Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4]Br.[S:6]([O-:9])([O-:8])=[O:7].[Na+:10].[Na+].C>O>[CH2:2]([S:6]([O-:9])(=[O:8])=[O:7])[CH2:3][CH2:4][S:6]([O-:9])(=[O:8])=[O:7].[Na+:10].[Na+:10]
Reactant: BrCCCBr
Reactant: O=S([O-])[O-]
Agent: C
Agent: [Na+]
Solvent: O
Product: O=S(=O)([O-])CCCS(=O)(=O)[O-]
Yield: 85.6 %

Procedure:
This compound was prepared by a modification of the method described in Stone, G. C. H. (1936) J. Am. Chem. Soc., 58:488. 1,3-Dibromopropane (40.4 g, 0.20 mol) was treated with sodium sulfite (60.3 g, 0.50 mol) in water at reflux temperature for 48 h. Inorganic salts (sodium bromide and sodium sulfite) were removed by successive treatment of the resultant reaction mixture with barium hydroxide and silver(I)oxide. The solution was then neutralized with Amberlite-120(acid form) and decolorized with Norit-A. Barium ions were removed by treatment of the aqueous solution with Amberlite-120(sodium form) ion-exchange resin. The solvent was removed on a rotary evaporator, and the crude product was recrystallized from water-ethanol several times to give the title compound (42.5 g). The small amount of trapped ethanol was removed by dissolving the crystals in a minimum amount of water and then concentrating the solution to dryness. The pure product was further dried under high vacuum at 56° C. for 24 h: mp>300° C.;1H NMR (D2)δ: 3.06-3.13(m, 4 H, H-1 and H-3), 2.13-2.29(m, 2H, H-2);13C NMR (D2O) δ:52.3(C-1 and C-3), 23.8(C-2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1I.C([Li])(C)(C)C.CCCCC.[N:20]1[C:27]([Cl:28])=[N:26][C:24](Cl)=[N:23][C:21]=1[Cl:22]>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[Cl:22][C:21]1[N:20]=[C:27]([Cl:28])[N:26]=[C:24]([C:3]2[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=2[Cl:1])[N:23]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Clc1ccc(Cl)c(I)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Clc1ccc(Cl)c(-c2nc(Cl)nc(Cl)n2)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 58.9 %

Procedure:
Alternatively, to a solution of 2,5-dichloro-iodobenzene (3.1 g, 11.4 mmol), hexamethylphosphoramide (6.6 ml) and tetrahydrofuran (20 ml), cooled to −78° C., was added a solution of tert-butyl lithium in pentane (1.7 M, 8.7 ml, 14.8 mmol) over 20 minutes. After stirring at −78° C. for 3 hours, a solution of cyanuric chloride (3.14 g, 17.1 mmol) in tetrahydrofuran (15 ml) was added over 15 minutes. After stirring at −78° C. for 1 hour, the mixture was warmed to −20° C. over 30 minutes. The reaction was quenched by slow addition of hydrochloric acid (1 M, 20 ml). The mixture was diluted with water (50 ml) and extracted with dichloromethane (3×40 ml). The combined extracts were washed with water (2×50 ml), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with dichloromethane-hexane (3:5) to provide 2,4-dichloro-6-(2,5-dichloro-phenyl)-[1,3,5]triazine (1.98 g, 59% yield).
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:17][C:13]=3[C:12](=[O:24])[N:11]([CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)[C:10]2=[O:38])=[N:5][N:4]=1)[CH3:2].[ClH:39]>C(Cl)Cl.O1CCOCC1>[ClH:39].[CH2:1]([C:3]1[O:7][C:6]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:17][C:13]=3[C:12](=[O:24])[N:11]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:10]2=[O:38])=[N:5][N:4]=1)[CH3:2]
Reactant: CCc1nnc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)o1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCc1nnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)o1

Procedure:
A solution of tert-butyl 4-{1-[(5-ethyl-1,3,4-oxadiazol-2-yl)methyl]-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (750 mg; compound B4) in DCM (20 ml) is reacted with a solution of hydrogen chloride in 1,4-dioxane (3 ml, 4.0 M) according to the procedure described in example B28 to afford the title compound as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]2[CH2:15][CH:14]3[N:16]([CH3:17])[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[C:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)#[N:19].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[CH3:17][N:16]1[CH:14]2[CH2:13][CH2:12][CH:11]1[CH2:10][C:9](=[CH:8][C:4]1[CH:3]=[C:2]([C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([C:18]#[N:19])[CH:25]=3)[CH:7]=[CH:6][CH:5]=1)[CH2:15]2
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CN1C2CCC1CC(=Cc1cccc(Br)c1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CN1C2CCC1CC(=Cc1cccc(-c3cccc(C#N)c3)c1)C2
Temperature: 130 °C
Yield: 97 %

