Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[CH2:9][N:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[Br-]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:8][CH:17]([CH3:22])[CH2:18][CH2:19][CH3:20])=[CH:21][CH:22]=1)[CH2:9][N:10]1[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCN(C[C@H](NC(=O)OC(C)(C)C)c2ccc(O)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCC(C)COc1ccc([C@H](CN2CCN(C)CC2)NC(=O)OC(C)(C)C)cc1
Temperature: 55 °C

Procedure:
A mixture of [(R)-1-(4-hydroxy-phenyl)-2-(4-methyl-piperazin-1-yl)-ethyl]-carbamic acid tert-butyl ester (57 mg, 0.17 mmol), K2CO3 (72 mg, 0.52 mmol) and 2-methylpenthyl bromide (60 ul, 0.42 mmol) in DMF (1 ml) was stirred at 55° C. for over night. After cool to rt, the mixture was diluted with EtOAc and washed with H2O and dried (MgSO4). Removal of the solvent provided the titled compound. MS (MH+).
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[C:5](F)=[CH:6][C:7]2[O:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=3)[C:9](=[O:22])[C:8]=2[CH:23]=1>>[Cl:3][C:4]1[C:5]([NH:2][CH3:1])=[CH:6][C:7]2[O:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=3)[C:9](=[O:22])[C:8]=2[CH:23]=1
Reactant: CN
Reactant: O=C1c2cc(Cl)c(F)cc2OCN1c1ccc([N+](=O)[O-])cc1
Product: CNc1cc2c(cc1Cl)C(=O)N(c1ccc([N+](=O)[O-])cc1)CO2
Yield: 81 %

Procedure:
Analogous to Ex. 3, methyl amine displacement was performed using 6-chloro-7-fluoro-3-(4-nitrophenyl)-2,3-dihydrobenzo[e][1,3]oxazin-4-one (0.21 g, 0.16 mmol) and methyl amine (0.3 ml, 2M solution in tetrahydrofuran) to give 0.134 mg (81%) of 6-chloro-7-(methylamino)-3-(4-nitrophenyl)-2,3-dihydrobenzo[e][1,3]oxazin-4-one. RP-HPLC: 2.38 min; ES-MS (M+H)+=334; 1H-NMR (DMSO-d6) δ (ppm): 3.1 (s, 3), 5.73 (s, 2), 6.2 (d, 1), 7.38 (d, 1), 7.61 (d, 2), 8.2 (d, 2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][N:10]([CH2:14][CH:15]=[CH2:16])[CH2:11][CH:12]=[CH2:13])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.Cl.[NH2:25][OH:26]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8](=[N:25][OH:26])[CH2:9][N:10]([CH2:14][CH:15]=[CH2:16])[CH2:11][CH:12]=[CH2:13])[CH:5]=[CH:6][CH:7]=1
Reactant: NO
Reactant: C=CCN(CC=C)CC(=O)c1cccc(Br)c1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: C=CCN(CC=C)CC(=NO)c1cccc(Br)c1
Temperature: 50 °C
Yield: 119.3 %

Procedure:
A solution of 1-(3-bromophenyl)-2-(diallylamino)ethanone (60 g, 204.7 mmol) in ethanol (720 mL) and pyridine (24.8 mL, 307 mmol) is stirred 15 minutes at 22° C. Hydroxylamine hydrochloride (17 g, 246 mmol) is added in portions to the solution over 1 hour. The reaction is warmed to 50° C. for 2 hours and then heated to 70° C. for 16 hours. The solvent is evaporated and the residue partitioned in water (300 mL) and methyl tert-butyl ether (300 mL). The organic layer is separated and washed with water (100 mL, 2×) and brine (100 mL). The organic layer is dried over sodium sulfate, filtered, and evaporated to dryness to give the title compound (75.5 g, 79%). ES/MS (m/e): 309 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10].[C:25]([N:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33])(=[O:27])[CH3:26]>>[C:25]([N:28]1[CH2:32][CH2:31][N:30]([C:2]2[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=2[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])[C:29]1=[O:33])(=[O:27])[CH3:26]
Reactant: CC(=O)N1CCNC1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3Br)CC2)c(C)c1
Product: CC(=O)N1CCN(c2cc(Cl)ccc2C(=O)N2CCN(c3ncc(C)cc3C)CC2)C1=O
Yield: 48.6 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 12 and using (2-bromo-4-chlorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (408.7 mg) described in Preparation Example 119 and 1-acetyl-2-imidazolidinone (128 mg), the title compound (221.5 mg) was obtained.
Reaction SMILES: C([Li])[CH2:2][CH2:3][CH3:4].[C:6]([Si:9]([CH:14]([CH3:16])[CH3:15])([CH:11](C)[CH3:12])Br)([CH3:8])=[CH2:7]>C1COCC1>[C:6]([Si:9]([C:11]#[CH:12])([CH:14]([CH3:16])[CH3:15])[CH:3]([CH3:4])[CH3:2])([CH3:8])=[CH2:7]
Reactant: C=C(C)[Si](Br)(C(C)C)C(C)C
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: C#C[Si](C(=C)C)(C(C)C)C(C)C
Temperature: 25 °C

Procedure:
The crude isopropenyldiisopropylbromosilane (10.6 g) was treated with 75 mmol of lithium acetylide. The lithium acetylide was formed by saturating an anhydrous THF solution (at −78° C., 200 mL) with acetylene gas that had been passed through a −78° C. cold trap to remove acetone. No further drying of the acetylene gas was undertaken. Once the solution was presumed to be saturated (after 1 hour of flushing the gas through), the solution was treated with n-butyllithium (30 mL, 2.5 M in hexanes, 75 mmol) in a careful dropwise manner so as to maintain the temperature very close to −78° C. After this addition was completed, the isopropenyldiisopropylbromosilane was added as a concentrated solution (˜5 M) in anhydrous THF dropwise to the reaction mixture. The temperature was maintained for an additional 1 hour, then allowed to gradually warm to room temperature. The reaction was quenched by the slow addition of a small amount of saturated ammonium chloride (about 5 mL) and additional water (50 mL). Pentane (100 mL) was added, and the organic layer was separated. The aqueous layer was extracted a second time with pentane (50 mL), and the organic layer separated. The organic layers were washed with water (3×50 mL), dried over MgSO4, filtered, and concentrated on the rotary evaporator. No further purification was performed. Analysis of the liquid product was performed by GC-MS Analysis Method 2. This showed that the area under the peak corresponding to the desired product, (isopropenyldiisopropylsilyl)acetylene with a molecular weight of 180, was 87.34% of the total integrated area indicating a high purity.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[C:10]([O:17][CH2:18][CH:19]1[O:21][CH2:20]1)[CH:9]=2.[C:29]([NH2:33])([CH3:32])([CH3:31])[CH3:30]>CO>[C:29]([NH:33][CH2:20][CH:19]([OH:21])[CH2:18][O:17][C:10]1[CH:9]=[C:8]2[C:13]([C:14](=[O:16])[CH:15]=[C:6]([C:5]3[CH:22]=[C:23]([O:27][CH3:28])[C:24]([O:25][CH3:26])=[C:3]([O:2][CH3:1])[CH:4]=3)[O:7]2)=[CH:12][CH:11]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: COc1cc(-c2cc(=O)c3ccc(OCC4CO4)cc3o2)cc(OC)c1OC
Reactant: CC(C)(C)N
Solvent: CO
Product: COc1cc(-c2cc(=O)c3ccc(OCC(O)CNC(C)(C)C)cc3o2)cc(OC)c1OC

