Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[CH:2]1.C(Cl)(=O)C(Cl)=O.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>ClCCl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([N:23]2[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]2)=[O:12])=[CH:2]1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1c[nH]c2ccccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CN1CCN(C(=O)c2c[nH]c3ccccc23)CC1
Reaction time: 4 h

Procedure:
1H-Indole-3-carboxylic acid (1.61 g, 0.01 moles) was stirred with oxalyl chloride (0.99 g, 0.011 moles) in 20 mL dichloromethane at 0 to 25° C. for 3-4 hours. After completion of the reaction (TLC), volatile substances were distilled off under the reduced pressure. The residue was taken in 20 mL dichloroethane and to this stirred solution, was added N-methylpiperazine (1.1 g, 0.011 moles). The reaction mixture was further stirred for next 3-5 hours, till the reaction completes (TLC). Reaction mixture was diluted with dichloromethane 20 mL), washed with water, brine and saturated solution of sodium bicarbonate. The organic layer was dried over sodium sulfate and the organic solvents were evaporated under vacuo. The product was purified using column chromatography on silica gel G stationary phase and suitable combinations of ethyl acetate and methanol in increasing gradient, as the mobile phase.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH2:14])[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[C:26]1[C:34](O)=[O:35].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][C:34]([C:26]2[NH:25][C:33]3[C:28]([CH:27]=2)=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:35])[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: N[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1)c1cc2ccccc2[nH]1

Procedure:
200 mg (0.550 mmol) of (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-4-piperidinamine are reacted in analogy to Example 4a with 106 mg (0.661 mmol) of indole-2-carboxylic acid, 168 mg (0.661 mmol) of bis(2-oxo-3-oxazolidinyl)phosphinic chloride and 169 μl (1.21 mmol) of triethylamine. The title compound ##STR87## is obtained (89 mg, 32%) as white crystals with melting point 254° C. TLC:methylene chloride/methanol/cone. ammonia (2000:50:1) Rf =0.56, FD-MS:M+ =505, 507; IR:3430, 3290, 1625 cm-1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:30]([O:32]C)=[O:31])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][C:21]2[C:26]([Cl:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=2[Cl:29])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Li+]>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:30]([OH:32])=[O:31])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][C:21]2[C:26]([Cl:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=2[Cl:29])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](Cc1ccc(OCCOc2c(Cl)cc(C)cc2Cl)cc1)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Cl)c(OCCOc2ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc2)c(Cl)c1

Procedure:
Methyl N-(tert-butoxycarbonyl)-O-[2-(2,6-dichloro-4-methylphenoxy)ethyl]tyrosinate from the previous step (1 eq.) was dissolved in a 2:1 (v/v) THF:MeOH solution (0.07 M). To this was then added lithium hydroxide (1.0 M aqueous solution, 5 eq.) and the resulting solution was stirred at RT for 16 h. The volatiles were then removed in vacuo. Following careful acidification of the resulting residue with 10% aq. HCl, the mixture was extracted with EtOAc. The combined organic extracts were washed with H2O and brine, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo afforded the title compound.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][C@@H:4]([C:7]2[CH:8]=[CH:9][C:10]([Cl:20])=[C:11]([NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH:12]=2)[CH2:3]1.[N+:21]([O-])([OH:23])=[O:22].NC(N)=N>OS(O)(=O)=O>[O:1]=[C:2]1[NH:6][CH2:5][C@@H:4]([C:7]2[C:8]([N+:21]([O-:23])=[O:22])=[CH:9][C:10]([Cl:20])=[C:11]([NH:13][C:14](=[O:19])[C:15]([F:18])([F:16])[F:17])[CH:12]=2)[CH2:3]1
Reactant: O=[N+]([O-])O
Reactant: O=C1C[C@H](c2ccc(Cl)c(NC(=O)C(F)(F)F)c2)CN1
Agent: N=C(N)N
Agent: O=S(=O)(O)O
Product: O=C1C[C@H](c2cc(NC(=O)C(F)(F)F)c(Cl)cc2[N+](=O)[O-])CN1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
N-(5-((3R)-5-Oxopyrrolidin-3-yl)-2-chlorophenyl)-2,2,2-trifluoroacetamide (7.6 g, 24.83 mmol) was dissolved in 25 mL of concentrated H2SO4 (1M solution). The mixture was then cooled to 0° C. and guanidine nitrate (24.83 mmol) was added portion-wise. The reaction mixture was stirred at 0° C. for 30 min. The mixture was then poured into a solution of ice/water. The mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with water and brine and dried over MgSO4. The solvent was removed to give the title compound (8.7 g, 98% yield). 1H-NMR (400 MHz, CD3OD): δ 2.42-2.48 (dd, J=16.8, 6.0 Hz, 1H), 2.69-2.75 (dd, J=16.8, 8.8 Hz, 1H), 3.37-3.39 (m, 1H), 3.74-3.80 (dd, J=10.4, 8.0 Hz, 1H), 7.89 (s, 1H), 8.13 (s, 1H); MS (ESI) m/z 352.03 (M+H)+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[N:21]1([CH2:27][CH:28]2[O:33][CH2:32][CH2:31][NH:30][CH2:29]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:30]4[CH2:31][CH2:32][O:33][CH:28]([CH2:27][N:21]5[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]5)[CH2:29]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: C1CCN(CC2CNCCO2)CC1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCOC(CN4CCCCC4)C3)c(F)cc2c1=O

