Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl.[CH3:11][O:12][C:13](=[O:17])[C@H:14]([NH2:16])[CH3:15].C(Cl)CCl.[C:22]([NH:32][C@H:33]([C:36](O)=[O:37])[CH2:34][OH:35])([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>C(Cl)Cl>[CH3:11][O:12][C:13](=[O:17])[C@H:14]([NH:16][C:34](=[O:35])[C@@H:33]([NH:32][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[CH2:36][OH:37])[CH3:15]
Reactant: COC(=O)[C@@H](C)N
Reactant: O=C(N[C@@H](CO)C(=O)O)OCc1ccccc1
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](C)NC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.1 %

Procedure:
Diisopropylethylamine (375 mL) was added dropwise to a cooled mixture of (R)-2-amino-propionic acid methyl ester hydrochloride (100 g, 0.716 mol), EDC (165 g, 0.86 mol), carbobenzyloxy-L-serine (171.4 g, 0.716 mol) and DCM (3.6 L). The resulting mixture was stirred under nitrogen at ambient temperature for 16 h. After removing solvent in vacuo at 40° C., the residue was diluted with saturated sodium carbonate (1 L), water (1 L) and extracted with EtOAc (2 L, 2×1 L). The combined organic phases were washed with 2 M hydrochloric acid (1 L), saturated brine solution (1 L), dried over magnesium sulfate and concentrated in vacuo at 40° C., to give the title compound (172 g) as a colourless solid. 1H NMR (Me-d3-OD): 7.44-7.28 (6H, m), 5.13 (2H, s), 4.46 (1H, d), 4.43 (1H, d), 4.25 (1H, t), 3.82-3.68 (5H, m), 1.39 (3H, d).
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CCCCCC.[C:33]([C:37]1[CH:38]=[C:39]([CH3:55])[C:40](=[C:42]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:41]=1)([CH3:36])([CH3:35])[CH3:34].Cl>C(OCC)C>[C:33]([C:37]1[CH:38]=[C:39]([CH3:55])[CH:40]([C:42]([C:10]2[C:9]3[CH2:8][C:7]4[C:15](=[CH:16][CH:17]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=4)[C:14]=3[CH:13]=[CH:12][C:11]=2[C:18]([CH3:21])([CH3:20])[CH3:19])([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH:41]=1)([CH3:34])([CH3:35])[CH3:36]
Reactant: CC(C)(C)c1ccc2c(c1)Cc1cc(C(C)(C)C)ccc1-2
Reactant: CC1=CC(C(C)(C)C)=CC1=C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1=CC(C(C)(C)C)=CC1C(c1ccccc1)(c1ccccc1)c1c(C(C)(C)C)ccc2c1Cc1cc(C(C)(C)C)ccc1-2
Temperature: 25 °C

Procedure:
In a 200 ml three-necked flask equipped with a magnetic stirrer chip and three-way cock thoroughly purged with nitrogen, 2.53 g of 2,7-di-tert-butyl-fluorene (9.10 mmol) was dissolved in 70 ml of dehydrated diethyl ether in a nitrogen atmosphere. To the solution, 6.4 ml of a n-butyl lithium/hexane solution (1.56M: 9.98 mmol) was gradually added dropwise in an ice bath and stirred at room temperature over night. To the reaction solution, a solution prepared by dissolving 3.01 g of 3-tert-butyl-1-methyl-6,6-diphenyl fulvene (10.0 mmol) in 40 ml of dehydrated diethyl ether was added and stirred with refluxing for 7 days. The reaction mixture was added to 100 ml of a hydrochloric acid aqueous solution (1N) and thereafter diethyl ether was added to separate an organic phase. The organic phase was washed with a saturated sodium bicarbonate aqueous solution and saturated brine. The organic phase was dried with anhydrous magnesium sulfate, thereafter the drying agent was filtered off and the solvent was distilled off from the filtrate under reduced pressure to give a reddish-brown liquid. The liquid was purified by a column chromatography using 180 g of silica gel (developing solvent: n-hexane) and the developing solvent was distilled off under reduced pressure. The remainder was re-crystallized using methanol and dried under reduced pressure, and thereby the aimed compound was obtained in an amount of 1.65 g (2.85 mmol) as a pale yellow solid (yield: 31%).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C@H:15]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)[C:16]([N:18]1[CH2:21][C:20]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19]1)=[O:17])(C)(C)C>ClCCl>[NH2:14][C@H:15]([CH2:33][C:34]1[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=1)[C:16]([N:18]1[CH2:21][C:20]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19]1)=[O:17]
Reactant: CCCCCC1(C2CCCCC2)CN(C(=O)[C@@H](Cc2ccc(OC)cc2)NC(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCC1(C2CCCCC2)CN(C(=O)[C@H](N)Cc2ccc(OC)cc2)C1
Reaction time: 2 h
Yield: 85.4 %

