Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:68])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:64]([CH3:67])[CH2:65][CH3:66])[C@H:24]([O:62][CH3:63])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:60][CH3:61])[C@@H:34]([CH3:59])[C:35]([NH:37][C@@H:38]([CH2:49][C:50]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[NH:52][CH:51]=1)[C:39]([NH:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])(O)=[O:2].[O:69]=[C:70]1[CH:74]=[CH:73][C:72](=[O:75])[N:71]1[CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][C:81]([NH:83][NH2:84])=[O:82]>>[O:75]=[C:72]1[CH:73]=[CH:74][C:70](=[O:69])[N:71]1[CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][C:81]([NH:83][NH:84][C:1](=[O:2])[CH2:4][CH2:5][CH2:6][N:7]([CH3:68])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:64]([CH3:67])[CH2:65][CH3:66])[C@H:24]([O:62][CH3:63])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:60][CH3:61])[C@@H:34]([CH3:59])[C:35]([NH:37][C@@H:38]([CH2:49][C:50]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[NH:52][CH:51]=1)[C:39]([NH:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:17])[CH3:18])=[O:13])[CH:9]([CH3:11])[CH3:10])=[O:82]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Reactant: NNC(=O)CCCCCN1C(=O)C=CC1=O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)NNC(=O)CCCCCN1C(=O)C=CC1=O)C(C)C

Procedure:
This compound was prepared in analogy to the synthesis described in Intermediate 157, from 20 mg (21 μmol) of N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-(benzylamino)-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide and commercially available 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanehydrazide.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:37])=[C:4]([C:33]([F:36])=[CH:34][CH:35]=1)[O:5][C:6]1[CH2:10][N:9]([C@@H:11]([CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:12]([NH:14]C2C=CN(CC(O)(C)C)N=2)=[O:13])[C:8](=[O:32])[CH:7]=1.[CH3:38][O:39][C:40](=[O:48])[C:41]1[CH:46]=[CH:45][C:44](N)=[N:43][CH:42]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)C(C)C)(C)C>ClCCl.C(OCC)(=O)C>[CH3:38][O:39][C:40](=[O:48])[C:41]1[CH:46]=[CH:45][C:44]([NH:14][C:12](=[O:13])[C@@H:11]([N:9]2[CH2:10][C:6]([O:5][C:4]3[C:33]([F:36])=[CH:34][CH:35]=[C:2]([Cl:1])[C:3]=3[F:37])=[CH:7][C:8]2=[O:32])[CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[N:43][CH:42]=1
Reactant: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3c(F)ccc(Cl)c3F)=CC2=O)n1
Reactant: COC(=O)c1ccc(N)nc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3c(F)ccc(Cl)c3F)=CC2=O)nc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 23.4 %

Procedure:
A solution of (S)-2-[4-(3-chloro-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid (prepared as in Example 72, 510 mg, 1.28 mmol) in dichloromethane (20 mL) was treated with 6-amino-nicotinic acid methyl ester (252 mg, 1.67 mmol), bromotripyrrolidinophosphonium hexafluorophosphate (1.20 g, 2.57 mmol) and N,N-diisopropylethylamine (438 mg, 2.52 mmol). The reaction mixture was stirred for 5 h at 25° C., under nitrogen. The reaction mixture was diluted with ethyl acetate, washed with saturated ammonium chloride, water, a saturated sodium chloride solution and dried over sodium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g, 0% to 50% ethyl acetate/hexanes) to afford 6-{(S)-2-[4-(3-chloro-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionylamino}-nicotinic acid methyl ester (160 mg, 24%) as a tan solid: HR-ES-MS m/z calculated for C26H26ClF2N3O5 [M+H]+ 534.1602, observed 534.1606; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.73-1.36 (m, 6H) 1.37-1.93 (m, 7H) 3.86 (s, 3H) 4.33 (d, J=18.5 Hz, 1H) 4.64 (d, J=18.5 Hz, 1H) 5.04 (dd, J=11.3, 5.0 Hz, 1H) 5.27 (s, 1H) 7.45 (td, J=9.5, 2.1 Hz, 1H) 7.68 (ddd, J=9.5, 8.1, 5.6 Hz, 1H) 8.13-8.19 (m, 1H) 8.29 (dd, J=8.8, 2.4 Hz, 1H) 8.87 (dd, J=2.4, 0.8 Hz, 1H) 11.32 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH2:15])[CH2:10][CH2:9]1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)CCO>[N:3]1[CH:4]=[CH:5][N:6]=[CH:7][C:2]=1[N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH2:15])[CH2:10][CH2:9]1
Reactant: NCC1CCNCC1
Reactant: Clc1cnccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)CCO
Product: NCC1CCN(c2cnccn2)CC1
Temperature: 25 °C
Yield: 67.5 %