Procedure:
By the use of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro -4-oxoquinoline-3-carboxylic acid and 2-(piperidinomethyl)morpholine, the reaction is similarly carried out as Example 11 to give 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-[2-(piperidinomethyl)morpholino]quinoline-3-carboxylic acid 1/2 hydrate, melting at 160°-162° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[CH3:16][O:17][CH2:18][C@H:19]1[CH2:23][CH2:22][CH2:21][NH:20]1>>[CH3:16][O:17][CH2:18][C@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1[C:13]([C:9]1[CH:10]=[N:11][O:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)=[O:15]
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: COC[C@H]1CCCN1
Product: COC[C@H]1CCCN1C(=O)c1cnoc1-c1ccc(C)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and (R)-2-methoxymethyl-pyrrolidine (6.9 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (5.9 mg). Calcd for C17H20N2O3: 300.1474, found 300.1478.
Reaction SMILES: [ClH:1].O[C@H](COC1C=CC(C(C)(C)C)=CC=1)[CH2:4][NH:5]C(C)(C)CC1C=CC(OC)=CC=1.Cl.[OH:31][CH:32]([CH2:47][O:48][C:49]1[CH:54]=[CH:53][C:52](OC)=[CH:51][CH:50]=1)[CH2:33][NH:34][C:35]([CH3:46])([CH3:45])[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1.Cl.OC(COC1C=CC(C(C)(C)C)=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1>>[ClH:1].[OH:31][CH:32]([CH2:47][O:48][C:49]1[CH:50]=[CH:51][CH:52]=[C:53]([C:4]#[N:5])[CH:54]=1)[CH2:33][NH:34][C:35]([CH3:46])([CH3:45])[CH2:36][C:37]1[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(OC)cc2)cc1
Reactant: COc1ccc(CC(C)(C)NC[C@H](O)COc2ccc(C(C)(C)C)cc2)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2ccc(C(C)(C)C)cc2)cc1
Agent: Cl
Product: COc1ccc(CC(C)(C)NCC(O)COc2cccc(C#N)c2)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 339 (M-15,.1), 234 (15), 233 (100), 121 (21), 102 (7), 90 (6).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CS(C)=O.O>[CH2:17]([C:5]1([CH2:13][CH2:14][CH2:2][CH2:3][CH2:4][CH2:12][CH2:11][CH3:10])[C:4]2[CH:3]=[C:2]([Br:1])[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: Brc1ccc2c(c1)Cc1cc(Br)ccc1-2
Reactant: CCCCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCCCC1(CCCCCCCC)c2cc(Br)ccc2-c2ccc(Br)cc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
In a 3-neck round-bottom flask (1,000 ml) equipped with a reflux condenser and an electronic thermometer, 2,7-dibromofluorene (64.8 g, 200 mmol, 1 eq.), 1-bromooctane (154.5 g, 800 mmol, 4 eq.), and tetrabutylammonium bromide (6.44 g, 20 mmol, 1/10 eq.) were dissolved in DMSO (dimethyl sulfoxide, 500 ml) under the protection of nitrogen. An aqueous solution of sodium hydroxide (32.0 g, 0.8 mol, 4 eq.) in water (40 ml) was dropped into the resulting light yellow solution with the speed of dropping controlled not to pass 60° C. The resulting brownish red reaction mixture was heated and stirred at 60° C. overnight. After it was allowed to cool down to room temperature, water (500 ml) was poured and the resulting mixture was stirred