Procedure:
To a solution of 3-[(3-bromophenyl)methylidene]-8-methyl-8-azabicyclo[3.2.1]octane (1.17 g, 4 mmol) in p-dioxane (15 mL) and H2O (5 mL) was added (3-cyanophenyl) boronic acid (0.705 g, 4.80 mmol), Pd(PPh3) (0.185 g, 0.16 mmol), and K2CO3 (1.658 g, 12 mmol) and then the mixture was heated in a microwave oven at 130° C. for 20 min. The organic layer of the reaction mixture was separated, concentrated and purified by Combiflash chromatograph to afford 1.22 g (97%) of the title compound. LC-MS m/z 315 (M+H)+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][CH2:16][CH:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1.[C:26]1(=[O:32])[O:31][C:29](=[O:30])[CH2:28][CH2:27]1>ClC(Cl)C>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([NH:15][CH2:16][CH:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:26](=[O:32])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH:23]=3)[CH2:18]2)(=[O:14])=[O:13])=[CH:10][CH:11]=1
Reactant: O=C1CCC(=O)O1
Reactant: O=S(=O)(NCC1Cc2ccccc2C1)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: O=C(O)CCC(=O)c1ccc2c(c1)CC(CNS(=O)(=O)c1ccc(Cl)cc1)C2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.7 %

Procedure:
Suspended in 35 ml of dichloroethane were 6.82 g (51.2 mmol) of anhydrous aluminum chloride, and 4.26 g (13.3 mmol) of 2-[(4-chlorophenyl)sulfonylaminomethyl]indane prepared in Referential Example 1 were added thereto. While chilling with ice water, 2.07 g (20.6 mmol) of succinic anhydride were added to this suspension in small portions. Thereafter, the mixture was stirred at room temperature for 1.5 hours, and the liquid reaction mixture was poured into ice water. A crystal deposited was collected by filtration, washed with water and then recrystallized from acetic acid to obtain 4.75 g of a colorless crystal. Yield: 85%.
Reaction SMILES: O[CH:2]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[N+:16]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])([O-:18])=[O:17].[OH-].[K+].C(O)C>O>[N+:16]([CH:19]([CH:2]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:20]([O:22][CH2:23][CH3:24])=[O:21])([O-:18])=[O:17]
Reactant: OC1c2ccccc2Oc2ccccc21
Reactant: CCOC(=O)C[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(C1c2ccccc2Oc2ccccc21)[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 0.75 h

