Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([NH2:10])=[N:5][C:6]([CH3:9])=[N:7][CH:8]=1.C(N(CC)CC)C.[CH2:18]([O:25][C:26]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:27]=1[CH2:28][CH2:29][NH:30][CH2:31]2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH2:18]([O:25][C:26]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:27]=1[CH2:28][CH2:29][N:30]([CH2:2][C:3]1[C:4]([NH2:10])=[N:5][C:6]([CH3:9])=[N:7][CH:8]=1)[CH2:31]2)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1ncc(CCl)c(N)n1
Reactant: c1ccc(COc2cccc3c2CCNC3)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ncc(CN2CCc3c(cccc3OCc3ccccc3)C2)c(N)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.2 %

Procedure:
A suspension of 0.098 g (0.00051 mol) of 5-chloromethyl-2-methyl-pyrimidin-4-ylamine in 2 ml of dimethylformamide was treated with 0.21 ml (0.0015 mol) of triethylamine and 0.145 g (0.00061 mol) of 5-benzyloxy-1,2,3,4-tetrahydro-isoquinoline (WO 94/20459) and the mixture was stirred at room temperature under argon for 18 hours The solvent was distilled off in a high vacuum. The residue was partitioned between dichloro-methane/water, extracted and dried over MgSO4. After removing the solvent the residue was chromatographed on silica gel with ethyl acetate as the eluent. 0.153 g (84%) of 5-(5-benzyloxy-3,4-dihydro-1H-isoquinolin-2-ylmethyl)-2-methyl-pyrimidin-4-ylamine was obtained as a yellowish oil. MS (ISP): me/e=361 (C22 H25N4O+).
Reaction SMILES: [Na+].[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([CH2:11][CH2:12][S:13]S(=O)(=O)[O-])=[CH:3]1.O.P(=O)(O)(O)O.O=O>C(OCC)C>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([CH2:11][CH2:12][SH:13])=[CH:3]1
Reactant: O=S(=O)([O-])SCCc1coc2ccccc12
Agent: O=O
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: SCCc1coc2ccccc12

