Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:22])[CH2:15][S:16]([CH2:19][CH2:20]Cl)(=[O:18])=[O:17])([CH3:3])[CH3:2].[C:23]1([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:22])[CH2:15][S:16]([CH2:19][CH2:20][N:32]1[CH2:33][CH2:34][N:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:30][CH2:31]1)(=[O:18])=[O:17])([CH3:3])[CH3:2]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CS(=O)(=O)CCCl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CS(=O)(=O)CCN1CCN(c2ccccc2)CC1
Yield: 70.7 %

Procedure:
A mixture of 3.46 g of N-(2,6-diisopropylphenyl)-2(2-chloroethylsulfonyl)acetamide synthesized in (1) above, 1.62 g of N-phenylpiperazine, and 50 ml of toluene was heated under reflux for 4 hours. To the reaction mixture was added 100 ml of ethyl acetate, and the mixture was washed successively with a sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography using a mixture of ethyl acetate and hexane at a ratio varying from 1:1 to 1:0 as a developing solvent. The solvent was evaporated, and the residue was dissolved in ethyl acetate and crystallized from a 4N hydrochloric acid solution in ethyl acetate to obtain 3.33 g of the title compound as white powder (m.p.=197.0°-200.0° C.).
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16](=[O:25])[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:8][C@H:7]([NH:26][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:6]1=[O:35].CO.O.O[Li].O>C1COCC1>[O:35]=[C:6]1[N:5]([CH2:4][C:3]([OH:36])=[O:2])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16](=[O:25])[CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:8][C@@H:7]1[NH:26][C:27](=[O:34])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)CN1C(=O)[C@@H](NC(=O)c2ccccc2)CN(C(=O)CCc2ccccc2)c2ccccc21
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CN1C(=O)[C@@H](NC(=O)c2ccccc2)CN(C(=O)CCc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 64 h
Yield: 19 %

Procedure:
(3S)-2-Oxo-3-benzoylamino-5-(3-phenylpropionyl-2,3,4,5-tertrahydro-1H-1,5-benzodiazepine-1-acetic acid methyl ester (602a; 1.25 g, 2.57 mmol) was dissolved in 11 ml of THF, MeOH and H2O (5:5:1) and treated with LiOH.H2O (42 mg, 0.62 mmol) stirred at RT for 64 h. The reaction was concentrated in vacuo, diluted with H2O and acidified with aq. 1N HCl to give 230 mg of 603a as a white solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8](O)[CH3:9].S(=O)(=O)(O)O>O>[F:1][C:2]([F:7])([F:6])[C:3]([O:5][CH2:8][CH3:9])=[O:4]
Reactant: CCO
Reactant: O=C(O)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)C(F)(F)F

