Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[F:33][C:34]1[CH:35]=[C:36]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[CH2:37]Br.C(N(C(C)C)CC)(C)C>CC#N.CCOC(C)=O>[F:33][C:34]1[CH:35]=[C:36]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[CH2:37][N:18]1[CH2:19][CH2:20][CH2:21][CH:16]([C:14]2[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([OH:32])=[O:3])[CH:11]=[C:12]([C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=3)[CH:13]=2)[CH2:17]1
Reactant: Fc1cc(CBr)cc(C(F)(F)F)c1
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCNC2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(Cc3cc(F)cc(C(F)(F)F)c3)C2)c1
Yield: 85 %

Procedure:
To a solution of compound 33b, 4-Methyl-2-(5-piperidin-3-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (44.6 mg, 0.10 mmol) in CH3CN (5 ml) was added 3-Fluoro-5-trifluoromethyl benzyl bromide) (77 mg, 0.3 mmol) and diisopropylethylamine (35 μl, 0.20 mmol). The reaction was microwaved at 130° C. for 10 minutes, then diluted with EtOAc and washed with brine, sat. NaHCO3, and brine, dried and filtered. Purification by silica gel chromatography (Isco) gave the desired product, (53 mg, 85%). Calcd for C34H36F7N1O2 (M+H) 623.64, Found 624.3
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]3[C:24](O)=[O:25])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:27]([O:31][C:32](=[O:44])[NH:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:36]=1[CH2:42][NH2:43])([CH3:30])([CH3:29])[CH3:28].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]3[C:24](=[O:25])[NH:43][CH2:42][C:36]3[CH:37]=[C:38]([Cl:41])[CH:39]=[CH:40][C:35]=3[CH2:34][NH:33][C:32]([O:31][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:44])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CN
Reactant: O=C(O)[C@@H]1CCCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.3 %

Procedure:
A mixture of crude (S)-1-[{(9H-Fluoren-9-yl)methoxy}carbonyl]piperidine-2-carboxylic acid (0.75 g, 2.21 mmol), tert-butyl[2-(aminomethyl)-4-chlorobenzyl]carbamate (0.52 g, 1.93 mmol), HOBT (0.26 g, 1.93 mmol), and EDC.HCl (0.48 g, 2.51 mmol) in DMF (5 mL) was stirred under nitrogen at room temperature for 16 h. The reaction mixture was quenched with water (20 mL) and diluted with EtOAc (50 mL). The organic layer was washed sequentially with saturated aqueous NaHCO3 solution (50 mL) and brine solution (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase combiflash column chromatography (C18; eluent: 10-100% acetonitrile:water) to afford the title compound (0.89 g) as a white solid.
Reaction SMILES: Br.[F:2][CH:3]([F:20])[O:4][C:5]1[N:9]([CH3:10])[N:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[C:6]=1[CH2:15][S:16]C(=N)N.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:20][CH:3]([F:2])[O:4][C:5]1[N:9]([CH3:10])[N:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[C:6]=1[CH2:15][SH:16]
Reactant: Cn1nc(C(F)(F)F)c(CSC(=N)N)c1OC(F)F
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(C(F)(F)F)c(CS)c1OC(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
To a solution of 1.00 g (2.60 mmol) of 2-(5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole-4-ylmethyl)-isothiourea hydrobromide in 2 ml of N,N-dimethylformamide were added 0.43 g (3.12 mmol) of anhydrous potassium carbonate and 1 ml of water, followed by 1 hour of stirring at room temperature. After the completion of the reaction was confirmed, the reaction solution was poured into water and extracted with diethyl ether. The resulting organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure to obtain 0.66 g (purity: 84.9%, yield: 82.4%) of (5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole-4-yl)-methanethiol.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][S:4][CH:3]1[C:7]([O:9][CH3:10])=[O:8].[CH3:11][C:12]1[CH:13]=C(O)[CH:15]=[C:16]([CH:18]=1)[OH:17]>>[OH:17][C:16]1[C:15]2[C:2]3[CH2:6][CH2:5][S:4][C:3]=3[C:7](=[O:8])[O:9][C:10]=2[CH:11]=[C:12]([CH3:13])[CH:18]=1
Reactant: COC(=O)C1SCCC1=O
Reactant: Cc1cc(O)cc(O)c1
Product: Cc1cc(O)c2c3c(c(=O)oc2c1)SCC3

