Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([NH:21][CH:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:35].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:35].[ClH:35].[CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([NH:21][CH:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)NC1CCNCC1
Reaction time: 24 h

Procedure:
To a solution of 1.44 g of tert-butyl 4-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)piperidine-1-carboxylate in 15 ml of ethyl acetate was added 3.8 ml of a 4 M hydrogen chloride/ethyl acetate solution, followed by stirring for 1 day. The reaction mixture was concentrated under reduced pressure, and to the obtained residue were added ethyl acetate and ethanol. The resulting solid was collected by filtration and dried to obtain 1.29 g of 8-(cyclohexylmethoxy)-2-methyl-N-(piperidin-4-yl)imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride.
Reaction SMILES: [Br:1][C:2]1[C:11]([F:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:13])[CH:3]=1.[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][C:2]1[C:11]([F:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:13][Br:14])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(F)c(Br)cc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1cc(F)c(Br)cc1CBr
Yield: 92 %

Procedure:
A mixture of methyl 4-bromo-5-fluoro-2-methylbenzoate (1.0 g, 4.0 mmol) (Ellanoval Laboratories Cat. No. 38-0304), N-bromosuccinimide (900. mg, 5.06 mmol) and benzoyl peroxide (50 mg, 0.2 mmol) in carbon tetrachloride (50 mL) was refluxed under a nitrogen atmosphere for 4 h. After cooling the mixture was diluted with methylene chloride. The organic solution was washed with brine, then dried over Na2SO4. After filtration the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (1.2 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]3=[N:19][N:20]=[C:21](S(C)=O)[N:11]3[N:10]=2)=[CH:5][CH:4]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]3=[N:19][N:20]=[C:21]([N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)[N:11]3[N:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2nn3c(S(C)=O)nnc3c3ccccc23)cc1
Reactant: C1CCNC1
Product: COc1ccc(-c2nn3c(N4CCCC4)nnc3c3ccccc23)cc1
Yield: 45 %

Procedure:
A mixture of 6-(4-methoxyphenyl)-3-(methylsulfinyl)-1,2,4-triazolo[3,4-a]phthalazine (3.5 g) and pyrrolidine (30 ml) is heated to 120°/140° C. in a steel bomb for 16 hours. The mixture is then cooled, and the excess of the amine is evaporated off yielding a residue which is washed carefully with a small amount of water and crystallized from 70% ethanol. Yield: 45%. M.p. 196°-98° C.
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[C:16]([O:20][C:21]([NH:23][C:24]1[CH:29]=[N:28][CH:27]=[CH:26][N:25]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17].CN([CH:33]=[O:34])C>O1CCCC1>[C:16]([O:20][C:21]([NH:23][C:24]1[C:29]([CH:33]=[O:34])=[N:28][CH:27]=[CH:26][N:25]=1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)Nc1cnccn1
Reactant: CN(C)C=O
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1nccnc1C=O
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
After adding 4 ml of n-butyllithium (2.46 M, n-hexane solution) to a solution of 1.384 g of 2,2,6,6-tetramethylpiperidine in tetrahydrofuran (15 ml) at −20° C. under a nitrogen atmosphere, the mixture was stirred for 30 minutes while cooling on ice. The reaction mixture was cooled to −70° C., and then a solution of 800 mg of 2-(tert-butoxycarbonylamino)pyrazine in tetrahydrofuran (3 ml) was added dropwise, the mixture was stirred for 1 hour, 3 ml of N,N-dimethylformaldehyde was added, and stirring was continued for 30 minutes. After removing the cooling bath and stirring for 30 minutes, water was added and extraction was performed with ethyl acetate. The extract was dried and concentrated and then purified by silica gel column chromatography (solvent: ethyl acetate/n-hexane) to obtain 72 mg of crude 2-(tert-butoxycarbonylamino)pyrazine-3-carboxaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:29][C:30]([C@@H:32]2[CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:34][N:33]2C(OC(C)(C)C)=O)=[O:31])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:29][C:30]([C@@H:32]2[CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:34][NH:33]2)=[O:31])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2NCC2CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2NCC2CC2)CC1)[C@@H]1Cc2ccccc2CN1
Reaction time: 0.5 h