Procedure:
in a first stage, trifluoroacetic acid is brought into contact with a slight excess of ethanol in the presence of concentrated sulfuric acid and a solvent, the solvent having a boiling point higher than that of trifluoroacetic acid and specific gravity relative to water less than 1 and which solvent does not form an azeotrope with ethyl trifluoroacetate, and then carrying out a phase separation and removing the sulfuric layer, followed, if required, by an additional stage in which concentrated sulfuric acid is added to complete the esterification;
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][C:6]([CH3:12])([CH3:11])[CH2:7][C:8](Cl)=[O:9].[N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[CH2:23][O:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29]([CH2:34][C:35]([CH3:41])([CH3:40])[C:36]([O:38][CH3:39])=[O:37])=[CH:28]2.C(C(C(C([O-])=O)O)O)([O-])=O>C(Cl)Cl>[CH3:5][C:6]([CH3:12])([CH3:11])[CH2:7][C:8]([C:28]1[C:27]2[C:31](=[CH:32][CH:33]=[C:25]([O:24][CH2:23][C:14]3[CH:15]=[CH:16][C:17]4[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:13]=3)[CH:26]=2)[NH:30][C:29]=1[CH2:34][C:35]([CH3:41])([CH3:40])[C:36]([O:38][CH3:39])=[O:37])=[O:9]
Reactant: COC(=O)C(C)(C)Cc1cc2cc(OCc3ccc4ccccc4n3)ccc2[nH]1
Reactant: CC(C)(C)CC(=O)Cl
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)C(C)(C)Cc1[nH]c2ccc(OCc3ccc4ccccc4n3)cc2c1C(=O)CC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a suspension of AlCl3 (5.7 g, 42 mmol) in CH2Cl2 (30 mL) at 0° C. was added 3,3-dimethylbutanoyl chloride (2.4 mL. 17 mmol). After 15 minutes at 0° C., a solution of the ester from step C (3.0 g, 7.7 mmol) in CH2Cl2 (10 mL) was added by double-tipped needle. The mixture was stirred a further 20 minutes, at which point it was poured into a mixture of 0.5M Na, K tartrate (150 mL) and ice (100 g). The product was extracted with EtOAc, and the organic layer was washed successively with 0.5M NaK tartrate, H2O, and brine. The solvent was then removed and yellow/orange oil (3.5 g) was used without purification in the following step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([S:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:6][CH2:7][CH2:8][CH3:9])[CH3:2].Cl[CH2:23][C:24]1[CH:37]=[CH:36][C:27]([O:28][CH2:29][CH2:30][N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:21])[C:5]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:28][CH2:29][CH2:30][N:31]([CH2:32][CH3:33])[CH2:34][CH3:35])=[CH:36][CH:37]=1)([S:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)(=[O:11])=[O:12])[CH2:6][CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: CCCCC(C(=O)OCC)S(=O)(=O)c1ccc(OC)cc1
Reactant: CCN(CC)CCOc1ccc(CCl)cc1
Product: CCCCC(Cc1ccc(OCCN(CC)CC)cc1)(C(=O)OCC)S(=O)(=O)c1ccc(OC)cc1

Procedure:
2-[4-(2-Diethylaminoethoxy)benzyl]-2-(4-methoxy-benzenesulfonyl)hexanoic acid ethyl ester was prepared according to the general method as outlined in example 12. Starting from 2-(4-methoxy-benzenesulfonyl)hexanoic acid ethyl ester (4 g, 12.7 mmol) and (2-(4-chloromethyl-phenoxy)ethyl]diethylamine (3.38 g, 14 mmol). Yield 8.21 g crude (100%); brown oil; MS: 520.4 (M+H)+.
Reaction SMILES: Cl[C:2]1[S:10][C:9]2[C:8]([C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[O:12])=[N:7][C:6]([NH:18][CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[N:5][C:4]=2[CH:3]=1.[CH3:26][NH2:27].O>CC(N(C)C)=O>[CH3:26][NH:27][C:2]1[S:10][C:9]2[C:8]([C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[O:12])=[N:7][C:6]([NH:18][CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[N:5][C:4]=2[CH:3]=1
Reactant: CN
Reactant: O=C(c1cccs1)c1nc(NCc2cccnc2)nc2cc(Cl)sc12
Solvent: CC(=O)N(C)C
Solvent: O
Product: CNc1cc2nc(NCc3cccnc3)nc(C(=O)c3cccs3)c2s1
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 58 %

Procedure:
A stirred solution of Example 5 (0.4 g, 1 mmol) in dimethyl acetamide (10 ml) was treated with methylamine (2.0M in MeOH, 4.96 ml, 1.10 mmol). The solution was heated to 150° C. in a sealed tube for 1 h. The solution was cooled to room temperature and slowly poured onto stirred iced water (100 ml). After 15 min stirring, a light orange solid was filtered. Recrystallisation from hot ethyl acetate gave the title compound in 58% yield, >95% purity. LC-MS m/z=382.0 [M+H]+; RT=2.73; LC-MS method 1. 1H NMR: δH (400 MHz, D6-DMSO) 2.89 (3H, d, J 5.0 Hz), 4.67 (2H, d, J 6.0 Hz), 5.81 (1H, s), 7.23 (1H, t, J 4.5 Hz), 7.77 (1H, d, J 8.0 Hz), 7.96 (1H, b), 8.09 (1H, d, J=5.0 Hz), 8.41 (1H, d, J=5.0 Hz), 8.36-8.50 (1H, b), 8.61 (1H, bd)
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[CH2:20]([NH2:24])[CH2:21][CH2:22][CH3:23]>>[CH2:20]([NH:24][C:17]([C:15]1[CH:16]=[C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])[CH:12]=[N:13][CH:14]=1)=[O:19])[CH2:21][CH2:22][CH3:23]
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Reactant: CCCCN
Product: CCCCNC(=O)c1cncc(-c2cc(CC)c(=O)[nH]c2C)c1