Procedure:
Following the procedure similar to that described in Example 1B hereinabove, methyl 3-oxo-2,3,4,5-tetrahydrothiophene-2-carboxylate is reacted with 5-methylresorcinol to give 1,2-dihydro-9-hydroxy-7-methyl-4-oxo-4H-thieno[2,3-c][1]benzopyran.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]([OH:13])=[C:5]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:4]=1.[CH:18]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1)([CH3:20])[CH3:19]>O1CCCC1>[C:9]([C:7]1[CH:8]=[C:3]([CH2:2][NH:28][C:25]2[CH:24]=[CH:23][C:22]([NH:21][CH:18]([CH3:20])[CH3:19])=[CH:27][CH:26]=2)[CH:4]=[C:5]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:6]=1[OH:13])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)Nc1ccc(N)cc1
Reactant: CC(C)(C)c1cc(CBr)cc(C(C)(C)C)c1O
Solvent: C1CCOC1
Product: CC(C)Nc1ccc(NCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1

Procedure:
4-Bromomethyl-2,6-di-tert-butyl-phenol (2.42 g, 0.008 mole) was dissolved in 50 mL of dry tetrahydrofuran. In a separate conical flask N-Isopropyl-benzene-1,4-diamine (2.40 g, 0.016 mole) was dissolved in 25 mL of tetrahydrofuran and solution was transferred to a cylindrical funnel with pressure equalizing tube. Three-necked round-bottomed flask containing solution of 4-Bromomethyl-2,6di-tert-butyl-phenol was kept in oil-bath at 85° C. Solution in the flask was continuously stirred with the help of magnetic stirrer. N-Isopropyl-benzene-1,4-diamine solution was added drop-by-drop, from funnel to the flask in acidic medium for a span of 4-5 hours till all the solution was poured out. The reaction was terminated after that and the final reaction mixture was allowed to attain room temperature. The product was purified using silica gel column chromatography. Product was identified by 1H-NMR. The yield of 2,6di-tert-butyl4-[(4isopropylamino-phenylamino)methyl]-phenol is 2.025 g (68%).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:9]1[CH2:13][C:12](=[O:14])[NH:11][C:10]1=[O:15].N1CCCCC1>C(O)C>[CH:1](=[C:13]1[S:9][C:10](=[O:15])[NH:11][C:12]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccccc1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1NC(=O)C(=Cc2ccccc2)S1

Procedure:
13.6 ml (135.0 mmol) benzaldehyde, 23.7 g (202.5 mmol) 2,4-thiazolidindione and 2.7 ml (27.0 mmol) piperidine are stirred in 400 ml ethanol under reflux for 13 hours. The resulting precipitate is filtered off and dried: Yield 17.1 g (61%).
Reaction SMILES: BrCCCC[O:6]C1C=C2C(=CC=1)NC(=O)CC2.SC1C=CN=CC=1.[N:25]1[CH:30]=[CH:29][C:28]([S:31][CH2:32][CH2:33][CH2:34][CH2:35][O:36][C:37]2[CH:38]=[C:39]3[C:44](=[CH:45][CH:46]=2)[NH:43][C:42](=[O:47])[CH2:41][CH2:40]3)=[CH:27][CH:26]=1.OO>>[N:25]1[CH:30]=[CH:29][C:28]([S:31]([CH2:32][CH2:33][CH2:34][CH2:35][O:36][C:37]2[CH:38]=[C:39]3[C:44](=[CH:45][CH:46]=2)[NH:43][C:42](=[O:47])[CH2:41][CH2:40]3)=[O:6])=[CH:27][CH:26]=1
Reactant: O=C1CCc2cc(OCCCCSc3ccncc3)ccc2N1
Reactant: O=C1CCc2cc(OCCCCBr)ccc2N1
Agent: OO
Agent: Sc1ccncc1
Product: O=C1CCc2cc(OCCCCS(=O)c3ccncc3)ccc2N1