Procedure:
The thiosulfuric acid S-[2-(benzofuran-3-yl)ethyl]ester sodium salt just prepared (3.63 g, contains x mol of water) was suspended in 50 per cent strength phosphoric acid (60 ml) with exclusion of oxygen (argon atmosphere). The reaction mixture obtained was then covered with a layer of diethyl ether (75 ml) and heated under reflux (7 h), with vigorous stirring, until solid was no longer to be observed in the aqueous phase. After cooling, the two phases were separated and the aqueous phase was extracted with diethyl ether (4×15 ml). The combined ethereal phases were washed with water (2×10 ml) and dried over sodium sulfate. The residue (yellowish oil, 1.71 g) obtained after removal of the diethyl ether contained, according to NMR, approx. 80% of the desired thiol Ind-94. Simple purification and dissolving experiments showed that Ind-94 is relatively unstable and by-products already form on standing in an ethereal solution (detection by NMR spectroscopy). The crude product obtained was therefore employed for the thioether synthesis without further working up.
Reaction SMILES: OC(C)(C)CN1C=C[C:6]([NH:9][C:10](=[O:30])[C@@H:11]([N:16]2[CH2:20][C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])=[CH:18][C:17]2=[O:29])[CH2:12][CH:13]([CH3:15])[CH3:14])=[N:5]1.Cl.CN(C)[CH2:36][CH2:37][CH2:38]N=C=NCC.ON1C2C=CC=CC=2N=N1.NC1[S:60][N:59]=[C:58]([CH2:61][C:62]([OH:64])=[O:63])N=1>ClCCl>[CH2:38]([O:64][C:62](=[O:63])[CH2:61][C:58]1[N:5]=[C:6]([NH:9][C:10](=[O:30])[C@@H:11]([N:16]2[CH2:20][C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])=[CH:18][C:17]2=[O:29])[CH2:12][CH:13]([CH3:15])[CH3:14])[S:60][N:59]=1)[CH:37]=[CH2:36]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(CC(C)(C)O)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Reactant: Nc1nc(CC(=O)O)ns1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: C=CCOC(=O)Cc1nsc(NC(=O)[C@H](CC(C)C)N2CC(Oc3ccccc3Cl)=CC2=O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (prepared as in Example 64, 132 mg, 0.41 mmol) in dichloromethane (2.00 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (91 mg, 0.47 mmol) and 1-hydroxybenzotriazole (62 mg, 0.46 mmol). The resulting solution was stirred for 5 min before (5-amino-[1,2,4]thiadiazol-3-yl)-acetic acid ally ester hydrochloride (1:1) (100 mg, 0.50 mmol) was added and the resulting mixture stirred at 25° C. overnight. The mixture was washed with saturated ammonium chloride (1 mL), evaporated and the crude product purified by HPLC (Gilson semi-prep; Supelcosil ABZ+Plus 12 μM 25 cm×21.2 mm column 20-95% acetonitrile/water) which afforded (5-{(S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoylamino}-[1,2,4]thiadiazol-3-yl)-acetic acid allyl ester (145 mg, 70%) as a light yellow solid: HR-ES-MS m/z calculated for C23H25ClN4O5S [M+H]+ 505.1307, observed 505.1306; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.91 (d, J=6.4 Hz, 3H), 0.95 (d, J=6.4 Hz, 3H), 1.36-1.57 (m, 1H), 1.58-1.76 (m, 1H), 1.77-1.96 (m, 1H), 3.97 (s, 2H), 4.30 (d, J=18.0 Hz, 1H), 4.50 (d, J=18.0 Hz, 1H), 4.59 (d, J=5.6 Hz, 2H), 4.83 (s, 1H), 5.01 (dd, J=11.3, 5.6 Hz, 1H), 5.16-5.35 (m, 2H), 5.77-6.01 (m, 1H), 7.37 (ddd, J=8.0, 1.5 Hz, 1H), 7.47 (td, J=8.0, 1.5 Hz, 1H), 7.54 (dd, J=8.0, 1.5 Hz, 1H), 7.66 (dd, J=8.0, 1.5 Hz, 1H), 13.43 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])[NH2:5].[Br:12]N1C(=O)CCC1=O>C(OCC)(=O)C>[Br:12][C:6]1[CH:7]=[C:8]([N+:9]([O-:11])=[O:10])[C:2]([F:1])=[CH:3][C:4]=1[NH2:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc([N+](=O)[O-])c(F)c1
Solvent: CCOC(C)=O
Product: Nc1cc(F)c([N+](=O)[O-])cc1Br
Temperature: 22 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
A flask was charged with 3-fluoro-4-nitroaniline (1.0 equiv) followed by ethyl acetate (10 vol) and stirred to dissolve all solids. N-Bromosuccinimide (1.0 equiv) was added as a portion-wise as to maintain internal temperature of 22° C. At the end of the reaction, the reaction mixture was concentrated in vacuo on a rotavap. The residue was slurried in distilled water (5 vol) to dissolve and remove succinimide. (The succinimide can also be removed by water workup procedure.) The water was decanted and the solid was slurried in 2-propanol (5 vol) overnight. The resulting slurry was filtered and the wetcake was washed with 2-propanol, dried in vacuum oven at 50° C. overnight with N2 bleed until constant weight was achieved. A yellowish tan solid was isolated (50% yield, 97.5% AUC). Other impurities were a bromo-regioisomer (1.4% AUC) and a di-bromo adduct (1.1% AUC). 1H NMR (500 MHz, DMSO) δ 8.19 (1 H, d, J=8.1 Hz), 7.06 (br. s, 2 H), 6.64 (d, 1 H, J=14.3 Hz).
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])[CH2:7][CH:6]([OH:20])[CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[NH2:1][CH:4]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])[CH2:7][CH:6]([OH:20])[CH2:5]1
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCC(N=[N+]=[N-])CC(O)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cn1ncc([N+](=O)[O-])c1N1CCC(N)CC(O)C1
Temperature: 65 °C