Procedure:
3′,4′,5′-Trimethoxy-7-(2,3-epoxy-propoxy)-flavone, 31 (2.1 g, 5.47 mmol) and tert-butyl amine (1.75 mL, 16.4 mmol) in dry methanol (130 mL) were reacted in a similar manner to that described under 34 to afford 40. Yield 2.1 g (84%); mp 119-120° C.; MS (FAB) 458 (M++1); IR (KBr) 3403, 1631; 1H NMR (200 MHz, CDCl3) δ 8.11 (d, J=9.5 Hz, 1H), 7.10 (s, 2H), 7.02-6.99 (m, 2H), 6.70 (s, 1H), 4.14-4.11 (m, 3H), 3.96 (s, 6H), 3.93 (s, 3H), 2.86-2.81 (m, 2H), 1.14 (s, 9H). Analysis Calcd for C25H31NO7: C, 65.63; H, 6.83; N, 3.06. Found: C, 65.47; H, 6.77; N, 3.12.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:25][N:26]([CH:28]=O)[CH3:27]>>[C:25]1([N:26]2[CH2:28][CH2:6][N:5]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]4[CH:18]=[C:17]5[C:12]([CH:13]=[CH:14][CH:15]=[N:16]5)=[CH:11][CH:10]=4)[CH:3]=3)[CH2:4][CH2:27]2)[CH:17]=[CH:18][CH:9]=[CH:10][CH:11]=1
Reactant: Clc1cc(Nc2ccc3cccnc3c2)ncn1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc(N2CCN(c3cc(Nc4ccc5cccnc5c4)ncn3)CC2)cc1

Procedure:
This compound could be prepared from (6-chloro-pyrimidin-4-yl)-quinolin-7-yl-amine and I-phenyl-piperazine in the presence of K2CO3 and DMF.
Reaction SMILES: [NH2:1][P:2]([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])[OH:3].[CH2:13]([O:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(OCC)C.Cl>O>[CH2:13]([O:20][C:21]([NH:1][P:2]([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:3])[OH:4])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NP(=O)(O)CCc1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: O=C(NP(=O)(O)CCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
Compound 2 (1.1 g, 6 mmole) is dissolved in 10 ml of water and then the pH of this solution is adjusted to 9.5 with the aid of a 4N soda solution. To this mixture cooled in an icebath is gently added benzylchloroformate (1.2 ml, 7.5 mmole), whilst maintaining the pH of the reaction at 9.5 by successive soda additions. Stirring of the reaction mixture is maintained at 0° C. for 30 min. and then for 1 h at ambient temperature. After diethyl ether treatment, the mixture is cooled, and then acidified by the addition of hydrochloric acid. The product which precipitates is filtered, washed with cold water and dried. The expected compound 3 is obtained with a 76% yield (1.5 g), RF(1)=0.57, RF(2)=0.76, m.p. 110° C.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[C:11](O)(=O)[CH3:12]>>[CH3:11][C:12]1[NH:10][C:1](=[O:9])[C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:4]=1
Reactant: NC(=O)c1ccccc1N
Reactant: CC(=O)O
Product: Cc1nc2ccccc2c(=O)[nH]1

Procedure:
A solution of anthranilamide (13.6 g; 100 mmol) in acetic acid (100 ml) was refluxed for 60 h. The reaction mixture was evaporated to dryness, suspended in H2O, filtered and washed thoroughly with NaHCO3 until the filtrate had a pH of 8–8.5.
Reaction SMILES: [N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:23][C:24]1[C:29]2[N:30]=[C:31]([NH2:33])[S:32][C:28]=2[CH:27]=[CH:26][CH:25]=1>>[N:1]1([S:11]([C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH:33][C:31]3[S:32][C:28]4[CH:27]=[CH:26][CH:25]=[C:24]([CH3:23])[C:29]=4[N:30]=3)=[O:20])=[CH:21][CH:22]=2)(=[O:12])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cccc2sc(N)nc12
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1
Product: Cc1cccc2sc(NC(=O)c3ccc(S(=O)(=O)N4CCCc5ccccc54)cc3)nc12

