Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C@@H:2]1[CH2:6][N:5]([C:7](=[O:17])[CH2:8][O:9][Si](C(C)(C)C)(C)C)[C@H:4]([C:18]#[N:19])[CH2:3]1.O.C(O)(=O)C>O1CCCC1>[F:1][C@@H:2]1[CH2:6][N:5]([C:7](=[O:17])[CH2:8][OH:9])[C@H:4]([C:18]#[N:19])[CH2:3]1
Reactant: CC(C)(C)[Si](C)(C)OCC(=O)N1C[C@@H](F)C[C@H]1C#N
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CO
Temperature: 50 °C
Reaction time: 7.5 h
Yield: 96.5 %

Procedure:
(2S,4S)-4-fluoro-1-[2-(tert-butyldimethylsilyloxy)acetyl]pyrrolidine-2-carbonitrile (5.50 g) was dissolved in tetrahydrofuran (37 mL). To this solution, water (37 mL) and acetic acid (115 mL) were sequentially added and the mixture was stirred at 50° C. for 7.5 hours and then at 70° C. for 9 hours. Subsequently, the reaction mixture was concentrated under reduced pressure and the resulting pale brown tar-like residue was triturated with diethyl ether. The resulting solid was collected by filtration and dried under reduced pressure to give (2S,4S)-4-fluoro-1-(2-hydroxyacetyl)pyrrolidine-2-carbonitrile as a pale brown solid (3.19 g).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][C:11]1[CH:22]=[CH:21][C:14]2[C:15]([CH2:18][CH2:19][OH:20])=[CH:16][O:17][C:13]=2[CH:12]=1.CCN(C(C)C)C(C)C.[O:32](S(C)(=O)=O)[S:33]([CH3:36])(=O)=[O:34]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][C:11]1[CH:22]=[CH:21][C:14]2[C:15]([CH2:18][CH2:19][O:20][S:33]([CH3:36])(=[O:34])=[O:32])=[CH:16][O:17][C:13]=2[CH:12]=1
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: OCCc1coc2cc(Oc3nc4ccccc4s3)ccc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCCc1coc2cc(Oc3nc4ccccc4s3)ccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 105.3 %

Procedure:
To a solution of 2-[6-(benzothiazol-2-yloxy)-benzofuran-3-yl]-ethanol (0.32 g, 1.0 mmol) in DCM (15 mL) was added 4-dimethylaminopyridine (13 mg, 0.10 mmol), DIEA (0.22 mL, 1.2 mmol) and Ms2O (0.22 g, 1.2 mmol) and the resulting solution was stirred (rt, 15 min). The reaction mixture was diluted with DCM (40 mL). The organic layer was washed with saturated NH4Cl (2×50 mL), brine (2×50 mL), dried, filtered and concentrated in vacuo to provide the title compound as a clear oil (0.41 g, 100%). MS (ESI): mass calcd. for C18H15NO5S2, 389.5; m/z found, 390.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)([CH3:8])[C:3]([O:5]CC)=[O:4].[OH-].[Li+]>O1CCCC1.CO.O>[CH3:8][C:2]([O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(C)OC1CCCCO1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(OC1CCCCO1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
To a solution of ethyl 2-methyl-2-(tetrahydro-2H-pyran-2-yloxy)propanoate (0.5 g, 2.31 mmol) in tetrahydrofuran (2 mL) and methanol (6 mL) was added a solution of lithium hydroxide (0.277 g, 11.56 mmol) in water (6 mL). The resulting mixture was stirred at room temperature overnight. The organic solvents were removed under reduced pressure and the resulting aqueous phase was acidified using hydrochloric acid 2N until pH=4. The formed precipitate was extracted with ethyl ether (3×25 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulphate and concentrated to yield the title compound (0.42 g, 96%) as a colourless oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[CH:14]\[O:15][CH3:16])/[C:10]([O:12][CH3:13])=[O:11].CC(C)=[O:19]>O.[N+]([O-])([O-])=O.[Ag+]>[OH:19][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[CH:14]\[O:15][CH3:16])/[C:10]([O:12][CH3:13])=[O:11]
Reactant: CO/C=C(/C(=O)OC)c1ccccc1CBr
Reactant: CC(C)=O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: CO/C=C(/C(=O)OC)c1ccccc1CO
Temperature: 2 °C
Reaction time: 0.67 h
Yield: 54 %