Procedure:
2.5 ml of trifluoroacetic acid are added, at 0° C., to 0.48 g (0.99 mmol) of tert-butyl[(R)-2-(3-cyclohexyl-3-pentylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]carbamate dissolved in 10 ml of dichloromethane. After 2 hours, the solvents are evaporated off. The residue is taken up in dichloromethane and washed with 1N sodium hydroxide. The organic phases are combined, dried over MgSO4, filtered and concentrated. 327 mg of (R)-2-amino-1-(3-cyclohexyl-3-pentylazetidin-1-yl)-3-(4-methoxyphenyl)propan-1-one are obtained with a yield of 86%.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br-:19]>[Al+3].[Cl-].[Cl-].[Cl-]>[Br:19][CH:8]([CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[O:10]
Reactant: [Br-]
Reactant: COc1ccc(C(=O)CCC2CCCCC2)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)C(Br)CC2CCCCC2)cc1
Yield: 96.6 %

Procedure:
A procedure similar to step 3 of Example 1 was used. 3-cyclohexyl-1-(4-methoxy-phenyl)-propan-1-one prepared in the step 2 and bromide were used as starting materials, and anhydrous AlCl3 was used as catalyst, a colorless oily product was obtained in a yield of 96.6%. 1H-NMR (CDCl3, 400 MHz) δ: 0.85˜1.30 (5H, m), 1.45˜1.85 (6H, m), 2.04 (2H, t, J=8.08 Hz, CH2CHBr), 3.89 (3H, s, OCH3), 5.24 (1H, t, J=7.48 Hz, CHBr), 6.96 (2H, d, J=9.16 Hz, ArH), 8.02 (2H, d, J=8.68 Hz, ArH); ESI-MS m/e (%): 346.9 (M+Na, 100), 327.3 (M+1, 71).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.I[CH:10]1[CH2:13][O:12][CH2:11]1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]([CH:10]2[CH2:13][O:12][CH2:11]2)[C:4](=[O:8])[CH:3]=1
Reactant: O=c1cc(Br)cc[nH]1
Reactant: IC1COC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1cc(Br)ccn1C1COC1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 4-bromopyridin-2(1H)-one (173 mg), 3-iodooxetane (184 mg), and K2CO3 (414 mg) in N,N-dimethylformamide (15 mL) was stirred at 100° C. for 2 h. The reaction mixture was stirred at room temperature for one more hour and then quenched with H2O (30 mL). The resulting mixture was extracted with ethyl acetate (3×20 mL) and the combined organic phase was dried (Na2SO4) and concentrated to give the crude product, which was purified by preparative TLC to give the title compound. Yield: 68 mg (30% of theory).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([CH3:24])[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[ClH:32]>ClCCl.O1CCOCC1>[ClH:32].[CH3:24][C:17]1[N:16]=[C:15]([NH:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:20]=[CH:19][C:18]=1[N+:21]([O-:23])=[O:22].[ClH:32]
Reactant: Cc1nc(NC2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(NC2CCNCC2)ccc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
4-(6-Methyl-5-nitro-pyridin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (590 mg; 1.75 mmol, prepared in accordance with Example 99) is dissolved in dichloromethane (10 mL) and trifluoroacetic acid (2 mL) is added under stirring. After 30 minutes, the reaction mixture is concentrated under reduced pressure and the residue obtained is co-evaporated with dichloromethane (2×10 mL). The product is then diluted in dioxane (6 mL) and a 4N solution of hydrochloric acid in dioxane (3 mL) is added. The precipitate formed is filtered and dried under high vacuum at 40° C. to afford the desired product as hydrochloride (477 mg; 1.75 mmol).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:38]=[CH:39][CH:40]=1)[C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[C:20]([O:22][CH:23]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:45]>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:38]=[CH:39][CH:40]=1)[C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[C:20]1[O:22][C:23]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:45]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: O=C(c1ccccc1)C(OC(=O)C1CCCCN1C(=O)c1cccc(OCc2ccccc2)c1)c1ccccc1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: O=C(c1cccc(OCc2ccccc2)c1)N1CCCCC1c1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 25 °C
Yield: 37.4 %