Procedure:
Prepared analogous to Example 122 from 6-(4-bromo-butoxy)-3,4-dihydro-carbostyril and 4-mercapto-pyridine and subsequent oxidation of the intermediate 6-[4-(4-pyridyl-mercapto)-butoxy]-3,4-dihydro-carbostyril (m.p. 128°-133° C.) with hydrogen peroxide analogous to Example 123.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:36])[CH2:11][C@H:12]([C:22]1[O:23][C:24]([CH3:35])=[C:25]([C:27]([NH:29][CH2:30][C:31]([O:33]C)=[O:32])=[O:28])[N:26]=1)[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1.O>[CH2:1]([O:8][NH:9][C:10](=[O:36])[CH2:11][C@H:12]([C:22]1[O:23][C:24]([CH3:35])=[C:25]([C:27]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:28])[N:26]=1)[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CNC(=O)c1nc([C@H](CCCC2CCCCC2)CC(=O)NOCc2ccccc2)oc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1oc([C@H](CCCC2CCCCC2)CC(=O)NOCc2ccccc2)nc1C(=O)NCC(=O)O
Reaction time: 1 h
Yield: 39.3 %

Procedure:
A solution of methyl ({[2-((1R)-1-{2-[(benzyloxy)amino]-2-oxoethyl}-4-cyclohexylbutyl)-5-methyl-1,3-oxazol-4-yl]carbonyl}amino)acetate (Preparation 99) (158 mg, 0.32 mmol) in 1,4-dioxan (5 ml) was treated with sodium hydroxide solution (1M) (470 l, 0.47 mmol). The mixture was stirred for 1 hour under a nitrogen atmosphere. The reaction mixture was diluted in water and washed with ethyl acetate. The aqueous layer was acidified with solid citric acid and extracted with ethyl acetate. The organic layers were dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure to afford the title compound (61 mg).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[N:5][C:6]2[CH:7]([C:13]([NH2:15])=O)[CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19]>N1C=CC=CC=1.S>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[N:5][C:6]2[CH:7]([C:13](=[S:19])[NH2:15])[CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: NC(=O)C1CCCc2cc(C(F)(F)F)cnc21
Agent: S
Solvent: c1ccncc1
Product: NC(=S)C1CCCc2cc(C(F)(F)F)cnc21
Temperature: 0 °C

Procedure:
The amide (1 mol) is dissolved in dry pyridine saturated with H2S gas and treated with P2S5 (1 mol) then heated at reflux for 45 min. while maintaining a slow stream of H2S gas. The reaction mixture is evaporated to dryness in vacuo and cooled to 0° C, made alkaline with 10% sodium hydroxide and the solution extracted with chloroform (3 times). The combined extracts are washed with brine, dried and evaporated in vacuo to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:3]=1[CH2:4][O:5][CH2:6][C:7]#[C:8][CH2:9]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:36]>C(OCC)C>[F:1][C:2]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:3]=1[CH2:4][O:5][CH2:6][C:7]#[C:8][CH2:9][Br:36]
Reactant: BrC(Br)(Br)Br
Reactant: OCC#CCOCc1cc(Br)ccc1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: Fc1ccc(Br)cc1COCC#CCBr
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of 4-(2-fluoro-5-bromobenzyloxy)-but-2-ynyl alcohol (8.9 g, 32.6 mmol) in diethyl ether (109 ml) was treated with triphenylphosphine (11.1 g, 42.4 mmol) and carbon tetrabromide (14.1 g, 42.4 mmol). The cloudy solution was stirred at ambient temperature for about 14 hours. The precipitate was removed by filtration and the filtrate was concentrated. The desired title intermediate was purified from the filtrate by flash chromatography. Yield 9.83 grams (90%) as a clear oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[C:5]([O:10]C)[N:4]=1.[CH3:12]COCC>>[NH2:9][C:7]1[NH:8][CH:3]([S:2][CH3:1])[N:4]([CH3:12])[C:5](=[O:10])[CH:6]=1
Reactant: CCOCC
Reactant: COc1cc(N)nc(SC)n1
Product: CSC1NC(N)=CC(=O)N1C
Yield: 60 %