Procedure:
9-Hydroxyxanthene (9.9 g, 50 mmol) and ethyl nitroacetate (6.1 mL, 55 mol) are mixed and heated at 100° C. (oil bath) for 1.5 hours. After cooling, a waxy mixture is suspended in 40 mL of absolute alcohol and 40 mL of 1.25M of ethanolic potassium hydroxide solution is added. The solution is stirred for 45 minutes at room temperature and ethanol is stripped off. The remaining solid is suspended in water and extracted with diethyl ether. The aqueous portion is acidified with 85% phosphoric acid to pH 2 to 3 to give a white suspension which is cooled overnight. The precipitate is collected by filtration and dried in a vacuum oven at 50° C. This gives 9.18 g of the title compound as a white solid; mp 89°-91° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[CH:22]=[C:21]([N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[CH:20]=[CH:19][C:18]=3[NH:29][C:30]([C:32]3[CH:33]=[C:34]([CH:46]=[CH:47][CH:48]=3)[CH2:35][S:36][CH2:37][CH2:38][C:39]([O:41]C(C)(C)C)=[O:40])=[O:31])=[O:16])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[CH:22]=[C:21]([N:23]4[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]4)[CH:20]=[CH:19][C:18]=3[NH:29][C:30]([C:32]3[CH:33]=[C:34]([CH:46]=[CH:47][CH:48]=3)[CH2:35][S:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:31])=[O:16])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-n2ccc(NC(=O)c3cc(N4CCCCC4)ccc3NC(=O)c3cccc(CSCCC(=O)OC(C)(C)C)c3)n2)cc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-n2ccc(NC(=O)c3cc(N4CCCCC4)ccc3NC(=O)c3cccc(CSCCC(=O)O)c3)n2)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.4 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of tert-butyl 3-(3-(2-(1-(3,4-dimethylphenyl)-1H-pyrazol-3-ylcarbamoyl)-4-(piperidin-1-yl)phenylcarbamoyl)benzylthio)propanoate (150 mg, 0.22 mmol, 1.00 equiv) in dichloromethane (4 mL), and trifluoroacetic acid (2 mL). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product (100 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 85.3 mg (62%) of a white solid. 1H-NMR (300 MHz, DMSO, ppm): δ 11.70 (s, 1H), 11.44 (s, 1H), 8.41 (m, 2H), 7.91 (s, 1H), 7.78 (m, 1H), 7.68 (m, 1H), 7.62 (m, 1H), 7.58 (m, 3H), 7.40 (m, 1H), 7.23 (m, 1H), 6.92 (s, 1H), 3.86 (s, 2H), 3.36 (m, 4H), 2.62 (m, 2H), 2.29 (m, 6H), 1.60 (m, 6H). MS (ES, m/z): 612 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]([C@H:20]2[N:24]3[C:25](=[O:37])[C:26]([NH:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=CC=4)=[CH:27][N:28]=[C:23]3[CH2:22][CH2:21]2)=[O:19])=[CH:12][CH:11]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].C(OC(=O)NC(C1C=CC(CNC([C@H]2N3C(=O)C(N)=CN=C3CC2)=O)=CC=1)=N)(C)(C)C.C1(=O)CCCC1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([O:5][C:6](=[O:38])[NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]([C@H:20]2[N:24]3[C:25](=[O:37])[C:26]([NH:29][CH:30]4[CH2:31][CH2:36][CH2:35][CH2:34]4)=[CH:27][N:28]=[C:23]3[CH2:22][CH2:21]2)=[O:19])=[CH:12][CH:11]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(NCc4ccccc4)c(=O)n32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(N)c(=O)n32)cc1
Agent: [Na+]
Solvent: O=C1CCCC1
Product: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(NC4CCCC4)c(=O)n32)cc1
Yield: 57.3 %

Procedure:
Following a procedure similar to that for the preparation of intermediate 1k, intermediate 1j (115.2 mg, 0.27 mmol), cyclopentanone (68.1 mg, 0.81 mmol) and NaBH(OAc)3 (217.5 mg, 1.03 mmol) yielded 76.5 mg (57.3%) of intermediate 6a. MS (ESI) 496.1 (M+H+).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[C:6]([F:14])[CH:5]=1)(=[O:3])[CH3:2].[Br:15]Br.C(OCC)C>C(Cl)(Cl)Cl.C(O)C>[Br:15][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[C:6]([F:14])[CH:5]=1)=[O:3]
Reactant: CC(=O)Nc1ccc(C(C)=O)cc1F
Reactant: BrBr
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CC(=O)Nc1ccc(C(=O)CBr)cc1F
Temperature: 0 °C
Yield: 50.1 %

Procedure:
N-(4-Acetyl-2-fluoro-phenyl)-acetamide (3.55 g, 18.2 mmol) was dissolved in boiling chloroform (100 mL). Under reflux conditions, a solution of bromine (0.86 mL, 17.5 mmol) in chloroform (20 mL) was added. The reaction mixture was refluxed for an additional 20 min. then cooled, concentrated to give an orange residue. The residue was taken up in ethanol (50 mL) and then diethyl ether (20 mL) was added and the resulting solution cooled to 0° C. A yellow solid precipitated over 48 h and was collected by filtration, washed with cold ethanol (10 mL) and dried to give 2.40 g (8.77 mmol) of the desired product as a yellow powder. Yield: 48.2%; mp 184° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H, NH, 8.29 (t, J=8.0 Hz, 1H), 7.88–7.83 (m, 2H), 4.90 (s, 2H, CH2), 2.17 (s, 3H, Me).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:14][O:13]1.C(Cl)Cl>CO>[CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[C@@H:12]1[CH2:14][O:13]1
Reactant: Cc1c(C2CO2)ccc2c1COC2=O
Solvent: ClCCl
Solvent: CO
Product: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Reaction time: 0.04 h