Procedure:
A mixture of 2-oxo-1,2-diphenylethyl 1-(3-benzyloxybenzoyl)-2-piperidinecarboxylate (288 mg) and ammonium acetate (427 mg) in acetic acid (1.4 ml) was stirred under reflux for 3 hours, cooled to room temperature, and partitioned between ethyl acetate and aqueous NaHCO3. The organic layer was washed with aqueous NaHCO3 (twice) and brine, dried over MgSO4, and evaporated in vacuo. The residue was chromatographed over silica gel to afford 1-(3-benzyloxybenzoyl)-2-(4,5-diphenyl-2-oxazolyl)piperidine (104 mg) as amorphous powder. (+) APCI-MS (m/z): 515 (M+ +1) IR (Nujol): 1630 cm-1NMR (CDCl3, δ): 1.45-2.05 (6H, m), 2.4-3.75 (2H, m), 4.7-5.25 (3H, m), 7.01-7.37 (15H, m), 7.57-7.67 (4H, m)
Reaction SMILES: Cl[C:2]1[CH:19]=[C:18](F)[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[N:12][NH:13]2)=[CH:9][CH:8]=1)=[O:5].[NH4+].[OH-].[NH2:26]C1C=C(F)C([N+]([O-])=O)=CC=1C(NC1C=C2C(C=NN2)=CC=1)=O.[CH3:49][CH:50]1[CH2:55][NH:54][CH2:53][CH:52]([CH3:56])[NH:51]1>O1CCOCC1>[NH2:26][C:18]1[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][C:3]([C:4]([NH:6][C:7]2[CH:15]=[C:14]3[C:10]([CH:11]=[N:12][NH:13]3)=[CH:9][CH:8]=2)=[O:5])=[C:2]([N:54]2[CH2:53][CH:52]([CH3:56])[NH:51][CH:50]([CH3:49])[CH2:55]2)[CH:19]=1
Reactant: Nc1cc(F)c([N+](=O)[O-])cc1C(=O)Nc1ccc2cn[nH]c2c1
Reactant: CC1CNCC(C)N1
Reactant: O=C(Nc1ccc2cn[nH]c2c1)c1cc([N+](=O)[O-])c(F)cc1Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC1CN(c2cc(N)c([N+](=O)[O-])cc2C(=O)Nc2ccc3cn[nH]c3c2)CC(C)N1
Temperature: 25 °C

Procedure:
A solution of 2-chloro-4-fluoro-N-(1H-indazol-6-yl)-5-nitrobenzamide (1 mmol) in dioxane (2 mL) was reacted with aqueous NH4OH using the conditions described in Example 115. After the formation of 2-amino-4-fluoro-N-(1H-indazol-6-yl)-5-nitrobenzamide was complete, the reaction mixture was charged with 2,6-dimethylpiperazine (6 mmol). The contents were heated at reflux for 10 h, and the reaction mixture was cooled to RT. The contents were poured onto ice cold water with vigorous stirring. The solid formed was collected by filtration, washed with water, and dried in vacuo to provide the product, 4-amino-2-(3,5-dimethyl-piperazin-1-yl)-N-(1H-indazol-6-yl)-5-nitrobenzamide as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[O:14]=[C:15]1[CH2:19][CH2:18][CH2:17][N:16]1[CH2:20][C:21](OC)=[O:22].[O-]CC.[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([C:21](=[O:22])[CH2:20][N:16]2[CH2:17][CH2:18][CH2:19][C:15]2=[O:14])[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: COC(=O)CN1CCCC1=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C(C#N)C(=O)CN2CCCC2=O)cc1OC
Temperature: 25 °C
Yield: 25.5 %