Procedure:
The compound soluble in ether was 2-methylmercapto-4-amino-6-methoxypyrimidine. This compound was removed from the solid residue by repeated washings with ether and filtering out of the solid residue. The solid residue was then recrystallized from alcohol to give 43 as slender prisms (yield=60%, m.p. 255° C.).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][C:15]([CH:20]=[CH:21][N+:22]([O-])=O)=[C:14]2[C:10]=1[CH2:11][CH2:12][CH2:13]2.O>CCOCC>[CH3:7][O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][C:15]([CH2:20][CH2:21][NH2:22])=[C:14]2[C:10]=1[CH2:11][CH2:12][CH2:13]2
Reactant: COc1cc(C=C[N+](=O)[O-])c2c(c1OC)CCC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: COc1cc(CCN)c2c(c1OC)CCC2
Reaction time: 4 h
Yield: 85.6 %

Procedure:
To a slurry of 15.0 g (0.395 mole) of LiAlH4 and 500 ml of anhydrous ether in a 5 liter 3-necked flask fitted with a condenser, mechanical stirrer and dropping funnel was added 20.0 g (0.084 mole) of 4,5 -dimethoxy-7-nitrovinylindane dissolved in 2 liters of ether. The addition was made over a period of about 4 hours while refluxing the ether slurry. When the addition was completed, refluxing was continued for an additional 1 to 2 hours. After the addition of 20 g of diatomaceous earth and then 70 ml of water slowly, dropwise, with cooling in an ice bath, the supernatant ether was decanted, the salts were washed with fresh ether several times followed by decantation and finally filtration. The solvent was removed by distillation and more thoroughly on a rotary evaporator. Cooling in an ice bath gave 15.91 g (90%) of 4,5-dimethoxy-7 -aminoethylindane as a slightly yellow solid, m.p., 45°-48°C. High vacuum distillation gave an analytical sample. Anal. Calcd. for C13H19NO2 : C, 70.55; H, 8.65; N, 6.32. Found: C, 70.22; H, 8.49; N, 6.18.
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[N:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[C:3]=1[C:21]#[N:22].[NH:23]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[F-].[K+].O>CS(C)=O>[N:23]1([C:2]2[N:6]([C:7]3[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=3)[N:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[C:3]=2[C:21]#[N:22])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C1CCCNCC1
Reactant: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(C#N)c2Cl)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(C#N)c2N2CCCCCC2)cc1
Temperature: 20 °C
Reaction time: 48 h

Procedure:
5—Chloro-(4-methanesulfonyl-phenyl)-3-trifluoromethyl-1H-pyrazole-4-carbonitrile (70 mg, 0.2 mmol) and azepane (40 mg, 0.4 mmol) were dissolved in dry dimethylsulfoxide (DMSO) (2 ml) and potassium fluoride (0.35 mg, 0.6 mmol) was added to the DMSO solution. The resulting mixture was stirred at 20° C. for a period of 48 hours. Analytical HPLC indicated the reaction completion. The reaction mixture was poured into water (15 ml) and the resulting mixture was extracted with ethyl acetate (20 ml). The organic extract was dried over magnesium sulfate and concentrated with a rotary evaporator. The desired product was isolated by chromatography on silica gel column. MS:395, r.t.: 2.6 min.
Reaction SMILES: [NH:1]1[C:64](=[O:65])[C@H:60]([CH:61]([CH3:63])[CH3:62])[N:59]([CH3:66])[C:57](=[O:58])[C@@H:49]([CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[NH:48][C:46](=[O:47])[C@H:34]([CH2:35][C:36](=[O:45])[O:37]CC2C=CC=CC=2)[NH:33][C:31](=[O:32])[CH2:30][NH:29][C:27](=[O:28])[C@@H:2]1[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:26])[NH:8][S:9]([C:12]1[C:24]([CH3:25])=[C:23]2[C:17]([O:18][C:19]([CH2:22]2)([CH3:21])[CH3:20])=[C:15]([CH3:16])[C:13]=1[CH3:14])(=[O:11])=[O:10].[H][H]>C1COCC1.[Pd]>[NH:1]1[C:64](=[O:65])[C@H:60]([CH:61]([CH3:63])[CH3:62])[N:59]([CH3:66])[C:57](=[O:58])[C@@H:49]([CH2:50][C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[NH:48][C:46](=[O:47])[C@H:34]([CH2:35][C:36](=[O:37])[OH:45])[NH:33][C:31](=[O:32])[CH2:30][NH:29][C:27](=[O:28])[C@@H:2]1[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:26])[NH:8][S:9]([C:12]1[C:24]([CH3:25])=[C:23]2[C:17]([O:18][C:19]([CH2:22]2)([CH3:20])[CH3:21])=[C:15]([CH3:16])[C:13]=1[CH3:14])(=[O:10])=[O:11]
Reactant: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@@H]2NC(=O)[C@H](C(C)C)N(C)C(=O)[C@@H](Cc3ccccc3)NC(=O)[C@H](CC(=O)OCc3ccccc3)NC(=O)CNC2=O)c(C)c2c1OC(C)(C)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@@H]2NC(=O)[C@H](C(C)C)N(C)C(=O)[C@@H](Cc3ccccc3)NC(=O)[C@H](CC(=O)O)NC(=O)CNC2=O)c(C)c2c1OC(C)(C)C2
Yield: 83 %