Procedure:
Racemic 4-methyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one was resolved on a ChiralPak® AD-H column (5×25 cm) under SFC conditions on a Berger MGIII preparative SFC instrument. The racemate was diluted to 50 mg/ml in 1:1 DCM:MeOH. The separation was accomplished using 10% EtOH/CO2, flow rate 200 ml/min, 100 bar, 25° C. 500 ul Injections were spaced every 2.12 mins. The faster eluting (2R)-epoxide (I-15B) eluted at 5.2 min, and the slower eluting (2S)-epoxide (I-15A) eluted at 5.6 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[N:20]3[C:14]([CH2:15][N:16]([C:25]([C:27]4[CH:32]=[CH:31][C:30]([C:33]5[C:34]([C:39]([O:41]C(C)(C)C)=[O:40])=[CH:35][CH:36]=[CH:37][CH:38]=5)=[CH:29][CH:28]=4)=[O:26])[C:17]4[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=4[CH2:19]3)=[CH:13][CH:12]=2)=[O:10])[CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[N:20]3[C:14]([CH2:15][N:16]([C:25]([C:27]4[CH:32]=[CH:31][C:30]([C:33]5[C:34]([C:39]([OH:41])=[O:40])=[CH:35][CH:36]=[CH:37][CH:38]=5)=[CH:29][CH:28]=4)=[O:26])[C:17]4[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=4[CH2:19]3)=[CH:13][CH:12]=2)=[O:10])[CH:2]=1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 53.6 %

Procedure:
To a solution of tert-butyl 4′-{[3-{[(pyridin-3-ylmethyl)amino]carbonyl}-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]carbonyl}-1,1′-biphenyl-2-carboxylate of Example 64 (0.710 g, 1.186 mmol) in dry dichloromethane (10 mL) was added trifluoroacetic acid (10 mL) and the reaction mixture stirred at room temperature under nitrogen for 1.75 hours. The reaction mixture was then concentrated in vacuo and the resulting solid dissolved in ethyl acetate (50 mL). The organic phase was extracted with 2 M sodium hydroxide (2×50 mL) and the combined aqueous extracts acidified to pH 1 by the addition of concentrated hydrochloric acid. The resulting white suspension was cooled to 4° C. for 1 hour, the solid product filtered, washed with water and then dried in vacuo at 50° C. overnight to afford the title compound (0.345 g, 54%) as a white solid, m.p. 189-191° C.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[OH:10][CH2:11][C@@H:12]([C@H:14]([C@@H:16]([C@@H:18]([CH2:20][OH:21])[OH:19])[OH:17])[OH:15])[OH:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:20]([C@@H:18]([C@H:16]([C@@H:14]([C@@H:12]([CH2:11][OH:10])[OH:13])[OH:15])[OH:17])[OH:19])[OH:21])=[CH:4][CH:3]=1
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Reactant: Cc1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: Cc1ccc(C=C(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO)cc1
Reaction time: 0.75 h

Procedure:
A reactor was charged with 120 g (1 mole) of p-methylbenzaldehyde, 270 g (1 mole) of a 70% aqueous solution of D-sorbitol and 10 g of p-toluenesulfonic acid, and they were reacted at 35° C. with stirring. Shortly, a large amount of fine white crystals precipitated in the mixture within the reactor, and became creamy in 45 minutes. The torque of the stirrer became about three times as high as that at the start of the reaction. At this time, the amount of mono-p-methylbenzylidene sorbitol formed was 43% of theory.
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:23][CH2:22]2)[CH2:10]1)=[O:7])(C)(C)C.[F:44][C:45]1[CH:46]=[C:47]([CH:51]=[CH:52][CH:53]=1)C(Cl)=O>>[F:44][C:45]1[CH:53]=[C:52]([C:6]([NH:8][C@H:9]2[CH2:13][C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C@@H:11]([CH2:20][N:21]3[CH2:22][CH2:23][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]4[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=4)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:25][CH2:26]3)[CH2:10]2)=[O:7])[CH:51]=[CH:47][CH:46]=1
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](NC(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](NC(=O)c3cccc(F)c3)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(S)-((t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 33 in Step A and 3-fluorobenzoyl chloride in Step B, the title compound was prepared.
Reaction SMILES: [CH3:1][C@H:2]1[C:17](=[O:18])[NH:16][C@H:15]([C@@H:19]2[CH2:23][C@@H:22]([CH3:24])[C:21](=[O:25])[O:20]2)[CH2:14][C@H:13]([CH3:26])[CH2:12][CH2:11][CH:10]=[CH:9][CH2:8][CH2:7][CH2:6][CH2:5][S:4](=[O:28])(=[O:27])[CH2:3]1>C(N)CCC>[CH2:15]([NH:16][C:21](=[O:25])[C@H:22]([CH3:24])[CH2:23][C@@H:19]([C@@H:15]1[CH2:14][C@H:13]([CH3:26])[CH2:12][CH2:11][CH:10]=[CH:9][CH2:8][CH2:7][CH2:6][CH2:5][S:4](=[O:28])(=[O:27])[CH2:3][C@@H:2]([CH3:1])[C:17](=[O:18])[NH:16]1)[OH:20])[CH2:14][CH2:13][CH3:12]
Reactant: C[C@@H]1CCC=CCCCCS(=O)(=O)C[C@@H](C)C(=O)N[C@H]([C@@H]2C[C@@H](C)C(=O)O2)C1
Solvent: CCCCN
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@@H]1C[C@H](C)CCC=CCCCCS(=O)(=O)C[C@@H](C)C(=O)N1

Procedure:
A solution of 99 mg (0.21 mmol) (3S,6S,8R)-3,8-dimethyl-6-((2S,4R)-4-methyl-5-oxo-tetra-hydro-furan-2-yl)-1,1-dioxo-1lambda*6*-thia-5-aza-cyclohexadec-11-en-4-one in 1.5 ml butylamine is heated at 65° C. for two hours. The mixture is evaporated and the residue chromatographed on silica gel (EtOAc/hexane 1:1) to yield the title compound as a white solid.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[C:17]([O:19][CH3:20])=[O:18])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24]>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:24][C:23]1[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=1[CH3:21])=[CH:13][CH:12]=[CH:11][C:10]=2[C:17]([O:19][CH3:20])=[O:18])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccccc1N
Reactant: CCCC(=O)c1cnc2c(C(=O)OC)cccc2c1Cl
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(C(=O)OC)cccc2c1Nc1ccccc1C
Reaction time: 8 h
Yield: 60.6 %

Procedure:
A solution of methyl 3-butyryl-4-chloroquinoline-8-carboxylate (3.8 g) and 2-methylaniline (1.6 ml, 15 mmol) in 1,4-dioxan (20 ml) was heated at reflux for 30 minutes, then left to stand overnight. The solid was filtered off and washed with ethyl acetate, then converted to free base and recrystallised from methanol to obtain methyl 3-butyryl-4-(2-methylphenylamino)quinoline-8- carboxylate (2.86 g, 56%), m.p. 113-115°.
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:54])[CH2:14][O:15][C:16]1[CH:21]=[C:20]([O:22][CH2:23][C:24](=[O:37])[N:25]2[CH2:29][CH2:28][CH2:27][C@@H:26]2[C:30]([O:32]C(C)(C)C)=[O:31])[CH:19]=[C:18]([O:38][CH2:39][C:40]([N:42]2[CH2:46][CH2:45][CH2:44][C@@H:43]2[C:47]([O:49]C(C)(C)C)=[O:48])=[O:41])[CH:17]=1)=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:47]([C@H:43]1[CH2:44][CH2:45][CH2:46][N:42]1[C:40](=[O:41])[CH2:39][O:38][C:18]1[CH:19]=[C:20]([CH:21]=[C:16]([O:15][CH2:14][C:13](=[O:54])[N:9]2[CH2:10][CH2:11][CH2:12][C@@H:8]2[C:6]([OH:7])=[O:5])[CH:17]=1)[O:22][CH2:23][C:24]([N:25]1[CH2:29][CH2:28][CH2:27][C@@H:26]1[C:30]([OH:32])=[O:31])=[O:37])([OH:49])=[O:48]
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)COc1cc(OCC(=O)N2CCC[C@@H]2C(=O)OC(C)(C)C)cc(OCC(=O)N2CCC[C@@H]2C(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@H]1CCCN1C(=O)COc1cc(OCC(=O)N2CCC[C@@H]2C(=O)O)cc(OCC(=O)N2CCC[C@@H]2C(=O)O)c1
Reaction time: 8 h
Yield: 91.4 %