Procedure:
The title compound was prepared according to the procedure described in Example 3 (Step b) using tert-butyl 3-{N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-(2-[(cyclopropylmethyl)-amino]phenyl}piperidyl)-2-oxoethyl]carbamoyl}(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (Step a) (431 mg, 0.64 mmol) and 50% TFA in CH2Cl2 (20 mL). Purification by reverse phase preparative HPLC [Phenomenex; 5 μm 250×21.2 mm, 5% to 95% CH3CN (0.1% TFA) in H2O (0.1% TFA) over 30 min, then 100% CH3CN (0.1% TFA) for 2 min] provided the title compound (TFA salt) as a white foam (207 mg). MS (ESI, pos. ion) m/z: 571 (M+1); (ESI, neg. ion) m/z: 569 (M−1). Calc'd for C34H39ClN4O2: 570.28. Anal. Calcd for C34H39ClN4O2-2.4C2HF3O2: C, 55.16; H, 4.94; N, 6.63. Found: C, 55.18; H, 5.13; N, 6.61.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:16]=[CH:17][C:18]([N+:21]([O-])=O)=[N:19][CH:20]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1>C(OCC)(=O)C.[Pt]>[NH2:21][C:18]1[CH:17]=[CH:16][C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:10][CH2:11]2)=[CH:20][N:19]=1
Reactant: COc1ccc(N2CCN(c3ccc([N+](=O)[O-])nc3)CC2)cc1
Agent: [Pt]
Solvent: CCOC(C)=O
Product: COc1ccc(N2CCN(c3ccc(N)nc3)CC2)cc1
Reaction time: 12 h

Procedure:
A suspension of the product of part (i) (0.65 g, 2.0 mmole) in ethyl acetate (30 ml) was hydrogenated over 5% platinum on carbon (25 mg) at 45 p.s.i. (310 kPa) and at 50° for 12 hours, followed by 45 hours at room temperature. The resulting mixture was filtered to remove the catalyst, concentrated under reduced pressure and the residue triturated with ether to yield the desired product, m.p. 182°-188° (0.28 g, 50%), which was used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH:8](C(C(OCC)=O)C(OCC)=O)[CH3:9])=[CH:3][CH:2]=1.[C:21](=[O:24])(O)[O-:22].[Na+]>Cl>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH:8]([CH3:9])[C:21]([OH:22])=[O:24])=[CH:3][CH:2]=1
Reactant: O=C([O-])O
Reactant: CCOC(=O)C(C(=O)OCC)C(C)Cc1ccncc1
Agent: Cl
Agent: [Na+]
Product: CC(Cc1ccncc1)C(=O)O
Yield: 76.9 %

Procedure:
Compound diethyl 2-(1-(pyridin-4-yl)propan-2-yl)malonate (2.50 g, 9.43 mmol) was refluxed in cone. HCl (30 ml) for 16 h. The pH of the reaction mixture was adjusted to 6 by adding solid sodium bicarbonate and extracted with ethyl acetate. The combined ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to afford 1.20 g (76.9%) of 2-((pyridin-4-yl)methyl)propanoic acid as an off-white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][C:34](=[O:36])[CH3:35])=[CH:29][CH:28]=2)O1>>[CH3:15][C:13]1([CH3:16])[CH2:14][CH:9]([NH:8][C:4]2[N:3]=[C:2]([C:27]3[CH:32]=[CH:31][C:30]([CH2:33][C:34](=[O:36])[CH3:35])=[CH:29][CH:28]=3)[CH:7]=[CH:6][N:5]=2)[CH2:10][C:11]([CH3:18])([CH3:17])[NH:12]1
Reactant: CC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Product: CC(=O)Cc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)cc1