Procedure:
To a solution of 5-azido-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-3-ol, Intermediate 18 (3.4 g, 16 mmol) in THF (40 mL) and water (8 mL), was added triphenylphosphine (1.89 g, 7.2 mmol) and the mixture was heated at 65° C. for 16 hr. The solvents were removed under reduced pressure to afford 5-amino-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-3-ol (contaminated with triphenylphosphine oxide) as a viscous oil. To this amine in DCM (40 mL), di-tert-butyl dicarbonate (4.49 g, 20.6 mmol) and DIPEA (4.78 mL, 27.4 mmol) were added and the mixture stirred at room temperature for 60 hr. The solvent was removed under reduced pressure and the residue purified by silica gel column chromatography (0-100% EtOAc/isohexane) to give tert-butyl 6-hydroxy-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ylcarbamate as a yellow oil (2.6 g). To a solution of this oil (2.6 g, 10.2 mmol) in DCM (50 mL) was added deoxo-Fluor® (50% in THF, 6.7 mL, 18.6 mmol) and the mixture was stirred at room temperature for 16 hr. The mixture was diluted with DCM (30 mL), cooled in an ice/water bath and quenched by the dropwise addition of saturated aqueous NaHCO3 (30 mL). The resulting mixture was stirred for 10 min. The organic layer was separated, dried over Na2SO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-50% EtOAc/isohexane) gave tert-butyl 6-fluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ylcarbamate (1.07 g, 66% over three steps) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.14-7.97 (m, 1H), 5.04-4.46 (m, 3H), 3.96-2.99 (m, 6H), 2.42-1.64 (m, 5H), 1.70-1.22 (m, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:15])[CH2:11][C:12]([OH:14])=O)=[CH:5][CH:4]=1.ClC(N(C)C)=C(C)C.[NH2:24][C:25]([CH3:41])([CH2:31][C:32](=[O:40])[C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=1)[C:26]([O:28][CH2:29][CH3:30])=[O:27].N1C=CC=CC=1>C(Cl)Cl.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:15])[CH2:11][C:12]([NH:24][C:25]([CH3:41])([CH2:31][C:32](=[O:40])[C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:14])=[CH:7][CH:8]=1
Reactant: COc1ccc(NC(=O)CC(=O)O)cc1
Reactant: CCOC(=O)C(C)(N)CC(=O)c1ccc(C)cc1
Agent: CC(C)=C(Cl)N(C)C
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C(C)(CC(=O)c1ccc(C)cc1)NC(=O)CC(=O)Nc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87.5 %

Procedure:
To a solution of Intermediate 6B (0.388 g, 1.855 mmol) in DCM (10 mL) under argon was added 1-chloro-N,N,2-trimethylprop-1-en-1-amine (0.293 g, 2.192 mmol) and the reaction mixture was stirred at rt for 20 min. A solution of Intermediate 102B (0.4204 g, 1.686 mmol) in DCM (1.000 mL) followed by pyridine (0.409 mL, 5.06 mmol) were added and the reaction mixture was stirred at rt for 2.5 h. The reaction mixture was concentrated to give a dark oil which was dissolved in EtOAc (15 mL) and washed with water (5 mL). The organic phase was dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (80 g silica gel) to provide the desired product (0.650 g, 88%) as an orange oil. LCMS Anal. Calc'd for C24H28N2O6 440.19, found [M+H] 441.2. 1H NMR (500 MHz, CDCl3) δ 7.83 (d, J=8.25 Hz, 2H), 7.24 (d, J=7.98 Hz, 2H), 4.14 (dd, J=7.15, 2.75 Hz, 2H), 3.65 (d, J=17.61 Hz, 1H), 3.20 (d, J=17.61 Hz, 1H), 2.40 (s, 3H), 2.18-2.27 (m, 2H), 1.39 (s, 3H), 1.19 (t, J=7.01 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=[O:14].O.FC(F)(F)C(O)=O>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH2:9][OH:14])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(CO)c1ccc(F)cc1
Reaction time: 8 h
Yield: 42.9 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 4′-fluoroacetophenone (1.15 g, 8.32 mmol) in acetonitrile (42 ml) was treated with [bis(trifluoroacetoxy)iodo]benzene (7.16 g, 16.6 mmol) followed by water (8.3 ml) and trifluoroacetic acid (1.3 ml). The resultant solution was heated under reflux for 2 hr before standing overnight at ambient temperature. The solvent was then removed in vacuo; water (30 ml) was added and the mixture extracted with dichloromethane (3×30 ml). The combined extracts were washed with saturated sodium hydrogen carbonate solution (30 ml) followed by brine (30 ml) and dried (MgSO4). The solvent was removed in vacuo to give the crude 1-(4-fluorophenyl)-2-hydroxyethanone which was purified by flash chromatography (silica) eluting with ethyl acetate and 40°-60° C. petroleum ether (3:1) to give a white solid (0.55 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([NH:15][CH:16]=[O:17])[CH:5](O)[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[CH2:7].S(Br)(Br)=O.[P:23]([O:30]CC)([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26]>C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3](=[O:18])[CH:4]([NH:15][CH:16]=[O:17])/[CH:5]=[C:6](\[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)/[CH2:7][P:23]([O:27][CH2:28][CH3:29])([O:24][CH2:25][CH3:26])=[O:30]
Reactant: C=C(c1ccccc1)C(O)C(NC=O)C(=O)OC
Reactant: CCOP(OCC)OCC
Agent: O=S(Br)Br
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOP(=O)(C/C(=C/C(NC=O)C(=O)OC)c1ccccc1)OCC