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and n-butyl amine to afford the title compound. MS: m/e=314 (M+H).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@@H:7]([OH:8])[C@@H:6]([OH:9])[CH:5]=[CH:4]1.N1C=CN=C1.Cl[Si:16]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[O:17][Si:18](Cl)([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20]>CN(C=O)C>[CH:22]([Si:18]1([CH:19]([CH3:21])[CH3:20])[O:8][C@H:7]2[C@@H:6]([OH:9])[CH:5]=[CH:4][C@@H:3]2[CH2:2][O:1][Si:16]([CH:26]([CH3:28])[CH3:27])([CH:29]([CH3:31])[CH3:30])[O:17]1)([CH3:24])[CH3:23]
Reactant: CC(C)[Si](Cl)(O[Si](Cl)(C(C)C)C(C)C)C(C)C
Reactant: OC[C@H]1C=C[C@H](O)[C@@H]1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)[Si]1(C(C)C)OC[C@H]2C=C[C@H](O)[C@@H]2O[Si](C(C)C)(C(C)C)O1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 82.4 %

Procedure:
To a stirred mixture of triol 10 (5.8 g, 44.6 mmol) and imidazole (21.2 g, 312.3 mmol) in DMF (300 mL), 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (14.7 mL, 46.8 mmol) was added drop wise at 0° C. under nitrogen. The mixture was stirred at room temperature for 2.5 h, quenched with water (200 mL) and extracted with ethyl acetate (3×200 ml). The combined organic layer was washed with brine (2×100 ml), followed by with water and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (EtOAc: Hexane 1:30 to 1:5) to give 11 (13.7 g, 82%) as an oil. [α]24D +45.87° (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 0.93-1.04 (m, 28H), 2.90 (m, 1H), 3.16 (d, J=2.0 Hz, 1H), 3.51 (m, 1H), 4.01 (dd, J=3.0, 11.0 Hz, 1H), 4.21 (t, 5.6 Hz, 1H), 4.47-4.45 (m, 1H), 5.60 (dd, J=1.5, 6.0 Hz, 1H), 5.86 (dd, J=3.0, 6.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 12.6, 12.7, 12.9, 13.2, 13.3, 13.4, 17.0, 17.1, 17.2, 17.3, 17.4, 17.6, 54.6, 66.7, 74.7, 76.3, 132.5, 134.4; HR-MS Calcd. For (C18H36O4Si2+Na)+ 395.2152. found 395.2052.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[S:12][C:13]4[C:19]([C:20]5[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=5)=[C:18]([C@H:27]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:28]([O:30]CC)=[O:29])[C:17]([CH3:38])=[CH:16][C:14]=4[N:15]=3)=[CH:8][CH:9]=2)[N:4]([CH3:39])[N:3]=1.C1COCC1.[OH-].[Na+]>CCO>[NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[S:12][C:13]4[C:19]([C:20]5[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=5)=[C:18]([C@H:27]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])[C:28]([OH:30])=[O:29])[C:17]([CH3:38])=[CH:16][C:14]=4[N:15]=3)=[CH:8][CH:9]=2)[N:4]([CH3:39])[N:3]=1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(N)nn(C)c4c3)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc2nc(-c3ccc4c(N)nn(C)c4c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 100 °C

Procedure:
A vial was charged with (S)-ethyl 2-(2-(3-amino-1-methyl-1H-indazol-6-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (60 mg), THF (1.5 mL), EtOH (absolute, 1 mL), and 2M aq NaOH (1 mL). The vessel was sealed and heated to 100° C. for 2 h. The reaction was cooled to 23° C., and filtered (0.45 micron teflon syringe filter). The filtrate was purified by reverse phase HPLC, eluting by 5-100% acetonitrile in H2O with 0.1% TFA to give the desired product. LCMS-ESI+: calc'd for C28H27ClN4O3S: 535.2, 537.2 (M+H+); Found: 535.2, 537.2 (M+H+). 1H NMR (400 MHz, CD3OD): δ 8.06 (s, 1H), 7.87 (s, 1H), 7.82 (d, J=8.5 Hz, 1H), 7.78-7.65 (m, 2H), 7.64-7.54 (m, 3H), 5.27 (s, 1H), 3.90 (s, 3H), 2.63 (s, 3H), 0.98 (s, 9H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=[N:3]1.S(Cl)(Cl)=O.[NH2:14][C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][CH:32]=1)[C:18]([C:20]1[CH:28]=[C:27]2[C:23]([CH2:24][C:25](=[O:29])[NH:26]2)=[CH:22][CH:21]=1)=[O:19]>C1COCC1>[O:29]=[C:25]1[CH2:24][C:23]2[C:27](=[CH:28][C:20]([C:18]([C:17]3[CH:16]=[C:15]([NH:14][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=4)=[O:9])[CH:32]=[CH:31][CH:30]=3)=[O:19])=[CH:21][CH:22]=2)[NH:26]1
Reactant: Cn1nccc1C(=O)O
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cn1nccc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Temperature: 79 °C
Reaction time: 2 h
Yield: 55.9 %

Procedure:
A dry 25 mL flask was charged with 2-Methyl-2H-pyrazole-3-carboxylic acid (0.110 g, 0.873 mmol) and thionyl chloride (5 mL) and allowed to stir at 79° C. for 2 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (5 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.200 g, 0.794 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux for 2 h. The reaction mixture was then allowed to cool to room temperature. The room temperature reaction mixture was concentrated in vacuo, and the crude residue was dissolved in EtOH (5 mL). The ethanolic solution was treated with 1M NaOH(aq) (2 mL) and stirred for 30 min. The basic solution was acidified to a pH of 1 with 1M HCl(aq) yielding a tan precipitate. The tan solids were filtered to afford the pure 2-Methyl-2H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.160 g, 0.444 mmol, 56%).
Reaction SMILES: ClC(Cl)C.[O-:5][S:6]([O-:8])=[O:7].[CH3:9][N:10]([CH3:13])[CH:11]=[O:12]>>[CH3:9][N:10]([CH3:13])[CH:11]=[O:12].[S:6](=[O:8])(=[O:7])=[O:5]
Reactant: O=S([O-])[O-]
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Product: O=S(=O)=O

Procedure:
8.8 g of dimethyl formamide was admixed with 100 ml of dichloroethane and 8.0 g of sulfuric anhydride was added dropwise to the mixture at 15° C to give white needle-like crystals of dimethyl formamidesulfur trioxide complex in stoichometrical amount.
Reaction SMILES: C([O:9][C@@H:10]1[C@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@@H:13]([CH2:24][O:25]C(=O)C2C=CC=CC=2)[O:12][C@H:11]1[N:34]1[C:38]2[N:39]=[CH:40][NH:41][C:42](=[O:43])[C:37]=2[S:36][C:35]1=[O:44])(=O)C1C=CC=CC=1>N>[C@@H:11]1([N:34]2[C:38]3[N:39]=[CH:40][NH:41][C:42](=[O:43])[C:37]=3[S:36][C:35]2=[O:44])[O:12][C@H:13]([CH2:24][OH:25])[C@@H:14]([OH:15])[C@H:10]1[OH:9]
Reactant: O=C(OC[C@H]1O[C@@H](n2c(=O)sc3c(=O)[nH]cnc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: N
Product: O=c1[nH]cnc2c1sc(=O)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 57 %

