Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([S:10]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=O)(=[O:12])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:22][C:23]1[CH:32]=[CH:31][C:26]2[N:27]=[C:28]([NH2:30])[S:29][C:25]=2[CH:24]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[N:1]1([S:10]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([NH:30][C:28]2[S:29][C:25]3[CH:24]=[C:23]([CH3:22])[CH:32]=[CH:31][C:26]=3[N:27]=2)=[O:18])(=[O:12])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc2nc(N)sc2c1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCc3ccccc32)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc2nc(NC(=O)c3cccc(S(=O)(=O)N4CCc5ccccc54)c3)sc2c1

Procedure:
3-(indolin-1-ylsulfonyl)benzoic acid (3) (200 mg, 0.66 mmol) and 6-methylbenzo[d]thiazol-2-amine (90 mg, 0.55 mmol) in DMF (4 mL) was added DIPEA (213 mg, 1.65 mmol) and pybop (429 mg, 0.82 mmol). using method C. The residue was purified using flash chromatography eluting with 0-30% EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give 3-(indolin-1-ylsulfonyl)-N-(6-methylbenzo[d]thiazol-2-yl)benzamide as a white solid. Yield: 78 mg (32%). 1H-NMR: 8.58 (s, 1H), 8.38 (d, J=8 Hz, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.82 (s, 1H), 7.77-7.65 (m, 3H), 7.53 (d, J=8.5 Hz, 1H), 7.30 (dd, J=8.5, 1.0 Hz, 1H), 7.22 (t, J=8.0 Hz, 1H), 7.16 (d, J=7.0 Hz, 1H), 6.99 (dt, J=7.5, 7.5, 1.0 Hz, 1H), 4.02 (t, J=8.5 Hz, 2H), 2.92 (t, J=8.5 Hz, 2H), 2.43 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH2:9])=[CH:4][N:3]=1.Br[C:11]1[CH:19]=[CH:18][C:17]2[NH:16][C:15]3[CH:20]4[CH2:26][CH2:25][N:23]([CH2:24][C:14]=3[C:13]=2[CH:12]=1)[CH2:22][CH2:21]4>>[CH3:1][C:2]1[N:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:11]2[CH:19]=[CH:18][C:17]3[NH:16][C:15]4[CH:20]5[CH2:26][CH2:25][N:23]([CH2:24][C:14]=4[C:13]=3[CH:12]=2)[CH2:22][CH2:21]5)=[CH:6][CH:7]=1
Reactant: Brc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Reactant: C=Cc1ccc(C)nc1
Product: Cc1ccc(/C=C/c2ccc3[nH]c4c(c3c2)CN2CCC4CC2)cn1

Procedure:
The product of Example 1C (133 mg, 1.11 mmol) and the product of Example 8A (180 mg, 0.62 mmol) were processed as described in Example 1D to provide the title compound: 1H NMR (500 MHz, methanol-d4) δ ppm 2.03-2.14 (m, 4 H), 2.52 (s, 3 H), 2.98-3.04 (m, 1 H), 3.08 (dt, J=14.0, 6.9 Hz, 2 H), 3.20-3.29 (m, 2 H), 4.27 (s, 2 H), 7.05 (d, J=16.2 Hz, 1 H), 7.27 (d, J=8.2 Hz, 2 H), 7.33 (d, J=16.2 Hz, 1 H), 7.35-7.38 (m, 1 H), 7.49 (s, 1 H), 7.94 (dd, J=7.9, 2.1 Hz, 1 H), 8.50 (d, J=1.8 Hz, 1 H); MS (APCI) m/z 330 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([CH2:9][CH2:10][NH2:11])[N:8]=1)[CH3:2].[C:12](O)(=O)C.C=O>CO>[CH2:1]([NH:3][C:4]1[S:5][C:6]2[CH2:12][NH:11][CH2:10][CH2:9][C:7]=2[N:8]=1)[CH3:2]
Reactant: CCNc1nc(CCN)cs1
Reactant: CC(=O)O
Agent: C=O
Solvent: CO
Product: CCNc1nc2c(s1)CNCC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 162.9 %