Procedure:
A solution of 2 g of cyclo(Arg(Pbf)-Gly-Asp(OBzl)-DPhe-NMeVal) in 26 ml of THF is mixed with 0.5 g of Pd/C (10%). Hydrogen is passed through for 2 hours, the mixture is freed of the catalyst and the solvent is removed in vacuo. The product crystallizes after addition of 32 ml of acetone, and is filtered off and dried. Cyclo(Arg(Pbf)-Gly-Asp-DPhe-NMeVal) is obtained in a yield of 83%.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([C:9](Cl)=[O:10])=[N:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=1[O:21][CH3:22].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH3:22][O:21][C:14]1[CH:15]=[C:16]([CH3:20])[C:17]([C:9]([C:7]2[S:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][N:6]=2)=[O:10])=[C:18]([CH3:19])[C:13]=1[CH3:12]
Reactant: O=C(Cl)c1ncc([N+](=O)[O-])s1
Reactant: COc1cc(C)cc(C)c1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc(C)c(C(=O)c2ncc([N+](=O)[O-])s2)c(C)c1C
Reaction time: 3 h

Procedure:
One gram of 5-nitrothiazole-2-carboxylic acid chloride in 10 ml. of methylene chloride is combined with 850 mg. of 2,3,5-trimethylanisole and then with 1.6 g. of aluminum chloride. After three hours of agitation at room temperature, the reaction mixture is poured on 50 ml. of 1N HCl and extracted with ethyl acetate. After drying of the solution and evaporating the solvent under vacuum, the crystalline residue is recrystallized from methanol/chloroform.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][CH:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.CC(C)([O-])C.[Na+].Br[CH2:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:23][C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=3)[CH2:7][CH:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: Clc1ncc2c(n1)N1CCOCC1CN2
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CN2CC3COCCN3c3nc(Cl)ncc32)cc1
Temperature: 100 °C
Yield: 23 %

Procedure:
2-Chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 350 mg, 1.544 mmol) was dissolved in DMSO (10 mL). Sodium tert-butoxide (223 mg, 2.316 mmol) was added, followed 5 minutes later by the addition of methyl 4-(bromomethyl)benzoate (531 mg, 2.316 mmol) to give a brown suspension. The reaction mixture was heated to 100° C. in a microwave on high absorbance for 30 minutes. The reaction mixture was diluted with ethyl acetate and washed with aqueous saturated NH4Cl (2×15 mL) and brine (2×15 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was loaded onto an ISCO® silica gel cartridge (24 g) and eluted using an ethyl acetatehexane gradient. The product was collected and concentrated in vacuo to afford the title compound as a yellow oil (133 mg, 23%). ESI-MS m/z [M+H]+ calc'd for C18H19ClN4O3, 375.1; found 375.4.
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1.[S:21]1[CH2:25][C:24](=[O:26])[NH:23][C:22]1=[O:27].N1CCCCC1>CCO>[OH:1][CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8](/[CH:9]=[C:25]2/[C:24](=[O:26])[NH:23][C:22](=[O:27])[S:21]/2)=[CH:7][CH:6]=1
Reactant: COc1ccccc1C(O)COc1ccc(C=O)cc1
Reactant: O=C1CSC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccccc1C(O)COc1ccc(/C=C2\SC(=O)NC2=O)cc1
Yield: 80.2 %

