Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[C:28](=[O:29])[N:4]2[C:5]([C:12]([O:14]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:13])=[C:6](/[CH:9]=[CH:10]\[CH3:11])[CH2:7][S:8][C@H:3]12.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[NH2:1][CH:2]1[C:28](=[O:29])[N:4]2[C:5]([C:12]([OH:14])=[O:13])=[C:6](/[CH:9]=[CH:10]\[CH3:11])[CH2:7][S:8][C@H:3]12
Reactant: C/C=C\C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: C/C=C\C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
54.5 g (0.123 mol of benzhydryl 7-amino-3-[(Z)-1-propen-1-yl]-3-cephem-4-carboxylate (Example 10) are added to a stirred solution of 500 ml of trifluoroacetic acid (TFA) and 31 ml of anisole, which is cooled to 0° C. The mixture is stirred at room temperature for 1 hour and is then concentrated in vacuo at 30° C. and the oily residue is stirred with 600 ml of ether for 1 hour. The precipitate is filtered off with suction and washed with 300 to 400 ml of ether and the residue on the filter is dried in vacuo for 3 hours. The trifluoroacetate is suspended in 300 ml of water, the suspension is cooled to +5° C. and the pH is brought to 0.2-0.4 with 12N HCl. The resulting clear solution is cooled to +5° C. and stirred with 4 g of active charcoal for 10 minutes. The active charcoal is filtered off with suction over kieselguhr and rinsed with about 50 ml of 0.1N HCl. The filtrate is brought to pH 2.1 at +5° C. with 20% strength NaOH and the product which has precipitated out is left to stand in a refrigerator for 1 hour in order to bring the crystallization to completion. The crystal sludge is filtered off with suction, washed with 100 ml of water and 300 ml of acetone and dried in vacuo.
Reaction SMILES: [C:1]([C@H:5]1[N:9]([CH3:10])[C:8](=[O:11])[C@H:7]([CH3:12])[N:6]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([CH3:4])([CH3:3])[CH3:2].[Li+].CC([N-]C(C)C)C.C1COCC1.CCCCCCC.Br[CH2:41][CH2:42][CH2:43][CH2:44][Cl:45].[NH4+].[Cl-]>C1COCC1>[C:1]([C@H:5]1[N:9]([CH3:10])[C:8](=[O:11])[C@:7]([CH2:41][CH2:42][CH2:43][CH2:44][Cl:45])([CH3:12])[N:6]1[C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H]1C(=O)N(C)[C@H](C(C)(C)C)N1C(=O)OC(C)(C)C
Reactant: ClCCCCBr
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CN1C(=O)[C@@](C)(CCCCCl)N(C(=O)OC(C)(C)C)[C@H]1C(C)(C)C
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 81 %

Procedure:
To a solution of (2S,5S)-tert-butyl 2-(tert-butyl)-3,5-dimethyl-4-oxoimidazolidine-1-carboxylate (D43) (430 mg, 1.59 mmol) in dry THF (15 ml) cooled to −78° C., LDA 2M in THF/heptane (1.2 ml, 2.38 mmol) was added and the reaction mixture stirred at this temperature for 40 min before adding 1-bromo-4-chloro-butane (0.27 ml, 2.38 mmol). The reaction was allowed to warm to RT and left stirring for 3 hrs. The resulting solution was treated with NH4Cl sat sol (5 ml) and extracted with Et2O (3×10 ml). The organic phases were collected and washed with NaCl sat sol, dried over Na2SO4 and evaporated in vacuo to afford a residue which was purified by Biotage SNAP-Si column (25 g) eluting with cHex/Et2O 60/40. Collected fractions after solvent evaporation afforded the title compound (D44) (465 mg).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12](=[O:33])[CH:13]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH:30]4[CH2:32][CH2:31]4)(=[O:29])=[O:28])=[CH:23][CH:22]=3)[O:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[N:10][C:5]2=[CH:4][CH:3]=1.[Li+].[Cl-].[CH2:36]([Sn](CCCC)(CCCC)C=C)[CH2:37]CC>C1COCC1.CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:30]1([S:27]([C:24]2[CH:25]=[CH:26][C:21]([CH:13]([O:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:12]([NH:11][C:9]3[S:8][C:6]4[C:5]([N:10]=3)=[CH:4][CH:3]=[C:2]([CH:36]=[CH2:37])[N:7]=4)=[O:33])=[CH:22][CH:23]=2)(=[O:29])=[O:28])[CH2:32][CH2:31]1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=C(Nc1nc2ccc(Br)nc2s1)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=Cc1ccc2nc(NC(=O)C(OC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)sc2n1
Yield: 66.7 %