Procedure:
(E)-Methyl 2-[2-(bromomethyl)phenyl]-3-methoxypropenoate (15 g) was dissolved in acetone (200 ml) and the solution was cooled to 2° C. A solution of silver nitrate (22.35 g) in water (200 ml) at 4° C. was added to this. The temperature rose to 12° C. After stirring for 40 minutes the green/grey precipitate which had formed was filtered off and the filtrate partitioned between water and diethyl ether. The diethyl ether layer was washed with brine, dried over anhydrous sodium sulphate and evaporated under reduced pressure to give an oil which was purified by chromatography on silica gel, eluting with diethyl ether, to give (E)-methyl 2-[2-(hydroxymethyl)phenyl]-3-methoxypropenoate as a viscous oil (6.33 g, 54%). 1H NMR (CDCl3): 2.3(t,1H), 3.7(s,3H), 3.8(s,3H), 4.5(d,2H), 7.1(m,1H), 7.2-7.4(m,2H), 7.5(m,1H), 7.6(s,1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17](=[O:22])/[CH:18]=[C:19](\[NH2:21])/[CH3:20].[CH3:23][C:24]1[N:28]([CH2:29][CH2:30][O:31][CH2:32][C:33](=O)[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:27]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[N:26][N:25]=1>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[C:18]([C:17](=[O:22])[NH:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][N:10]=2)=[C:19]([CH3:20])[NH:21][C:33]([CH2:32][O:31][CH2:30][CH2:29][N:28]2[C:27]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)=[N:26][N:25]=[C:24]2[CH3:23])=[C:34]1[C:35]([O:37][CH2:38][CH3:39])=[O:36]
Reactant: O=Cc1ccccc1Cl
Reactant: C/C(N)=C/C(=O)Nc1ccccn1
Reactant: CCOC(=O)CC(=O)COCCn1c(C)nnc1-c1ccccc1
Solvent: CCO
Product: CCOC(=O)C1=C(COCCn2c(C)nnc2-c2ccccc2)NC(C)=C(C(=O)Nc2ccccn2)C1c1ccccc1Cl
Yield: 17.7 %

Procedure:
2-Chlorobenzaldehyde (0.3 g, 2.12 mmole), N-(pyrid-2-yl)-3-aminocrotonamide (0.38 g, 2.12 mmole) (obtained from N-(pyrid-2-yl)-3-oxobutanamide by reaction with ethanolic ammonia at room temperature for 16 hours) and ethyl 4-[2-(3-methyl-5-phenyl-4H-1,2,4-triazol-4-yl)ethoxy]-3-oxobutanoate (0.7 g, 2.12 mmole) were dissolved in absolute ethanol (25 ml) and the mixture heated under reflux for 5 hours. The solution was cooled and concentrated to dryness under reduced pressure. The residue was chromatographed on silica, eluting with ethyl acetate containing 15% ethanol. Appropriate fractions were combined, concentrated under vacuum and the residue triturated with ethyl acetate to yield the title product as a white amorphous solid (0.23 g, 20%), m.p. 167°-169° C. Found: C,64.92; H,5.61; N,13.39. C33H33ClN6O4 requires C,64.65; H,5.43; N,13.71%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[F:38])[CH2:5][N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([NH:14][C@@H:15]([C:20]2[S:21][C:22]([C:25]3[C:33]4[C:28](=[N:29][CH:30]=[CH:31][CH:32]=4)[NH:27][CH:26]=3)=[CH:23][CH:24]=2)[CH2:16][C:17](O)=[O:18])=[O:13])[C:7]1=[O:34].CN(C)C=O.[CH2:44]([NH2:46])[CH3:45].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>>[CH2:44]([NH:46][C:17]([CH2:16][C@@H:15]([NH:14][C:12]([C:8]1[C:7](=[O:34])[N:6]([CH2:5][C:4]2[CH:35]=[CH:36][C:37]([F:38])=[C:2]([F:1])[CH:3]=2)[CH:11]=[CH:10][CH:9]=1)=[O:13])[C:20]1[S:21][C:22]([C:25]2[C:33]3[C:28](=[N:29][CH:30]=[CH:31][CH:32]=3)[NH:27][CH:26]=2)=[CH:23][CH:24]=1)=[O:18])[CH3:45]
Reactant: O=C(O)C[C@@H](NC(=O)c1cccn(Cc2ccc(F)c(F)c2)c1=O)c1ccc(-c2c[nH]c3ncccc23)s1
Reactant: CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCNC(=O)C[C@@H](NC(=O)c1cccn(Cc2ccc(F)c(F)c2)c1=O)c1ccc(-c2c[nH]c3ncccc23)s1
Reaction time: 2 h

Procedure:
(R)-3-{[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-3-[5-(1H-pyrrolo[2,3-b]pyridin-3-yl)-thiophen-2-yl]-propionic acid (0.040 g, 0.000075 mol;) was dissolved in N,N-Dimethylformamide (3 mL, 0.04 mol;) and Ethylamine (7 mg, 0.0001 mol;) then N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (0.037 g, 0.000097 mol;) was added. The reaction was allowed to stir for 2 hours and LC-MS showed disappearance of starting material and appearance of product at 1.28 562.10. The reaction was purified by Gilson Preparative HPLC and the pure fractions were concentrated. ES (+) MS m/e=562.10; NMR (400 MHz, DMSO-d6) δ ppm 0.92 (t, 3H, J=7 Hz), 2.76 (m, 2H), 2.95 (m, 2H), 5.22 (m, 2H), 5.66 (m, 1H), 6.66 (t, 1H, J=8 Hz), 6.99 (d, 1H, J=3 Hz), 7.14-7.21 (m, 3H), 7.38-7.49 (m, 2H), 7.79 (m, 1H), 8.2-8.25 (m, 2H), 8.29 (m, 1H), 8.4 (dd. 1H), 10.22 (d, 1H), 11.95 (s, 1H)
Reaction SMILES: [OH:1][C:2]1([C:11]([OH:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:3]1[C:4]([OH:6])=[O:5].[C:14](O)(=[O:16])C.[BH4-].[Na+].Cl>O1CCCC1>[CH3:14][O:1][C:2]1([C:11]([OH:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:3]1[C:4]([OH:6])=[O:5].[CH3:14][O:16][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:2]=1[CH2:11][O:13][C:4]2=[O:6]
Reactant: CC(=O)O
Reactant: O=C(O)C1C=CC=CC1(O)C(=O)O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(C(=O)O)C=CC=CC1C(=O)O
Product: COc1cccc2c1COC2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Anhydrous 2-methoxyphthalic acid (640 mg), which was prepared with using anhydrous 2-hydroxyphthalic acid by the same procedure as reference example 12, was suspended in tetrahydrofuran (20 ml). Acetic acid (430 mg) and sodium borohydride (135 mg) were added to the suspension. The mixture was stirred for 30 min. at room temperature and for 2 hr. at 50°C. The reaction solution was cooled. 1N hydrochloric acid (7 ml) was added to the cooled solution. The solution was stirred for 15 min. The reaction solution was evaporated. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=2:1→1:1) to give the title compound (314 mg) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:8]([CH2:19][N:20]1[C:24]3=[N:25][CH:26]=[N:27][C:28]([NH2:29])=[C:23]3[C:22](I)=[N:21]1)=[CH:7]2.[C:31](=[O:34])([O-])[O-].[Na+].[Na+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:29][C:28]1[N:27]=[CH:26][N:25]=[C:24]2[N:20]([CH2:19][C:8]3[C:9]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[Cl:18])=[N:10][C:11]4[C:6]([CH:7]=3)=[CH:5][CH:4]=[CH:3][C:2]=4[Cl:1])[N:21]=[C:22]([C:11]3[CH:6]=[C:31]([OH:34])[CH:4]=[CH:3][CH:2]=3)[C:23]=12
Reactant: O=C([O-])[O-]
Reactant: Nc1ncnc2c1c(I)nn2Cc1cc2cccc(Cl)c2nc1-c1ccccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1cccc(O)c1)nn2Cc1cc2cccc(Cl)c2nc1-c1ccccc1Cl

Procedure:
Prepared according to Procedure J using 1-((8-chloro-2-(2-chlorophenyl)quinolin-3-yl)methyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.100 g, 0.18 mmol), 3-(hydroxyphenyl)boronic acid (0.050 g, 0.37 mmol, 2 eq), tetrakis(triphenylphosphine)palladium (0.021 g, 0.018 mmol, 0.1 eq) and 2M aq sodium carbonate (0.54 mL, 1.08 mmol, 6 eq) in DMF (1 mL). 3-(4-Amino-1-((8-chloro-2-(2-chlorophenyl)quinolin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenol [PI3Kδ IC50=14 nM] was obtained after purification as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.52 (1 H, s), 8.31 (1 H, s), 7.91-8.00 (2 H, m), 7.86 (1 H, dd, J=7.4, 1.2 Hz), 7.52 (1 H, t, J=7.8 Hz), 7.35 (1 H, d, J=8.2 Hz), 7.07-7.28 (3 H, m), 6.97-7.05 (1 H, m), 6.78-6.93 (2 H, m), 6.70 (1 H, dd, J=8.2, 1.6 Hz), 5.36-5.57 (2 H, m) Mass Spectrum (ESI) m/e=513.1 and 515.0 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=[C:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH:12]=2)=[N:8][CH:9]=1)[CH3:2].[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:31](=O)[O:32]C2C=CC=CC=2)[N:25]=1.C(N(CC)CC)C>CS(C)=O.O>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=2)[CH:17]=[C:18]2[CH2:23][CH2:22][N:21]([C:31]([NH:30][C:26]3[N:25]=[N:24][CH:29]=[CH:28][CH:27]=3)=[O:32])[CH2:20][CH2:19]2)=[N:8][CH:9]=1)[CH3:2]
Reactant: O=C(Nc1cccnn1)Oc1ccccc1
Reactant: CCOc1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOc1ccc(Oc2cccc(C=C3CCN(C(=O)Nc4cccnn4)CC3)c2)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.7 %

Procedure:
To a solution of 5-ethoxy-2-(3-(piperidin-4-ylidenemethyl)phenoxy)pyridine (0.22 g, 0.708 mmol) in DMSO (4 mL) was added phenyl pyridazin-3-ylcarbamate (0.152 g, 0.708 mmol) followed by triethylamine (0.265 mL, 2.12 mmol). The resulting mixture was stirred at RT for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic extract was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (38% acetone, 62% hexane) to give the title compound (0.225 g, 73% yield). 1H NMR (500 MHz, CDCl3): δ 8.80 (s, 1H), 8.29 (s, 1H), 7.87 (d, J=3.0 Hz, 1H), 7.41 (d, J=4.0 Hz, 1H), 7.34-7.23 (m, 1H), 6.99-6.93 (m, 3H), 6.86 (d, J=9.0 Hz, 1H), 6.39 (s, 1H), 4.02 (q, J=7.0 Hz, 2H), 3.67 (s, 2H), 3.57 (s, 2H), 2.6-2.5 (m, 2H), 2.47 (m, 2H), 1.40 (t, J=7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 157.32, 156.79, 155.24, 151.82, 147.4, 138.74, 137.55, 133.57, 129.40, 127.97, 126.82, 124.89, 124.56, 120.55, 118.91, 112.52, 64.61, 45.66, 44.66, 35.78, 29.14, 14.82; m/z (432.1, M+ H+); HPLC: 98.76%.
Reaction SMILES: [CH2:1]([C@@:17]1([CH2:22][O:23]CC2C=CC=CC=2)[NH:20][C:19](=[O:21])[CH2:18]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>[Pd].CO.C(O)(=O)C>[CH2:1]([C@@:17]1([CH2:22][OH:23])[NH:20][C:19](=[O:21])[CH2:18]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC[C@]1(COCc2ccccc2)CC(=O)N1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCC[C@]1(CO)CC(=O)N1
Reaction time: 16 h
Yield: 95.8 %

Procedure:
A mixture of 400 mg of (R)-4-hexadecyl-4-[(phenylmethoxy)methyl]-2-azetidinone, 50 mg of 10% palladium-on-carbon and 20 ml of methanol:acetic acid (1:1) is hydrogenated for 16 hours, then filtered and evaporated. The residue is recrystallized from petroleum ether/ethyl acetate, to give 300 mg of the desired compound as a white solid, mp. 82° C.
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[CH3:6]N.[C:8]1(C)[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][CH:9]=1>>[P:1]([Cl:5])([Cl:3])(=[O:2])[O:14][C:13]1[CH:8]=[CH:9][C:10]([CH3:6])=[CH:11][CH:12]=1
Reactant: CN
Reactant: Cc1ccccc1O
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ccc(OP(=O)(Cl)Cl)cc1
Reaction time: 2 h

Procedure:
To a mixture of 225 g. phosphoryl chloride and methylamine there is added 109 g. cresol over a period of 2 hours at a temperature of 105°C. The temperature is held at 105°-110°C. for two hours to afford cresyl phosphorodichloridate.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[CH3:15][S:16](Cl)(=[O:18])=[O:17].[Cl-].[Al+3].[Cl-].[Cl-].[C:24](Cl)(=[O:26])[CH3:25].Cl>ClCCl.C1(C)C=CC=CC=1>[C:24]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:16]([CH3:15])(=[O:18])=[O:17])=[C:3]([CH3:8])[CH:4]=1)(=[O:26])[CH3:25]
Reactant: Cc1ccccc1N
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)c1ccc(NS(C)(=O)=O)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
To a solution of o-toluidine (10.7 ml, 100 mmol) and pyridine (8.49 ml, 105 mmol) in dichloromethane (20 mL) was added methanesulfonyl chloride (7.74 ml, 100 mmol) dropwise over 15 minutes at 0° C. The reaction mixture was stirred at room temperature for 1 hour. After cooling to 0° C., aluminum chloride (33.3 g, 250 mmol) was added carefully to the reaction mixture. Then acetyl chloride (10.7 ml, 150 mmol) was added dropwise over 20 minutes at 5-20° C. The reaction mixture was stirred at room temperature for 0.5 hours, the reaction was monitored by using TLC and 1H-NMR, and after completion of the reaction, the reaction mixture was diluted with toluene and poured into 2N HCl aqueous solution with stirring at 0° C. The precipitate solid was filtered, washed with H2O and heptane, and dried in vacuo to give the title compound (20.3 g, 89.3 mmol, 89% yield in 2 steps) as a light orange powder.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=O)[CH:9]=2)[N:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[C:21]([F:24])([F:23])[F:22])[N:3]=1.[O:25]=[C:26]1[N:30]([CH2:31][C:32]([OH:34])=[O:33])[C:29](=[O:35])[CH2:28][S:27]1>>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8](/[CH:11]=[C:28]3/[C:29](=[O:35])[N:30]([CH2:31][C:32]([OH:34])=[O:33])[C:26](=[O:25])[S:27]/3)[CH:9]=2)[N:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[C:21]([F:22])([F:23])[F:24])[N:3]=1
Reactant: O=Cc1ccc2c(c1)c(Br)nn2Cc1ccc(Cl)cc1C(F)(F)F
Reactant: O=C(O)CN1C(=O)CSC1=O
Product: O=C(O)CN1C(=O)S/C(=C\c2ccc3c(c2)c(Br)nn3Cc2ccc(Cl)cc2C(F)(F)F)C1=O

Procedure:
[(5Z)-5-({3-Bromo-1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]acetic acid was prepared from 3-bromo-1-(4-chloro-2-trifluoromethylbenzyl)-1H-indazole-5-carbaldehyde and (2,4-dioxothiazolidin-3-yl)acetic acid following General Procedure F.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[N:10]=[C:9]([CH2:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[C:8]([F:17])=[C:7]([NH:18]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=1)C.OS(O)(=O)=O.CC#N>O>[NH2:18][C:7]1[C:8]([F:17])=[C:9]([CH2:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[N:10]=[C:5]([CH:4]=[O:3])[CH:6]=1
Reactant: CCOC(OCC)c1cc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c(Cc2nccs2)n1
Agent: O=S(=O)(O)O
Solvent: CC#N
Solvent: O
Product: Nc1cc(C=O)nc(Cc2nccs2)c1F
Yield: 71.9 %

Procedure:
Following the procedure of Example 12, 6-(diethoxymethyl)-3-fluoro-2-(thiazol-2-ylmethyl)-N-tritylpyridin-4-amine (471 mg, 0.85 mmol), conc H2SO4 (0.5 mL), CH3CN (10 mL) and H2O (10 mL) gave the title compound (0.145 g, 71%) as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 9.88 (s, 1H), 7.72 (d, J=3.3 Hz, 1H), 7.28 (d, J=6.7 Hz, 1H), 7.26 (d, J=3.4 Hz, 1H), 4.59 (d, J=2.8 Hz, 2H), 4.56 (br s, 2H); 19F NMR (376 MHz, DMSO-d6) δ −142.44; HRMS-ESI (m/z) [M+H]+ calcd for C10H8FN3OS, 237.0372. found, 237.0363.
Reaction SMILES: [NH2:1][C:2](=[O:25])[CH2:3][O:4][CH2:5][CH:6]([NH:14]C(=O)OCC1C=CC=CC=1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[H][H].[C:28]([N:38]1[CH2:45][CH2:44][CH2:43][C@H:39]1[C:40]([OH:42])=O)([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>[Pd].CO>[NH2:1][C:2](=[O:25])[CH2:3][O:4][CH2:5][CH:6]([NH:14][C:40]([C@@H:39]1[CH2:43][CH2:44][CH2:45][N:38]1[C:28]([O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:29])=[O:42])[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: [H][H]
Reactant: NC(=O)COCC(Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CO
Product: NC(=O)COCC(Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 14 h

Procedure:
A stirred suspension of 1.52 g (0.0044 mol) of (±)-phenylmethyl [1-[(2-amino-2-oxoethoxy)methyl]-2-phenylethyl]-carbamate and 0.35 g of 20% palladium on carbon in a 100 ml of methanol is exposed to hydrogen gas for 15 minutes, the suspension is purged with nitrogen gas, filtered, and the solvent evaporated in vacuo at 30° C. The residue is dissolved in 100 ml of dichloromethane, the solution is cooled to 0° C. and 1.196 g (0.0048 mol) of carbobenzyloxyproline, 0.734 g (0.0048 mol) of 1-hydroxybenzotriazole and 0.99 g (0.0048 mol) of dicyclohexylcarbodiimide are added. The mixture is allowed to reach room temperature and stirred for 14 hours, filtered, the solvent evaporated in vacuo, and the residue dissolved in 200 ml of dichloromethane and washed successively with a 5% aqueous solution of sodium carbonate, 2×200 ml, 10% aqueous solution of citric acid, 2×200 ml and a saturated aqueous solution of sodium chloride, 2×200 ml. The dichloromethane layer is separated, dried over sodium sulfate, evaporated in vacuo and the residue purified by chromatography using silica gel and eluting with dichloromethane-methanol (95:5) to give (2S)-phenylmethyl 2-[[[1-[(2-amino-2-oxoethoxy)methyl]-2-phenylethyl]amino]carbonyl]-1-pyrrolidinecarboxylate (center on chain in 2 position is a mixture of isomers), 0.8 g; mp 137°-142°; [α]D25 -45.1° (c 1.09, methanol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][CH:8]([NH2:30])[C:9]([NH:11][CH:12]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[CH3:32]CN(C(C)C)C(C)C.BrC[C:43]([O:45][CH3:46])=[O:44]>C1COCC1>[C:1]([O:5][C:6](=[O:31])[CH2:7][CH:8]([N:30]([C:43]([O:45][CH3:46])=[O:44])[CH3:32])[C:9]([NH:11][CH:12]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)CC(N)C(=O)NC(Cc1c[nH]c2ccccc12)C(=O)OC(C)(C)C
Reactant: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N(C)C(CC(=O)OC(C)(C)C)C(=O)NC(Cc1c[nH]c2ccccc12)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 79.4 %

Procedure:
To a suspension of the dipeptide of Example 57 (100 mg, 0.23 mmol) in dry THF (2 mL) was added DIPEA (40 μL, 0.46 mmol). After the mixture became a homogenous solution, it was cooled to 0° C. and methyl bromoacetate (22 μL, 0.23 mmol) was introduced as a solution in dry THF (0.5 mL). The light suspension, which appeared shortly after, was stirred at 0° C. for 10 min and then at room temperature for 5 hours. The mixture was then concentrated in vacuum, dissolved in ethyl acetate and washed with H2O and brine. Drying (Na2SO4) and evaporation gave the title compound (92 mg) as a yellow foam. Flash chromatography (CH2Cl2 to 5% methanol in CH2Cl2) gave the desired product in 62% yield: 1HNMR (CDCl3, 300 MHz) □ 8.52 (br s, 1H), 7.82 (d, 1H), 7.59 (d, 1H), 7.38-7.02 (m, 4H), 4.75 (m, 1H), 4.18 (m, 1H), 3.68 (s, 3H), 3.61-3.21 (m and dd, 3H), 3.14 (dd, 1H), 2.85 (m, 2H), 1.42 (s, 9H), 1.36 (s, 9H); MS (Pos. FAB) 504.5 (MH)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C([O-])([O-])=O.[Na+].[Na+].[CH2:24]([CH2:27]OC)OC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][N:14]1[CH2:15][CH2:16][N:11]([C:4]2[CH:3]=[C:2]([C:4]3[CH:3]=[CH:2][CH:7]=[CH:6][C:24]=3[CH3:27])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=2)[CH2:12][CH2:13]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(Br)c2)CC1
Reactant: COCCOC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccccc1-c1cc(N2CCN(C)CC2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 14 h

Procedure:
A mixture of 200mg (0.666 mmol) 1-(3-bromo-4-nitro-phenyl)-4-methyl-piperazine (as prepared in the previous step), 136 mg (0.999 mmol) and 77.0 mg (0.0666 mmol) of tetrakis(triphenylphosphine)palladium (0) under Ar was added 4.0 mL of degassed dimethoxyethane (DME) and 400 μL (0.799 mmol) of 2.0 M aq Na2CO3. The mixture was heated with stirring under Ar at 80° C. for 14 h. The cooled (RT) mixture was concentrated and chromatographed on a 10-g silica SPE column with 1-5% MeOH in dichloromethane-hexane (1:1). The product fractions were treated with 80 mg of decolorizing carbon, filtered, concentrated, and then rechromatographed on a similar column with 1-3% EtOH-dichloromethane to afford 265 mg of the title compound as a yellow resin (75% purity by 1H-NMR as a mixture with triphenylphosphine) that was used in the following reaction without further purification: Mass spectrum (ESI, m/z): Calcd. for C11H21N3O3, 312.2 (M+H), found 312.2.