Procedure:
4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32 mmol) was treated with 4-methylbenzo[d]thiazol-2-amine (44 mg, 0.24 mmol) using method B. The residue was purified using flash chromatography eluting with 0-30% EtOAc in hexanes to give 4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(4-methylbenzo[d]thiazol-2-yl)benzamide as a white solid. Yield: 24 mg (21%). 1H-NMR: 8.22 (d, J=8.5 Hz, 2H), 7.84 (d, J=8.0 Hz, 1H), 7.76 (d, J=8.5 Hz, 2H), 7.62 (d, J=8.5 h, 1H), 7.31-7.08 (m, 5H), 3.85-3.79 (m, 2H), 2.62 (s, 3H), 2.45 (t, J=7.0 Hz, 2H), 1.66-1.58 (m, 2H).
Reaction SMILES: CS(O[CH:6]([CH2:21][CH3:22])[CH2:7][CH2:8][CH:9](OS(C)(=O)=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=O)=O.[NH2:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([Cl:32])[CH:25]=1>C1(C)C=CC=CC=1>[Cl:32][C:26]1[CH:25]=[C:24]([N:23]2[CH:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:8][CH2:7][CH:6]2[CH2:21][CH3:22])[CH:31]=[CH:30][C:27]=1[C:28]#[N:29]
Reactant: N#Cc1ccc(N)cc1Cl
Reactant: CCC(CCC(OS(C)(=O)=O)c1ccccc1)OS(C)(=O)=O
Solvent: Cc1ccccc1
Product: CCC1CCC(c2ccccc2)N1c1ccc(C#N)c(Cl)c1

Procedure:
Dissolve methanesulfonic acid 4-methanesulfonyloxy-1-phenyl-hexyl ester (1.01 g, 2.88 mmol) in toluene (20 mL) in a reaction tube. Add 4-amino-2-chlorobenzonitrile (1.10 g, 7.2 mmol), purge with nitrogen and cap. Heat the reaction in a 120° C. oil bath for 17 h. Cool, concentrate, and purify by silica gel chromatography using 5-30% EtOAc/hexanes to obtain 0.22 g (25%0 of the title compound as a clear oil. MS (ESI+): 311 (M+1)+, 309 (M−1)−.
Reaction SMILES: [CH2:1]([CH:4]1[NH:8][S:7](=[O:10])(=[O:9])[NH:6][C:5]1=[O:11])[CH2:2][CH3:3].[C:12]1([S:18][CH2:19]Cl)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:12]1([S:18][CH2:19][N:6]2[C:5](=[O:11])[CH:4]([CH2:1][CH2:2][CH3:3])[NH:8][S:7]2(=[O:9])=[O:10])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCSc1ccccc1
Reactant: CCCC1NS(=O)(=O)NC1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CCCC1NS(=O)(=O)N(CSc2ccccc2)C1=O
Yield: 62.6 %

Procedure:
To a mixture of 4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (5.1 g, 28.65 mmol)suspended in 210 ml of toluene was added phenylthiomethyl chloride (4.93 g, 31.49 mmol) and tetrabutylammonium bromide (0.92 g, 2.86 mmol). The resulting mixture was refluxed for 18 hours, cooled, filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography to afford 5.39 g (63%) of 2-phenylthiomethyl-4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula VI: R1 =H; R2 =propyl; R3 =H).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([NH:6][C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=2[N+:14]([O-:16])=[O:15])[CH2:3]1.C=O.[C:19](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C.C(OCC)(=O)C>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([NH:6][CH:4]2[CH2:5][N:2]([CH3:19])[CH2:3]2)=[C:8]([N+:14]([O-:16])=[O:15])[CH:9]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1NC1CNC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CN1CC(Nc2ccc(Br)cc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.2 %

Procedure:
To a mixture of azetidin-3-yl-(4-bromo-2-nitro-phenyl)-amine, hydrochloride (27.7 mmol, 8.54 g) in acetonitrile (100 mL) and 37% aqueous formaldehyde (83.0 mmol, 6.28 mL, 3.00 equiv.) at 0° C. add sodium triacetoxyborohydride (88.6 mmol, 18.8 g) slowly. Stir at room temperature under nitrogen overnight. Remove volatiles under reduced pressure. Dilute with ethyl acetate, wash with 10% aqueous sodium bicarbonate twice, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 8.5 g of an orange solid. Purify on a 120 g silica column eluting with 5% methanol in dichloromethane to obtain the title compound (5.92 g, 75%). LC-MS m/z (79Br/81Br) 286.0/288.0 [M+H]+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[CH:33][CH:34]=[C:35]([Cl:38])[CH:36]=5)[C:31]([Cl:39])=[CH:30][C:29]4=[O:40])[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.Cl.C(OCC)(=O)C>C(OCC)(=O)C>[ClH:38].[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][CH:20]3[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[CH:33][CH:34]=[C:35]([Cl:38])[CH:36]=5)[C:31]([Cl:39])=[CH:30][C:29]4=[O:40])[CH2:24][CH2:25]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cc(Cl)c3ccc(Cl)cc32)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=c1cc(Cl)c2ccc(Cl)cc2n1CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Yield: 133.7 %