Procedure:
To a stirring solution of 4-[2-hydroxy-2-(2-methoxyphenyl)ethoxy]benzaldehyde (1.71 g, 6.28 mmol) in absolute EtOH (50 mL) was added 2,4-thiazolidinedione (0.81 g, 6.91 mmol) and piperidine (0.68 mL, 6.9 mmol), and the resulting solution was heated to reflux. The reaction was refluxed overnight and then evaporated in vacuo. The residue was dissolved in EtOAc and this solution was washed with aqueous HOAc (pH 5-6), brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was adsorbed onto silica gel and chromatographed on silica gel eluting with 20-40% EtOAc/DCM. Fractions containing product were combined and evaporated in vacuo to give 1.87 g (80%) of the title compound as a light yellow solid. MS (ESI−) for C19H17NO5S m/z 370.1 (M−H)−.
Reaction SMILES: [CH2:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:5]1=[O:19])[CH2:2][CH3:3].[O:20]=[S:21]1(=[O:38])[C:25]2[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:24]=2[C:23](=[O:31])[N:22]1[CH2:32][CH2:33][CH2:34][C:35](=O)[CH3:36]>>[O:38]=[S:21]1(=[O:20])[C:25]2[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:24]=2[C:23](=[O:31])[N:22]1[CH2:32][CH2:33][CH2:34][CH:35]([N:16]1[CH2:17][CH2:18][CH:13]([N:6]2[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:4]([CH2:1][CH2:2][CH3:3])[C:5]2=[O:19])[CH2:14][CH2:15]1)[CH3:36]
Reactant: CCCn1c(=O)n(C2CCNCC2)c2ccccc21
Reactant: CC(=O)CCCN1C(=O)c2cc(Cl)ccc2S1(=O)=O
Product: CCCn1c(=O)n(C2CCN(C(C)CCCN3C(=O)c4cc(Cl)ccc4S3(=O)=O)CC2)c2ccccc21

Procedure:
Starting with 4-(3-n-propyl-2-oxo-1-benzimidazolinyl)piperidine and 1,1-dioxido-2-(4-oxo-pentyl)-5-chloro-1,2-benzisothiazol-3(2H)-one and following the procedure of Example 13, the title compound is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH2:7][OH:8].C(N(C(C)C)CC)(C)C.[C:20]([Si:24]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)Cl)([CH3:23])([CH3:22])[CH3:21].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH2:7][O:8][Si:24]([C:20]([CH3:23])([CH3:22])[CH3:21])([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:9]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCc1cc(Br)ccc1Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCc1cc(Br)ccc1Cl)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 5-Bromo-2-chlorobenzylalcohol (5.15 g) in N,N-dimethylformamide (50 ml) was added diisopropylethylamine (19.8 ml) and tert-butyldiphenylchlorosilane (11.9 ml), and the mixture was stirred at room temperature for 2 days. Under ice-cooling, to the mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with successively with 0.4 M aqueous hydrochloric acid solution (twice), water, a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by an aminosilane-treated silica gel column chromatography (hexane) to give 5-bromo-2-chloro-1-(tert-butyldiphenylsiloxymethyl)benzene 77 (10.79 g) as colorless oil. APCI-Mass m/Z 476/478 (M+NH4).
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([C:6](=[O:13])C(=O)[NH:8]2)=[CH:4][CH:3]=1.[OH-:14].[Na+].OO.Cl>>[NH2:8][C:9]1[C:10]([CH3:11])=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[C:6]([OH:13])=[O:14]
Reactant: [OH-]
Reactant: Cc1c(Cl)ccc2c1NC(=O)C2=O
Agent: Cl
Agent: OO
Agent: [Na+]
Product: Cc1c(Cl)ccc(C(=O)O)c1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixed solution of 1.3 g of 6-chloro-7-methyl-1H-indole-2,3-dione and 50 ml of a 2N aqueous sodium hydroxide solution was added dropwise to 2 g of aqueous hydrogen peroxide (30%), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was adjusted to pH 4 by an addition of 2N hydrochloric acid, and a deposited precipitate was collected by filtration to obtain 0.6 g of 2-amino-4-chloro-3-methylbenzoic acid of the formula: