Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1[O:3][CH2:4][C:5]([CH3:16])([CH2:7][O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]=1.[OH-].[K+].O>C(O)C>[NH2:6][C:5]([CH3:16])([CH2:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:4][OH:3]
Reactant: CC1=NC(C)(COCc2ccccc2)CO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(N)(CO)COCc1ccccc1

Procedure:
2,4-Dimethyl-4-benzyloxymethyloxazoline (80 grams, prepared by a similar method to that described in Example 1) and potassium hydroxide (100 grams) in aqueous ethanol were heated together under reflux for 4 days. The volume of the reaction mixture was reduced under reduced pressure and water (300 milliliters) was then added. The aqueous mixture was extracted with ether (3 × 250 milliliters) and the extracts dried and the solvent removed under reduced pressure. The residue was distilled under reduced pressure to give 2-amino-3-benzyloxy-2-methylpropanol as a colorless liquid, boiling point 128°-129°C at 1.1 Torr.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)(=O)=O.[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.[Na]>CN(C=O)C>[N:17]1([CH2:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[CH:10]3)[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: CS(=O)(=O)OCc1ccc2ncccc2c1
Reactant: c1c[nH]cn1
Agent: [Na]
Solvent: CN(C)C=O
Product: c1cnc2ccc(Cn3ccnc3)cc2c1
Temperature: 70 °C
Yield: 27 %

Procedure:
The title product from Step A above was dissolved in anhydrous DMF (10 mL) and sodium imidazole (0.367 g, 4.08 mmoles) was added. The mixture was heated at 70° C. under argon for 2 h and then evaporated to dryness. The product was chromatographed on silica gel to give the title compound (0.1559 g, 27%): FABMS: m/z 210.0 (MH+); δH (CDCl3) 5.34 (1H, s, CH2), 6.97 (1H, s, Im-H5), 7.15 (1H, s, Im-H4), 7.44 (1H, dd, Ar—H3), 7.52 (2H, m, Ar—Hs and Ar—H7), 7.64 (1H, s, Im-H2), 8.12 (2H, d, Ar—H4 and Ar—H8) and 8.95 ppm (1H, d, Ar—H2); δH (CDCl3) CH2: 50.6; CH: 119.4, 121.8, 125.9, 128.4, 130.1, 130.5, 136.0, 137.6, 151.0; C: 128.2, 134.6, 147.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[C:14]3[N:15]([CH3:19])[C:16](=O)[NH:17][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:24])=O>C(OCC)(=O)C>[Cl:24][C:16]1[N:15]([CH3:19])[C:14]2[C:9]([C:7]([C:6]3[CH:20]=[CH:21][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[O:8])=[CH:10][CH:11]=[CH:12][C:13]=2[N:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(C(=O)c2cccc3[nH]c(=O)n(C)c23)cc1
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)c2cccc3nc(Cl)n(C)c23)cc1
Temperature: 100 °C
Yield: 80 %

Procedure:
A mixture of 145 mg (0.514 mmol) of 7-(4-methoxybenzoyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one was dissolved in 1.5 mL of phosphorous oxychloride and heated at 100° C. for 18 h. The reaction was allowed to cool to room temperature and concentrated in vacuo. The residue thus obtained was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated in vacuo to give 124 mg (80%) of the title compound, which was used in the next step without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH3:20])[C:7]([N:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]=[CH:10]1)=[O:8].[N-:21]=[N+:22]=[N-:23].C([N+](CCCC)(CCCC)CCCC)CCC>CC(C)=O>[N:21]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH3:20])[C:7]([N:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]=[CH:10]1)=[O:8])=[N+:22]=[N-:23]
Reactant: CN(CCCCCl)C(=O)n1cnc(-c2ccccc2)c1
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC(C)=O
Product: CN(CCCCN=[N+]=[N-])C(=O)n1cnc(-c2ccccc2)c1
Temperature: 25 °C