Procedure:
2-Ethylamino-4-(2-aminoethyl)thiazole (0.20 g, 1.17 mmol) and acetic acid (0.02 ml, 0.35 mmol) were dissolved in methanol (15 ml) and treated with formaldehyde (0.095 ml of a 37% aqueous solution, 1.17 mmol). The reaction was allowed to stir at room temperature for 15 minutes; it was then concentrated in vacuo and subjected to column chromatography (eluant: 89:10:1 chloroform: methanol: concentrated aqueous ammonium hydroxide). This provided the title product as a yellow solid (0.105 g, 0.57 mmol, 49% yield).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([NH:14][C:15]([CH2:21][CH3:22])([CH2:19][CH3:20])[C:16](O)=[O:17])=[O:13])[CH:9]=[CH:8][C:7]=2[C:23]([F:26])([F:25])[F:24])[CH2:3][CH2:2]1.Cl.[F:28][C:29]1([F:33])[CH2:32][NH:31][CH2:30]1>>[F:28][C:29]1([F:33])[CH2:32][N:31]([C:16]([C:15]([NH:14][C:12]([C:10]2[CH:9]=[CH:8][C:7]([C:23]([F:24])([F:26])[F:25])=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:13])([CH2:19][CH3:20])[CH2:21][CH3:22])=[O:17])[CH2:30]1
Reactant: CCC(CC)(NC(=O)c1ccc(C(F)(F)F)c(OCC2CC2)n1)C(=O)O
Reactant: FC1(F)CNC1
Agent: Cl
Product: CCC(CC)(NC(=O)c1ccc(C(F)(F)F)c(OCC2CC2)n1)C(=O)N1CC(F)(F)C1

Procedure:
In analogy to the procedure described in Example 293, 2-[(6-cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carbonyl)-amino]-2-ethyl-butyric acid (Example 252 b) and 3,3-difluoroazetidine hydrochloride (CAN 288315-03-7) were condensed to the title product. MS (EI): m/e=450.0 [M+H]+.
Reaction SMILES: CS(Cl)(=O)=O.[NH2:6][C:7]1[S:8][CH:9]=[C:10]([C:12](=[N:16][O:17][CH:18]2[CH2:21][S:20][CH2:19]2)[C:13]([OH:15])=O)[N:11]=1.C(N(C(C)C)CC)(C)C.[NH2:31][C@@H:32]1[C:49](=[O:50])[N:34]2[C:35]([C:46]([O-:48])=[O:47])=[C:36]([CH2:39][N+:40]3[N:41]([CH3:45])[CH:42]=[CH:43][CH:44]=3)[CH2:37][S:38][C@H:33]12.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C>CN(C)C=O.O1CCCC1.C(OCC)C>[NH2:6][C:7]1[S:8][CH:9]=[C:10]([C:12](=[N:16][O:17][CH:18]2[CH2:21][S:20][CH2:19]2)[C:13]([NH:31][C@@H:32]2[C:49](=[O:50])[N:34]3[C:35]([C:46]([O-:48])=[O:47])=[C:36]([CH2:39][N+:40]4[N:41]([CH3:45])[CH:42]=[CH:43][CH:44]=4)[CH2:37][S:38][C@H:33]23)=[O:15])[N:11]=1
Reactant: Nc1nc(C(=NOC2CSC2)C(=O)O)cs1
Reactant: Cn1ccc[n+]1CC1=C(C(=O)[O-])N2C(=O)[C@@H](N)[C@H]2SC1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ccc[n+]1CC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)C(=NOC3CSC3)c3csc(N)n3)[C@H]2SC1
Reaction time: 0.17 h
Yield: 24.5 %