Procedure:
By reaction of the 2-formylamino-3-hydroxy-4-phenyl-4-pentenoic acid methyl ester with thionyl bromide and subsequent treatment with triethyl phosphite in a manner analogous to that described in Example 1, and after chromatography (silica gel; ethyl acetate/hexane 4:1), E-2-formylamino-4-phenyl-5-diethylphosphono-3-pentenoic acid methyl ester is obtained in the form of a colourless oil. 1H-NMR (CDCl3): 2.98 (d, 2H,C(5)-H); 5.03 (dd, 1H, C(2)-H); 5.77 (dd, 1H, C(3)-H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.[CH3:22][O:23][C:24](=[O:40])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.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>[CH3:22][O:23][C:24](=[O:40])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:2]2[N:3]=[C:4]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)[C:5]3[N:10]=[CH:9][S:8][C:6]=3[N:7]=2)[CH:26]=1
Reactant: COC(=O)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: COc1ccc(Nc2nc(Cl)nc3scnc23)cc1OC
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+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cccc(-c2nc(Nc3ccc(OC)c(OC)c3)c3ncsc3n2)c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 80.6 %

Procedure:
To a stirred solution of (5-chloro-thiazolo[5,4-d]pyrimidin-7-yl)-(3,4-dimethoxy-phenyl)-amine (0.90 g, 2.79 mmol) and 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (0.95 g, 3.62 mmol) in 100 mL of 1,4-dioxane were added Na2CO3 (0.93 g, 8.8 mmol) and 5 mL of water at room temperature. Then the mixture was degassed with nitrogen for 15 minutes. Pd(PPh3)4 (0.32 g, 0.279 mmol) was added in one portion and the reaction mixture was stirred at 100° C. for 16 hours under nitrogen. The solvent was evaporated and the residue was purified by silica gel chromatography (silica gel 200-300 mesh, CH2Cl2:methanol=100:1) to give 3-[7-(3,4-dimethoxy-phenylamino)-thiazolo[5,4-d]pyrimidin-5-yl]-benzoic acid methyl ester (0.95 g, 81%) as a yellow sold. LC-MS: 423.1 [M+H]+, tR=1.68 min.
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1(O)[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]1.Cl.C(OCC)C>C1COCC1.O>[C:1]1([CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH2:15][C:14]2[C:9]([CH:8]=1)=[CH:10][CH:11]=[CH:12][CH:13]=2
Reactant: Cc1ccccc1C1(O)Cc2ccccc2C1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccccc1C1=Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 63 %

Procedure:
To a solution of 2-(o-tolyl)-2-indanol (10.0 g, 44.6 mmol) in THF (200 mL) was added a solution of concentrated hydrochloric acid (40 mL) in water (60 mL). The solution was stirred at room temperature overnight (12 h). Diethyl ether (200 mL) and water added. Aqueous layer was extracted with diethyl ether (3*200 mL). All etheral layers were combined, washed with water (50 mL), brine (50 mL), dried over anhydrous magnesium sulphate, and concentrated. Kugelrohr distillation yielded 5.8 g of 2-(o-tolyl)-1H-indene (150° C./0.3 mm Hg). 1H-N.M.R. (CDCl3) d 2.49(s, 3H), d 3.78 (d, J=0.90 Hz, 2H), d 6.94(br s, 1H), d 7.18-7.50(m, 8H).
Reaction SMILES: [Li]CCCC.Br[C:7]1[S:8][CH:9]=[CH:10][N:11]=1.[CH2:12]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[N+:28]([O-:30])=[O:29])[CH:23]=[O:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH4+].[Cl-]>CCOCC.C1COCC1>[CH2:12]([O:19][C:20]1[CH:21]=[C:22]([CH:23]([C:7]2[S:8][CH:9]=[CH:10][N:11]=2)[OH:24])[CH:25]=[CH:26][C:27]=1[N+:28]([O-:30])=[O:29])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Brc1nccs1
Reactant: O=Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc(C(O)c2nccs2)cc1OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of n-BuLi (1.9 mL, 2.5 M in hexane) in ether (8 mL) at −78° C. is added 2-bromothiazole (0.34 mL, 3.80 mmol) dropwise. The yellow solution is stirred at −78° C. for 30 min and 3-benzyloxy-4-nitrobenzaldehyde (83, step A) (0.81 g, 3.16 mmol) in THF (2 mL) is added. After stirring for 30 min, the purple suspension is poured into a sat. NH4Cl solution (50 mL) and is extracted with EtOAc. The organic layer is washed with brine, dried over MgSO4 and concentrated. The residue is then purified by column chromatography to give the title compound: (M+1)+=343.
Reaction SMILES: C(=N[NH:15][C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][N:20]=[CH:21]2)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:26][C:27]1([CH3:35])[CH2:32][NH:31][C:30](=[O:33])[CH2:29][C:28]1=O.[OH-].[Na+].Cl>C(O)(=O)C.O.CO>[CH3:26][C:27]1([CH3:35])[C:28]2[NH:15][C:16]3[C:25](=[CH:24][CH:23]=[C:22]4[CH:21]=[N:20][CH:19]=[CH:18][C:17]4=3)[C:29]=2[C:30](=[O:33])[NH:31][CH2:32]1
Reactant: CC1(C)CNC(=O)CC1=O
Reactant: c1ccc(C(=NNc2cccc3cnccc23)c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: CC1(C)CNC(=O)c2c1[nH]c1c2ccc2cnccc21
Yield: 56.5 %

Procedure:
A mixture of N-benzhydrylidene-N′-isoquinolin-5-yl-hydrazine (154 mg, 0.48 mmol) and 5,5-dimethylpiperidine-2,4-dione (98 mg, 0.69 mmol), dissolved in acetic acid (2 mL) and water (8 drops), was submitted to microwaves for 40 minutes at 150° C. The mixture was treated with concentrated NaOH to pH 9 and was extracted three times with ethyl acetate. Purification by flash chromatography of the concentrated residue, with dichloromethane/methanol/acetic acid/water 30/2/0.5/0.2→30/4/1/0.5 as eluant, afforded a solid product, which was dissolved in methanol and treated with 1.25M HCl in methanol to pH 1. The solvent was removed under vacuum and the residue was treated with diethylether. The resulting solid was filtered, washed with diethylether, and dried under vacuum, affording 72 mg of the title compound as hydrochloric salt (28%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]#[CH:6])[CH3:2].[CH3:10][C:11]1([CH3:18])[C:15]([CH3:17])([CH3:16])[O:14][BH:13][O:12]1.C(N(CC)CC)C>O1CCCC1.[H-].[Cl-].C1([Zr+2]C2C=CC=C2)C=CC=C1>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])/[CH:5]=[CH:6]/[B:13]1[O:14][C:15]([CH3:17])([CH3:16])[C:11]([CH3:18])([CH3:10])[O:12]1)[CH3:2]
Reactant: C#CC(OCC)OCC
Reactant: CC1(C)OBOC1(C)C
Agent: C1=CC([Zr+2]C2C=CC=C2)C=C1
Agent: [Cl-]
Agent: [H-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(/C=C/B1OC(C)(C)C(C)(C)O1)OCC
Temperature: 50 °C
Yield: 43.1 %

Procedure:
A mixture of 3,3-diethoxy-1-propyne (18.5 g, 0.144 mol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (27.6 g, 0.216 mol) and bis(cyclopentadienyl)zirconium chloride hydride (1.9 g, 0.007 mol) in tetrahydrofuran (75 mL) was heated at 50° C. for 2 days. Triethylamine (2 mL) was added and the solvent was removed in vacuo. The residue was distilled at 90° C. at 10 torr. The residue was purified by column chromatography on neutral alumina using 89:10:1 dichloromethane:ethyl acetate:triethylamine as an eluent. The solvent was removed in vacuo to give the title compound (15.9 g, 53%) as a brown oil. 1H NMR (DMSO-d6, 400 MHz) δ 6.48 (dd, 1H), 5.75 (d, 1H), 4.85 (d, 1H), 3.55–3.67 (m, 2H), 3.40–3.52 (m, 2H), 1.22 (s, 12H), 1.17 (t, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:14]([O:23][CH3:24])(=[O:22])[C:15]1[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=1)[NH2:17].N1C=CC=CC=1.O>C(Cl)Cl>[CH3:24][O:23][C:14](=[O:22])[C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH:17][S:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11]
Reactant: COC(=O)c1ccccc1N
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Nitrobenzenesulfonyl chloride (2.22 g, 10 mmol) is added to a solution of methyl anthranilate (1.51 g, 10 mmol) in 20 mL of DCM at RT, followed by slow addition of pyridine (0.97 mL, 12 mmol). The reaction is stirred 16 h at RT. Water (1 mL) is added. After 1 h, the mixture is partitioned between DCM (40 mL) and water (30 mL). The organic phase is washed with water (30 mL) and brine (30 mL), dried over anhydrous magnesium sulfate and concentrated under vacuum to an orange solid. The solid is redissolved in DCM (30 mL), and hexane (100 mL) is added. The solution is concentrated to approximately 60 mL at which point an orange solid rapidly precipitated. The solid is collected by filtration and dried under vacuum to give 2-(4-nitro-benzenesulfonylamino)-benzoic acid methyl ester.
Reaction SMILES: [OH:1][C:2]1([CH3:17])[CH2:6][N:5](C(OC(C)(C)C)=O)[C@H:4]([CH:14]([CH3:16])[CH3:15])[CH2:3]1.[C:18]([OH:24])([C:20]([F:23])([F:22])[F:21])=[O:19]>C(Cl)Cl>[CH3:17][C:2]1([OH:1])[CH2:3][C@@H:4]([CH:14]([CH3:16])[CH3:15])[NH:5][CH2:6]1.[C:18]([OH:24])([C:20]([F:23])([F:22])[F:21])=[O:19]
Reactant: CC(C)[C@@H]1CC(C)(O)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@@H]1CC(C)(O)CN1
Reaction time: 16 h

Procedure:
To tert-butyl (2S)-4-hydroxy-4-methyl-2-(propan-2-yl)pyrrolidine-1-carboxylate (532.2 mg, 2.18 mmol) dissolved in DCM (5.5 mL) was added TFA (1.8 mL). The mixture was stirred for 16 hours. The mixture was concentrated to give (5S)-3-methyl-5-(propan-2-yl)pyrrolidin-3-ol as a TFA salt. 1H NMR (500 MHz, CDCl3) δ 3.76 (s, 1H), 3.49-3.34 (m, 2H), 2.29-2.17 (m, 1H), 2.06-1.95 (m, 2H), 1.51 (s, 3H), 1.07-0.97 (m, 7H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:13])[N:6]([CH:8]([CH3:12])[C:9](O)=[O:10])[CH:7]=1.CSC.B>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:13])[N:6]([CH:8]([CH3:12])[CH2:9][OH:10])[CH:7]=1
Reactant: CC(C(=O)O)n1cc(Br)ccc1=O
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: CC(CO)n1cc(Br)ccc1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.6 %

Procedure:
To a solution of 2-(5-bromo-2-oxopyridin-1(2H)-yl)propanoic acid (3.36 g, 13.7 mmol) in 50 mL of THF was added borane-dimethyl sulfide (3.89 ml, 41.0 mmol) via a syringe. The reaction was stirred at rt for 16 hours and was quenched with 10 mL of 1N HCl. The mixture was extracted with 70 mL of EtOAc twice. The combined organic phases were washed with brine and dried over Na2SO4. The solution was concentrated in vacuo to give a light yellow oil (2.50 g, 78.9% yield) which was used in the next step without further purification. MS (ESI pos. ion) m/z (MH+): 231.9. Calc'd Exact Mass for C8H10BrNO2: 230.99.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[NH2:19][C:20]([C:23]1[N:27]=[C:26]([NH2:28])[O:25][N:24]=1)([CH3:22])[CH3:21]>>[NH2:28][C:26]1[O:25][N:24]=[C:23]([C:20]([NH:19][C:15]([C:7]2[CH:6]=[N:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:17])([CH3:22])[CH3:21])[N:27]=1
Reactant: CC(C)(N)c1noc(N)n1
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Agent: Cl
Product: CC(C)(NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1)c1noc(N)n1

Procedure:
The title compound was synthesized in analogy to Example 6, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g) and 3-(1-amino-1-methyl-ethyl)-[1,2,4]oxadiazol-5-ylamine hydrochloride (1:1) (Example 57b) as starting materials, and isolated (57 mg, 75%) as off-white solid; LC-MS (UV peak area, ESI) 100%, 359.1825 (M+H).