briefly and totally transferred into a separatory funnel (2,000 ml). The aqueous layer was separated and extracted with hexane (3×200 ml). The hexane extracts were combined, washed with 1 M hydrochloric acid (2×50 ml) and then with water (4×100 ml), and dried over MgSO4 (magnesium sulfate) overnight. The drying agent was filtered away and the filtrate was removed on a rotary evaporator. The reddish yellow residue was slowly poured into well-stirred methanol (1,000 ml) in an Erlenmeyer flask (2,000 ml). The resulting yellow precipitates were filtered out, crashed, washed with methanol (3×100 ml), and dried under suction and then in a vacuum oven at 40° C. and 3 in./Hg overnight. A white crystal (98.0 g) was collected with the yield of 89.3% with a melting point 63-65° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:20][CH:21]([OH:30])[CH2:22][S:23][CH2:24][CH2:25][C:26]([O:28]C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH2:37].[OH-].[Na+]>O1CCCC1>[CH2:1]([O:8][C:9]1[C:14]([CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:20][C:21]([OH:30])([OH:37])[CH2:22][S:23][CH2:24][CH2:25][CH2:26][OH:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: COC(=O)CCSCC(O)Cc1cccc(C2CCCC2)c1OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCCSCC(O)(O)Cc1cccc(C2CCCC2)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1 g (2.33 mmol) of methyl 7-(2-benzyloxy-3-cyclopentylphenyl)-6-hydroxy-4-thiaheptanoate (Example 1) is dissolved in 3 ml of tetrahydrofuran, and the solution is added dropwise to 250 mg of lithium aluminum hydride in 20 ml of tetrahydrofuran. The mixture is left to stir at room temperature for 30 min and then, with caution, 0.25 ml of water, 0.25 ml of 15% strength sodium hydroxide solution and 0.73 ml of water are successively added. The precipitate is filtered off, the filtrate is washed once with saturated brine and dried over magnesium sulfate, and the solvent is removed by distillation in vacuo. The residue is purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 1:1). 745 mg of 7-(2-benzyloxy-3-cyclopentylphenyl)-6-hydroxy-4-thiaheptane-1,6-diol are obtained.
Reaction SMILES: [CH:1]1([N:7]([CH:29]2[CH2:34][CH2:33][NH2+:32][CH2:31][CH2:30]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][N:20]([S:23](=[O:28])(=[O:27])[N:24]([CH3:26])[CH3:25])[CH2:19][CH2:18]3)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[CH:36]1([C:41](Cl)=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH3:25][N:24]([CH3:26])[S:23]([N:20]1[CH2:21][CH2:22][N:17]([CH2:16][C:13]2[S:12][C:11]([NH:10][C:8]([N:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH:29]3[CH2:30][CH2:31][N:32]([C:41]([CH:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)=[O:42])[CH2:33][CH2:34]3)=[O:9])=[N:15][CH:14]=2)[CH2:18][CH2:19]1)(=[O:28])=[O:27]
Reactant: O=C(Cl)C1CCCC1
Reactant: CN(C)S(=O)(=O)N1CCN(Cc2cnc(NC(=O)N(C3CCCCC3)C3CC[NH2+]CC3)s2)CC1
Agent: [Cl-]
Product: CN(C)S(=O)(=O)N1CCN(Cc2cnc(NC(=O)N(C3CCCCC3)C3CCN(C(=O)C4CCCC4)CC3)s2)CC1