Procedure:
A mixture of chloropyrazine (14.3 g), 1-(piperid-4-yl)methylamine (14.25 g), sodium carbonate (11.4 g) and 3-methyl-1-butanol (100 ml) was stirred and heated under reflux for 64 hours, cooled to ambient temperature and filtered. The solvent was removed in vacuo and the residual oil was distilled to give 1-[1-(pyrazin-2-yl)piperid-4-yl]methylamine as a pale yellow oil (16.2 g), b.p. 136°-160° C. at 0.6 mbar.
Reaction SMILES: [SH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[H-].[Na+].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].I[CH:37]([CH3:39])[CH3:38]>CN(C)C=O.[Cl-].[NH4+].O1CCCC1>[CH:37]([S:1][C:2]1[C:3]([CH2:4][OH:6])=[CH:7][CH:8]=[CH:9][N:10]=1)([CH3:39])[CH3:38]
Reactant: O=C(O)c1cccnc1S
Reactant: CC(C)I
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Sc1ncccc1CO
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 2-mercaptonicotinic acid (700 mg) in dimethylformamide (7 ml), 1.35 ml of 2-iodopropane and 541 mg of sodium hydride were added under ice-cooling, and the reaction solution was stirred at room temperature for 4 hours, at 60° C. for 2 hours. The reaction solution was cooled, then diluted with a saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The combined organic layers were washed with a saturated saline solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to afford a crude product as a yellow oil. To a solution of lithium aluminum hydride (428 mg) in tetrahydrofuran (7 ml), a solution of the crude product in tetrahydrofuran (3 ml) was added under ice-cooling, and the reaction solution was stirred at the same temperature for 30 minutes. To the reaction solution was added sodium sulfate decahydrate, and the mixture was further stirred at the same temperature for 1 hour. The reaction solution was Celite-filtered, the filtrate was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (95:5-50:50)) to afford the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C(Cl)Cl.[NH2:13][CH2:14][C:15]1[CH:29]=[CH:28][C:18]([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:17][CH:16]=1.[BH4-].[Na+]>CC(O)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:13][CH2:14][C:15]2[CH:29]=[CH:28][C:18]([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CN)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NCc1ccc(CNCc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.1 %

Procedure:
To a solution of 4-fluorobenzaldehyde (496 mg, 4.00 mmol) in a mixed solvent of CH2Cl2 (10 mL) and 2-propanol (2 mL) at rt was added tert-butyl 4-(aminomethyl)benzylcarbamate (945 mg, 4.00 mmol, Aldrich). The reaction mixture was stirred at rt overnight. The next morning, sodium borohydride (296 mg, 8.0 mmol) was added, and the mixture was stirred at rt for 2 h. The reaction mixture was quenched by adding 3 mL of MeOH and 3 mL of saturated aq NaHCO3. The mixture was extracted with EtOAc (3×50 mL). The combined organic extracts were dried, concentrated and purified by flash column chromatography on silica gel eluting with CH2Cl2/EtOAc to give the title compound (0.69 g, 48%) as a viscous material. MS (ESI): 345.1 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23](Cl)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:27]1[CH:31]=[CH:30][CH:29]=[N:28]1>CC#N>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:27]3[CH:31]=[CH:30][CH:29]=[N:28]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: c1cn[nH]c1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCC(F)(F)CC1
Solvent: CC#N
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3cccn3)ccc2n1CC1CCC(F)(F)CC1
Yield: 75.1 %