Procedure:
Methanesulfonyl chloride (0.61 ml) was added to a solution of 2-(2-aminothiazol-4-yl)-2-(3-thietanyloxyimino)acetic acid (syn isomer, 0.99 g) and N,N-diisopropyl-N-ethylamine (1.33 ml) in N,N-dimethylformamide (20 ml) at -55° to -50° C., and the mixture was stirred for 10 minutes to produce an activated acid solution. To a solution of bis(trifluoroacetic acid) salts of 7β-amino-3-(2-methyl- 1-pyrazolio)methyl-3-cephem-4-carboxylate (2 g) and N,O-bis(trimethylsilyl)acetamide (3.79 ml) in tetrahydrofuran (20 ml) was added the above activated acid solution under ice-cooling, and the reaction mixture was stirred at the same temperature for an hour. The resultant mixture was poured into diethyl ether, and the precipitates were collected by filtration. The precipitates were suspended in water (20 ml), and the suspension was adjusted to pH 5 with 5% aqueous solution of sodium bicarbonate and subjected to column chromatography on macroporous non-ionic adsorption resin "Diaion HP-20" (Trademark, manufactured by Mitsubishi Chemical Industries) and eluted with 10% aqueous solution of isopropyl alcohol. The fractions containing the object compound were collected, evaporated in vacuo to remove isopropyl alcohol, and lyophilized to give 7β-[2-(2-aminothiazol-4-yl)-2-(3-thietanyloxyimino)acetamido]-3-(2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate (syn isomer, 0.5 g).
Reaction SMILES: S(=O)(=O)(O)O.Cl.[CH:7]([C:10]1[CH:15]=[CH:14][C:13]([NH:16]N)=[CH:12][CH:11]=1)([CH3:9])[CH3:8].[CH3:18][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C:20]1=O>O1CCOCC1>[CH:7]([C:10]1[CH:15]=[CH:14][C:13]2[NH:16][C:22]3[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][C:21]=3[C:12]=2[CH:11]=1)([CH3:9])[CH3:8]
Reactant: CC(C)c1ccc(NN)cc1
Reactant: CN1CCCCC1=O
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CC(C)c1ccc2[nH]c3c(c2c1)CN(C)CC3
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Sulfuric acid is added to a solution of 4-isopropyl phenyl hydrazine hydrochloride (1 equiv.) in dioxane, and stirred for 5 min. at RT. N-Methyl piperidone (0.76-1.4 equiv.) is added and the mixture is heated at 80° C. for 2 h. After completion, as monitored by TLC, the reaction mixture is concentrated under reduced pressure and basified to pH 10 using 10% aqueous KOH solution, extracted with EtOAc, dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator to provide the desired compound.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1.CC(O)=O.CCOC(C)=O.[H][H]>CO.[Pd]>[N:8]1([CH2:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[CH:17][CH:16]=[CH:15]3)[C:6]2=[N:7][CH:2]=[CH:3][N:4]=[C:5]2[N:10]=[N:9]1
Reactant: [H][H]
Reactant: Brc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: c1cnc2ccc(Cn3nnc4nccnc43)cc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 20 %

Procedure:
A solution of 6-(6-bromo-[1,2,3]triazolo[4,5-b]pyrazin-1-ylmethyl)-quinoline (200 mg, 0.586 mmol) in MeOH (10 mL):AcOH (1 mL): EtOAc (1 mL) was degassed 3 times with nitrogen. To this solution was added Pd/C (20 mg). A balloon containing hydrogen was added via syringe and the reaction was allowed to stir for 18 hours at room temperature. The reaction did not complete and more Pd/C was added (20 mg) and stirred for 18 hours at room temperature. The reaction was stopped when LCMS showed a ratio of 1:1 (product:starting material). The reaction was filtered over celite and washed with EtOAc (50 mL). The filtered solution was concentrated and purified by Biotage silica gel column chromatography with EtOAc: Hexanes to give 30 mg of the product 6-[1,2,3]triazolo[4,5-b]pyrazin-1-ylmethyl-quinoline (20% yield).
Reaction SMILES: [CH:1]1[N:2]=[C:3]([CH2:10][C:11]([OH:13])=[O:12])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[C:14]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CO>[CH3:14][O:12][C:11](=[O:13])[CH2:10][C:3]1[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[CH:1][N:2]=1
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Reactant: O=C(O)Cc1ncc2ccccn12
Solvent: CO
Product: COC(=O)Cc1ncc2ccccn12
Temperature: 25 °C