Procedure:
To mixture of N-(5-Bromo-thiazolo[5,4-b]pyridin-2-yl)-2-(4-cyclopropanesulfonyl-phenyl)-2-(tetrahydro-pyran-4-yloxy)-acetamide (Example-A95) (0.135 g, 0.24 mmol), Pd(PPh3)4 (0.014 g, 0.012 mmol) and LiCl (0.031 g, 0.73 mmol) in THF:DMF (1:1, 5 mL) under inert atmosphere was added tributyl(vinyl)stannane (0.23 g, 0.73 mmol) and heated under reflux for 8 hrs. Solvent was removed in vacuo and taken into brine and extracted with ethyl acetate (3×5 mL), washed with water and brine, dried (Na2SO4) and concentrated in vacuo to afford titled compound (0.080 g)
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH:7]1[CH:8]=[C:9]([CH2:12][NH:13][C:14]2C(C(O)=O)=[CH:18][C:17]([S:23]([NH2:26])(=[O:25])=[O:24])=[C:16]([Cl:27])[CH:15]=2)[O:10][CH:11]=1>ClCCl>[NH2:26][S:23]([C:17]1[C:16]([Cl:27])=[CH:15][C:14]([NH:13][CH2:12][C:9]2[O:10][CH:11]=[CH:7][CH:8]=2)=[C:1]([CH:18]=1)[C:2]([Cl:4])=[O:3])(=[O:24])=[O:25]
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(NCc2ccco2)cc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: NS(=O)(=O)c1cc(C(=O)Cl)c(NCc2ccco2)cc1Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of oxalyl chloride (0.040 mole) in dichloromethane (20 mL) is added dropwise to an ice bath cooled solution of furosemide (5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoic acid), (10) (Aldrich) (0.040 mole) in dichloromethane (50 mL). The reaction is stirred at ambient temperature for 5 hours. The reaction solution is washed with 5% aqueous sodium bicarbonate, with water, and then with a saturated sodium chloride solution. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo to give 5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyl chloride (13). See eg., D. L. Musso, et. al., J. Med. Chem., (2003) 46: 409.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1[CH:9]=[C:10]2[CH:16]=[C:15]([CH:17]([OH:25])[CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:14]([S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:11]2=[N:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1[CH:9]=[C:10]2[CH:16]=[C:15]([C:17](=[O:25])[CH2:18][CH:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[N:14]([S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:27])=[O:28])[C:11]2=[N:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cnc2c(c1)cc(C(O)CC1CCOCC1)n2S(=O)(=O)c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cnc2c(c1)cc(C(=O)CC1CCOCC1)n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
To a solution of {1-benzenesulfonyl-2-[1-hydroxy-2-(tetrahydro-pyran-4-yl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-carbamic acid tert-butyl ester (1.5 g, 3.0 mmol) in dichloromethane (15 mL) was added Dess-Martin periodinane (4.44 g, 10.4 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 1 h and then quenched with a saturated aqueous sodium bicarbonate solution (20 mL). The mixture was extracted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (3×20 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. The residue was purified by flash column chromatography (silica gel from QingDao, 200-300 mesh, 50% ethyl acetate/hexanes) afforded [1-benzenesulfonyl-2-(2-tetrahydro-pyran-4-yl-acetyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-carbamic acid tert-butyl ester (1.0 g, 67%) as a light yellow solid: LC/MS m/e calcd for C25H29N3O6S [M+H]+ 500.59, observed 500.2.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([C:9]1[CH:16]=[CH:15][C:12]([CH2:13]O)=[CH:11][CH:10]=1)[CH2:6][CH2:7][CH3:8]>CCOCC>[Cl:3][CH2:13][C:12]1[CH:15]=[CH:16][C:9]([CH2:5][CH2:6][CH2:7][CH3:8])=[CH:10][CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: CCCCc1ccc(CO)cc1
Solvent: CCOCC
Product: CCCCc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 104.9 %

Procedure:
Thionyl chloride (2.5 ml, 34 mmol) was added to a solution of 4-n-butylbenzyl alcohol (2.0 g, 12 mmol) in ether (25 ml), and this mixture was stirred at room temperature for 3 hours. After concentration of the mixture, excess thionyl chloride was removed by azeotropic distillation with benzene to give the title compound (2.3 g). This compound was used in the following reaction without purification.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH:12]([CH2:15][OH:16])[CH2:13][OH:14])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:17]([O:24][CH2:25][CH:26]=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:17]([O:24][CH2:25][C@H:26]1[O:14][CH2:13][C@H:12]([CH:9]2[CH2:8][CH2:7][CH:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:11][CH2:10]2)[CH2:15][O:16]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCCCC[C@H]1CC[C@H](C(CO)CO)CC1
Reactant: O=CCOCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCC1CCC([C@H]2CO[C@H](COCc3ccccc3)OC2)CC1

Procedure:
A solution of 100 mmol of trans-2-(4-pentylcyclohexyl)propane-1,3-diol, 100 mmol of benzyloxyacetaldehyde and 10 mmol of p-toluenesulfonic acid in 500 ml of toluene is heated at the boil on a water separator until the water separation is complete. Conventional work-up gives trans/trans-2-benzyloxymethyl-5- (4-pentylcyclohexyl)-1,3-dioxane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH:10][N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:24][CH2:25][CH2:26]Br>C(#N)C>[Br:24][CH2:25][CH2:26][N:10]1[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:12][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[N:9]1
Reactant: CCOC(=O)c1cc(-c2ccc(F)cc2)n[nH]1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc(-c2ccc(F)cc2)nn1CCBr
Yield: 45.8 %

Procedure:
To a solution of Intermediate 1B (135 g, 576 mmol) and potassium carbonate (159 g, 1153 mmol) in acetonitrile (1400 mL) was added 1,2-dibromoethane (59.6 mL, 692 mmol) and the resulting reaction mixture was refluxed for 4 h. Acetonitrile was removed under reduced pressure and the residue was diluted with water. The aqueous layer was extracted with DCM (2×500 mL) The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by ISCO using 880 g REDISEP® column and 1% methanol in chloroform as eluent. Combined fractions were concentrated to afford Intermediate 1C (90 g, 45%). MS(ES): m/z=343 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.91-7.97 (m, 2H), 7.41 (s, 1H), 7.24-7.30 (m, 2H), 4.96 (t, J=6.34 Hz, 2H), 4.36 (q, J=7.11 Hz, 2H), 3.90 (t, J=6.34 Hz, 2H), 1.35 (t, J=7.12 Hz, 3H).
Reaction SMILES: N1C=CC=CC=1.[C:7]1([CH2:13][C:14](Cl)=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:17]1([CH:23]([O:30][C:31]([C:33]2[N:38]3[C:39](=[O:42])[C@@H:40]([NH2:41])[C@H:37]3[S:36][CH2:35][C:34]=2[O:43][CH3:44])=[O:32])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCl>[C:17]1([CH:23]([O:30][C:31]([C:33]2[N:38]3[C:39](=[O:42])[C@@H:40]([NH:41][C:14](=[O:15])[CH2:13][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[C@H:37]3[S:36][CH2:35][C:34]=2[O:43][CH3:44])=[O:32])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: CCl
Solvent: c1ccncc1
Product: COC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Reaction time: 0.5 h