Procedure:
The title compound was prepared from (4-chloro-pyrimidin-2-yl)(2,2,6,6-tetramethyl-piperidin-4-yl)-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propan-2-one according to Method C (Example 178). Yield: 160 mg (78%).
Reaction SMILES: [O:1]=[C:2]([N:5]1[C@H:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][O:7][C:6]1=[O:17])[CH2:3][CH3:4].[CH3:18][C@@H:19]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH:20]=[O:21]>>[O:1]=[C:2]([N:5]1[C@H:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][O:7][C:6]1=[O:17])[C@H:3]([CH3:4])[C@H:20]([OH:21])[C@@H:19]([CH3:18])[CH2:22][O:23][Si:24]([C:27]([CH3:29])([CH3:28])[CH3:30])([CH3:25])[CH3:26]
Reactant: CCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: C[C@H](C=O)CO[Si](C)(C)C(C)(C)C
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O)[C@@H](C)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1

Procedure:
This material is prepared from (R)-3-(1-oxopropyl)-4-(phenylmethyl)-2-oxazolidinone and 2-(S)-methyl-3-t-butyldimethylsiloxypropanal following the method of Evans and Gage, as described in Org. Syn., Vol. 68, 19xx, p. 83.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[CH2:20]([O:22][C@H:23]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:24][C:25]1[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31](O)=[O:32])=[CH:27][CH:26]=1)[CH3:21].C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:31](=[O:32])[CH2:30][O:29][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][C@H:23]([O:22][CH2:20][CH3:21])[C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:35][CH:34]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Reactant: CCCCCCCNCc1cccc(OC)c1OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCN(Cc1cccc(OC)c1OC)C(=O)COc1ccc(C[C@H](OCC)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.8 %

Procedure:
To a solution of N-(2,3-dimethoxybenzyl)-N-heptylamine (1.46 g, 5.5 mmol) and {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (1.48 g, 5.0 mmol) in methylene chloride (50 mL) at 0° C. were added N,N-diisopropylethylamine (2.0 mL, 11.5 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (1.93 g, 6.0 mmol) and the reaction mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was taken up in ethyl acetate (200 mL) and the organic phase was washed with saturated aqueous NaHCO3 (3×100 mL), 5% HCl (3×100 mL), and brine (100 mL), dried over Na2SO4, and concentrated in vacuo. Purification on silica gel (100 g) with methanol (0-2% gradient) in methylene chloride as the eluent and collection of pure fractions yielded 1.57 g (58%) of a pale yellow oil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]([NH2:26])([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([CH3:25])[CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH2:15][CH3:16])[CH:8]=1.[N:27]#[C:28]Br>C(Cl)(Cl)Cl>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:6]2([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH2:15][CH3:16])[CH:8]=3)[C:2]3=[N:1][CH2:5][CH2:4][N:3]3[C:28]([NH2:27])=[N:26]2)=[CH:18][C:19]=1[CH3:25]
Reactant: N#CBr
Reactant: CCCOc1cccc(C(N)(C2=NCCN2)c2ccc(OC)c(C)c2)c1
Solvent: ClC(Cl)Cl
Product: CCCOc1cccc(C2(c3ccc(OC)c(C)c3)N=C(N)N3CCN=C32)c1
Temperature: 60 °C

Procedure:
A solution of [4,5-dihydro-1H-imidazol-2-yl(4-methoxy-3-methylphenyl)(3-propoxyphenyl)methyl]amine (0.6 g) in chloroform is treated with cyanogen bromide (0.581 g), heated at 60° C. for 5 days and filtered through a pad of silica. The silica pad was eluted with ethyl acetate, followed by elution with (40:5:5) ethyl acetate: methanol: ammonium hydroxide. The eluents were combined and concentrated in vacuo to give a thick yellow oil, which was purified by Gilson preparative reverse phase HPLC system YMC Pro C18, 20 mm×50 mm ID, 5 uM column; 2 mL injection; Solvent A: 0.02% NH4OH/water; Solvent B:0.02% NH4OH/acetonitrile; Gradient: Time O: 95% A; 2 min: 95% A; 14 min: 10% A, 15 min: 10% A, 16 min: 95% A; Flow rate 22.5 mL/min; Detection: 254 nm DAD to afford the title compound was as an off-white, amphorous solid (0.131 g), characterized by LCMS analysis. LCMS Conditions: HP 1100 HPLC system; Waters Xterra MS C18, 2 mm (i.d.)×50 mm (length), 3.5 um column, set at 50° C.; Flow rate 1.0 mL/min; Solvent A: 0.02% NH4OH in water; Solvent B 0.02% NH4OH in ACN; Gradient: Time O: 10% B; 2.5 min 90% B; 3 min 90% B; Sample concentration: ˜2.0 mM; Injection volume: 5 uL; Detection: 220 nm, 254 nm DAD; retention time: 2.34 min, [M−H] 377, [M+H] 379.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([CH3:14])([CH3:13])[CH2:11][NH2:12])[CH:5]=[C:4]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH:3]=1.C(N(CC)CC)C.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([S:37](Cl)(=[O:39])=[O:38])[CH:32]=1>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([CH3:14])([CH3:13])[CH2:11][NH:12][S:37]([C:33]2[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=2)(=[O:39])=[O:38])[CH:5]=[C:4]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH:3]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CC(C)(CN)CNc1cc(-c2c[nH]c3ncccc23)cc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(CNc1cc(-c2c[nH]c3ncccc23)cc(Cl)n1)CNS(=O)(=O)c1cccnc1
Reaction time: 4 h
Yield: 36.2 %

