Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].N1C=CC=CC=1.Cl[C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19]>C(OCC)(=O)C>[CH:21]([O:20][C:18]([NH:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8])=[O:19])([CH3:23])[CH3:22]
Reactant: COC(=O)c1sccc1N
Reactant: CC(C)OC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)c1sccc1NC(=O)OC(C)C
Temperature: 60 °C
Yield: 89.2 %

Procedure:
22.1 g (0.141 mol) of methyl 3-aminothiophene-2-carboxylate was dissolved in 100 ml of ethyl acetate, and to this was added 11.7 g (0.148 mol) of pyridine. 18.1 g (0.148 mol) of isopropyl chloroformate was added dropwise while cooling with ice over 30 minutes. After completion of the addition, the solution was heated to 60° C. and stirred with heating for 3 hours. After completion of the reaction, the reaction solution was washed sequentially with a 5% aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=7/3) to obtain 30.6 g of the intended compound as a crystal (yield: 85%). The crystal herein obtained was not analyzed and used for the next reaction.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26]([O:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([Br:37])=[CH:33][C:32]=2[CH3:38])=[O:27])[CH:20]=1)[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C=C([C@H](NC(OCC2C=CC=CC=2)=O)CC(OCC)=O)C=CC=1.BrC1C=CC(CCO)=C(C)C=1>>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26]([O:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([Br:37])=[CH:33][C:32]=2[CH3:38])=[O:27])[CH:20]=1)[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C[C@H](NC(=O)OCc1ccccc1)c1cccc(NC(=O)OCCc2ccc(Br)cc2C)c1
Agent: CCOC(=O)C[C@@H](NC(=O)OCc1ccccc1)c1cccc(N)c1
Agent: Cc1cc(Br)ccc1CCO
Product: CCOC(=O)C[C@@H](NC(=O)OCc1ccccc1)c1cccc(NC(=O)OCCc2ccc(Br)cc2C)c1
Yield: 56 %

Procedure:
Using a procedure analogous to that used to prepare 34D, 39C (1.12 g, 3.3 mmol) was reacted with 30B (700 mg, 3.3 mmol) to afford 39D (1.07 g, 56%) as a colorless oil. MS (ESI) m/z 583.13/585.13 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[OH:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:13](OC(=O)C)(=O)[CH3:14].[OH-].[Na+]>O>[CH3:13][C:14]1[O:12][C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: Nc1cnc2ccccc2c1O
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nc2cnc3ccccc3c2o1

Procedure:
3-Aminoquinolin-4-ol (6 g) was refluxed with acetic anhydride (8 eq.) until analysis by thin layer chromatography indicated that the reaction was complete. The reaction mixture was cooled, diluted with ice and water, made basic with 10% sodium hydroxide and then extracted with dichloromethane. The extract was washed with water and brine, dried over magnesium sulfate and then concentrated under vacuum. The residue was purified by column chromatography (silica gel eluting with methanol/ethyl acetate) to provide 5.1 g of 2-methyloxazolo[4,5-c]quinoline.
Reaction SMILES: [CH3:1][C:2]1([NH:5][C:6]2[N:11]=[C:10](S(C)(=O)=O)[C:9]([C:16]#[N:17])=[CH:8][N:7]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.Cl.[NH2:28][C@H:29]1[CH2:34][C@@H:33]([OH:35])[C@H:32]([CH3:36])[CH2:31][CH2:30]1>>[OH:35][C@H:33]1[C@H:32]([CH3:36])[CH2:31][CH2:30][CH:29]([NH:28][C:10]2[C:9]([C:16]#[N:17])=[CH:8][N:7]=[C:6]([NH:5][C:2]3([CH3:1])[CH2:4][CH2:3]3)[N:11]=2)[CH2:34]1
Reactant: C[C@@H]1CC[C@@H](N)C[C@H]1O
Reactant: CC1(Nc2ncc(C#N)c(S(C)(=O)=O)n2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCC(Nc2nc(NC3(C)CC3)ncc2C#N)C[C@H]1O
Temperature: 90 °C
Reaction time: 16 h
Yield: 30 %