Procedure:
Prepared in 75% (229 mg) yield as described in general procedure (N) from 4-{1-cyclohexyl-3-[5-(4-dimethylsulfamoyl-piperazin-1-ylmethyl)-thiazol-2-yl]-ureido}-piperidinium; chloride (275 mg, 0.5 mmol) and cyclopentanecarbonyl chloride (80 mg, 0.6 mmol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([OH:12])[CH:6]=1.Br[CH2:15][CH2:16][O:17][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([O:12][CH2:15][CH2:16][O:17][Si:18]([CH:22]([CH3:23])[CH3:24])([CH:19]([CH3:21])[CH3:20])[CH:25]([CH3:26])[CH3:27])[CH:6]=1
Reactant: COC(=O)Cc1cc(O)cc(O)c1
Reactant: CC(C)[Si](OCCBr)(C(C)C)C(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Product: COC(=O)Cc1cc(O)cc(OCCO[Si](C(C)C)(C(C)C)C(C)C)c1

Procedure:
A mixture of 9.39 g (51.5 mmol) of (3,5-dihydroxy-phenyl)-acetic acid methyl ester (prepared according to U. Eder, G. Sauer, G. Haffer, G. Neef, R. Wiechert, U.S. Pat. No. 4,066,674), 11.38 g (61.8 mmol) of 1-bromo-2-triisopropylsilyloxy-ethane and 14.50 g (51.5 mmol) of cesium carbonate is stirred at RT for 1 hour and at 60° C. for another hour. The reaction mixture is then treated with saturated aqueous sodium carbonate and extracted with ethyl acetate. The layers are separated and the organic layer is washed three times with saturated aqueous sodium carbonate. The aqueous layers are combined and extracted three times with ethyl acetate. The combined organic solutions are then washed with saturated brine, dried, filtered and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (85:15 hexane/ethyl acetate then 70:30 hexane/ethyl acetate and finally pure ethyl acetate) to afford above title compound as a yellow oil.
Reaction SMILES: [IH:1].[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[N:13]([CH2:14][CH2:15][OH:16])[C:12](SC)=[N:11][CH2:10]1.[NH3:19]>CO>[IH:1].[NH2:19][C:12]1[N:13]([CH2:14][CH2:15][OH:16])[CH:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[Cl:2])[CH2:10][N:11]=1
Reactant: N
Reactant: CSC1=NCC(c2ccccc2Cl)N1CCO
Agent: I
Solvent: CO
Product: NC1=NCC(c2ccccc2Cl)N1CCO

Procedure:
A mixture of 18.3 parts of 5-(o-chlorophenyl)-2-(methylthio)-2-imidazoline-1-ethanol hydroiodide and 40 parts of methanol saturated with ammonia is stirred and refluxed for 2 hours. The solvent is evaporated and the solid residue is treated with 20 parts of 2-propanol. The product is filtered off and recrystallized from 50 parts of water, yielding 2-amino-5-(o-chlorophenyl)-2-imidazoline-1-ethanol hydroiodide, m.p. 181.6°C.
Reaction SMILES: [CH2:1](OC(=O)O[C@H]1C[C@@H](N2C=NC3C2=NC(Cl)=NC=3Cl)C=C1)C.[Cl:23][C:24]1[N:32]=[C:31]2[C:27]([N:28]=[CH:29][N:30]2[C@@H:33]2[CH2:37][C@H:36]([N:38]3[N:42]=[N:41][C:40]([CH2:43][CH3:44])=N3)[C@@H:35]([OH:45])[C@H:34]2[OH:46])=[C:26]([NH:47][CH2:48][CH:49]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[N:25]=1.C(C1C=NNN=1)C>>[Cl:23][C:24]1[N:32]=[C:31]2[C:27]([N:28]=[CH:29][N:30]2[CH:33]2[CH2:37][CH:36]([N:38]3[CH:1]=[C:40]([CH2:43][CH3:44])[N:41]=[N:42]3)[CH:35]([OH:45])[CH:34]2[OH:46])=[C:26]([NH:47][CH2:48][CH:49]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[N:25]=1
Reactant: CCOC(=O)O[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)[C@H](O)[C@@H]2O)n1
Agent: CCc1cn[nH]n1
Product: CCc1cn(C2CC(n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)C(O)C2O)nn1

Procedure:
This compound is prepared from carbonic acid (1S,4R)-4-(2,6-dichloro-purin-9-yl)-cyclopent-2-enyl ester ethyl ester (Intermediate AC) using a procedure analogous to that of (1R,2S,3R,5S)-3-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(5-ethyl-tetrazol-2-yl)-cyclopentane-1,2-diol (Intermediate BA6) by replacing 5-ethyl-2H-tetrazole with 4-ethyl-2H-[1,2,3]triazole (first step a). MS (ES+) m/e 545.24 (MH+)
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:32])[O:13][C:14](=O)[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:17]=2)=[CH:3]1.[OH-].[NH4+:34]>CN(C=O)C.O.CO.C(Cl)Cl>[NH4+:2].[OH-:13].[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:32])[NH:34][C:14](=[O:13])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:17]=2)=[CH:3]1
Reactant: Cn1cc(C2=C(c3cccc(OCCN4CCOCC4)c3)C(=O)OC2=O)c2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(C2=C(c3cccc(OCCN4CCOCC4)c3)C(=O)NC2=O)c2ccccc21
Temperature: 140 °C
Yield: 99 %

Procedure:
3-(1-Methylindol-3-yl)-4-[3-(2-morpholin-4-ylethyloxy)phenyl]furan-2,5-dione was then dissolved in DMF (5 mL) and ammonium hydroxide (10 mL) was added. The resulting mixture was heated at 140° C. for 4 h, then cooled to room temperature, and diluted with water. The product was extracted into EtOAc. The EtOAc layer was washed with NaCl (sat.) and dried over sodium sulfate. Purificaiton on a silica gel column with 5% (10% NH4OH in MeOH) in CH2Cl2 gave 3-(1-methylindol-3-yl)4-[3-(2-morpholin-4-ylethyloxy)phenyl]-1H-pyrrole-2,5-dione (0.21 g, >99% yield).
Reaction SMILES: [CH3:1][C:2]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[N:16]([CH3:40])[C:17]3[C:22]([N:23]=2)=[C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:20]=[C:19]([N:30]2[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[N:32]=[C:31]2[CH3:39])[N:18]=3)[CH2:10][CH2:9]1)([CH3:7])[C:3]([O:5]C)=[O:4].[OH-].[Li+]>>[CH3:7][C:2]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[N:16]([CH3:40])[C:17]3[C:22]([N:23]=2)=[C:21]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[N:20]=[C:19]([N:30]2[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[N:32]=[C:31]2[CH3:39])[N:18]=3)[CH2:10][CH2:9]1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(C)(C)N1CCC(Cc2nc3c(N4CCOCC4)nc(-n4c(C)nc5ccccc54)nc3n2C)CC1
Agent: [Li+]
Agent: [OH-]
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCN(C(C)(C)C(=O)O)CC3)n(C)c2n1

