Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(O[C:16]2[C@H:17]([CH3:40])[C@@H:18]3[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]3[C:20]=2[C:21]([O:23]CC2C=CC([N+]([O-])=O)=CC=2)=[O:22])(C2C=CC=CC=2)=O)C=CC=CC=1.[SH:41][C@@H:42]1[CH2:46][N:45]([CH3:47])[C@H:44]([C:48](=[O:69])[NH:49][CH2:50][CH2:51][N:52](C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[C:53]([NH2:55])=[NH:54])[CH2:43]1>>[NH:52]([CH2:51][CH2:50][NH:49][C:48]([C@@H:44]1[CH2:43][C@H:42]([S:41][C:16]2[C@H:17]([CH3:40])[C@@H:18]3[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]3[C:20]=2[C:21]([OH:23])=[O:22])[CH2:46][N:45]1[CH3:47])=[O:69])[C:53]([NH2:55])=[NH:54]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Reactant: CN1C[C@@H](S)C[C@H]1C(=O)NCCN(C(=N)N)C(=O)OCc1ccc([N+](=O)[O-])cc1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@H]3C[C@@H](C(=O)NCCNC(=N)N)N(C)C3)[C@H](C)[C@H]12

Procedure:
A procedure similar to that described in Example 101 was repeated, but using 4-nitrobenzyl (1R,5R,6S)-2-(diphenylphosphoryloxy)-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (prepared as described in Preparation 123) and (2S,4S)-4-mercapto-1-methyl-2-[2-(4-nitrobenzyloxycarbonylguanidino)ethylcarbamoyl]pyrrolidine (prepared as described in Preparation 103) as starting materials, in relative proportions similar to those used in that Example, to obtain the title compound.
Reaction SMILES: CS(O[CH2:6][C:7]1[O:8][CH:9]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[C:30]3[C:25](=[C:26]([C:31]([F:34])([F:33])[F:32])[CH:27]=[CH:28][CH:29]=3)[N:24]=[CH:23][CH:22]=2)[C:11](=[O:13])[CH:12]=1)(=O)=O.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>ClCCl>[F:34][C:31]([F:33])([F:32])[C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:25]=1[N:24]=[CH:23][CH:22]=[C:21]2[O:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:14][C:10]1[C:11](=[O:13])[CH:12]=[C:7]([CH2:6][N:39]2[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]2)[O:8][CH:9]=1
Reactant: CN1CCNCC1
Reactant: CS(=O)(=O)OCc1cc(=O)c(OCCCCCOc2ccnc3c(C(F)(F)F)cccc23)co1
Solvent: ClCCl
Product: CN1CCN(Cc2cc(=O)c(OCCCCCOc3ccnc4c(C(F)(F)F)cccc34)co2)CC1
Temperature: 45 °C
Reaction time: 1 h
Yield: 15 %

Procedure:
Methanesulfonic acid 4-oxo-5-[5-(8-trifluoromethyl-quinolin-4-yloxy)-pentyloxy]-4H-pyran-2-ylmethyl ester 19 (94 mg, 0.187 mmol) was dissolved in dichloromethane (5 mL). 1-Methyl-piperazine (52 μL, 0.47 mmol) was added via syringe. The mixture was stirred at 45° C. for 1 h. CH2Cl2 (75 ml) was added and the solution washed with NaHCO3 10% (3×50 mL) and brine (3×50 mL). The organic layer was dried over MgSO4, filtered and evaporated. The crude product was purified by column chromatography on silica using as eluent CH2Cl2:MeOH=9:1. 5-(5-(8-(Trifluoromethyl)quinolin-4-yloxy)pentyloxy)-2-((4-methylpiperazin-1-yl)methyl)-4H-pyran-4-one EHT 5847 was obtained (13.6 mg, 15% yield) as a white foam.
Reaction SMILES: C[O:2][C:3](=[O:17])[CH2:4][NH:5][C:6](=[O:16])[CH2:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[OH-].[Na+].Cl>O1CCCC1.O>[C:12]([O:11][C:9]([NH:8][CH2:7][C:6]([NH:5][CH2:4][C:3]([OH:17])=[O:2])=[O:16])=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: COC(=O)CNC(=O)CNC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(=O)NCC(=O)O
Reaction time: 0.5 h