Procedure:
To the reaction mixture of 2-(1-methylcyclopropylamino)-4-(methylsulfonyl)pyrimidine-5-carbonitrile from the previous step was added DIEA (2.14 mL, 12.22 mmol) and (1R,2R,5R)-5-amino-2-methylcyclohexanol hydrochloride (0.371 g, 2.241 mmol; synthesis described herein). The reaction was stirred at 90° C. for 16 h. Upon completion of reaction, as indicated by LCMS and TLC, the reaction mixture was concentrated and purified by silica gel chromatography using a gradient of 0%-60% ethyl acetate in hexanes. The product fractions were combined and concentrated to afford 4-((3R,4R)-3-hydroxy-4-methylcyclohexylamino)-2-(1-methylcyclopropylamino)pyrimidine-5-carbonitrile (0.185 g, 30% yield) as a pale yellow solid. MS (ESI) m/z 302.1 [M+1]+
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10])=[CH2:2].C(O)(=[O:13])C.BrN1C(=O)CCC1=O.[OH-].[Na+]>O1CCOCC1.O>[CH3:10][O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH:1]1[CH2:2][O:13]1
Reactant: C=Cc1ccccc1OC
Reactant: CC(=O)O
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccccc1C1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.8 %

Procedure:
To a solution of 2-vinyl anisole (5.0 g, 0.037 mol) and acetic acid (2.1 mL, 37 mmol) in dioxane (33 mL) and H2O (78 mL) at 0° C. was added N-bromosuccinimide (7.30 g, 40.1 mmol) in three portions. The reaction was allowed to warm to RT and after 1 hour, 2M NaOH (50 mL) was added. The reaction was left to stir at RT overnight. The reaction mixture was partitioned between water and EtOAc, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to give 7.56 g slightly tinted oil. This was dissolved in dioxane, 2N NaOH was added and the reaction was stirred at RT overnight. Repeated aqueous work-up gave 5.60 g of the title compound as a nearly colorless oil.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]([CH3:19])[C:6]1[C:15]([N+:16]([O-])=O)=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][N:7]=1.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.[H][H]>ClCCl.[NH4+].[O-][V](=O)=O.[Pt]>[CH3:19][N:5]1[CH2:4][C:3](=[O:2])[NH:16][C:15]2[CH:14]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=[N:7][C:6]1=2
Reactant: COC(=O)CN(C)c1ncc(C(=O)OC)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: O=[V](=O)[O-]
Agent: [Pt]
Agent: [NH4+]
Solvent: ClCCl
Product: COC(=O)c1cnc2c(c1)NC(=O)CN2C
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.8 %

Procedure:
Methyl 6-((2-methoxy-2-oxoethyl)(methyl)amino)-5-nitronicotinate (2.7 g, 9.53 mmol) was dissolved in dichloromethane (10 mL). To the yellow solution was added ammonium metavanadate (30.0 mg, 0.256 mmol), triphenyl phosphite (aprox 30 ul, 0.097 mmol), and Pt/C (300 mg, 5% w/w). The reaction mixture was pressurized with hydrogen gas (110 psi) and stirred at room temperature for 16 h. The reaction was then depressurized and diluted with dichloromethane (100 mL) which was then refluxed for 30 min. The hot solution was filtered through a pad of celite and washed with hot dichloromethane (3×20 mL). The filtrate was concentrated in vacuo to yield the title compound (1.45 g, 68%) as a white solid. [M+H] calc'd for C10H11N3O3, 222; found, 222.
Reaction SMILES: [CH3:1][C:2]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])=[CH:3][C:4](=[O:8])[CH:5]=[CH:6][CH3:7].B(F)(F)F.CCOCC>C1C=CC=CC=1>[CH3:1][C:2]1[CH:3]([C:4](=[O:8])/[CH:5]=[CH:6]/[CH3:7])[C:12]([CH3:13])([CH3:14])[CH2:11][CH2:10][CH:9]=1
Reactant: CC=CC(=O)C=C(C)CCC=C(C)C
Agent: FB(F)F
Solvent: c1ccccc1
Solvent: CCOCC
Product: C/C=C/C(=O)C1C(C)=CCCC1(C)C
Temperature: 0 °C
Yield: 50 %