Procedure:
To a solution of Example 74 (55.0 mg, 0.167 mmol) in DMF (1 mL) was added triethylamine (0.070 mL, 0.50 mmol) and pyridine-3-sulfonyl chloride (35.5 mg, 0.200 mmol). After 4 hours, the reaction was quenched with 20% brine and extracted with EtOAc (2×). The organic layers were combined, concentrated, and purified by reverse-phase HPLC as described in Example 56 to give the title compound (28.5 mg) as trifluoroacetic acid salts. 1H NMR (500 MHz, DMSO-d6) ppm 0.89 (s, 6H), 2.68 (d, J=7.02 Hz, 2H), 3.13 (s, 2H), 6.80 (s, brd, 1H), 6.89 (d, J=1.22 Hz, 1H), 6.94 (s, 1H), 7.22 (dd, J=8.09, 4.73 Hz, 1H), 7.60 (dd, J=7.63, 4.58 Hz, 1H), 7.77 (t, J=6.87 Hz, 1H), 8.12-8.18 (m, 2H), 8.28-8.35 (m, 2H), 8.77 (d, J=6.41 Hz, 1H), 8.94 (d, J=2.14 Hz, 1H), 12.19 (s, 1H). MS (APCI+) m/z 471.2 (M+H)+.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:16][C:17]#[N:18])=[CH:8][N:9]2[S:12]([CH3:15])(=[O:14])=[O:13])=[CH:5][C:4]=1[F:19].[CH2:20](N)[CH2:21][NH2:22]>C(O)C>[Br:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:16][C:17]3[NH:22][CH2:21][CH2:20][N:18]=3)=[CH:8][N:9]2[S:12]([CH3:15])(=[O:14])=[O:13])=[CH:5][C:4]=1[F:19]
Reactant: NCCN
Reactant: CS(=O)(=O)n1cc(CC#N)c2cc(F)c(Br)cc21
Agent: Cl
Solvent: CCO
Product: CS(=O)(=O)n1cc(CC2=NCCN2)c2cc(F)c(Br)cc21
Reaction time: 72 h

Procedure:
Hydrogen chloride gas was bubbled through a cold (0° C.) suspension of (6-Bromo-5-fluoro-1-methanesulfonyl-1H-indol-3-yl)-acetonitrile (0.215 g, 0.65 mmol) in anhydrous ethanol (20 ml) for 15 minutes. The reaction mixture was refrigerated for 72 hours and the solvent was removed under reduced pressure. The solid residue was re-dissolved in anhydrous methanol (10 ml), and ethylene diamine (0.05 ml, 0.77 mmol) was added. The reaction mixture was heated to reflux for 24 hours and the solvent was removed under reduced pressure. The resulting residue was purified by flash column chromatography over silica gel eluting with 7% methanol in dichloromethane with 0.1% concentrated ammonium hydroxide to give 6-Bromo-3-(4,5-dihydro-1H-imidazol-2-ylmethyl)-5-fluoro-1-methanesulfonyl-1H-indole, which was recrystallized from methanol and ether (0.133 g, 55%). 1H NMR (DMSO) d: 3.56 (s, 3H), 3.82(s, 4H), 4.07 (s, 2H), 7.84 (s, 1H), 7.90 (d, 1H, J=9.1 Hz), 8.10 (d, 1H, J=5.8 Hz), 10.23 (bs, 1H). M+H: 374.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[NH:10][C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])#[N:2].[OH-:21].[Na+].OO>C(O)C>[CH3:19][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]1[NH:2][C:1](=[O:21])[C:3]2[C:4](=[CH:5][C:6]([CH3:9])=[CH:7][CH:8]=2)[N:10]=1
Reactant: [OH-]
Reactant: COc1ccccc1C(=O)Nc1cc(C)ccc1C#N
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: COc1ccccc1-c1nc2cc(C)ccc2c(=O)[nH]1
Temperature: 80 °C
Yield: 56 %