Procedure:
Compound 47 (4.3) (1 mmol) was taken in anhydrous acetone (25 mL) and tetra-n-butylammonium azide (2 mmol) was added and the reaction was refluxed for 8 h. The reaction was cooled to RT and solvent was evaporated on Rotavapor to give a crude compound which on purification by Biotage SP1 provided pure N-(4-azidobutyl)-N-methyl-4-phenyl-1H-imidazole-1-carboxamide (48/4.4).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[C:13](=[O:24])[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[C:17]([CH:22]=O)[CH:16]=4)[N:11]=2)=[CH:3][CH:2]=1.[CH3:25][CH:26]1[NH:31][CH2:30][CH2:29][NH:28][CH2:27]1>>[CH3:25][CH:26]1[NH:31][CH2:30][CH2:29][N:28]([CH2:22][C:17]2[CH:16]=[C:15]3[C:20]([CH:21]=[C:12]([C:10]4[N:11]=[C:7]([C:4]5[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=5)[S:8][CH:9]=4)[C:13](=[O:24])[NH:14]3)=[CH:19][CH:18]=2)[CH2:27]1
Reactant: O=Cc1ccc2cc(-c3csc(-c4ccncc4)n3)c(=O)[nH]c2c1
Reactant: CC1CNCCN1
Product: CC1CN(Cc2ccc3cc(-c4csc(-c5ccncc5)n4)c(=O)[nH]c3c2)CCN1

Procedure:
This compound was prepared according to the method described in example 8768 employing 3-(2-pyridin-4-yl-thiazol-4-yl)-1H-quinolin-2-one-7-carbaldehyde and 3-methylpiperazine to give a yellow solid. MS m/z: 418.3 (M+1).
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([C:11]([F:14])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:19])([F:18])[F:17])[S:3]1.C(N(CC)CC)C.[F:28][C:29]([F:41])([F:40])[O:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34](Cl)=[O:35]>C1(C)C=CC=CC=1>[F:28][C:29]([F:40])([F:41])[O:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34]([NH:1][C:2]1[S:3][C:4](=[C:15]([F:20])[C:16]([F:17])([F:18])[F:19])[C:5]([C:7]([F:10])([F:9])[F:8])([C:11]([F:12])([F:13])[F:14])[N:6]=1)=[O:35]
Reactant: N=C1NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Reactant: O=C(Cl)c1cccc(OC(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(NC1=NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1)c1cccc(OC(F)(F)F)c1
Temperature: 103 °C
Reaction time: 3 h

Procedure:
In toluene (10 ml) were dissolved 2-imino-4,4-bis(trifluoromethyl)-5-(tetrafluoroethylidene)-1,3-thiazolidine (1.0 g) and triethylamine (0.6 ml), and a solution of 3-trifluoromethoxybenzoyl chloride (0.5 g) dissolved in toluene (10 ml) was gradually added thereto under cooling and the mixture was stirred at 103° C. for 3 hours.
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[NH2:12][C:13]1[C:14]([C:20]([NH:22][NH:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=O)=[N:15][C:16]([Br:19])=[CH:17][N:18]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Br:19][C:16]1[N:15]=[C:14]([C:20]2[O:29][C:24]([C:25]([CH3:26])([CH3:27])[CH3:28])=[N:23][N:22]=2)[C:13]([NH2:12])=[N:18][CH:17]=1
Reactant: CC(C)(C)C(=O)NNC(=O)c1nc(Br)cnc1N
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)c1nnc(-c2nc(Br)cnc2N)o1
Temperature: 70 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
p-Toluenesulfonyl chloride (164 g, 861.60 mmol) was added portion wise to a suspension of 3-amino-6-bromo-N′-pivaloylpyrazine-2-carbohydrazide (227 g, 718.00 mmol) and N,N-diisopropylethylamine (297 mL, 1795.01 mmol) in acetonitrile (2200 mL). The mixture was stirred for 2 hours at 70° C. The reaction was left to cool to room temperature overnight. The reaction mixture was partitioned between ethyl acetate (2 L) and sodium bicarbonate solution (2 L). The organic layer was washed with saturated brine, dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting brown/beige solid was triturated with hot MTBE (1000 mL) and isolated by filtration and dried to afford 5-bromo-3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-amine as a yellow solid (187 g, 87%). The mother liquors were evaporated to dryness. The crude solid was triturated with MTBE (500 mL) filtered and washed with 100 mL of MTBE. The resulting solid was air dried overnight to afford a second crop of 5-bromo-3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-amine (36 g, 17%): 1H NMR Spectrum: (DMSO-d6) 1.43 (9H, s), 7.70 (2H, s), 8.39 (1H, s); Mass Spectrum [M+H]+=298.
Reaction SMILES: [OH:1][CH:2]([CH2:11][OH:12])[CH2:3][S:4][CH2:5][C@@H:6]([C:8]([OH:10])=[O:9])[NH2:7].[C:13]1([CH2:26][O:27][C:28](C2CC(=O)N(O)C2=O)=[O:29])[C:25]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[CH:16]=[CH:15][CH:14]=1>C(=O)([O-])[O-].[Na+].[Na+].C(#N)C.O>[C:13]1([CH2:26][O:27][C:28]([NH:7][C@H:6]([C:8]([OH:10])=[O:9])[CH2:5][S:4][CH2:3][CH:2]([OH:1])[CH2:11][OH:12])=[O:29])[C:25]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[CH:16]=[CH:15][CH:14]=1
Reactant: N[C@@H](CSCC(O)CO)C(=O)O
Reactant: O=C(OCc1cccc2c1Cc1ccccc1-2)C1CC(=O)N(O)C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C(N[C@@H](CSCC(O)CO)C(=O)O)OCc1cccc2c1Cc1ccccc1-2
Reaction time: 2 h
Yield: 63.8 %