Procedure:
To 1 mL of an ethyl acetate solution containing 104 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(4,7-dichloro-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 2 mL of 4 mol/L hydrogen chloride/ethyl acetate was added, and stirred at room temperature. The resulting solid was filtered to give 62 mg of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-4,7-dichloroquinolin-2(1H)-one hydrochloride as a pale yellow solid.
Reaction SMILES: [H-].[Na+].CI.[CH3:5]N(C=O)C.[CH2:10]([O:17][C@@H:18]([CH3:31])[C@@H:19]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:20]([OH:22])=[O:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH2:10]([O:17][C@@H:18]([CH3:31])[C@@H:19]([N:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH3:5])[C:20]([OH:22])=[O:21])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C[C@H](OCc1ccccc1)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: C[C@H](OCc1ccccc1)[C@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 67 %

Procedure:
In a round bottom flask, under argon atmosphere, commercially available (2R,3S)-3-benzyloxy-2-(tert-butoxycarbonyl-amino)-butanoic acid was dissolved in dry THF (15 mL). Subsequently at 0° C., NaH (60% dispersion in mineral oil, 0.21 g, 5.33 mmol) was added in one portion. The reaction mixture was left to stir at the same temperature for 10 min and then MeI (0.95 mL, 15.22 mmol) followed by DMF (0.75 mL) were sequentially added. The reaction was left for 2.0 h at 0° C. and for 15 h at rt, then quenched with H2O (15 mL), diluted with EtOAc (30 mL) and acidified to pH 2 by dropwise addition of 2.0 N HCl aqueous solution. The organic layer was separated and the aqueous phase was back-extracted with EtOAc (2×30 mL). The organic phase was dried over Na2SO4, filtered and concentrated to dryness. The crude mixture was purified by column chromatography using a Teledyne ISCO apparatus eluting with Cy:TBME (60:40) to give the title compound (1.1 g, 67%), as a mixture of two rotamers (2:1 ratio), as a colorless oil. 1H NMR (DMSO-d6) δ 1.13-1.20 (m, 6H), 1.36 (s, 9H, minor rotamer), 1.41 (s, 9H, major rotamer), 2.84 (s, 3H, minor rotamer), 2.87 (s, 3H, major rotamer), 4.13-4.24 (m, 2H), 4.34-4.40 (m, 2H), 4.49 (d, J=5.5 Hz, 1H, minor rotamer), 4.57-4.62 (m, 2H), 4.71 (d, J=5.2 Hz, 1H, major rotamer), 7.23-7.35 (m, 10H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:14](OC(=O)C)(=[O:16])[CH3:15]>O1CCCC1>[N+:1]([C:4]1[CH:5]=[C:6]([S:10]([NH:13][C:14](=[O:16])[CH3:15])(=[O:11])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Solvent: C1CCOC1
Product: CC(=O)NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Reaction time: 0.5 h

Procedure:
A solution of 3-nitrobenzenesulfonamide (615 mg) in 10 ml of dry tetrahydrofuran was cooled to 0° C. and mixed with 0.34 ml of acetic anhydride and 166 mg of 4-N,N-dimethylaminopyridine. The reaction mixture was stirred for 30 minutes, quenched with 10% citric acid solution, and diluted with ethyl acetate. The reaction mixture was extracted with ethyl acetate. The organic extracts were washed with brine, dried, concentrated in vacuo to yield 946 mg of the title compound in pure form.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@:11]([OH:19])([CH2:13]OS(C)(=O)=O)[CH2:10][C@H:9]1[C:20](=[O:31])[NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[F:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:32]=[N+:33]=[N-:34].[Na+]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@:11]([CH2:13][N:32]=[N+:33]=[N-:34])([OH:19])[CH2:10][C@H:9]1[C:20](=[O:31])[NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[F:30])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1C[C@](O)(COS(C)(=O)=O)C[C@H]1C(=O)NCc1cccc(Cl)c1F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@](O)(CN=[N+]=[N-])C[C@H]1C(=O)NCc1cccc(Cl)c1F
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of (2S,4S)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-hydroxy-4-methanesulfonyloxy methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (580 mg, 1.21 mmol) (prepared as described Scheme B13) in DMF (20 mL) was added sodium azide (392 mL, 6.03 mmol) and the solution was stirred for 16 h at 80° C. The reaction mixture was diluted with EtOAc, washed with a saturated aqueous solution of NaHCO3 (3 times). The organic layers were dried (Na2SO4), filtered and concentrated. The crude material was purified by flash column chromatography on silica gel (c-hexane/EtOAc 1:1) to give the desired material. MS (LC/MS): 430.1/432.1 [M+H]+, 374.1 [MH−tBu]+, 332 [MH−Boc]+; tR (HPLC conditions f): 2.22 min.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21]C(=O)C(F)(F)F)=[CH:17][C:16]=3[CH2:28][C:29]([O:31]C)=[O:30])(=[O:14])=[O:13])[CH:9]=[CH:10][C:5]=2[CH2:4][O:3]1.[OH-].[Na+]>CO.O>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([S:12](=[O:13])(=[O:14])[NH:11][C:8]2[CH:9]=[CH:10][C:5]3[CH2:4][O:3][B:2]([OH:1])[C:6]=3[CH:7]=2)=[C:16]([CH2:28][C:29]([OH:31])=[O:30])[CH:17]=1
Reactant: COC(=O)Cc1cc(NC(=O)C(F)(F)F)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.3 %

Procedure:
To a stirred solution of methyl 2-(2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-(2,2,2-trifluoroacetamido)phenyl)acetate (134 mg, 0.28 mmol) in 2 mL of MeOH and water (1:1, v/v) was added NaOH (34 mg, 0.85 mmol). The reaction mixture was stirred at room temperature for 16 hours. After MeOH was removed in vacuo, the residue was dissolved in water and acidified with 0.5N HCl. The mixture was extracted with ethyl acetate three times, and washed with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The crude residue was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give the title compound as an off-white solid (51 mg, yield 50%). MS calcd for (C15H15BN2O6S): 362.1. MS found (ESI negative): (M−H)−=361.1. 1H NMR (DMSO-d6) δ (ppm): 9.78 (s, 1H), 9.10 (bs, 1H), 7.41 (d, J=8.4 Hz, 1H), 7.35 (s, 1H), 7.14 (d, J=8.4 Hz, 1H), 7.04 (d, J=8.0 Hz, 1H), 6.34 (s, 1H), 6.32 (d, J=8.8 Hz, 1H), 4.79 (s, 2H), 3.73 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)Br.[CH2:13]([N:15](CC)[CH2:16]C)C.Cl.CNC>O1CCCC1>[CH3:1][O:2][C:3](=[O:12])[CH:4]([N:15]([CH3:16])[CH3:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCN(CC)CC
Reactant: COC(=O)C(Br)c1ccccc1
Agent: CNC
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)C(c1ccccc1)N(C)C
Temperature: 60 °C

Procedure:
To a solution of α-bromophenylacetic acid methyl ester, 5.0 g (22.0 mmol) in 120 mL of tetrahydrofuran was added 12 mL (88.0 mmol) of triethylamine and 5.4 g (66.0 mmol) of dimethylamine hydrochloride. The reaction mixture was heated at 60° C. in a sealed tube for three hours, cooled to ambient temperature and concentrated to dryness. The residue was partitioned between 20% isopropanol/chloroform and water. The mixture was washed with saturated sodium bicarbonate, washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography using a methanol/chloroform gradient as eluent and concentrated to dryness to yield 1.86 g (44%) of the desired isomer as a yellow oil. MS (ion spray) 193.9 (M+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([CH2:23][N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: BrCC1CCCCC1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(CC3CCCCC3)CC1)O2

Procedure:
Compound 136 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (bromomethyl)cyclohexane and conditions outlined in procedure V. LCMS: 398 [M+H]; Rt=1.03 min.