Procedure:
To a mechanically stirred suspension of N-(2-cyano-5-methylphenyl)-2-methoxybenzamide (180 g, 0.67 mol) in 1.8 L ethanol under an N2 atmosphere was added 6 N sodium hydroxide solution (310 g in 1.25 L water). To the above mixture, 30% hydrogen peroxide (350 mL, 3.64 mol) was slowly added. The solution was then slowly heated to 80° C. and maintained at this temperature for 4 h. The reaction mixture was concentrated under reduced pressure to remove ethanol, giving a suspension, which was quenched with ice-cold water (1.8 L) and acidified with acetic acid to pH 5-6 to give a solid residue. The solid was filtered and washed with water, then dissolved in 5.5 L CH2Cl2 and washed with water (2×18 L). The organic layer was dried over sodium sulfate, and the solvent was removed under reduced pressure to give a light yellow solid (100 g, 54%). mp 165-170° C.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][N:4]([CH2:7][N:8]2[C:13](=[O:14])[CH2:12][N:11]([CH2:15][CH:16]([N:18]3[CH2:23][C:22](=[O:24])[N:21](CN4CCSCC4)[C:20](=[O:32])[CH2:19]3)[CH3:17])[CH2:10][C:9]2=[O:33])[CH2:3][CH2:2]1>O>[S:1]1[CH2:6][CH2:5][N:4]([CH2:7][N:8]2[C:13](=[O:14])[CH2:12][N:11]([CH2:15][CH:16]([N:18]3[CH2:19][C:20](=[O:32])[NH:21][C:22](=[O:24])[CH2:23]3)[CH3:17])[CH2:10][C:9]2=[O:33])[CH2:3][CH2:2]1
Reactant: CC(CN1CC(=O)N(CN2CCSCC2)C(=O)C1)N1CC(=O)N(CN2CCSCC2)C(=O)C1
Solvent: O
Product: CC(CN1CC(=O)N(CN2CCSCC2)C(=O)C1)N1CC(=O)NC(=O)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 43.3 %

Procedure:
Water (30 ml) was added to dl-1,2-bis(4-thiomorpholinomethyl-3,5-dioxopiperazin-1-yl)-propane (0.6 g) and the suspension thus obtained was stirred at room temperature for 5 hours. Then, the precipitates thus obtained were collected and were dried under a reduced pressure. Chloroform (10 ml) was added to the dried precipitates and the whole was stirred at room temperature for 20 minutes, then was filtered. The filtration residue was dried under a reduced pressure to give the titled compound (0.2 g; yield 43%).
Reaction SMILES: C[O:2][C:3](=[O:21])/[CH:4]=[CH:5]/[CH:6]=[C:7](/[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)\[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH-].[Na+]>CO>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13](/[C:7](/[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:6]/[CH:5]=[CH:4]/[C:3]([OH:21])=[O:2])=[CH:18][CH:17]=1
Reactant: CCCCC/C(=C\C=C\C(=O)OC)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCC/C(=C\C=C\C(=O)O)c1ccc(OC)cc1
Reaction time: 0.75 h
Yield: 81 %

Procedure:
As described in Example 99, (E,E)-5-(4-methoxyphenyl)-2,4-decadienoic acid methyl ester 6.1 g) was saponified in a refluxing mixture of methanol (25 mL) and 2N NaOH (25 mL). After 45 minutes the reaction was worked up in the usual way and the crude acid crystallized from 2-propanol to give 4.7 g of (E,E)-5-(4-methoxyphenyl)-2,4-decadienoic acid, mp 126°-127.5° C.
Reaction SMILES: C[O:2][C:3](=[O:30])[C@:4]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1)([CH3:19])[NH:5][C:6]([O:8][CH:9]1[CH:16]2[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:18][CH:10]1[CH2:11]3)[CH2:15]2)=[O:7]>CCCCC>[CH:10]12[CH2:18][CH:14]3[CH2:13][CH:12]([CH2:17][CH:16]([CH2:15]3)[CH:9]1[O:8][C:6]([NH:5][C@:4]([C:20]1[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=1)([C:3]([OH:30])=[O:2])[CH3:19])=[O:7])[CH2:11]2
Reactant: COC(=O)[C@](C)(NC(=O)OC1C2CC3CC(C2)CC1C3)c1ccc2ccccc2n1
Solvent: CCCCC
Product: C[C@](NC(=O)OC1C2CC3CC(C2)CC1C3)(C(=O)O)c1ccc2ccccc2n1
Yield: 61.1 %

Procedure:
Method was as described for Example 30, Step 5, but using N-(2-adamantyloxy-carbonyl)-2-(quinolin-yl)-alanine methyl ester (3.5 g, 8.3 mmol) to obtain N-(2-adamantyloxy-carbonyl)-2-(quinolin-yl)-alanine (2.0 g, 59.0%) as a beige solid from n-pentane.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:10][C@H:9]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:7]2([CH3:8])[C@H:6]1[N:25]([CH3:32])[C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[C@:19]1([CH3:20])[C:14](=[CH:15][C:16](=[O:24])[CH2:17][CH2:18]1)[CH2:13][CH2:12]3)(=[O:3])[CH3:2].C1(C)C=CC=CC=1>ClC1C=CC=CC=1>[C:1]([O:4][C@@H:5]1[CH2:10][C@H:9]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:7]2([CH3:8])[C@H:6]1[N:25]([CH3:32])[C:26](=[O:31])[C:27]([F:29])([F:28])[F:30])[C@:19]1([CH3:20])[C:14](=[CH:15][C:16](=[O:24])[CH:17]=[CH:18]1)[CH2:13][CH2:12]3)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]2(C)[C@H]1N(C)C(=O)C(F)(F)F
Solvent: Clc1ccccc1
Solvent: Cc1ccccc1
Product: CC(=O)O[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]2(C)[C@H]1N(C)C(=O)C(F)(F)F
Yield: 81.2 %

Procedure:
A solution of 16α-acetyloxy-17β-(N-trifluoroacetyl-methylamino)-androst-4-en-3-one (1.88 g) and diphenylselenic anhydride (1.7 g) in chlorobenzene (39 ml) was heated under reflux for 1 h. The solution was cooled, toluene was added and the solution was filtered through a column (7.5 cm×2.5 cm) of silica gel (0.063-0.2 mm). Elution with toluene removed diphenylselenide. Elution with ether yielded a fraction which was evaporated to dryness to give 16α-acetyloxy-17β-(N-trifluoroacetyl-methylamino)-androsta-1,4-dien-3-one as a yellow gum (1.52 g). A solution of the product in ethanol (40 ml) and aqueous sodium hydroxide solution (3 ml; 4 N) was heated under reflux for 1.5 h.; the solution was concentrated and cooled, then water was added to precipitate an off-white solid, which was filtered off, washed with water and dried in vacuo to give 16α-hydroxy-17β-methylamino-androsta-1,4-dien-3-one (1 g). The product was dissolved in ethanol (20 ml), a solution of maleic acid (0.37 g) in ethanol (10 ml) was added and the resulting solution was treated with charcoal, filtered and evaporated to give a pale yellow gum (1.44 g). Crystallisation from acetone gave 16α-hydroxy-17β-methylamino-androsta-1,4-dien-3-one (Z)-2-butenedioate (1:1) (salt) as colourless prisms (0.88 g), m.p. 184°-191° C. (decomp.), [α]D +14.2° (c 0.88 in ETOH).