Procedure:
S-(2,3-dihydroxypropyl)cysteine (2.45 g, 12.6 mmole) was dissolved in 9% sodium carbonate (20 ml). A solution of fluorenylmethoxycarbonyl-N-hydroxysuccinimide (3.45 g, 10.5 mmole) in acetonitrile (20 ml) was added and the mixture stirred for 2 h, then diluted with water (240 ml), and extracted with diethyl ether (25 ml×3). The aqueous phase was acidified to pH 2 with concentrated hydrochloric acid and was then extracted with ethyl acetate (70 ml×3). The extract was washed with water (50 ml×2) and saturated sodium chloride solution (50 ml×2), dried over sodium sulfate and evaporated to dryness. Recrystallisation from ether and ethyl acetate at −20° C. yielded a colourless powder (2.8 g, 6.7 mmole, 63.8%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]([CH3:16])([CH3:15])[C:12](O)=[O:13])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[NH2:23][C:24]1[S:25][CH:26]=[N:27][N:28]=1>>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]([CH3:16])([CH3:15])[C:12]([NH:23][C:24]3[S:25][CH:26]=[N:27][N:28]=3)=[O:13])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: Nc1nncs1
Reactant: CC(C)(C(=O)O)C(c1ccccc1)c1ccc2[nH]ncc2c1
Product: CC(C)(C(=O)Nc1nncs1)C(c1ccccc1)c1ccc2[nH]ncc2c1

Procedure:
The title compound was prepared from 3-(1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropanoic acid (Example 29(d)) (44 mg, 0.15 mmol) and 2-amino-1,3,4-thiadiazole using General Coupling Method A to give 29 mg (51% yield) of Example 30. MS found: (M+H)+=378.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:25])=[C:5]([C:16]([O:23][CH3:24])=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:15])=[C:11]([CH:14]=1)[CH:12]=[O:13].[OH-].[Na+].S(OC)(O[CH3:32])(=O)=O.Cl>C(O)C>[CH3:1][O:2][C:3]1[C:4]([CH3:25])=[C:5]([C:16]([O:23][CH3:24])=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:15][CH3:32])=[C:11]([CH:14]=1)[CH:12]=[O:13]
Reactant: COc1c(C)c(Cc2ccc(O)c(C=O)c2)c(OC)c(OC)c1OC
Reactant: COS(=O)(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)cc1C=O
Yield: 68.8 %

Procedure:
5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-hydroxybenzaldehyde (0.500 g, 1.45 mmol) was dissolved in ethanol (15 ml) and after adding thereto in sequence sodium hydroxide (0.064 g, 1.59 mmol) and dimethyl sulfate (0.200 g, 1.59 mmol), the solution was stirred at room temperature for 12 hours. After the completion of reaction, the reaction solution was poured into a cold diluted hydrochloric acid solution and extracted with ethyl acetate. The extract was washed with water and then dried, the solvent was removed by distillation and the obtained residue was purified by silica gel column chromatography (hexand:ethyl acetate=4:1) to obtain the titled compound (0.359 g, 0.998 mmol, 69%).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH:7]=[CH:6]2.C(=O)([O-])[O-].[K+].[K+].[Br:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24](Br)[C:23]=1[CH3:29]>CS(C)=O>[Br:21][C:22]1[C:23]([CH3:29])=[C:24]([N:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([N:2]([CH3:14])[CH3:1])[CH:4]=3)[C:9]2=[O:13])[CH:25]=[CH:26][CH:27]=1
Reactant: CN(C)c1ccc2c(=O)[nH]ccc2c1
Reactant: Cc1c(Br)cccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1c(Br)cccc1-n1ccc2cc(N(C)C)ccc2c1=O
Temperature: 150 °C
Yield: 44.4 %

Procedure:
6-Dimethylamino-2H-isoquinolin-1-one (50 mg, 0.27 mmol), cuprous iodide (10 mg, 0.053 mmol), and potassium carbonate (37 mg, 0.27 mmol) were deposited in sealed vessel. 3 mL DMSO and 2,6-dibromotoluene (133 mg, 0.532 mmol) were added. Argon was bubbled through the mixture for 2 minutes and the lid was tightly closed. This was heated at 150° C. for 5 hours. The resulting mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (30% ethyl acetate/hexanes) to yield 2-(3-Bromo-2-methyl-phenyl)-6-dimethylamino-2H-isoquinolin-1-one (43 mg, 0.12 mmol). MS (ESI) 357 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:14])=[CH:4][C:5](=[O:13])[N:6]([CH2:8][CH2:9][C:10]([OH:12])=O)[CH:7]=1.[N:15]1([C:21](=[O:24])[CH:22]=[CH2:23])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[C:21]([N:15]1[CH2:20][CH2:19][N:18]([C:10](=[O:12])[CH2:9][CH2:8][N:6]2[CH:7]=[C:2]([Br:1])[C:3]([CH3:14])=[CH:4][C:5]2=[O:13])[CH2:17][CH2:16]1)(=[O:24])[CH:22]=[CH2:23]
Reactant: C=CC(=O)N1CCNCC1
Reactant: Cc1cc(=O)n(CCC(=O)O)cc1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CC(=O)N1CCN(C(=O)CCn2cc(Br)c(C)cc2=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.9 %

Procedure:
A mixture of 3-(5-Bromo-4-methyl-2-oxopyridin-1(2H)-yl)propanoic acid (112 mg, 0.43 mmol), 1-(piperazin-1-yl)prop-2-en-1-one (80 mg, 0.43 mmol), HATU (163 mg, 0.43 mmol) and Et3N (0.2 mL, 1.43 mmol) in DMF (5 mL) was stirred at room temperature for 2 h. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via Isolera One (silica cartridge, 0-6% MeOH/DCM) to afford the desired product (22.8 mg, 14 yield). 1H NMR (300 MHz, CDCl3) δ: 7.73 (s, 1H), 6.55 (dd, J=10.5, 16.7 Hz, 1H), 6.46 (s, 1H), 6.32 (dd, J=1.8, 16.8 Hz, 1H), 5.75 (dd, J=1.8, 10.5 Hz, 1H), 4.20 (t, J=6.0 Hz, 2H), 3.4-3.6 (m, 8H), 2.86 (t, J=6.0 Hz, 2H), 2.22 (s, 3H). ESI-MS m/z: 382.05 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([NH2:11])[N:8]=[C:7](Cl)[N:6]=1)=[O:4].[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[C:16]([F:23])[C:15]=1[O:24][CH3:25]>C(COC)OC.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([NH2:11])[N:8]=[C:7]([C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[C:15]([O:24][CH3:25])[C:16]=2[F:23])[N:6]=1)=[O:4]
Reactant: COC(=O)c1cc(N)nc(Cl)n1
Reactant: COc1c(Cl)ccc(B(O)O)c1F
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cc(N)nc(-c2ccc(Cl)c(OC)c2F)n1
Temperature: 80 °C
Yield: 53.5 %

Procedure:
6-Amino-2-chloro-pyrimidine-4-carboxylic acid methyl ester (2.25 g, 12 mmol), 4-chloro-2-fluoro-3-methoxyphenylboronic acid (3.27 g, 16 mmol), and bis(triphenylphosphine)palladium(II)dichloride (842 mg, 1.2 mmol) were combined in 12 mL of dimethoxyethane and 12 mL of water. The reaction mixture was heated at 80° C. for 2 hours and the cooled reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with water, dried, and concentrated under vacuum. The product was purified by column chromatography to yield 6-amino-2-(4-chloro-2-fluoro-3-methoxy-phenyl)pyrimidine-4-carboxylic acid methyl ester (2.0 g, 53.5% yield): mp 188-190° C.: 1H NMR (CDCl3): δ 7.66 (dd, 1H), 7.22 (dd, 1H), 7.14 (s, 1H), 5.25 (br s, 2H), 4.0 (s, 3H), 3.99 (s, 3H).
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][N:26]4[CH:30]=[CH:29][N:28]=[N:27]4)[O:22][C:21]3=[O:31])=[CH:16][C:15]=2[F:32])[CH2:10]1)=O)(C)(C)C.Cl>ClCCl.C(O)C>[NH2:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][N:26]4[CH:30]=[CH:29][N:28]=[N:27]4)[O:22][C:21]3=[O:31])=[CH:16][C:15]=2[F:32])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: N[C@H]1CCN(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(5R)-3-(4-((3S)-3-(t-Butoxycarbonyl)aminopyrrolidin-1-yl)-3-fluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)oxazolidin-2-one (1.55 g, 3.47 mM), was dissolved in dichloromethane (8 ml), and treated with a solution of hydrogen chloride in ethanol (3.8M, 40 ml). After stirring 2 hours at ambient temperature, the mixture was evaporated to dryness to give product as a hydrochloride of sufficient quality to require no purification (1.64 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=O)[C:8]([C:13]#[N:14])=[CH:9][NH:10]2)=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:17]>>[Cl:17][C:7]1[C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=[CH:9][C:8]=1[C:13]#[N:14]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COc1ccc2c(=O)c(C#N)c[nH]c2c1
Product: COc1ccc2c(Cl)c(C#N)cnc2c1
Temperature: 165 °C

Procedure:
A mixture of 4.0 g (20 mmol) of 1,4-dihydro-7-methoxy-4-oxo-3-quinolinecarbonitrile and 8.3 g (40 mmol) of phosphorous pentachloride was heated at 165° C. for 3 hours. The mixture was diluted with hexanes and the solid was collected. The solid was mixed with brine and dilute sodium hydroxide solution and extracted several times with a mixture of tetrahydrofuran and ethyl acetate. The solution was dried over magnesium sulfate and filtered through a pad of silica gel giving 3.7 g of 4-chloro-7-methoxy -3-quinolinecarbonitrile as a white solid: mass spectrum (electrospray, m/e): M+H 218.9.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=2)[NH:11][CH:10]=1.[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:21]1([S:27]([N:11]2[C:12]3[C:17](=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=3)[C:9]([Br:8])=[CH:10]2)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=[N+]([O-])c1ccc2c(Br)c[nH]c2c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc2c(Br)cn(S(=O)(=O)c3ccccc3)c2c1
Reaction time: 8 h

Procedure:
Add triethyl amine (Et3N) (6.7 mL, 48 mmol, 4 eq) and DMAP (240 mg, 2.0 mmol, 0.1 eq) to a slurry of 3-bromo-6-nitro indole, 2 (4.82 g, 20 mmol) in 100 mL of CH2Cl2. Let the solution stir until the 3-bromo-6-nitro indole dissolves and then add benzenesulfonyl chloride (3.1 mL, 24 mmol, 1.2 eq). Let the solution stir overnight. Filter off the precipitate, which forms, wash the precipitate with CH2Cl2, and collect the filtrates to give 6.83 g of the title compound. Sequentially wash the combined filtrates with 1 M HCl, saturated sodium bicarbonate, and brine. Dry the organic layer over Na2SO4, filter, and then concentrate the filtrate. Boil the resulting solid in ˜30 mL of CH2Cl2 and a little MeOH, add 30 mL hexanes, let cool, and then filter off the precipitate to give another 1.3 g of the title compound. 1H NMR (DMSO-d6) δ 8.74 (d, 1H, J=2.2 Hz), 8.58 (s, 1H), 8.19 (dd, 1H, J=2.2, 8.8 Hz), 8.08-8.05 (m, 2H), 7.75-7.68 (m, 2H), 7.63-7.59 (m, 2H)—.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.Cl.[Br:17][C:18]1[CH:19]=[CH:20][C:21]2[O:27][CH2:26][CH2:25][NH:24][CH2:23][C:22]=2[CH:28]=1.C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[N:24]1[CH2:23][C:22]2[CH:28]=[C:18]([Br:17])[CH:19]=[CH:20][C:21]=2[O:27][CH2:26][CH2:25]1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Brc1ccc2c(c1)CNCCO2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COc1cc2nccc(N3CCOc4ccc(Br)cc4C3)c2cc1OC
Temperature: 25 °C
Yield: 70.4 %

Procedure:
A mixture of commercially available 4-chloro-6,7-dimethoxyquinoline (120 mg, 0.53 mmol), 7-bromo-2,3-dihydro-1,4-benzoxazepine hydrochloride (example 2, step 1) (200 mg, 0.53 mmol), diisopropylethylamine (0.14 g, 1.1 mmol), in NMP (2 mL) was stirred in a microwave reactor at 120° C. for 45 min. After cooling to room temperature, the reaction mixture was purified directly by silica gel flash chromatography (0-10% methanol-dichloromethane gradient) to give 4-[6,7-bis(methyloxy)quinolin-4-yl]-7-bromo-2,3,4,5-tetrahydro-1,4-benzoxazepine (155 mg, 70% yield), MS (EI) for C20H19N2O3: 415 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:7](=[O:12])[CH2:8][NH:9][C:10](=O)[C:4]=2[CH:3]=1.O=P(Cl)(Cl)[Cl:26]>C1(C)C=CC=CC=1>[Cl:26][C:10]1[C:4]2[CH:3]=[C:2]([Cl:1])[CH:23]=[CH:22][C:5]=2[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:7](=[O:12])[CH2:8][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(CN2C(=O)CNC(=O)c3cc(Cl)ccc32)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(CN2C(=O)CN=C(Cl)c3cc(Cl)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 120 %

Procedure:
In a 1 L 3-neck RBF equipped with magnetic stir bar, condenser and N2 inlet, C2 (45 g, 0.136 mol) was suspended in 400 mL of toluene. To this was added N,N-dimethylanaline (33 g, 0.272 mol) followed by the addition of POCl3 (23 g) and the reaction stirred for 3 min (RT). Reaction flask was placed into a 90° C. oil bath and the reaction mixture was heated for 5 h and then cooled. The reaction was quenched by adding 450 mL of ice water and stirred for 15 min. Organic layer was separated and quickly washed with cold water (2×250 mL) and brine (300 mL). Organic layer was dried over MgSO4, filtered and concentrated on a rotary evaporator to give 57 g of black crude product. Crude product was used for next step with no further purification. Yield 87.5%.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH:12]([O:25][C:26]([C:28]1[N:29]2[CH:32]([S:33][CH2:34][C:35]=1[CH2:36][CH:37]([Cl:39])[Cl:38])[CH:31]([NH:40][C:41](=[O:71])[C:42](=[N:68][O:69][CH3:70])[C:43]1[N:44]=[C:45]([NH:48][C:49]([C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[S:46][CH:47]=1)[C:30]2=[O:72])=[O:27])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl.C(OCC)(=O)C>[CH:12]([O:25][C:26]([C:28]1[N:29]2[CH:32]([S:33](=[O:9])[CH2:34][C:35]=1[CH2:36][CH:37]([Cl:39])[Cl:38])[CH:31]([NH:40][C:41](=[O:71])[C:42](=[N:68][O:69][CH3:70])[C:43]1[N:44]=[C:45]([NH:48][C:49]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)([C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)[C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)[S:46][CH:47]=1)[C:30]2=[O:72])=[O:27])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CC(Cl)Cl)CSC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CC(Cl)Cl)CS(=O)C12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 0.5 h
Yield: 73.7 %

Procedure:
A solution of meta-chloroperbenzoic acid (85% pure) (0.05 g) in methylene chloride (1 cc) is added all at once to a solution, cooled to -10° C., of product (8b) (0.2 g) in methylene chloride (5 cc). After 30 minutes at -10° C., the reaction mixture is diluted with ethyl acetate (20 cc) and washed with a saturated solution of sodium bicarbonate (2×10 cc) and a saturated solution of sodium chloride (2×10 cc). After the mixture has been dried over sodium sulphate and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C., crude syn isomer of 2-benzhydryloxycarbonyl-3-(2,2-dichloroethyl)-7-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-5-oxide (product 8) (0.15 g) is obtained in the form of a hard orange foam.