Procedure:
A mixture of 10 g. of 6,10-dimethyl-4-oxo-2,5,9-undecatriene prepared according to the method of paragraph (c) herebelow, 100 ml. of benzene and 1 g. of boron trifluoride etherate was heated to the reflux until the vapour phase chromatographic analysis of a sample showed that practically all the starting material had disappeared. The solution is cooled and stirred with ice-water. The organic layer was removed and treated as usual. Distillation of the residue of evaporation gave a 50% yield of trans-2,6,6-trimethyl-1-crotonoyl-2-cyclohexene of about 60% purity as shown by the vapour phase chromatographic analysis.
Reaction SMILES: CC([O-])(C)C.[K+].C1COCC1.[C:12]([C:14]1[CH:22]=[C:21]2[C:17]([C:18]([C:24](=O)[C:25]([O:27]C)=O)=[CH:19][N:20]2[CH3:23])=[CH:16][CH:15]=1)#[N:13].[CH3:30][N:31]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[CH:38]=2)[C:33]([CH2:46][C:47]([NH2:49])=[O:48])=[CH:32]1>>[CH3:23][N:20]1[C:21]2[C:17](=[CH:16][CH:15]=[C:14]([C:12]#[N:13])[CH:22]=2)[C:18]([C:24]2[C:25](=[O:27])[NH:49][C:47](=[O:48])[C:46]=2[C:33]2[C:34]3[C:39](=[CH:38][C:37]([N:40]4[CH2:41][CH2:42][O:43][CH2:44][CH2:45]4)=[CH:36][CH:35]=3)[N:31]([CH3:30])[CH:32]=2)=[CH:19]1
Reactant: Cn1cc(CC(N)=O)c2ccc(N3CCOCC3)cc21
Reactant: COC(=O)C(=O)c1cn(C)c2cc(C#N)ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cn1cc(C2=C(c3cn(C)c4cc(N5CCOCC5)ccc34)C(=O)NC2=O)c2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.2 %

Procedure:
A solution of t-BuOK in THF (1 M, 18.9 mL, 18.9 mmol) was added dropwise to a mixture of methyl (6-cyano-1-methyl-1H-indol-3-yl)glyoxylate (1.85 g, 7.64 mmol) and (1-methyl-6-morpholin-4-yl-1H-indol-3-yl)-acetamide (1.74 g, 6.36 mmol) at 0° C. The cooling bath was removed after 15 min and the mixture was stirred at room temperature for 3 h. Concentrated hydrochloric acid (37%, 10 mL) was added and the reaction mixture was stirred for a further 30 min. The mixture was made basic with aqueous NaHCO3 and extracted with CHCl3 (3×500 mL). The combined organic extracts were washed with aqueous Na2CO3 and dried (K2CO3). The extracts were filtered through a pad of silica gel, then evaporation of the solvents and crystallization of the crude product from acetone/EtOAc gave 1-methyl-3-[4-(1-methyl-6-morpholin-4-yl-1H-indol-3-yl)-2,5 -dioxo-2,5-dihydro-1H-pyrrole-3-yl-]-1H-indole-6-carbonitrile (2.05 g, 69%). Ref: Faul, M. M.; Winneroski, L. L.; Krumrich, C. A. J. Org. (Chem. 1998, 63, 6053.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:18]3=[N:19][C:20]4[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([CH:27]([O:32][CH:33]([F:35])[F:34])[C:28]([F:31])([F:30])[F:29])[C:21]=4[N:17]3[CH2:16][CH2:15][CH2:14]2)=[C:9]([CH3:36])[N:8]=1)(=O)=O.[CH:39]1([NH2:42])[CH2:41][CH2:40]1>>[Cl:26][C:25]1[C:20]2[N:19]=[C:18]3[N:13]([C:10]4[CH:11]=[CH:12][C:7]([NH:42][CH:39]5[CH2:41][CH2:40]5)=[N:8][C:9]=4[CH3:36])[CH2:14][CH2:15][CH2:16][N:17]3[C:21]=2[C:22]([CH:27]([O:32][CH:33]([F:35])[F:34])[C:28]([F:29])([F:30])[F:31])=[CH:23][CH:24]=1
Reactant: NC1CC1
Reactant: Cc1nc(OS(=O)(=O)C(F)(F)F)ccc1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Product: Cc1nc(NC2CC2)ccc1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Temperature: 60 °C
Reaction time: 25.5 h
Yield: 42 %