Procedure:
Add, to a solution of t-butoxycarbonyl-glycyl-glycine methyl ester (3.9 g.) in tetrahydrofuran (30 ml.) and water (30 ml.), 16 ml. of 1 N sodium hydroxide dropwise. Stir the mixture until homogenous (1 1/2 hours), then acidify to pH 3 with dilute hydrochloric acid and evaporate to dryness. Suspend the residue in acetone, filter and evaporate the filtrate to dryness to afford the title product (m.p. 125°-128° C.).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([CH3:38])[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[C:11]([C:15]3[N:16]=[C:17]4[C:23]([C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:22][N:21](COCC[Si](C)(C)C)[C:18]4=[N:19][CH:20]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:5]1>C(Cl)Cl.CO>[CH3:1][O:2][CH2:3][C:4]1([CH3:38])[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[C:11]([C:15]3[N:16]=[C:17]4[C:23]([C:24](=[O:29])[C:25]([CH3:27])([CH3:26])[CH3:28])=[CH:22][NH:21][C:18]4=[N:19][CH:20]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:5]1
Reactant: COCC1(C)CCN(c2cccc(-c3cnc4c(n3)c(C(=O)C(C)(C)C)cn4COCC[Si](C)(C)C)c2)C1
Solvent: ClCCl
Solvent: CO
Product: COCC1(C)CCN(c2cccc(-c3cnc4[nH]cc(C(=O)C(C)(C)C)c4n3)c2)C1
Yield: 50 %

Procedure:
1-{2-[3-(3-Methoxymethyl-3-methyl-pyrrolidin-1-yl)-phenyl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-2,2-dimethyl-propan-1-one was prepared following the same procedure using 1-[2-[3-(3-Methoxymethyl-3-methyl-pyrrolidin-1-yl)-phenyl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one as starting material. The product was obtained in 50% yield by SiO2 chromatography (DCM/MeOH 0-5% MeOH).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[S:16][CH3:17])[N:9]3[CH2:18][CH2:19][CH2:20][CH:21]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:8]=23)=[CH:4][CH:3]=1.C1C=C(C([O-])=[O:37])C(C(O[O-])=O)=CC=1.[Mg+2]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[S:16]([CH3:17])=[O:37])[N:9]3[CH2:18][CH2:19][CH2:20][CH:21]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:8]=23)=[CH:28][CH:29]=1
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Reactant: CCOC(=O)CC1CCCn2c1c(Cc1ccc(Cl)cc1)c1c(SC)cccc12
Agent: [Mg+2]
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)CC1CCCn2c1c(Cc1ccc(Cl)cc1)c1c(S(C)=O)cccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of the sulfide of Step 12 (270 mg, 0.6 mmol) in 30 ml of CH2Cl2/MeOH (10:1) mixture at 0° C. was added MMPP (312 mg, 0.6 mmol). The reaction mixture was stirred at 0° C. for 30 minutes and then quenched with saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with 70% EtOAc in Hexanes to provide 210 mg as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C:16]1([NH2:19])[CH2:18][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:21]1[C:22](=[O:39])[N:23]([C:28]2[CH:29]=[C:30]([CH:35]=[CH:36][C:37]=2[CH3:38])[C:31]([O:33][CH3:34])=[O:32])[CH:24]=[C:25]([Br:27])[N:26]=1>>[CH2:1]([O:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C:16]1([NH:19][C:21]2[C:22](=[O:39])[N:23]([C:28]3[CH:29]=[C:30]([CH:35]=[CH:36][C:37]=3[CH3:38])[C:31]([O:33][CH3:34])=[O:32])[CH:24]=[C:25]([Br:27])[N:26]=2)[CH2:18][CH2:17]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1(c2cccc(F)c2OCc2ccccc2)CC1
Reactant: COC(=O)c1ccc(C)c(-n2cc(Br)nc(Br)c2=O)c1
Product: COC(=O)c1ccc(C)c(-n2cc(Br)nc(NC3(c4cccc(F)c4OCc4ccccc4)CC3)c2=O)c1

Procedure:
Prepared using a similar method to Example 252h from 1-(2-(benzyloxy)-3-fluorophenyl)cyclopropanamine (Example 283b) and methyl 3-(3,5-dibromo-2-oxopyrazin-1(2H)-yl)-4-methylbenzoate (Example 252g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:13]=1.[Br:14]Br>CCOCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[CH:10]([Br:14])[CH2:9][CH2:8][CH2:7][C:6]=2[CH:13]=1
Reactant: O=C1CCCCc2cc(Br)ccc21
Reactant: BrBr
Solvent: CCOCC
Product: O=C1c2ccc(Br)cc2CCCC1Br
Temperature: 0 °C
Yield: 37.3 %

Procedure:
Example 3, 2-Bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (1.5 g, 5.9 mmol) was dissolved Et2O (25 mL), cooled to 0° C. and bromine (0.35 mL, 6.6 mmol) was added dropwise. The solution was stirred at 24° C. until TLC indicated reaction complete (2-18 h; scale dependent). The solvent was removed by rotory evaporation and the crude product applied to a 25 (M) Biotage® silica gel column. Gradient elution from 50-100% B (A=Hexanes; B=10% EtOAc/hex) over 500 mL and gave 2,6-dibromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one 700 mg, and 1.5 g of a second fraction containing dibromide (1:1). RT=2.2 minutes (condition 1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:11](Br)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].O>C(O)C>[CH2:22]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11]
Reactant: CCCCCCCCCCCCBr
Reactant: Oc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.5 %

Procedure:
In 200 g of ethanol were dissolved 86.5 g (0.5 mol) of 4-bromophenol and 22 g (0.55 mol) of sodium hydroxide. To the solution at 70° C., 137 g (0.55 mol) of n-dodecyl bromide was added dropwise. The solution was allowed to ripen for 4 hours and cooled to room temperature, after which 120 g of water was added. The oily matter separated therefrom was concentrated by a rotary evaporator, followed by vacuum distillation (boiling point 178-180° C./0.5 Torr), yielding 110 g of 4-n-dodecyloxyphenyl bromide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[H-].[Na+].[CH3:11][O:12][CH2:13]Cl>O1CCCC1>[CH3:11][O:12][CH2:13][O:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: COCCl
Reactant: Oc1cncc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1cncc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
Under argon atmosphere, into a solution of 5-chloro-3-pyridinol (5.0 g, 38.6 mmol) in 100 mL of dry tetrahydrofuran at room temperature was added 60% sodium hydride (1.85 g, 46.3 mmol). After stirring the mixture for 1 hour at room temperature, a solution of chloromethyl methyl ether (3.42 g, 42.6 mmol) in 10 mL of dry tetrahydrofuran was added over 10 min. The resulting mixture was heated to reflux for 16 hours. The solvent was evaporated, and the residue was diluted with ethyl acetate, then washed with 1N aq. NaOH. The combined organic layer was then concentrated to give the crude material. Column chromatography on silica gel, eluting with ethyl acetate/hexane (30/70, v/v/), gave the desired product (6.52 g, 97%).
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([N:10]([CH3:18])[CH2:11][CH2:12][C:13]([O:15]CC)=[O:14])=[O:9])([CH3:6])([CH3:5])[CH3:4]>C1COCC1.CCO.O>[C:3]([O:7][C:8]([N:10]([CH3:18])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CCOC(=O)CCN(C)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CN(CCC(=O)O)C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 73.1 %

Procedure:
To a mixture of sodium hydroxide (112 g, 2.8 mol) in THF (1200 mL) and EtOH (1800 mL) was added ethyl 3-(tert-butoxycarbonyl(methyl)amino)propanoate (300 g, 1.4 mol). The resulting mixture was stirred for 3 h. The mixture was diluted with water (1000 mL) and evaporated to remove volatiles. The water phase was washed with CH2Cl2 (800 mL×3). The inorganic layer was cooled in an ice bath and acidified with 1 N HCl until the pH was adjusted to 1-2. CH2Cl2 (1000 mL×4) was quickly added to extract the product acid. The organic phase was dried over anhydrous Na2SO4 and concentrated to give 3-(tert-butoxycarbonyl(methyl)amino)propanoic acid (208 g, 73.2%) as oil, which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:4]=1[NH2:5].N1C=CC=CC=1.[C:19](Cl)([O:21][CH2:22][CH:23]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20]>C1COCC1>[CH:34]1[C:35]2[CH:23]([CH2:22][O:21][C:19](=[O:20])[NH:5][C:4]3[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:3]=3[O:2][CH3:1])[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]=2[CH:31]=[CH:32][CH:33]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: COc1cc([N+](=O)[O-])ccc1N
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1cc([N+](=O)[O-])ccc1NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 5 h
Yield: 87.5 %

Procedure:
2-methoxy-4-nitroaniline (3 g, 17.8 mmol) was dissolved in THF (60 ml) and pyridine (1.6 ml, 19.6 mmol) was added. The reaction mixture was cooled to 0° C. and Fmoc-Cl (5.07 g, 19.6 mmol) was added in small portions. The reaction was allowed to come to ambient temperature and held for 5 hours. The reaction mixture was concentrated under reduced pressure. The crude product was purified by recrystallisation from CH2Cl2 and MeOH to afford the title compound (6.08 g, 88%). Data: (m/z)=391 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[N:10]=1)[C:5]([OH:7])=[O:6].[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1B(O)O.[Na].S(C1C=C(P(C2C=CC=C(S(O)(=O)=O)C=2)C2C=CC=C(S(O)(=O)=O)C=2)C=CC=1)(O)(=O)=O.C(NC(C)C)(C)C.Cl>CN(C=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:11][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([C:16]2[CH:15]=[CH:14][C:13]([F:12])=[CH:18][C:17]=2[F:19])[N:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cc(Cl)nc(Cl)c1
Reactant: OB(O)c1ccc(F)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Solvent: O
Product: O=C(O)c1cc(Cl)nc(-c2ccc(F)cc2F)c1
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 36.3 %

Procedure:
To a solution of 2,6-dichloroisonicotinic acid (2.43 g, 12.67 mmol) in DMF (38 mL) and water (12.7 mL) were added (2,4-difluorophenyl)boronic acid (2.0 g, 12.67 mmol), tri(m-sulfophenyl)phosphine sodium salt (0.54 g, 0.95 mmol), palladium(II) acetate (71.0 mg, 0.32 mmol) and diisopropylamine (6.3 mL, 44.3 mmol). The mixture was heated 50° C. After 2.5 h, the mixture was cooled to ambient temperature and stirred for 18 h. HCl (1.0 M in water) was added and the mixture was was extracted with ethyl acetate (3×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by reverse phase chromatography (C-18, 85% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (1.24 g). MS 270.0 (M+1).
Reaction SMILES: COC(=O)[C@H:4]([NH:16][CH2:17][CH2:18][NH:19][C:20]([O:22]C(C)(C)C)=O)[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[CH:15][C:6]=1[CH2:5][C@H:4]1[NH:16][CH2:17][CH2:18][NH:19][C:20]1=[O:22]
Reactant: COC(=O)[C@@H](Cc1ccc2ccccc2c1)NCCNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NCCN[C@@H]1Cc1ccc2ccccc2c1
Reaction time: 8 h
Yield: 89.6 %

Procedure:
(2R)-2-((2-(tert-butoxycarbonylamino)ethyl)amino)-3-(2-naphthyl)propionic acid methylester (3.4 g, 9.1 mmol) was stirred for 1 h in a mixture of TFA (5 ml) and methylene chloride(5 ml). The volatiles were removed in vacuo and the residue was dissolved in a mixture of water (40 ml) and methanol (100 ml). Sodium hydrogencarbonate (2.3 g) was added and the mixture was stirred overnight. The solvent was removed in vacuo and the residue was dissolved in water (40 ml) and extracted with ethyl acetate (10×50 ml). The combined organic phases were dried (magnesium sulphate) and the solvent was removed in vacuo to afford 1.96 g of (3R)-3-((2-naphthyl)methyl)piperazin-2-one.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]2[NH:10][N:11]=[C:12]([CH3:13])[C:3]=12.[CH:14]([S:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20])([CH3:16])[CH3:15]>C(O)(C)C>[CH:14]([S:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH:20][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]2[NH:10][N:11]=[C:12]([CH3:13])[C:3]=12)([CH3:16])[CH3:15]
Reactant: CSc1nc(Cl)c2c(C)n[nH]c2n1
Reactant: CC(C)Sc1ccccc1N
Solvent: CC(C)O
Product: CSc1nc(Nc2ccccc2SC(C)C)c2c(C)n[nH]c2n1
Temperature: 25 °C

Procedure:
A mixture of 4-chloro-3-methyl-6-methylmercaptopyrazolo[3,4-d]pyrimidine (A-3) (1.21 g, 5.63 mmol) and 2-(isopropylthio)aniline (A-4) (1.42 g, 8.50 mmol) in isopropanol (56 mL) was stirred at reflux for 3 h. After cooling down to ambient temperature, TEA (0.78 mL, 5.66 mmol) was added to the mixture, and the solution was again heated to reflux for 0.5 h. After cooling down to ambient temperature, the mixture was filtered to give the title compound (A-5) as white solid (1.30 g, 3.77 mmol). MS-ESI (m/z): 346 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([OH:13])=O)[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.CCN(C(C)C)C(C)C.[C:34]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])(=[O:37])[NH:35][NH2:36]>ClCCl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([NH:36][NH:35][C:34]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:13])[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(O)c1cccc2cccnc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NNC(=O)c1cccc2cccnc12
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a solution of 8-quinolinecarboxylic acid (750 mg, 4.33 mmol, commercially available from e.g. Sigma-Aldrich, Acros or Apollo) and oxalyl chloride (0.417 ml, 4.76 mmol) in dichloromethane (50 ml) stirred under argon at 0° C. was added neat DMF (34 μl, 0.439 mmol). The reaction mixture was stirred at 0° C. for 18 hr, then evaporated in vacuo and azeotroped with toluene (2×5 ml). The residue was dissolved in dichloromethane (50 ml), and to this were added DIPEA (0.908 ml, 5.20 mmol) and t-butyl carbazate (1259 mg, 9.53 mmol). The reaction mixture was stirred at room temp for 6 hr. The reaction mixture was partitioned between dichloromethane (˜50 ml) and saturated sodium bicarbonate solution (˜25 ml). The aqueous phase was extracted with dichloromethane (2×50 ml) and the combined organic extracts washed with saturated sodium bicarbonate solution (˜50 ml), dried over sodium sulphate and evaporated in vacuo to give the crude product as a burgundy gum. This was purified via Biotage (5:1 DCM/MeOH; 40+M Biotage column; flow rate 20 ml/min) to afford impure product as a burgundy foam. This was further purified via Biotage (1:1 Hex/EtOAc; 40+M Biotage column) and dried overnight in a vacuum oven at 40° C. to afford the required product as a fine, pale yellow powder in 947.8 mg.
Reaction SMILES: C[C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[CH2:17][CH2:18]C2C=CC=CC=2)=[O:15])=[N:10][CH:9]=1)(C)[C:3]([OH:5])=[O:4].ClCC[C:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:36].C(OC(=O)CSC1SC(N)=NC=1)C>>[CH3:31][C@H:28]1[CH2:29][CH2:30][C@H:25]([N:16]([CH2:17][CH2:18][C:35](=[O:36])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][CH2:2][C:3]([OH:5])=[O:4])=[CH:9][N:10]=2)[CH2:26][CH2:27]1
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Reactant: O=C(CCCl)c1ccccc1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: C[C@H]1CC[C@H](N(CCC(=O)c2ccccc2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-phenethyl-ureido]-thiazol-5-ylsulfanyl}-propionic acid using 3-chloro-1-phenyl-propan-1-one and (2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:18]#[C:19][C:20]4[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=4)[CH:14]=[CH:15][C:16]=3[OH:17])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][OH:37].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC>[C:1]12([C:11]3[CH:12]=[C:13]([C:18]#[C:19][C:20]4[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][OH:37])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: COC(=O)c1ccc(C#Cc2ccc(O)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Reactant: OCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1ccc(C#Cc2ccc(OCCCCCCO)c(C34CC5CC(CC(C5)C3)C4)c2)cc1

Procedure:
2 g (5.1 mmol) of methyl 4-[3-(1-adamantyl)-4-hydroxyphenylethynyl]benzoate, 1.1 ml (8.3 mmol) of 6-bromo-1-hexanol, 1.2 g (8.8 mmol) of potassium carbonate, 20 mg of potassium iodide and 100 ml of 2-butanone were introduced into a round-bottomed flask. The reaction mixture was heated at reflux for twelve hours and was evaporated to dryness, the residue was taken up in water and ethyl acetate and the organic phase was separated by settling, dried over magnesium sulfate and evaporated.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]2[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[N:17]([C:26](=[O:48])[CH2:27][NH:28][C:29]([NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([O:40]CC4C=CC=CC=4)=[O:39])[CH:33]=3)=[O:30])[CH:16]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]>[Pd].C(O)C>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]2[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[N:17]([C:26](=[O:48])[CH2:27][NH:28][C:29](=[O:30])[NH:31][C:32]3[CH:33]=[C:34]([CH:35]=[CH:36][CH:37]=3)[C:38]([OH:40])=[O:39])[CH:16]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)C2CC(C(=O)OC(C)(C)C)N(C(=O)CNC(=O)Nc3cccc(C(=O)OCc4ccccc4)c3)C2c2ccccc2F)cc1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)Nc1ccc(S(=O)(=O)C2CC(C(=O)OC(C)(C)C)N(C(=O)CNC(=O)Nc3cccc(C(=O)O)c3)C2c2ccccc2F)cc1
Yield: 63.7 %

Procedure:
The process is performed as described in Example 2A, but starting with 1.6 g of tert-butyl (2RS,4SR,5RS)-4-(4-acetamidophenyl)sulphonyl-1-{2-[3-(3-benzyloxycarbonylphenyl)ureido]acetyl}-5-(2-fluorophenyl)-2-pyrrolidinecarboxylate, 0.2 g of 10% palladium-on-charcoal and 100 cm3 of ethanol under a hydrogen atmosphere (130 kPa). After treatment, 0.9 g of (2RS,4SR,5RS)-3-(3-{2-[4-(4-acetamidophenyl)sulphonyl-2-tert-butoxycarbonyl-5-(2-fluorophenyl)-1-pyrrolidinyl]-2-oxoethyl}ureido)benzoic acid is obtained [Rf=0.3; eluent: methylene chloride/methanol (90/10); 1H NMR spectrum (300 MHz, (CD3)2SO, at a temperature of 393 K, δ in ppm): 1.55 (s, 9H: C(CH3)3); 2.12 (s, 3H: COCH3); 2.44 and 2.79 (2 mts, 1H each: CH2 at 3); 3.68 and 3.99 (mt and dd respectively (J=17 and 4.5 Hz), 1H each: COCH2N); 4.03 (mt, 1H: H4); 4.65 (broad t, J=7 Hz, 1H: H2); 5,72 (d, J=3 Hz, 1H: H5); 6.20 (t, J=4.5 Hz, 1H: NHCO); from 7.05 to 7.65 (mt, 6H: aromatic H); 7.80 (broad t, J=8 Hz, 1H: H of the aromatic at 5 (H6)); 7.88 (limiting AB, J=7.5 Hz, 4H: H of the aromatic at 4); 8.00 (mt, 1H: aromatic H (H2: ortho to the COOH)); 8.65 (s, 1H: CONHAr); 10.03 (s, 1H: ArNH)].
Reaction SMILES: [NH:1]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][CH2:17][C:18]([NH:20][C@H:21]([C:25]([NH:27][CH2:28][C:29]([O:31]CC1C=CC=CC=1)=[O:30])=[O:26])[CH:22]([CH3:24])[CH3:23])=[O:19])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].N(C(OC(C)(C)C)=O)[C@H](C(NCC(O)=O)=O)C>O>[NH:1]([C:39]([O:41][C:42]([CH3:44])([CH3:43])[CH3:45])=[O:40])[CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][CH2:17][C:18]([NH:20][C@H:21]([C:25]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:26])[CH:22]([CH3:24])[CH3:23])=[O:19])=[O:15])[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: CC(C)[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Agent: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Solvent: O
Product: CC(C)[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C)C(=O)NCC(=O)O

Procedure:
IV was hydrogenated and worked up as described for VIII to obtain the product in quantitative yield. Rf3 0.16. Anal. calcd. for C25H37N5O8 .H2O: C 54.23, H 7.10, N 12.65%. Found: C 54.14, H 6.93, N 12.21%.