Procedure:
To a mixture of [3,4-bis(methyloxy)phenyl]acetonitrile (1.0 g, 5.5 mmol) and methyl (2-oxopyrrolidin-1-yl)acetate (1.0 g, 7.0 mmol) in ethanol (4 mL) was added a sodium ethoxide solution (21%, 4.2 mL, 11 mmol), and the resulting mixture was heated at reflux for 18 hours. After cooling to room temperature, it was poured into a mixture of ice-water (50 mL). This aqueous mixture was washed with dichloromethane (3×20 mL) then acidified to pH 1. The acidified mixture was extracted with ethyl acetate (3×30 mL). The combined extract was washed with aqueous sodium bicarbonate solution, brine, dried over sodium sulfate, filtered and concentrated to give 2-[3,4-bis(methyloxy)phenyl]-3-oxo-4-(2-oxopyrrolidin-1-yl)butanenitrile as a brown oil (0.43 g, 1.4 mmol, 25% yield), MS (EI) for C16H18N2O4: 303 (MH+).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH3:11].C([Li])(C)(C)C.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.P(=O)(O)(O)O>C1COCC1.CCCCC>[CH3:11][N:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:2]([B:17]([OH:22])[OH:18])[C:3]=2[CH:4]=[CH:5]1
Reactant: Cn1ccc2c(Br)cccc21
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: O=P(O)(O)O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: Cn1ccc2c(B(O)O)cccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of Intermediate 67 (4.90 g) in anhydrous THF (30 ml) was cooled to −78° C. under argon gas atmosphere, then added dropwise with a 1.62 M solution of t-butyllithium in pentane (28.8 ml) over 30 minutes, and stirred for 30 minutes. This reaction mixture was added dropwise with (iPrO)3B (10.77 ml) over 10 minutes, stirred for 1 hour, then warmed to room temperature, and further stirred for 2.5 hours. The reaction mixture was poured into 1.2 N aqueous phosphoric acid (250 ml) containing ice, and extracted with diethyl ether (200 ml×3). The organic layer was extracted with 0.4 N aqueous sodium hydroxide (150 ml×3), and the aqueous layer was made acidic with 5 N hydrochloric acid under ice cooling, and extracted with diethyl ether (200 ml×3) again. The organic layer was washed with saturated brine and dried, and then the solvent was evaporated under reduced pressure. The residue was washed with hexane to obtain the title compound (Intermediate 68, 3.17 g).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[CH:5]=[O:6].S(=O)(=O)([OH:16])N.[O-]Cl=O.[Na+]>CC#N.O>[CH3:13][O:12][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([I:1])[C:9]=1[O:10][CH3:11])[C:5]([OH:16])=[O:6]
Reactant: COc1cc(C=O)cc(I)c1OC
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC#N
Product: COc1cc(C(=O)O)cc(I)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
To a stirred solution of 3-iodo-4,5-dimethoxybenzaldehyde (25.0 g, 85.6 mmol) in CH3CN (800 mL) at room temperature, was added a solution of sulfamic acid (10.65 g, 109 mmol) in H2O (135 mL). To this was added, dropwise, a solution of NaClO2 (12.65 g, 112 mmol) in H2O (135 mL) over 20 min period. After stirring for a further 30 min at room temperature, the solvent was removed in vacuo. The reaction was diluted with 1.0 M aqueous HCl (700 mL) and extracted with EtOAc (3×300 mL). The combined organic layers were washed with brine (600 mL), dried over Na2SO4 and concentrated in vacuo to give 3,4-dimethoxy-5-iodobenzoic acid (26 g). The product was used without further purification.
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=O)[CH3:5].COC(OC)[N:11]([CH3:13])C.O1CCCC1.Cl.Cl.[CH2:23]([NH:30]N)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O.C(OCC)(=O)C>[CH2:23]([N:30]1[C:4]([CH3:5])=[C:3]([C:2](=[O:7])[CH3:1])[CH:13]=[N:11]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(=O)CC(C)=O
Reactant: NNCc1ccccc1
Reactant: COC(OC)N(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)c1cnn(Cc2ccccc2)c1C
Temperature: 80 °C
Reaction time: 1 h
Yield: 63.2 %

Procedure:
A mixture of pentane-2,4-dione (10.01 g) and 1,1-dimethoxy-N,N-dimethylmethanamine (12.51 g) was stirred at 80° C. for 1 hr. Tetrahydrofuran (20 mL) was added to the reaction mixture, benzylhydrazine dihydrochloride (21.46 g) was added by small portions under ice-cooling, and the mixture was stirred at 60° C. for 30 min. The reaction mixture was allowed to cool to room temperature, ethyl acetate (100 mL) and water (100 mL) were added, and the separated aqueous layer was extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with brine (20 mL) and dried over anhydrous magnesium sulfate. Insoluble material was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (13.53 g) as a colorless oil.
Reaction SMILES: C(OC(N1CCC2C(SC(=O)N(C)C)=C([Cl:19])C=CC=2CC1)=O)(C)(C)C.C(OC([N:33]1[CH2:39][CH2:38][C:37]2[C:40]([S:46][C:47](=O)N(C)C)=[C:41]([Cl:45])[CH:42]=[C:43](Cl)[C:36]=2[CH2:35][CH2:34]1)=O)(C)(C)C.BrC[C:54]1[CH:63]=[CH:62][CH:61]=[CH:60][C:55]=1[C:56]([O:58][CH3:59])=[O:57]>>[ClH:19].[Cl:45][C:41]1[CH:42]=[CH:43][C:36]2[CH2:35][CH2:34][NH:33][CH2:39][CH2:38][C:37]=2[C:40]=1[S:46][CH2:47][C:54]1[CH:63]=[CH:62][CH:61]=[CH:60][C:55]=1[C:56]([O:58][CH3:59])=[O:57]
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: CN(C)C(=O)Sc1c(Cl)cc(Cl)c2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: COC(=O)c1ccccc1CBr
Product: COC(=O)c1ccccc1CSc1c(Cl)ccc2c1CCNCC2
Product: Cl

Procedure:
Use a method similar to the Example 347, using the 4:1 mixture of 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 3-tert-butoxycarbonyl-7,9-dichloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-benzo[d]azepine with methyl 2-(bromomethyl)benzoate. Use a method similar to the General Procedure 1-4 and purify by preparative reverse phase HPLC (Column: Xterra Prep RP18 19×250 mm; solvent A: 10 mM aqueous ammonium carbonate, solvent B: acetonitrile; 30-100% B over 20 minutes; flow rate 25 mL/min). Use a method similar to the General Procedure 2-2, to give the title compound as a white solid. MS (ES+) m/z: 362 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10]([C@:12]2([CH3:18])[CH2:16][CH2:15][CH2:14][N:13]2[CH3:17])=O)=[N:6][CH:7]=1.CCN(CC)CC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.ClC(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[CH3:17][N:13]1[CH2:14][CH2:15][CH2:16][C@:12]1([C:10]1[N:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]2=[N:8][N:9]=1)[CH3:18]
Reactant: CN1CCC[C@@]1(C)C(=O)NNc1ccc(F)cn1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCC[C@@]1(C)c1nnc2ccc(F)cn12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 48.5 %

Procedure:
To a solution of Intermediate 47a (668 mg, 2.64 mmol), Et3N (1.5 mL, 11 mmol) and Ph3P (1.4 g, 5.3 mmol) in THF (20 mL) at 0° C. was added hexachloroethane (1.25 g, 5.29 mmol). The mixture was stirred at 0° C. for 10 min, then at RT for 1 h. The mixture was partitioned between EtOAc/water and the aqueous extracted with EtOAc. The combined organics were dried (Na2SO4), filtered and concentrated in vacuo. Purification by FCC, using 0-10% MeOH in EtOAc, gave the title compound as a pale brown solid (300 mg, 49%). LCMS (Method 4): Rt 0.39, m/z 235 [MH+].
Reaction SMILES: [CH2:1]([C:8]([NH:10][C@@H:11]([CH3:14])[CH2:12][OH:13])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH2:1]([C:8]([NH:10][C@@H:11]([CH3:14])[CH:12]=[O:13])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](CO)NC(=O)Cc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: C[C@@H](C=O)NC(=O)Cc1ccccc1
Reaction time: 2 h

Procedure:
(S)-2-(benzylcarbonylamino)-propanol (5.00 g, 23.9 mmol) was dissolved in CH2Cl2 (200 mL) and treated with Dess-Martin periodinane (12.26 g, 1.1 eq). The mixture was stirred for 2 hours, then quenched with sodium thiosulphate, and the solvent removed in vacuo. The residue was then separated between sodium hydroxide (1M, 500 mL) and ethyl acetate (500 mL). The organics were washed with brine, dried (MgSO4) and evaporated in vacuo to yield a clear oil which was used immediately in the next step without further purification.
Reaction SMILES: [O:1]=[S:2]1(=[O:33])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[N:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[C:15]([O:22]S(C2C=CC(C)=CC=2)(=O)=O)=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2.C[O-].[Na+].C(O)(=O)C.O>CN(C=O)C>[O:33]=[S:2]1(=[O:1])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[N:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[C:15]([OH:22])=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2
Reactant: COC(=O)c1nc(N2CCCCS2(=O)=O)c2cccnc2c1OS(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1nc(N2CCCCS2(=O)=O)c2cccnc2c1O
Reaction time: 1 h