Procedure:
A mixture of 5-{9-chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-3,4-dihydropyrimido[1,2-a]benzimidazol-1(2H)-yl}-6-methylpyridin-2-yl trifluoromethanesulfonate (130.4 mg, 0.219 mmol) and cyclopropylamine (2.0 mL) was stirred at 60° C. for 25.5 hrs. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 10-60% ethyl acetate/n-hexane gradient mixture. The resulting solid was recrystallized from ethyl acetate/n-hexane to give a title compound as a colorless powder (45.6 mg, 0.909 mmol, 42%).
Reaction SMILES: I[CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[OH:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:20][CH2:19]1.C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C>FC(F)(F)S([O-])(=O)=O.[Ag+].ClCCl>[CH2:27]([O:26][C:24]([N:21]1[CH2:22][CH2:23][CH:18]([O:17][CH2:2][CH2:3][CH:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]2)[CH2:19][CH2:20]1)=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCI)CC1
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Agent: [Ag+]
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CCOC2CCN(C(=O)OCc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
tert-Butyl 4-(2-iodoethyl)piperidine-1-carboxylate (6.75 g) was mixed with dichloromethane (90 ml), and benzyl 4-hydroxypiperidine-1-carboxylate (4.0 g), silver trifluoromethane sulfonate (10.3 g), and 2,6-di-tert-butylpyridine (12 ml) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was filtered using Celite as a filtration adjuvant, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain tert-butyl 4-[2-({1-[(benzyloxy)carbonyl]piperidin-4-yl}oxy)ethyl]piperidine-1-carboxylate (3.4 g).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([OH:27])[CH:25]=3)[NH:20][CH:19]=2)[CH2:14][CH2:13]1.[OH-].[Na+]>C1COCC1>[CH3:11][N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[CH:25]=3)[NH:20][CH:19]=2)[CH2:14][CH2:13]1
Reactant: CN1CCC(c2c[nH]c3ccc(O)cc23)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1CCC(c2c[nH]c3ccc(OS(=O)(=O)c4ccccc4)cc23)CC1
Yield: 75.7 %

Procedure:
By a method similar to Example 31, using benzenesulfonyl chloride (280 μL, 2.2 mmol), 3-(1-methylpiperidin-4-yl)-5-hydroxy-1H-indole (418 mg, 1.8 mmol) in 0.2 N sodium hydroxide (10 mL, 2.0 mmol) and THF (6 mL) gave 650 mg of an off white solid. The crude product was recrystallized from ethyl acetate to give 505 mg (75%) of tan needles: mp=192-194° C.; MS(m/e): 370 (M+); Calculated for C20H22N2O3S: C, 64.84; H, 5.99; N, 7.56. Found: C, 64.92; H, 6.19; N, 7.67.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH2:13][CH2:14][OH:15])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+]>[Pd].C(O)(C)C.CO.C(O)(=O)C.O.[OH-].[Na+]>[OH:15][CH2:14][CH2:13][NH:12][C:6]1[C:5]2[C:10](=[CH:11][CH:2]=[CH:3][CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: OCCNc1ccnc2cc(Cl)ccc12
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Solvent: CC(=O)O
Product: OCCNc1ccnc2ccccc12
Yield: 100.6 %

Procedure:
A slurry of 0.86 g of palladium on carbon in isopropanol was pipetted into a Parr shaker and to this was added a solution of 10 g of 7-chloro-N-(2-hydroxyethyl)-4-quinolinamine and 6.1 g of sodium acetate in 260 ml of methanol and 7 ml of acetic acid. The mixture was hydrogenated at 51 psi (pounds per square inch) until no further reaction was observed. Upon filtration through celite and evaporation of solvents an oil resulted which was dissolved in water and basified with sodium hydroxide. A solid resulted which was recrystallized from isopropanol to give 8.5 g of purified compound with a melting point of 152°-154° C.
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[CH:10][NH:11]3)[CH:2]=1.C([OH:24])C.C(O)(=O)C.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CC(O)(C)C.[Zn]>[C:1]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:24])[NH:11]3)[CH:2]=1
Reactant: c1ccc(-c2cccc(-c3cccc4[nH]ccc34)c2)cc1
Reactant: CCO
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Product: O=C1Cc2c(cccc2-c2cccc(-c3ccccc3)c2)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
To the suspension of 4-bipheny-3-yl-1H-indole (3.5 g, 13 mmol) in t-BuOH:ethanol:acetic acid (82 mL:49 mL:269 mL) was added pyridinium tribromide (12.7 g, 40 mmol) portionwise. The mixture was stirred at room temperature for 3 hours, and then to the mixture was added acetic acid (63 mL). Zinc dust (4.39 g, 67 mmol) was added to the reaction mixture portionwise. After stirring for one hour, any unreacted zinc was filtered off and most of the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, washed with water (3×), sat. NaHCO3, brine, dried over Na2SO4, concentrated and triturated with ether to give 2.67 g (72%) of 4-biphenyl-3-yl-1,3-dihydro-indol-2-one.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].CCO.[BH4-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: OCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Bromobenzaldehyde (157 mmol) was dissolved in 300 mL of THF. At 0° C., 800 mL of EtOH was added, followed by NaBH4 (5.93 g, 157 mmol). The mixture was then stirred at r.t. (room temperature) for 1 hour and poured into cold 25% aq. (aqueous) NH4OAc. The organic solvents were evaporated and the residue was extracted with toluene:THF 1:1, dried over Na2SO4 and filtered through silica to yield the title compound.
Reaction SMILES: [C:1]([O:4][CH2:5][S:6][C:7]1[C:12]([F:13])=[CH:11][C:10]([C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:9][C:8]=1[F:26])(=[O:3])[CH3:2].[OH2:27].[OH2:28].O.O.O.O.C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=O.[Mg+2].O.[Cl-].[NH4+]>CO.ClCCl>[C:1]([O:4][CH2:5][S:6]([C:7]1[C:12]([F:13])=[CH:11][C:10]([C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:9][C:8]=1[F:26])(=[O:28])=[O:27])(=[O:3])[CH3:2]
Reactant: CC(=O)OCSc1c(F)cc(-c2c(-c3ccccc3)noc2C)cc1F
Reactant: O
Agent: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CO
Solvent: ClCCl
Product: CC(=O)OCS(=O)(=O)c1c(F)cc(-c2c(-c3ccccc3)noc2C)cc1F
Yield: 54 %

Procedure:
To a solution of {[2,6-difluoro-4-(5-methyl-3-phenyl-isoxazol-4-yl)phenyl]thio}methyl acetate in methanol (30 mL) and dichloromethane (70 mL) was added magnesium monoperoxyphthalate hexahydrate (8.6 g 80%, 14 mmol). The slurry was heated and held at reflux for 4 hours, then poured into water and extracted with dichloromethane (1×150 mL, 3×75 mL). The combined extracts were washed with dilute sodium chloride twice, dried with magnesium sulfate, and concentrated. The residue was dissolved in dichloromethane (40 mL) and methanol (20 mL), magnesium monoperoxyphthalate hexahydrate (4.5 g, 7.3 mmol) was added, and the mixture heated and held at reflux for 5 hours. Additional magnesium monoperoxyphthalate hexahydrate was added and the mixture heated and held at reflux for 18 hours. The reaction mixture was poured into dilute ammonium chloride and extracted with dichloromethane (1×200 mL, 2×50 mL). The combined extracts were washed twice with dilute ammonium chloride, dried with magnesium sulfate, and concentrated. Purification by silica gel chromatography using 30% ethyl acetate in hexanes gave white solids, which were dissolved in dichloromethane, washed with dilute sodium bicarbonate, dried with magnesium sulfate, and concentrated to provide {[2,6-difluoro-4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl}methyl acetate as a white solid (1.4 g, 54%). Recrystallization from ethyl acetate/hexanes gave an analytical sample of the product, MP 164.6-165.6° C. 1H NMR (CDCl3/400 MHz) 7.35-7.46 (m, 5H), 6.82-6.86 (m, 2H), 5.33 (s, 2H), 2.54 (s, 3H) 2.12 (s, 3H). HRMS m/z 408.0725 (M+H+, calcd 408.0717). Anal. Calcd for C19H15F2NO5S: C, 56.02; H, 3.71; N, 3.44; Found: C, 56.07; H, 3.61, N, 3.58.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:21]([C:22]([NH:24][C@H:25]([C:44]([O:46]C)=[O:45])[CH2:26][C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:43])[C:35]4[C:40]([Cl:41])=[CH:39][N:38]=[CH:37][C:36]=4[Cl:42])=[CH:29][CH:28]=3)=[O:23])[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+].CO>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:21]([C:22]([NH:24][C@H:25]([C:44]([OH:46])=[O:45])[CH2:26][C:27]3[CH:28]=[CH:29][C:30]([NH:33][C:34](=[O:43])[C:35]4[C:40]([Cl:41])=[CH:39][N:38]=[CH:37][C:36]=4[Cl:42])=[CH:31][CH:32]=3)=[O:23])[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cncc2Cl)cc1)NC(=O)C1Cc2ccccc2CN1S(=O)(=O)c1cc(Cl)cc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(Nc1ccc(C[C@H](NC(=O)C2Cc3ccccc3CN2S(=O)(=O)c2cc(Cl)cc(Cl)c2)C(=O)O)cc1)c1c(Cl)cncc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 71.4 %

Procedure:
N-[N-(3,5-Dichlorobenzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline-3 -carbonyl]-4-(N-(3,5-dichloroisonicotinoyl)amino)-phenylalanine, methyl ester (40 mg, 0.0543 mmol) was treated with a 0.2 N solution of NaOH in MeOH (0.0543 mmol, 0.272 mL). After stirring at rt for 6 h, TLC indicated disappearance of all starting material. The volatiles were removed under reduced pressure and the residue was partitioned between 5% citric acid and EtOAc. The aqueous layer was re-extracted with EtOAc (2X). The organic layers were combined and washed with brine and dried over anhydrous Na2SO4. The crude product was purified by flash column chromatography on silica gel eluted with a gradietn of CH2Cl2 and MeOH to afford N-[N-(3,5-dichlorobenzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carbonyl]-4 -(N-(3,5-dichloroisonicotinoyl)amino)-phenylalanine (28 mg, 72%) as a white foam, homogeneous by TLC (Rf=0.2 in 9:1 CH2Cl2:MeOH) Mass spectrum (LC/MS ESI) m/e 723 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:29]=[CH:30]/[O:31]C)[C:5]([O:27][CH3:28])=[C:6]([C:8]2[S:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=3)=[N:11][N:12]=2)[CH:7]=1.[I-].[Na+].C[Si](Cl)(C)C.O>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[S:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:21])[CH3:22])=[C:15]([C:23]([F:24])([F:25])[F:26])[CH:14]=3)=[N:11][N:12]=2)[C:5]([O:27][CH3:28])=[C:4]([CH2:29][CH:30]=[O:31])[CH:3]=1
Reactant: CO/C=C/c1cc(F)cc(-c2nnc(-c3ccc(OC(C)C)c(C(F)(F)F)c3)s2)c1OC
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1c(CC=O)cc(F)cc1-c1nnc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 103.1 %

Procedure:
To a solution of 2-{5-fluoro-2-(methyloxy)-3-[(E)-2-(methyloxy)ethenyl]phenyl}-5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,4-thiadiazole (D34) (170 mg) and sodium iodide (109 mg) in acetonitrile (20 mL) stirred under nitrogen at room temperature was added TMSCl (0.093 mL) dropwise. The reaction mixture was stirred at room temperature for 10 min. Water was added. The aqueous solution was extracted with EA for 3 times. The organic phase was washed with saturated Na2S2O3 solution and saturated brine, dried over sodium sulphate and evaporated in vacuo to afford the crude product [5-fluoro-3-{5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-yl}-2-(methyloxy)phenyl]acetaldehyde (D35) (170 mg) as a yellow oil. MS (ES): C21H18F4N2O3S requires 454. found 455.1 (M+H+).
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:11]=[C:10]([N+:12]([O-])=O)[CH:9]=[CH:8][C:7]=1[OH:15])(=[O:3])[CH3:2]>C(O)C.[H][H].[Pt]>[C:1]([NH:4][CH2:5][C:6]1[CH:11]=[C:10]([NH2:12])[CH:9]=[CH:8][C:7]=1[OH:15])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)NCc1cc([N+](=O)[O-])ccc1O
Agent: [Pt]
Solvent: CCO
Product: CC(=O)NCc1cc(N)ccc1O

Procedure:
2.3 g (0.012 mole) of the nitro compound of step 3 is dissolved in ethanol and hydrated with hydrogen using a platinum catalyst. After absorbing the theoretical quantity of hydrogen the catalyst is suction filtered off, acidified with hydrochloric acid, and the solvent is evaporated in a vacuum. The compound forms a non-crystallizing oil.