Procedure:
Following the procedure for 506, the methyl ester of methyl 2-methyl-2-(4-((9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-morpholino-9H-purin-8-yl)methyl)piperidin-1-yl)propanoate 507 was hydrolyzed with lithium hydroxide to give 525. LCMS m/z: 267.2 (2M+H+)
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([N:13]([CH2:55][CH3:56])[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:35])[C:22]2[CH:34]=[CH:33][CH:32]=[C:24]([C:25]([N:27]([CH2:29][CH2:30][OH:31])[CH3:28])=[O:26])[CH:23]=2)=[C:16]([C:36]2[CH:41]=[C:40]([C:42](=[O:54])[NH:43][C@@H:44]3[C:53]4[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=4)[CH2:47][CH2:46][CH2:45]3)[CH:39]=[CH:38][N:37]=2)[CH:15]=1)[CH3:12]>C(Cl)Cl>[CH2:55]([N:13]([CH2:11][CH3:12])[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:35])[C:22]2[CH:34]=[CH:33][CH:32]=[C:24]([C:25]([N:27]([CH3:28])[CH2:29][CH:30]=[O:31])=[O:26])[CH:23]=2)=[C:16]([C:36]2[CH:41]=[C:40]([C:42](=[O:54])[NH:43][C@@H:44]3[C:53]4[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=4)[CH2:47][CH2:46][CH2:45]3)[CH:39]=[CH:38][N:37]=2)[CH:15]=1)[CH3:56]
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCO)c2)c(-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CC=O)c2)c(-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of DMSO (4.8 mmol, 375 mg) in DCM (3 mL) at −78° C. was added a solution of oxalyl chloride (2.4 mmol, 305 mg) in DCM (0.4 mL). The mixture was stirred at −78° C. for 15 minutes. Then a solution of (S)—N1-(4-(diethylamino)-2-(4-((1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyridin-2-yl)phenyl)-N3-(2-hydroxyethyl)-N3-methylisophthalamide Example 194 (1.2 mmol, 742 mg) in DCM (1.7 mL) was added dropwise. The mixture was stirred at −78° C. for 3 h and quenched with triethylamine (0.85 mL). The mixture was stirred at −78° C. for 10 minutes, at 0° C. for 10 minutes, then diluted with water, and extracted with DCM (2×). The combined organic layers was washed with water (1×), dried, and concentrated. The residue was used without further purification.
Reaction SMILES: CS(O[CH2:6][C@H:7]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(=O)=O.[N-:22]=[N+:23]=[N-:24].[Na+].O>CN(C=O)C>[C:16]1([C@H:7]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][N:22]=[N+:23]=[N-:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](CN=[N+]=[N-])c1ccccc1
Temperature: 55 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
(S)-2-Phenyl-2-tert-butoxycarbonylaminoethyl methanesulfonate (15.77 g, 0.05 mol) was dissolved in 50 mL DMF followed by the addition of sodium azide (19.5 g, 0.3 mol). The mixture was stirred for 24 hrs at 55° C., cooled to room temperature, poured into cold water (500 mL) and stirred vigorously for 20 minutes. Precipitate was collected by filtration, washed with water and dried, affording 9.97 g of the title compound as a white solid. Yield: 76%; (MH)+=263; 1H NMR (DMSO-d6): 1.37 (s, 9H), 3.36-3.50 (m, 2H), 4.69-4.75 (m, 1H), 7.23-7.36 (m, 5H), 7.65-7.68 (d, J=9.2 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([Cl:16])[C:14]=1[NH2:15])C(OCC(C)C)=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:12]=[C:13]([Cl:16])[C:14]=1[NH2:15]
Reactant: CC(C)COC(=O)c1cc(Cl)c(N)c(Cl)c1
Solvent: O
Product: Nc1c(Cl)cccc1Cl
Temperature: 250 °C
Reaction time: 2.5 h
Yield: 93.8 %

Procedure:
0.2 mole=55.2 g of isobutyl 3,5-dichloro-4-amino-benzoate were initially introduced into an autoclave together with 250 ml of water. The mixture was stirred at 250° C. for 2.5 hours and the reaction gas formed was continuously removed to maintain a pressure of about 40 bar. The product was recovered by steam distillation. 32 g of 2,6-dichloroaniline were obtained, corresponding to a yield of 98%.