Procedure:
1 ml of pyridine and 0.5 ml of phenylacetic acid chloride are added at 0° C, under a nitrogen atmosphere, to a suspension of 0.250 g of 7β-amino-3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester in 25 ml of methyl chloride and the mixture is stirred for 30 minutes at this temperature. The reaction mixture is evaporated under reduced pressure; the residue is stirred for 10 minutes with 20 ml of a 1:1 mixture of dioxane and water and diluted with methylene chloride. The aqueous phase is separated off and extracted with methylene chloride. The combined organic phases are washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over sodium sulphate and evaporated under reduced pressure. The crude product is purified by means of preparative thin layer chromatography using, as the solvent, a 1:1 mixture of toluene and ethyl acetate. The zone visible under ultraviolet light of λ = 254 mμ (Rf~0.35) is eluted with a 4:1 mixture of acetone and methanol and gives 3-methoxy-7β-(α-phenylacetylamino)-3-cephem-4-carboxylic acid diphenylmethyl ester which is identical with the product obtainable by the process of Example 9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][NH:17][S:18]([CH2:21][CH2:22][CH3:23])(=[O:20])=[O:19])[CH:14]=2)[CH2:9][CH2:8][CH:7]1[NH:24]C(=O)OC(C)(C)C>Cl>[ClH:1].[NH2:24][CH:7]1[CH:6]([CH2:5][C:4]2[CH:32]=[CH:33][C:34]([Cl:35])=[C:2]([Cl:1])[CH:3]=2)[C:15]2[CH:14]=[C:13]([CH2:16][NH:17][S:18]([CH2:21][CH2:22][CH3:23])(=[O:20])=[O:19])[CH:12]=[CH:11][C:10]=2[CH2:9][CH2:8]1
Reactant: CCCS(=O)(=O)NCc1ccc2c(c1)C(Cc1ccc(Cl)c(Cl)c1)C(NC(=O)OC(C)(C)C)CC2
Agent: Cl
Product: CCCS(=O)(=O)NCc1ccc2c(c1)C(Cc1ccc(Cl)c(Cl)c1)C(N)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tert-butyl [1-(3,4-dichlorobenzyl)-7-{[(propylsulfonyl)amino]methyl}-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate (120 mg, 0.222 mmol, cf. example 39) was dissolved in 5 N isopropanolic hydrochloric acid (2 mL). The reaction mixture was stirred at room temperature for 1 h. The solvent was evaporated and the product was dried in vacuo. Yield: 101 mg (0.211 mmol, 95%).
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]1=O.C([O:16][CH2:17][CH:18]=[CH2:19])(=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl-].[NH4+]>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[CH2:3]([C:2]1([CH3:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:16][CH2:17][C:18]1=[O:19])[CH:4]=[CH2:5]
Reactant: CC1C(=O)CCc2ccccc21
Reactant: C=CCOC(C)=O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCC1(C)C(=O)CCc2ccccc21
Temperature: 25 °C
Reaction time: 96 h
Yield: 80.6 %

Procedure:
To a solution of 1-methyl-2-tetralone (10.0 g, 62.4 mmol), allyl acetate (7.42 mL, 68.7 mmol), cesium carbonate (20.3 g, 62.4 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.143 g, 0.156 mmol), 1,2-diaminocyclohexane-N,N′-bis(2′-diphenylphosphinobenzoyl) (0.215 g, 0.312 mmol) in tetrahydrofuran (300 mL) was bubbled a stream of nitrogen through the mixture for ten minutes. The solution was then stirred at room temperature for 4 days followed by the addition of ethyl acetate (200 mL) and a saturated aqueous solution of ammonium chloride. The organic layer was separated, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography employing 70-230 mesh silica gel eluting with a mixture of 10% ethyl acetate in hexane to provide the title compound as a light yellow oil (10.07 g, 90%). 1H NMR (300 MHz, CDCl3): δ 1.43 (s, 3 H), 2.46 m, 1 H), 2.63 m, 2 H), 2.78 m, 1 H), 3.03 m, 2 H), 4.90 m, 2 H), 5.40 m, 1 H), 7.18 (m, 2 H), 7.30 m, 2 H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)=[O:3].[Cl-].[Al+3].[Cl-].[Cl-].[Br:18]Br.O>C(Cl)(Cl)Cl>[Br:18][CH2:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:8][CH:9]=1)=[O:3]
Reactant: CC(=O)c1ccc(S(C)(=O)=O)cc1
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CS(=O)(=O)c1ccc(C(=O)CBr)cc1
Reaction time: 8 h
Yield: 78 %

Procedure:
To a solution of 4-(methylsulfonyl)acetophenone (4.85 g, 24.5 mmol) in CHCl3 (70 mL) was added aluminum chloride (1 mg) and bromine (1.1 mL) in CHCl3 (8.5 mL) dropwise. The mixture was stirred overnight, and poured into water. The whole was extracted with ethyl acetate (50 mL×2), the combined organic layer was dried over MgSO4, and concentrated in vacuo. The resulting residue was recrystallized from ethyl acetate/hexane (1/1) to give the subtitle compound (5.28 g, 78% yield).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1)=[O:6].[C:19]([O:23][C:24]([NH:26][C@@H:27]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)[C:28](O)=[O:29])=[O:25])([CH3:22])([CH3:21])[CH3:20].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[C:19]([O:23][C:24]([NH:26][C@@H:27]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)[C:28]([NH:3][CH2:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[CH:11][CH:12]=1)=[O:6])=[O:29])=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: NCC(=O)c1ccc(N2CCOCC2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccn1)C(=O)O
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccn1)C(=O)NCC(=O)c1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 34.7 %

Procedure:
To a solution of 2-amino-1-(4-morpholin-4-ylphenyl)ethan-1-one dihydrochloride (3.71 g), (2S)-(tert-butoxycarbonylamino)-3-(2-pyridyl)propanoic acid (5.73 g) and diphenylphosphoryl azide (3.48 g) in N,N-dimethylformamide (70 ml) was added dropwise N,N-diisopropylethylamine (4.41 ml) at 0° C. and the mixture was stirred for 20 minutes. The mixture was heated to ambient temperature and stirred for 8 hours. The resulting mixture was diluted with ethyl acetate (200 ml) and washed successively with water, a saturated aqueous sodium hydrogencarbonate solution and brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residual solid was triturated with ethyl acetate-diisopropyl ether (1: 2) to give (2S)-(tert-butoxycarbonylamino)-N-[2-(4-morpholin-4-ylphenyl)-2-oxoethyl]-3-(2-pyridyl)-propanamide (2.06 g) as off-white crystals.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@H:9]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[C:10]([N:12]1[CH2:17][CH2:16][C:15]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1)=[O:11].C(N(C(C)C)CC)(C)C.N1C=CC=CC=1O[C:54](=[S:62])OC1C=CC=CN=1>C(Cl)Cl>[CH:23]1([C:15]2([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH2:17][N:12]([C:10](=[O:11])[C@H:9]([N:8]=[C:54]=[S:62])[CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[CH2:13][CH2:14]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CCOC(=O)C1(C2CCCCC2)CCN(C(=O)[C@H](N)Cc2ccc(OC)cc2)CC1
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1(C2CCCCC2)CCN(C(=O)[C@@H](Cc2ccc(OC)cc2)N=C=S)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
To 500 mg (0.94 mmol) of ethyl 1-[(R)-2-amino-3-(4-methoxyphenyl)propionyl]-4-cyclohexylpiperidine-4-carboxylate trifluoroacetate dissolved in 5 mL of CH2Cl2 and 0.5 mL (2.8 mmol) of diisopropylethylamine are added 219 mg (0.94 mmol) of thiocarbonic acid O,O-bis(2-pyridyl)ester. After stirring the reaction medium for 2 hours at room temperature, the solvents are evaporated off and the crude product obtained is chromatographed on silica gel (eluent: 6/4 heptane/EtOAc). 421 mg of ethyl 4-cyclohexyl-1-[(R)-2-isothiocyanato-3-(4-methoxyphenyl)propionyl]piperidine-4-carboxylate in the form of a colourless oil are obtained in a yield of 97%.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH:5]1[O:9][CH2:8][CH2:7][O:6]1)[CH3:2].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:22][CH2:23][C:24](Cl)=[O:25]>O>[CH2:1]([N:3]([CH2:4][CH:5]1[O:9][CH2:8][CH2:7][O:6]1)[C:24](=[O:25])[CH2:23][Cl:22])[CH3:2]
Reactant: O=C(Cl)CCl
Reactant: CCNCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCN(CC1OCCO1)C(=O)CCl

Procedure:
N-Ethyl-N-(1,3-dioxolan-2-ylmethyl)amine (50 grams), benzene (100 ml), water (100 ml) and sodium carbonate (5.0 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The mixture was cooled to about 5° to 10° C. and chloroacetyl chloride (3 ml) was added dropwise with stirring. After the addition was completed stirring was continued until the reaction mixture reached room temperature. After this time the organic phase was separated from the aqueous phase and was washed with water. The washed solution was then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-ethyl-N-(1,3-dioxolan-2-ylmethyl)-α-chloroacetamide as an oil.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[CH2:11][CH2:10][CH2:9]2.[BrH:17]>O>[Br:17][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[CH2:11][CH2:10][CH2:9]2
Reactant: Nc1ccc2c(c1)CCCC2=O
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C1CCCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
A solution of NaNO2 (2.35 g, 34 mmol) in water (10 mL) was added dropwise to the solution of 6-amino-1,2,3,4-tetrahydronaphthalen-1-one (5.0 g, 31 mmol) in 25% HBr (16 mL) at 0° C. The suspension was then transferred to a stirred mixture of CuBr (8.9 g, 62 mmol) in 48% HBr (30 mL) at 0° C. The resulting mixture was allowed to warm to rt and stirred for 1 h. The mixture was extracted with EtOAc, dried (Na2SO4), and concentrated. The residue was purified by silica gel chromatography (0%-60% EtOAc/Hex) to give 5.6 g (80%) of the title compound as a light yellow oil. 1H NMR (400 MHz, CDCl3): δ 2.10-2.16 (2H, m), 2.64 (2H, t, J=6.4 Hz), 2.94 (2H, t, J=6.0 Hz), 7.42 (1H, s), 7.44 (1H, s), 7.87 (1H, d, J=8.9 Hz). [M+H] calc'd for C10H9BrO, 225, 227. found 225, 227.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1>CN(C=O)C>[Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([NH:30][CH2:29][C:28]2[CH:31]=[CH:32][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Reactant: COc1ccc(CN)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(CNc2c([N+](=O)[O-])c(Cl)nc3ccccc23)cc1
Yield: 93.4 %

Procedure:
The method described in Part A of Example 1 was used to treat 2,4-dichloro-3-nitroquinoline (10.0 g, 40.8 mmol) in DMF (100 mL) with triethylamine (8.53 mL, 61.2 mmol) and 4-methoxybenzylamine (4.85 mL, 40.8 mmol). After the precipitate was isolated by filtration, it was dried for three hours in a vacuum oven at 60° C. to provide 13.1 g of 2-chloro-N-(4-methoxybenzyl)-3-nitroquinolin-4-amine as a brown solid.