Procedure:
A suspension of imidazo[1,5-a]pyridin-3-ylacetic acid (Ellanovalabs, 2 g, 11.35 mmol) and camphorsulfonic acid (2.9 g, 12.49 mmol) in MeOH (120 mL) was refluxed for 4 h. Then allowed to cool to RT and concentrated under reduced pressure. The crude residue was diluted in CH2Cl2 and the organic layer was washed with a saturated aqueous solution of NaHCO3. The organics were dried (Na2SO4), filtered and concentrated. The material thus obtained was used in the next step without further purification: TLC, Rf (CH2Cl2/MeOH 9:1)=0.55; MS (UPLC/MS): 191.1 [M+H]+; tR (HPLC conditions f): 0.4 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:13]=[CH:14]/[C:15]([NH:17][C:18]2[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=2[C:20]([OH:22])=[O:21])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]#[CH:12]>C(OC(=O)C)(=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]#[CH:12])/[CH:13]=[CH:14]/[C:15]1[O:21][C:20](=[O:22])[C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[N:17]=1
Reactant: C#CCOc1ccc(/C=C/C(=O)Nc2ccccc2C(=O)O)cc1OC
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: C#CCOc1ccc(/C=C/c2nc3ccccc3c(=O)o2)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.3 %

Procedure:
A solution of (E)-2-[[3-(3-methoxy-4-propargyloxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.5 g, 1.4 mmol) in acetic anhydride (3 mL) was −5 heated to reflux and stirred for 3 h. The reaction was cooled to rt and the resulting suspension was diluted with water. The suspension was stirred at rt for 1 h and the precipitate was collected by filtration, providing (E)-2-(3-methoxy-4-propargyloxystyryl)-4H-benzo[d][1,3]oxazin-4-one (0.44 g, 93%) as a yellow crystalline solid; mp 177-178° C.; δH (500 MHz, DMSO-d) 3.59 (m, 1H, C≡CH), 3.85 (s, 3H, OCH3), 4.85 (s, 2H, OCH2), 6.96 (d, J=16.0 Hz, 1H, CH═CHCO), 7.07 (d, J5,6=8.0 Hz, 1H, H5′), 7.34 (d, J5′,6=8.0, 1H, H6′), 7.49 (s, 1H, H2′), 7.57 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.60 (d, J3,4=8.0 Hz, 1H, H3), 7.72 (d, J=16.0 Hz, 1H, CH═CHCO), 7.91 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 8.11 (d, J5,6=8.0 Hz, 1H, H6); νC (125 MHz, DMSO-d6) 55.7, 55.9, 78.5, 79.0, 110.8, 113.6, 117.0, 117.2, 122.3, 126.5, 128.0, 128.1, 128.3, 136.8, 141.2, 146.8, 148.5, 149.4, 157.2, 158.8; HRMS (ESI) calculated for C20H15NO4 [M+H]+ 334.1074, found 334.1074; νmax 970, 1136, 1270, 1471, 1743, 2135, 3268 cm−1.
Reaction SMILES: C(OC([NH:8][N:9]([C:13]([C:15]1[N:24]=[C:23]2[N:17]([CH2:18][CH2:19][O:20][C:21]3[CH:28]=[C:27]([Br:29])[CH:26]=[CH:25][C:22]=32)[CH:16]=1)=[O:14])[CH:10]([CH3:12])[CH3:11])=O)(C)(C)C.[ClH:30].O1CCOCC1>CO>[ClH:30].[ClH:30].[CH:10]([N:9]([C:13]([C:15]1[N:24]=[C:23]2[N:17]([CH2:18][CH2:19][O:20][C:21]3[CH:28]=[C:27]([Br:29])[CH:26]=[CH:25][C:22]=32)[CH:16]=1)=[O:14])[NH2:8])([CH3:12])[CH3:11]
Reactant: CC(C)N(NC(=O)OC(C)(C)C)C(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)N(N)C(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A solution of N′-(8-bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carbonyl)-N′-isopropyl-hydrazinecarboxylic acid tert-butyl ester (2.71 g, 5.83 mmol) in methanol (52 mL) was treated with 4N HCl in dioxane (5.83 mL, 23.3 mmol). The reaction mixture was stirred at 50° C. overnight before the reaction was concentrated in vacuo and the resultant residue triturated with diethyl ether to give 8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid N-isopropyl-hydrazide dihydrochloride as a pale yellow foam (2.69 g, quantitative yield). LCMS RT=4.17 min, [M+H]+=365/367
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:20])[S:9]([C:12]1[CH:16]=[CH:15][S:14][C:13]=1[C:17]([OH:19])=[O:18])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:23]=[N+:24]([O-:47])[CH:25]=[C:26]([Cl:46])[C:27]=1[CH2:28][C@@H:29]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH:38]([F:40])[F:39])=[C:33]([O:41][CH2:42][CH:43]2[CH2:45][CH2:44]2)[CH:32]=1)O.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]([CH3:20])[S:9]([C:12]1[CH:16]=[CH:15][S:14][C:13]=1[C:17]([O:19][C@H:29]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH:38]([F:39])[F:40])=[C:33]([O:41][CH2:42][CH:43]2[CH2:44][CH2:45]2)[CH:32]=1)[CH2:28][C:27]1[C:26]([Cl:46])=[CH:25][N+:24]([O-:47])=[CH:23][C:22]=1[Cl:21])=[O:18])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: CN(C(=O)OC(C)(C)C)S(=O)(=O)c1ccsc1C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CN(C(=O)OC(C)(C)C)S(=O)(=O)c1ccsc1C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Yield: 68.1 %