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazole-5-sulfonyl chloride (202 mg, 0.5 mmol) and pyrazol (186 mg, 2.7 mmol) in MeCN (6 mL). The crude product was purified by MPLC using Hex/EtOAc (1:1) on silica gel to give 164 mg (75%) of a white solid as the title compound. 1H NMR (400 MHz, CHLOROFORM-D) δ 1.43-1.54 (m, 1 H), 1.56 (s, 9 H), 1.59-1.80 (m, 4 H), 2.01-2.22 (m, 3 H), 2.49-2.79 (m, 1 H), 4.24 (d, J=7.42 Hz, 2 H), 6.38 (dd, J=2.73, 1.56 Hz, 1 H), 7.43 (d, J=8.59 Hz, 1 H), 7.70 (d, J=0.98 Hz, 1 H), 7.96 (dd, J=8.69, 1.66 Hz, 1 H), 8.15 (d, J=2.73 Hz, 1 H), 8.40 (d, J=1.76 Hz, 1 H); MS (ESI) (M+H)+=437.3; Anal. Calcd for C21H26F2N4O2S+0.2H2O (440.13): C, 57.31; H, 6.05; N, 12.73. Found: C, 57.23; H, 6.05; N, 12.83.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([O:6][CH3:7])=[O:5])[CH3:3].Cl.[CH3:9][C:10]([O:13][C:14]([NH:16][C@H:17]([C:20](OCC1C=CC([N+]([O-])=O)=CC=1)=[O:21])[CH2:18][OH:19])=[O:15])([CH3:12])[CH3:11].ON1C2C=CC=CC=2N=N1>CN(C=O)C.C(Cl)(Cl)Cl>[NH:16]([C:14]([O:13][C:10]([CH3:12])([CH3:11])[CH3:9])=[O:15])[C@H:17]([C:18]([NH:1][C@H:2]([C:4]([O:6][CH3:7])=[O:5])[CH3:3])=[O:19])[CH2:20][OH:21]
Reactant: COC(=O)[C@H](C)N
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)OC(C)(C)C

Procedure:
25 g of H-Ala-OMe, HCl and 66 g. of Boc-Ser-ONb are dissolved in 500 ml DMF. The product is cooled in an ice bath and 25 ml of NEM, 24 g of N-hydroxy benzotriazole are added wtih magnetic stirring and the pH is maintained at 6.5 or 7 by addition of NEM. The product is stirred for 18 hrs. at ambient temperature. After TLC monitoring, the medium is evaporated to 90% (13.33 Pa 35° C.). The oil obtained is dissolved in 1.500 ml of chloroform, the product is washed with a solution of saturated sodium chloride (twice), 5% potassium sulfate/bisulfate solution (3 times), saturated sodium bicarbonate (5 times). The solution is dried over Na2 `SO4 and evaporated to dryness. An oil is obtained which is dried to constant weight (30° C.13.33 Pa)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:14]([O-:16])=[O:15])[C:5]([O:12][CH3:13])=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:7]=1.[CH3:17][O:18][C:19]1[C:24](B(O)O)=[CH:23][CH:22]=[CH:21][N:20]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.CO>[C:8]([C:6]1[CH:7]=[C:2]([C:24]2[C:19]([O:18][CH3:17])=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:3]=[C:4]([N+:14]([O-:16])=[O:15])[C:5]=1[O:12][CH3:13])([CH3:11])([CH3:10])[CH3:9]
Reactant: COc1c([N+](=O)[O-])cc(Br)cc1C(C)(C)C
Reactant: COc1ncccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ncccc1-c1cc([N+](=O)[O-])c(OC)c(C(C)(C)C)c1
Temperature: 115 °C
Yield: 81.8 %

Procedure:
step 1—A mixture of 5-bromo-1-tert-butyl-2-methoxy-3-nitrobenzene (0.48 g, 1.7 mmol; CASRN 474554-50-2), 37 (0.28 g, 1.8 mmol), Pd(PPh3)3 (0.19 g, 0.17 mmol) and Na2CO3 (0.53 g, 5.0 mmol) in DCM/MeOH (3:1, 8 mL) was subjected to microwave heating to 115° C. for 35 min. The reaction mixture was filtered and the filtrate concentrated. The crude residue was purified by SiO2 chromatography eluting with EtOAc/hexane to afford 0.44 g (82%) of 3-(3-tert-butyl-4-methoxy-5-nitrophenyl)-2-methoxypyridine (98) as a yellow solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([N:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1(C)C=CC=CC=1>[CH2:6]([N:13]1[CH2:14][CH:15]=[C:16]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:17][CH2:18]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C1CCNC1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Solvent: Cc1ccccc1
Product: C1=C(N2CCCC2)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Yield: 102 %

Procedure:
Pyrrolidine (31.8 mL, 0.38 mol) was added to a solution of 1-benzyl-4-piperidinone (48.0 g, 0.25 mol) in toluene (180 mL) and the mixture refluxed under Dean-Stark conditions for 4.5 hours. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure to give the title compound as an orange oil (61.8 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:12]([CH3:16])=[C:13]([CH3:15])[N:14]=2)[CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:7]=1.[CH2:17]([C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:20]=1[CH2:21]Cl)[CH3:18].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(Cl)Cl.C(#N)C>[CH3:15][C:13]1[N:14]=[C:3]2[C:2]([NH:1][CH2:21][C:20]3[C:23]([CH3:27])=[CH:24][CH:25]=[CH:26][C:19]=3[CH2:17][CH3:18])=[CH:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][N:4]2[C:12]=1[CH3:16]
Reactant: COC(=O)c1cc(N)c2nc(C)c(C)n2c1
Reactant: CCc1cccc(C)c1CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: CCc1cccc(C)c1CNc1cc(C(=O)OC)cn2c(C)c(C)nc12
Yield: 37.3 %

Procedure:
Methyl 8-amino-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxylate (0.7 g, 3.2 mmol), 2-ethyl-6-methylbenzylchloride (0.54 g, 3.2 mmol), potassium carbonate (0.9 g, 6.4 mmol) and a cat. amount of potassium iodide were added to acetonitrile (20 ml) and were refluxed for 6 h. Following filtration, the acetonitrile was evaporated under reduced pressure to give an oil. The oily residue was solved in methylene chloride and washed with water. The organic layer was separated, dried over Na2SO4 and evaporated under reduced pressure to give a solid. Purification by column chromatography on silica gel using methylene chloride:ethylacetate (10:1) as eluent gave 0.42 g (38%) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][C:25]1[N:26]2[C:32]([CH3:33])=[C:31]([C:34](O)=[O:35])[N:30]=[C:27]2[S:28][CH:29]=1>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:34]([C:31]2[N:30]=[C:27]3[N:26]([C:32]=2[CH3:33])[C:25]([CH3:24])=[CH:29][S:28]3)=[O:35])=[O:10])[N:12]=1
Reactant: Cc1csc2nc(C(=O)O)c(C)n12
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2nc3scc(C)n3c2C)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 3,5-Dimethyl-imidazo[2,1-b]thiazole-6-carboxylic acid. LC-MS (basic): tR=0.88 min; [M+H]+=506.0.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:27][CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:14](=O)[CH2:15][CH:16]([CH3:25])[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:38]>C(O)(=O)C.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:14]3[NH:38][C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[C:16]([CH3:25])[CH:15]=3)[CH2:27][CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: [NH4+]
Reactant: CC(CC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1)C(=O)c1ccccn1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1cc(C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)[nH]c1-c1ccccn1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
To a solution of 5-[4-(cyclopropylsulfonyl)phenyl]-2-methyl-1-(pyridin-2-yl)-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (180 mg) in acetic acid (5 mL) was added ammonium acetate (472 mg), and the mixture was stirred at 110° C. for 30 min. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (140 mg, yield 81%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). MS: 451 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][CH:10]([CH3:13])[C:11]#[N:12].C[Si](C)(C)[N-][Si](C)(C)C.[Na+]>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:10]([CH3:13])([CH3:9])[C:11]#[N:12])=[N:3][CH:4]=1
Reactant: CC(C)C#N
Reactant: Brc1ccc(Br)nc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: CC(C)(C#N)c1ccc(Br)cn1
Temperature: 70 °C

Procedure:
2,5-Dibromopyridine (2 g, 8.44 mmol) was placed in a vial that was evacuated and backfilled with argon three times. Anhydrous dioxane (8.4 ml) was then added and the suspension was stirred. In a separate vial, 2-methylpropanenitrile (0.76 ml, 8.44 mmol) was added to a solution of sodium 1,1,1,3,3,3-hexamethyldisilazan-2-ide (28.1 ml of 0.6 M in toluene, 16.9 mmol). This was stirred for 10 minutes then added to the suspension. The reaction was heated to 70° C. for 1.5 hours. It was then cooled to room temperature, quenched with water, and extracted with ethyl acetate. Purification was performed via silica gel chromatography (0-75% ethyl acetate in hexane) to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:14])[CH2:10][CH2:11][C:12]#[CH:13])[CH:5]=[CH:6][CH:7]=1.[O:15](C(OC(C)(C)C)=O)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]([C:9](=[O:14])[CH2:10][CH2:11][C:12]#[CH:13])[C:16](=[O:15])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: C#CCCC(=O)Nc1cccc(Cl)c1
Product: C#CCCC(=O)N(C(=O)OC(C)(C)C)c1cccc(Cl)c1
Yield: 88.4 %

Procedure:
The title compound was prepared in accordance with the general method of Example 34(B), from N-(3-chlorophenyl)pent-4-ynamide (630 mg, 3.03 mmol) and (BOC)2O (795 mg, 3.64 mmol). The crude residue was purified over silicagel chromatography (prepacked 25 g silicagel column 100% DCM as eluent) to afford 824 mg of tert-butyl 3-chlorophenyl(pent-4-ynoyl)carbamate as a colorless oil (Yield: 88%).
Reaction SMILES: [CH:1](=[O:10])[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]([O:13][C:14](=[O:23])[CH2:15][C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:17])[CH3:12].[CH2:24]([O:26][C:27](=[O:32])/[CH:28]=[C:29](\[NH2:31])/[CH3:30])[CH3:25]>C(O)C>[CH:1](=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]([O:13][C:14](=[O:23])[CH2:15][C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:17])[CH3:12].[CH2:24]([O:26][C:27](=[O:32])/[CH:28]=[C:29](\[NH2:31])/[CH3:30])[CH3:25]
Reactant: O=CCCc1ccccc1
Agent: CCOC(=O)/C=C(/C)N
Agent: CCOC(=O)CC(=O)C(=O)OCC
Solvent: CCO
Product: O=CC=Cc1ccccc1

Procedure:
13.4 g of hydrocinnamaldehyde, 19 g of oxalacetic acid diethyl ester and 13 g of β-aminocrotonic acid ethyl ester in 40 ccs of ethanol are heated to the boil for several hours and subsequently evaporated in vacuo. Oil (yelloworange). a) In the same manner, 13.2 g of cinnamaldehyde, 19 g of oxalacetic acid diethyl ester and 13 g of β-aminocrotonic acid ethyl ester in 40 ccs of ethanol yield 2-methyl-4-styrryl1,4-dihydropyridine-3,5,6-tricarboxylic acid triethyl ester as an oil.
Reaction SMILES: N[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.Cl.N([O-])=O.[Na+].[C:18]([C:21]1[CH:34]=[CH:33][C:24](OCC2C=CC=CC=2)=[CH:23][CH:22]=1)(O)=[O:19]>CCOCC.O>[CH2:9]([O:8][C:6]([C:5]1[CH:11]=[CH:12][C:2]([O:19][CH2:18][C:21]2[CH:34]=[CH:33][CH:24]=[CH:23][CH:22]=2)=[CH:3][CH:4]=1)=[O:7])[CH3:10]
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)c1ccc(OCc2ccccc2)cc1

Procedure:
Ethyl 4-aminobenzoate (8.25g) in a mixture of conc. hydrochloric acid (12.5ml) and water (12.5ml.) at 0° C was diazotised by the addition of sodium nitrite (3.45g). The solution of the diazo compound was added to benzyl alcohol (20g) at 35° C with stirring then stirred at this temperature for 3 hr. The reaction mixture was cooled and 4-ethoxycarbonylphenoxy phenyl methane isolated by extraction with ether, m.p. 45° C.
Reaction SMILES: [N:1]1([C:7]2[S:8][C:9]3[C:10](=[O:17])[NH:11][CH2:12][CH:13]=[CH:14][C:15]=3[N:16]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Br:25]Br.N12CCCN=C1CCCCC2>C(Cl)Cl.CC(=O)OCC.O>[Br:25][C:14]1[C:15]2[N:16]=[C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[S:8][C:9]=2[C:10](=[O:17])[NH:11][CH2:12][CH:13]=1
Reactant: BrBr
Reactant: O=C1NCC=Cc2nc(N3CCOCC3)sc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: O
Product: O=C1NCC=C(Br)c2nc(N3CCOCC3)sc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 64.6 %

Procedure:
To a solution of 2-(morpholin-4-yl)-5,6-dihydro-4H-[1,3]thiazolo[5,4-c]azepin-4-one (3.41 g, 13.6 mmol) in DCM (42.0 mL) at 0° C. was added triethylamine (1.02 mL, 7.33 mmol), then a solution of bromine (1.15 mL, 22.4 mmol) in DCM (21.0 mL) was added dropwise and the reaction mixture was stirred at 0° C. for 3 hours. The solvent was evaporated and the residue was dissolved in benzene (80.0 mL) then added 1,8-diazabicyclo[5.4.0]undec-7-ene (6.09 mL, 40.7 mmol) and the solution was stirred at room temperature for 16 hours. The reaction mixture was diluted with EA and water, and a precipitate formed which was filtered and dried to give the product (2.90 g). In order to obtain additional product the layers were separated and the aqueous layer was extracted twice more with EA. The combined organic layer was then washed with brine then dried over anhydrous sodium sulfate and concentrated. The residue was adsorbed onto silica gel then purified using column chromatography on silica gel (40 gr Analogix column, gradient DCM to 5% MeOH in DCM over 15 minutes) to give 0.223 g additional product (total product: 3.02 g, 67%). LCMS: (AA) ES+ 331, 333. 1H NMR (300 MHz, d6-DMSO) δ: 8.14-7.89 (m, 1H), 6.69 (t, J=7.3 Hz, 1H), 3.81-3.62 (m, 4H), 3.55-3.38 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH2:14][CH2:15][C@:16]([CH3:30])([OH:29])[CH2:17]OS(C1C(C)=CC=CC=1)(=O)=O.[OH-].[Na+].C(Cl)Cl>C(O)C>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH2:14][CH2:15][C@:16]1([CH3:30])[O:29][CH2:17]1
Reactant: COc1c(C)c(C)c(OC)c(CC[C@](C)(O)COS(=O)(=O)c2ccccc2C)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: COc1c(C)c(C)c(OC)c(CC[C@@]2(C)CO2)c1C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
177 mg of (S)-4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-methyl-1-toluenesulphonyloxy-2-butanol are dissolved in 1 ml of ethanol and the solution is treated with 0.3 ml of alcoholic sodium hydroxide solution (1.5N). The mixture is left to stand at room temperature for 10 minutes, 30 ml of methylene chloride are then added and the mixture was dried over sodium sulphate and concentrated. There are obtained 105 mg of (S)-4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-methyl-1,2-epoxybutane. M.p. 47°-48° C.