Procedure:
A solution of 350 mg (0.47 mmol) (R)-1-[[3,5-bis-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-phenoxy]-acetyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 1.5 ml trifluoroacetic acid was stirred for 4 h at room temperature. The solvent was removed in vacuo and the residue suspended in 10 ml ether. The resulting suspension was stirred overnight. Filtration and drying gave 254 mg (92%) of the title compound as a light brown powder. MS m/e (%): 614 (M+Na+, 73), 609 (M+NH4+, 100), 592 (M+H+, 56).
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:2]1.[CH3:12][C:13]([NH2:24])([CH3:23])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1>>[OH:1][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:2][NH:24][C:13]([CH3:23])([CH3:12])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1
Reactant: COc1ccc(CC(C)(C)N)cc1
Reactant: CCCCCCCCC1CO1
Product: CCCCCCCCC(O)CNC(C)(C)Cc1ccc(OC)cc1
Yield: 21.8 %

Procedure:
Using the method of Example 5, supra, 1,2-epoxydecane (204 mg, 1.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (197 mg, 1.1 mmol) were used to prepare 73 mg of the title compound as a clear, colorless oil: GC/EI-MS, m/z (rel. int.) 214 (M-121, 100), 196 (27.8), 163 (10), 121 (2.2); 1H-NMR (CDCl3) δ 7.08 (2H, d, J=8.6), 6.83 (2H, d, J=8.6), 3.79 (3H, s), 3.53 (1H, m), 2.79 (1H, dd, J=11.7 and 2.9), 2.67 (2H, s), 2.42 (1H, dd, J=12.6 and 9.6), 1.26 (18 H, m), 1.08 (3H, s), 0.88 (3H, t, J=6.6); 13C-NMR (CDCl3) δ 158.2, 131.4, 129.8, 113.5, 77.2, 69.8, 55.2, 53.8, 47.8, 46.5, 35.1, 31.9, 29.8, 29.7, 29.6, 29.3, 26.6, 26.4, 25.7, 22.7, 14.1; FT-IR (film) cm-1 3399 (broad s), 1612, 1512, 1246, 1039, 823.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]([OH:15])=O)=[N:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.[NH2:16][C:17]([CH2:24][CH3:25])([CH2:22][CH3:23])[C:18]([NH:20][CH3:21])=[O:19]>>[CH2:22]([C:17]([NH:16][C:13]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:7]([O:8][CH2:9][CH:10]2[CH2:11][CH2:12]2)[N:6]=1)=[O:15])([C:18](=[O:19])[NH:20][CH3:21])[CH2:24][CH3:25])[CH3:23]
Reactant: O=C(O)c1ccc(Cl)c(OCC2CC2)n1
Reactant: CCC(N)(CC)C(=O)NC
Product: CCC(CC)(NC(=O)c1ccc(Cl)c(OCC2CC2)n1)C(=O)NC

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-chloro-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 83 b) and 2-amino-2-ethyl-N-methyl-butyramide (Example 70 b) as starting materials, MS (EI): m/e=354.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:25])[C:5]([C:22]([OH:24])=[O:23])=[CH:6][N:7]2[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][CH2:33][CH2:34][NH2:35].C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:35][CH2:34][CH2:33][NH:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:25])[C:5]([C:22]([OH:24])=[O:23])=[CH:6][N:7]2[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2CCc1ccccc1
Reactant: NCCNc1ccccn1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Nc1c(F)c(NCCNc2ccccn2)cc2c1c(=O)c(C(=O)O)cn2CCc1ccccc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 76.4 %

Procedure:
A suspension of 5-amino-6,7-difluoro-1,4-dihydro-4-oxo-1-(2-phenylethyl)-3-quinolinecarboxylic acid (101 mg, 0.292 mmol), 2-(2-pyridylamino)ethylamine (60.2 mg, 0.436 mmol), and triethylamine (60.7 μL, 0.435 mmol) in DMSO (1.5 mL) was stirred at 100° C. for 3 h. The reaction mixture was poured into ice-water and the resulting precipitates were collected by filtration. Recrystallization of the filtered precipitates from CH2Cl2-EtOH gave 5-amino-6-fluoro-1,4-dihydro-4-oxo-1-(2-phenylethyl)-7-[2-(2-pyridylamino)ethylamino]-3-quinolinecarboxylic acid (103 mg, 76%) as a pale brown powder.