Procedure:
To a solution of 3-(N-(tert-butoxycarbonyl)-N-methylsulfamoyl)-thiophene-2-carboxylic acid (Int. 34) (150 mg, 0.467 mmol) in DCM (5 ml), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (196 mg, 0.467 mmol), EDC (268 mg, 1.400 mmol) and DMAP (28.5 mg, 0.233 mmol) were added and the mixture was reacted at RT overnight. The solvent was removed and the crude was purified by flash chromatography on silica gel (DCM/MeOH=95/5) affording (S)-4-(2-(3-(N-(tert-butoxycarbonyl)-N-methylsulfamoyl)thiophene-2-carbonyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) phenyl)ethyl)-3,5-dichloropyridine 1-oxide (Int. 35) (230 mg, 0.318 mmol, MS/ESI+722.8 [MH]+).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:23][C:24]1([CH3:40])[O:28][C@@H:27]([C@@H:29]2[C@@H:33]3[O:34][C:35]([CH3:38])([CH3:37])[O:36][C@@H:32]3[CH:31]([OH:39])[O:30]2)[CH2:26][O:25]1.CC(O)(C)C>C(Cl)Cl>[CH3:23][C:24]1([CH3:40])[O:28][C@@H:27]([C@@H:29]2[C@@H:33]3[O:34][C:35]([CH3:38])([CH3:37])[O:36][C@@H:32]3[C:31](=[O:39])[O:30]2)[CH2:26][O:25]1
Reactant: CC1(C)O[C@H]2[C@@H]([C@H]3COC(C)(C)O3)OC(O)[C@H]2O1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: CC1(C)O[C@H]2[C@@H]([C@H]3COC(C)(C)O3)OC(=O)[C@H]2O1
Reaction time: 0.25 h
Yield: 77.9 %

Procedure:
In a 1000 mL round bottom flask, Dess-Martin periodinane (110 g, 261.62 mmol, Spectrochem, India) was added to a solution of (3aS,6R,6aS)-6-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-ol (45 g, 174 mmol) in anhydrous DCM (900 mL) at rt. The resulting mixture was stirred for 15 minutes and treated with t-BuOH (14.16 g, 191.4 mmol, Rankem, India) at rt. The resulting reaction mixture was stirred at rt for 3 days under an argon atmosphere. Upon completion of the reaction (TLC, 30% EtOAc-hexanes, Rf, 0.55), the reaction mixture was quenched with aqueous Na2S2O3 (1000 mL) and extracted with DCM (4×250 mL). The combined organic extracts were washed with saturated NaHCO3 (500 mL), brine (200 mL), and then dried over anhydrous Na2SO4. The solution was concentrated under reduced pressure, and the residue obtained was washed with n-pentane to give (3aS,6R,6aS)-6-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-4(3aH)-one as a colorless solid (35 g, 78%): 1H NMR (400 MHz, CDCl3) δ 4.87 (dd, J=3.2, 5.2 Hz, 1H), 4.83 (d, J=5.2 Hz, 1H), 4.43-4.31 (m, 1H), 4.38-4.37 (m, 1H), 4.13 (dd, J=5.7, 9.2 Hz, 1H), 4.06 (dd, J=5.6, 9.2 Hz, 1H), 1.48 (s, 3H), 1.46 (s, 3H), 1.42 (s, 3H), 1.39 (s, 3H).
Reaction SMILES: [NH2:1][C:2](=[C:5]([Cl:7])[Cl:6])[C:3]#[N:4].[N+:8]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)([O-:10])=[O:9]>C1(C)C=CC=CC=1>[N+:8]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[N:1][C:2](=[C:5]([Cl:7])[Cl:6])[C:3]#[N:4])=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: N#CC(N)=C(Cl)Cl
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Product: N#CC(N=Cc1ccc([N+](=O)[O-])cc1)=C(Cl)Cl
Reaction time: 8 h

Procedure:
A solution of 2-amino-3,3-dichloropropenonitrile (15.0 g, 0.11 mole) and 4-nitrobenzaldehyde (15.1 g, 0.10 mmol) in toluene (200 ml) was refluxed for 23 hours. The mixture was evaporated, methanol (100 ml) was added and the mixture was allowed to stand overnight. After filtration, the title compound was isolated as a brown-yellow solid.
Reaction SMILES: C([O:4][CH:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:6][CH2:7][CH:8]1[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]C)=[O:20])[C:11](=[O:23])[CH2:10][S:9]1)(=O)C.C(OC1(CCC2N(CCCCCCC(OC)=O)C(=O)CS2)CCCCC1)(=O)C>>[OH:4][C:5]1([CH2:6][CH2:7][CH:8]2[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:11](=[O:23])[CH2:10][S:9]2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CCCCCC(CCC1SCC(=O)N1CCCCCCC(=O)OC)OC(C)=O
Agent: COC(=O)CCCCCCN1C(=O)CSC1CCC1(OC(C)=O)CCCCC1
Product: O=C(O)CCCCCCN1C(=O)CSC1CCC1(O)CCCCC1

Procedure:
This compound is prepared essentially by the method as described in Example 1, Step B, except that the methyl 7-[2-(3-acetyloxyoctyl)-4-oxo-3-thiazolidinyl]heptanoate is replaced by methyl 7-{2-[2-(1-acetyloxycyclohexyl)ethyl]-4-oxo-3-thiazolidinyl}heptanoate. Chromatographic purification of the resulting product on silica gel affords the title compound as a pale yellow, viscous oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]#[N:7].Cl.[NH2:9][OH:10].CCN(C(C)C)C(C)C>CCO>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6](=[N:9][OH:10])[NH2:7]
Reactant: NO
Reactant: N#Cc1nccs1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: NC(=NO)c1nccs1
Yield: 93.1 %

Procedure:
Hydroxylamine hydrochloride (9.03 g, 130 mmol) was added to a solution of 1,3-thiazole-2-carbaldehyde (14.71 g, 130 mmol) and pyridine (10.5 mL, 130 mmol) in DCM (100 mL). The reaction mixture was stirred overnight at room temperature and then washed twice with water. The organic layer was dried over MgSO4 and then evaporated under reduced pressure to give 15.26 g of 1,3-thiazole-2-carbaldehyde oxime (yield 92%). 1,3-thiazole-2-carbaldehyde oxime (15.23 g, 119 mmol, 1 equiv) was dissolved in 80 mL of dioxane and then TEA (41.4 mL, 2.5 equiv) was added. The reaction mixture was cooled to 0° C. and then trifluoroacetic anhydride (18.3 mL, 1.1 equiv) was added dropwise to the reaction. The solution was stirred overnight at room temperature and then evaporated. The residue was dissolved in DCM and then washed twice with water. The organic layer was dried over MgSO4 and then evaporated under reduced pressure to give 1,3-thiazole-2-carbonitrile. This compound was used in the next step without further purification. 1,3-thiazole-2-carbonitrile (13.11 g, 119 mmol, 1 equiv), hydroxylamine hydrochloride (12.4 g, 1.5 equiv) and DIEA (33 mL, 1.6 equiv) were mixed in absolute EtOH (150 mL). The reaction mixture was refluxed 4 h and then the solvent was evaporated under reduced pressure. The residue was dissolved in AcOEt, washed twice with water and once with brine. The organic layer was dried over MgSO4 and then evaporated under reduced pressure to give 15.86 g of 1,3-thiazole-2-amidoxime (yield 93% over two steps).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18](O)=[O:19])=[C:13]([C:15](=[O:17])[NH2:16])[N:14]=[C:7]3[C:6]=2[CH:21]=1.Cl.[O:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:29][CH:26]4[CH2:27][CH2:28][O:23][CH2:24][CH2:25]4)=[O:19])=[C:13]([C:15]([NH2:16])=[O:17])[N:14]=[C:7]3[C:6]=2[CH:21]=1
Reactant: NC1CCOCC1
Reactant: NC(=O)c1nc2n(c1C(=O)O)CCOc1ccc(Br)cc1-2
Agent: Cl
Product: NC(=O)c1nc2n(c1C(=O)NC1CCOCC1)CCOc1ccc(Br)cc1-2
Yield: 63 %

Procedure:
10-bromo-2-carbamoyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-3-carboxylic acid was reacted with tetrahydro-pyran-4-ylamine hydrochloride similarly to as described in example 2 with non-critical modifications to afford 117 mg (63%) 10-bromo-N3-tetrahydropyran-4-yl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide. 10-bromo-N3-tetrahydropyran-4-yl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide was reacted with (3R)-3-ethynyl-3-hydroxy-1-methyl-pyrrolidin-2-one similarly to as described in General Procedure F with non-critical modifications to afford 14 mg (11%) of 10-[2-[(3R)-3-hydroxy-1-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-N3-tetrahydropyran-4-yl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@H:11]([NH2:13])[CH3:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].S1C=CC=C1C=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([NH2:13])[CH3:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc([C@H](C)N)cc1OC
Agent: O=Cc1cccs1
Solvent: ClCCl
Product: COc1ccc(C(C)N)cc1OC
Temperature: 20 °C
Reaction time: 16 h

Procedure:
To a solution of 43.8 g of (S)-1-(3,4-dimethoxyphenyl)ethylamine in 400 cm3 of dichloromethane are added, with stirring at a temperature in the region of 20° C., 16.8 cm3 of 2-thiophenecarboxaldehyde and 35 g of 4Å molecular sieves. The reaction mixture is stirred for 16 hours at a temperature in the region of 20° C., and then filtered through a sinter funnel containing Celite. The sinter funnel is washed with 3 times 50 cm3 of dichloromethane and the filtrates are combined and then concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. 45.95 g of (S)-N-(2-thienyl)-methylidene]-[1-(3,4-dimethoxyphenyl)ethylamine are thus obtained in the form of a colourless oil for which the characteristics are the following: