magnesium sulfate. The solution was concentrated and the product crystallized from ethyl acetate-benzene (seeding); yield: 8.51 g., m.p. 155°-156°.
Reaction SMILES: [CH2:1]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:15][CH2:16][C:17](Cl)=[O:18]>ClCCCl>[CH2:1]([N:8]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:17](=[O:18])[CH2:16][Cl:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)NCc1ccccc1
Reactant: O=C(Cl)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: CC(C)(C)N(Cc1ccccc1)C(=O)CCl
Reaction time: 1 h

Procedure:
To a stirred and cooled mixture of 33 parts of N-benzylN-tert.-butylamine in 60 parts of sodium hydroxide solution 20% and 160 parts of 1,2-dichloroethane are added dropwise 34 parts of 2-chloroacetyl chloride at a temperature between -5° and -10° C. Upon completion, stirring is continued at the same temperature for one hour. The reaction mixture is allowed to reach room temperature and the organic layer is separated, washed with water, dried and evaporated, yielding 43 parts of N-benzylN-tert.-butyl-2-chloroacetamide as a residue.
Reaction SMILES: C([O:5][C:6](=[O:38])[C@@H:7]([NH:28][S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:31])=[O:30])[CH2:8][NH:9][C:10]([C:12]1[CH:13]=[C:14]2[N:19]([C:20](=[O:22])[CH:21]=1)[CH:18]=[C:17]([O:23][CH2:24][CH2:25][CH2:26][NH2:27])[CH:16]=[CH:15]2)=[O:11])(C)(C)C.C(N(CC)CC)C.[CH3:46][N:47]=[C:48]=[O:49]>C(#N)C>[C:32]1([S:29]([NH:28][C@@H:7]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[C:14]3[N:19]([C:20](=[O:22])[CH:21]=2)[CH:18]=[C:17]([O:23][CH2:24][CH2:25][CH2:26][NH:27][C:48]([NH:47][CH3:46])=[O:49])[CH:16]=[CH:15]3)=[O:11])[C:6]([OH:5])=[O:38])(=[O:30])=[O:31])[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)c1cc(=O)n2cc(OCCCN)ccc2c1)NS(=O)(=O)c1ccccc1
Reactant: CN=C=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CNC(=O)NCCCOc1ccc2cc(C(=O)NC[C@H](NS(=O)(=O)c3ccccc3)C(=O)O)cc(=O)n2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
To a mixture of (S)-3-{[7-(3-amino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-2-benzenesulfonylamino-propionic acid tert-butyl ester (10.0 mg, 0.015 mmol) in anhydrous acetonitrile (0.5 ml) were added triethylamine (4 μl, 0.030 mmol) and methyl isocyanate (1 μl, 0.015 mmol). The mixture was stirred for 5 minutes at 0° C. and 30 minutes at room temperature, quenched with water and extracted with dichloromethane (3x). The combined organic layers were dried (MgSC4) and concentrated to give 4.1 mg (81% yield) of desired product.