Procedure:
Compound 9 (1.0 g, 1.63 mmol) was combined with methanolic ammonia (saturated at 0° C., 50 mL) and heated at 90° C. for 14 h in a steel bomb. The solvent was evaporated and the residue was treated with hot benzene which was decanted off. The resulting solid was purified by silica gel flash chromatography using chloroform and then CHCl3 --MeOH (6:1) to yield 280 mg (57%) of 10 after crystallization from water: mp 216°-218° C.: UV λmax (pH 1) 217 nm (ε25300), 259 (9700), 286 (6300): 1H NMR (DMSO-d6) δ5.85 (d, J=5.1 Hz, 1H, C1, H), 8.30 (s, 1H, C5H), 13.09 (b, 1H, N6H, exchanges with D2O), and other sugar protons. Anal. Calcd. for C10H11N3O 6 S: C, 39.87: H, 3.68: N, 13.95: S, 10.64. 3.61: N, 14.06: S, 10.43.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([NH:12][C:13]1[CH:33]=[CH:32][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24]C(=O)OC(C)(C)C)[CH:19]=2)=[CH:15][C:14]=1[F:34])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(OCC)(=O)C>[NH2:24][C:20]1[CH:19]=[C:18]([O:17][C:16]2[CH:32]=[CH:33][C:13]([NH:12][C:10](=[O:11])[O:9][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[C:14]([F:34])[CH:15]=2)[CH:23]=[CH:22][N:21]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc(NC(=O)OCc3ccccc3)c(F)c2)ccn1
Agent: Cl
Solvent: CCOC(C)=O
Product: Nc1cc(Oc2ccc(NC(=O)OCc3ccccc3)c(F)c2)ccn1
Yield: 95.9 %

Procedure:
A 4N solution of hydrochloric acid in ethyl acetate (120 ml) was cooled in an ice bath. tert-Butyl [4-(4-benzyloxycarbonylamino-3-fluorophenoxy)pyridin-2-yl]carbamate (3.92 g) was added thereto while stirring, followed by stirring in an ice bath for 10 min. The reaction mixture was then stirred at room temperature for 3.5 hr. The reaction mixture was concentrated under reduced pressure. Ethyl acetate (150 ml) and a saturated aqueous solution of sodium hydrogencarbonate (70 ml) were added thereto, and liquid-liquid separation was carried out. The aqueous layer was extracted with ethyl acetate (50 ml). The combined organic layer was washed with brine and dried over anhydrous sodium sulfate. The organic layer after drying was concentrated under reduced pressure. The resultant crystals were suspended in a mixed solvent of hexane-ethyl acetate (5:1). The crystals were collected by filtration and washed with a mixed solvent of hexane-ethyl acetate (5:1). The crystals were sucked to dryness at room temperature to provide the titled compound as pale yellow crystals (2.93 g, 95.9%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:16]([CH3:20])[C:17]([NH2:19])=[O:18].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([S:8][CH:16]([CH3:20])[C:17]([NH2:19])=[O:18])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(Br)C(N)=O
Reactant: Sc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(Sc1cccc(Br)c1)C(N)=O
Temperature: 70 °C
Reaction time: 3.5 h
Yield: 98.4 %

Procedure:
To a mixture of 5.0 g 3-bromobenzenethiol and 5.96 g potassium carbonate in 50 ml DMF were added 3.86 g 2-bromopropionamide at RT. The mixture was warmed up and stirred at 70° C. for 3.5 hrs. After cooling, 200 ml water were added and the mixture extracted 3 times with dichloromethane. Drying and evaporation of the organic phases yielded 6.5 g of the title product which was used without further purification.
Reaction SMILES: [NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14]([OH:16])=O)[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH2:39]([NH2:47])[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1COCC1>[NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14]([NH:47][CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:16])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: NCCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)NCCc1ccccc1
Temperature: -15 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a stirred solution of Boc-Asp(OBzl), 5.0 g (15.5 mmol) and N-methyl morpholine (15.5 mmol) in 50 mL of dry THF under an Ar atmosphere was added isobutylchloroformate (15.5 mmol) at -15° C. After a few minutes, phenethylamine 2.0 mL (15.5 mmol) in 15 mL of dry THF was added. The mixture was maintained at -15° C. for 15 min. and allowed to warm to room temperature. After stirring for an additional 2 hours, the reaction mixture was filtered and the filtrate was concentrated in vacuo to dryness. The resulting residue was dissolved in ethyl acetate (100 mL) and washed successively with 1M HCl (2×50 mL), water (50 mL), 10% sodium carbonate (2×50 mL), and brine (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to yield 5.59 gm (85%) of an amorphous white solid.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]([OH:10])[C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.CO[C:15](OC)([CH3:17])[CH3:16].B(F)(F)F.CCOCC.C(N(CC)CC)C>CC(C)=O>[OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]2[O:10][C:15]([CH3:17])([CH3:16])[O:8][C:7]2=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)C(O)c1ccc(O)cc1
Reactant: COC(C)(C)OC
Agent: FB(F)F
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC1(C)OC(=O)C(c2ccc(O)cc2)O1
Reaction time: 3 h
Yield: 98.1 %

Procedure:
To a solution of commercial 4-hydroxy-mandelic acid (10.0 gr, 0.05 mol) in acetone (160 ml), 2,2-dimethoxypropane (56 mL, 0.45 mol) and BF3.Et2O (0.4 ml, 0.48 mol)) were added under vigorous stirring. The solution was left stirring for 3 hours. After adding of triethylamine (TEA) (2 mL), the solvent was evaporated under vacuum and the crude diluted in a saturated solution of Na2HCO3 (30 ml) and extracted with EtOAc (3×30 ml). The collected organic extracts were washed with brine (2×25 mL), dried over Na2SO4 and evaporated under vacuum to give the intermediate 5-(4-hydroxyphenyl)-2,2-dimethyl-1,3-dioxolan-4-one (10.21 g) as yellow oil, pure enough to be used in the further step without any purification.
Reaction SMILES: [C:1]1([CH:7]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([C:25]([C:29]([O:31]CC)=[O:30])=[C:26]([CH3:28])[N:27]=4)[N:24]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[C:34]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([C:25]([C:29]([OH:31])=[O:30])=[C:26]([CH3:28])[N:27]=4)[N:24]=3)[CH2:13][CH2:14]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCOC(=O)c1c(C)nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2c1C(=O)O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 36.3 %

Procedure:
770 mg of ethyl [6-[3-[4-(diphenylmethoxy)piperidino]propylamino]-2-methylimidazo[1,2-b]pyridazin-3-yl]carboxylate was dissolved in 5 ml of ethanol; 3.2 ml of a 1 N aqueous solution of sodium hydroxide was added, followed by stirring at room temperature for 3.5 hours. After cooling, the mixture was concentrated under reduced pressure. The residue was diluted with water, washed with ethyl acetate and adjusted to pH 4.5 by the addition of 1 N hydrochloric acid. The crystal precipitated was collected by filtration, washed with water and ethyl acetate and dried to yield 265 mg of the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].COC1C=CC(S(Cl)(=O)=O)=CC=1>[OH-].[Na+]>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: N[C@H](CC(=O)O)C(=O)O
Agent: COc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Product: N[C@@H](CC(=O)O)C(=O)O
Temperature: 70 °C
Reaction time: 5 h

Procedure:
D-Aspartic acid (2.66 g) is suspended in 2N NaOH (30 mL) and 4-methoxyphenylsulfonyl chloride (4.12 g) is added. The mixture is stirred at 70° C. for 5 hours (clear solution), cooled down to room temperature and extracted with methylene chloride. The aqueous phase, after acidifying with 12N HCl, is extracted with ethyl acetate. The combined organic phases are with brine, dried (Na2SO4) and concentrated under reduced pressure to give N-[4-methoxyphenyl)sulfonyl]-D-aspartic acid as a white solid.