Procedure:
To a solution of methyl 5-(1,1-dioxido-1,2-thiazinan-2-yl)-8-{[(4-methylphenyl)sulfonyl]oxy}-1,6-naphthyridine-7-carboxylate (6.0 g, 12.2 mmol) in DMF (50 mL) under nitrogen at zero degrees C. was added sodium methoxide (49.40 mL, 24.70 mmol, 0.5 M in Methanol). The cold solution was allowed to stir for one hour. Acetic acid (1.64 mL, 27.4 mmol) was added followed by water to precipitate the product. The mixture was allowed to stand for one hour. The crude reaction was filtered and the solids were washed with 1:1 methanol:water and dried in vacuo to afford the desired product.
Reaction SMILES: C(O[CH:5]([C:28]1[N:41]=[C:31]2[N:32]=[C:33]([CH3:40])[C:34]3[CH2:35][CH2:36][CH2:37][CH2:38][C:39]=3[N:30]2[N:29]=1)[C:6]1(Br)[C:12](=[O:13])[N:11]2[C@@H:7]1[S:8][CH:9]=[C:10]2[C:14]([O:16]CC1C=CC([N+]([O-])=O)=CC=1)=[O:15])(=O)C.C(#N)C>C1COCC1.[Pd]>[CH3:40][C:33]1[C:34]2[CH2:35][CH2:36][CH2:37][CH2:38][C:39]=2[N:30]2[N:29]=[C:28](/[CH:5]=[C:6]3\[C@@H:7]4[N:11]([C:12]\3=[O:13])[C:10]([C:14]([OH:16])=[O:15])=[CH:9][S:8]4)[N:41]=[C:31]2[N:32]=1
Reactant: CC(=O)OC(c1nc2nc(C)c3c(n2n1)CCCC3)C1(Br)C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CS[C@@H]21
Agent: [Pd]
Solvent: CC#N
Solvent: C1CCOC1
Product: Cc1nc2nc(/C=C3/C(=O)N4C(C(=O)O)=CS[C@H]34)nn2c2c1CCCC2
Temperature: 3 °C

Procedure:
4-nitrobenzyl (5R)-6-[(acetyloxy)(5-methyl-6,7,8,9-tetrahydro[1,2,4]triazolo[1,5-a]quinazolin-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (600 mg, 0.93 mmol) was dissolved in THF (20 mL) and acetonitrile (20 mL) and phophate buffer (6.5 pH) (20 ml) and hydrogenated over Pd/C (10%) (200 mg) under 40 psi pressure. At the end, reaction mixture was filtered, cooled to 3° C., and 0.1 N NaOH was added to adjust the pH to 8.5. The filtrate was washed with ethyl acetate and the aqueous layer was separated. The aqueous layer was concentrated under high vacuum at 35° C. to give a yellow precipitate. The product was purified by HP21 resin reverse phase column chromatography. Initially the column was eluted with deionized water (2 L) and latter with 10% acetonitrile:water. The fractions containing the product were collected and concentrated under reduced pressure at room temperature. The yellow solid was washed with acetone, filtered and dried. Yield: 37 mg, 11%; as yellow crystals; mp 250° C. (Dec); (M+H+Na) 392.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:2]1.[F:13][C:14]([F:24])([F:23])[C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.ClCCl>[F:13][C:14]([F:23])([F:24])[C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][N:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])[CH2:2]1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CN(Cc2cccc(C(F)(F)F)c2)C1

Procedure:
To a solution of tert-butyl azetidin-3-ylcarbamate (0.34 g, 2 mmol) in dichloroethane was added 3-(trifluoromethyl)benzaldehyde (0.45 g, 2.6 mmol) and sodium triacetoxyborohydride (0.64 g, 3 mmol). The resultant mixture was stirred at room temperature for 16 hours, and then the mixture was diluted with dichloromethane and washed with aqueous NaHCO3 solution. The organic layer was separated, dried over MgSO4, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 30-70% ethyl acetate/hexane to yield the title compound.