Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20](O)=[O:21])[CH:18]=3)[CH:13]([CH3:23])[CH2:12]2)(=[O:10])=[O:9])[CH:7]=1.[NH2:26][C:27]1[CH:37]=[CH:36][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:29][CH:28]=1>>[CH2:34]([O:33][C:31](=[O:32])[C:30]1[CH:29]=[CH:28][C:27]([NH:26][C:20]([C:17]2[CH:18]=[C:19]3[C:14]([CH:13]([CH3:23])[CH2:12][N:11]3[S:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:24][CH3:25])(=[O:9])=[O:10])=[CH:15][CH:16]=2)=[O:21])=[CH:37][CH:36]=1)[CH3:35]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CC(C)c2ccc(C(=O)O)cc21
Reactant: CCOC(=O)c1ccc(N)cc1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CC3C)cc1

Procedure:
1-(5-Chloro-2-methoxy-benzenesulfonyl)-3-methyl-2,3-dihydro-1H-indole-6-carboxylic acid was reacted with ethyl 4-aminobenzoate in analogy to example 62, step 4, yielding 4-{[1-(5-chloro-2-methoxy-benzenesulfonyl)-3-methyl-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid ethyl ester. White foam, MS (ISP) 529.1 (M+H).
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[N:14][OH:15])[C:10]([F:13])([F:12])[F:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.O>C1COCC1>[F:13][C:10]([F:11])([F:12])[C:9]1[C:3]2[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=2[O:15][N:14]=1
Reactant: ON=C(c1ccc(O)cc1O)C(F)(F)F
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Oc1ccc2c(C(F)(F)F)noc2c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 100.2 %

Procedure:
To a solution of 1-(2,4-dihydroxyphenyl)-2,2,2-trifluoroethanone oxime (Example 70, 0.25 g, 1.13 mmol) in THF (15 mL) was added triphenylphosphine (0.63 g, 2.4 mmol) and the mixture was cooled to 0° C. A solution of DEAD (0.48 mL, 2.3 mmol) in THF (10 mL) was slowly added while the temperature was kept at 0° C., after which the reaction mixture was stirred at 0-5° C. for 4 h. Water (30 mL) was added and the mixture was extracted with EtOAc (3×). The combined organic phases were washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (EtOAc/hexane (v/v) 1:10 to 3:2 gradient) gave 0.23 g of the title compound with minor impurities. The material was used without further purification. GC-MS [M+H]+: 204.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[N:22]([C:23]=2[C:24]([OH:26])=O)[CH:21]=[CH:20][S:19]3)[CH2:3][CH2:2]1.[NH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29][CH2:28]1.C(N(CC)CC)C>ClCCl>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[N:22]([C:23]=2[C:24]([N:27]2[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH2:30][CH2:29][CH2:28]2)=[O:26])[CH:21]=[CH:20][S:19]3)[CH2:2][CH2:3]1
Reactant: COc1cccc(/C=C/c2nc3sccn3c2C(=O)O)c1OCC1CC1
Reactant: c1ccc2c(c1)CCCN2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(/C=C/c2nc3sccn3c2C(=O)N2CCCc3ccccc32)c1OCC1CC1

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (100 mg, 0.269 mmol) with 1,2,3,4-tetrahydroquinoline (39 μL, 0.296 mmol) in the presence of triethylamine (68 mg, 0.674 mmol) in dichloromethane (5 mL) gave 79 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.21-0.22 (m, 2H), 0.45-0.47 (m, 2H), 1.09-1.11 (m, 1H), 1.97-2.00 (m, 2H), 2.85-2.87 (m, 2H), 3.66 (d, J=6.6 Hz, 2H), 3.76 (s, 3H), 3.83-3.85 (m, 2H), 6.75 (d, J=16.2 Hz, 1H), 6.85-6.93 (m, 4H), 6.98-7.03 (m, 2H), 7.13-7.15 (m, 1H), 7.26 (d, J=4.2 Hz, 1H), 7.56 (s, 1H), 7.61-7.64 (m, 1H); ESI-MS (m/z) 486.45 (MH)+.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.B(Br)(Br)[Br:19]>ClCCCl.C(Cl)Cl>[BrH:19].[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: BrB(Br)Br
Reactant: COc1ccc2c(OCC(=O)O)ccnc2c1
Solvent: ClCCCl
Solvent: ClCCl
Product: Br
Product: O=C(O)COc1ccnc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 139.8 %

Procedure:
To a pressure vial was added 2-(7-methoxyquinolin-4-yloxy)acetic acid (1.00 g, 4.29 mmol) in DCE (0.6 M, 7 mL). The vial was cooled in an ice bath and to the solution was added BBr3 (1.62 ml, 17.2 mmol). The reaction was allowed to warm to room temperature and stirred overnight. While some starting material remained, the reaction was stopped and diluted with DCM (keep in hood due to fuming). The solids were filtered and dried over high vacuum to yield a light brown crude solid (˜1.8 g). The material was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[NH:4][C:5]([O:7][CH3:8])=[O:6].[CH:13](O)([CH3:15])[CH3:14].CCCCCC>S(=O)(=O)(O)O>[F:1][C:2]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:10]=[CH:9][C:3]=1[NH:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)Nc1ccccc1F
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Product: COC(=O)Nc1ccc(C(C)C)cc1F
Temperature: 70 °C
Yield: 53.3 %

Procedure:
2-Fluoro-N-methoxycarbonylaniline (1.00 g, 5.92 mmol) prepared as described in Example 1 was dissolved in 77.6% sulfuric acid (5.00 g) to prepare a solution. Isopropyl alcohol (0.400 g, 6.51 mmol) was added to the solution under a nitrogen atmosphere while stirring and heating the solution at 70° C. The mixture was vigorously stirred for 3 hr. The reaction solution was cooled to room temperature. n-Hexane (10 mL) was then added to the cooled reaction solution to carry out extraction for separation of the mixture into a sulfuric acid layer and an organic layer, and this extraction was carried out once again. The organic layers thus obtained were combined, and the combined organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine in that order. The solvent was then removed from the organic layer by distillation to give 666 mg of 2-fluoro-4-isopropyl-N-methoxycarbonylaniline as an oil. The oil was further subjected to separation and purification by column chromatography on silica gel to give 206 mg of 2-fluoro-4-isopropyl-N-methoxycarbonylaniline (yield 17.0%).
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)=[CH:8][C:6]=1[NH2:7])([CH3:3])[CH3:2].Cl.[C:22](=N)(OC)[CH3:23].C(=O)([O-])O.[Na+]>CO>[O:13]1[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=[C:12]1[C:9]1[CH:10]=[CH:11][C:5]2[N:4]([CH:1]([CH3:3])[CH3:2])[C:22]([CH3:23])=[N:7][C:6]=2[CH:8]=1
Reactant: COC(C)=N
Reactant: CC(C)Nc1ccc(-c2nc3ccccc3o2)cc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1C(C)C
Yield: 100 %

Procedure:
To a methanol (5 mL) solution of 2-(2-isopropylaminoanilin-5-yl)benzoxazole (see Working Example 80-2) (180 mg, 0.673 mmol) was added methyl acetimidate hydrochloride (111 mg, 1.01 mmol), and this was heated to reflux for 2 hours. After the reaction was complete, saturated aqueous sodium hydrogen carbonate solution was added, and this was extracted with ethyl acetate. After the organic layer obtained was dried over anhydrous sodium sulfate, it was filtered and concentrated. The crystals obtained were purified by silica gel column chromatography to yield the title compound (196 mg, quant.) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:9]=[C:10]([CH:24]=[CH:25][CH:26]=2)[CH2:11][S:12][C:13]2[NH:14][C:15](=O)C3[C:21]([CH3:22])=[CH:20][NH:19][C:17]=3[N:18]=2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:31]I.CO[CH2:35][CH2:36][O:37]C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:9]=[C:10]([CH:24]=[CH:25][CH:26]=2)[CH2:11][S:12][C:13]2[N:14]([CH3:15])[C:36](=[O:37])[C:35]3[C:21]([CH3:22])=[CH:20][N:19]([CH3:31])[C:17]=3[N:18]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1c[nH]c2nc(SCc3cccc(C(=O)c4ccc(Cl)cc4)c3)[nH]c(=O)c12
Reactant: COCCOC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1cn(C)c2nc(SCc3cccc(C(=O)c4ccc(Cl)cc4)c3)n(C)c(=O)c12

Procedure:
Under argon gas, 2-[3-(4-chlorobenzoyl) benzyl]thio-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (1.31 g) was suspended in anhydrous DME (32 ml) and, under ice-cooling and stirring, 60% sodium hydride-oil (269 mg) was added in two installments. The mixture was stirred for 15 minutes, after which methyl iodide (1.18 g) was added. Then, the mixture was further stirred at room temperature overnight. This reaction mixture was diluted with ethyl acetate, washed with saturated aqueous NaCl solution, and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by flash column chromatography (hexane: ethyl acetate=4:1-2.5:1) to provide the title compound (950 mg). 1H-NMR (CDCl3) δ: 2.39(3H,d,J=1.0 Hz), 3.53(3H,s), 3.54(3H,s), 4.52(2H,s), 6.42(1H,d,J=1.0 Hz), 7.36(2H,d,J=8.6 Hz), 7.35-7.50(1H,m), 7.65-7.72(2H,m), 7.69(2H,d,J=8.6 Hz), 7.97(1H,d,J=1.6 Hz).
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.[NH2:10][CH2:11][CH2:12][C:13]1[N:17]=[CH:16][NH:15][CH:14]=1.C1(=O)N([O:23][C:24](=O)[C@H:25]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])C(=O)CC1.CN(C)C=O>O>[C:30]([O:29][C:27]([NH:26][C@H:25]([C:24]([NH:10][CH2:11][CH2:12][C:13]1[N:17]=[CH:16][NH:15][CH:14]=1)=[O:23])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:28])([CH3:32])([CH3:33])[CH3:31]
Reactant: NCCc1c[nH]cn1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NCCc1c[nH]cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.8 %

Procedure:
Triethylamine (3.5 ml) is added to a mixture of histamine dihydrochloride (1.84 g), N-tert-butoxycarbonyl-L-phenylalanine succinimido ester (3.62 g), dimethylformamide (20 ml) and water (5 ml) under ice-cooling and then the mixture is stirred at room temperature for three hours. The reaction mixture is concentrated under reduced pressure to remove solvent and ethyl acetate is added to the residue and then, insoluble materials are filtered off. The filtrate is washed with an aqueous sodium bicarbonate solution and water, dried, and then concentrated to remove solvent. The residue is crystallized with ether to give N-(N-tert-butoxycarbonyl-L-phenylalanyl)histamine (2.5 g). The product (1.79 g) thus obtained is dissolved in 15% hydrogenbromide-acetic acid solution and the solution is stirred at room temperature for 30 minutes. The reaction mixture is concentrated under reduced pressure to give N-(L-phenylalanyl) histamine dihydrobromide (2.1 g). The thus-obtained product (2.1 g) is dissolved in dimethylformamide, and N-tert-butoxycarbonyl-L-phenylalanine succinimido ester (1.81 g) and triethylamine (2.1 ml) are added thereto and then the mixture is stirred overnight. Ethyl acetate is added to the reaction mixture, and insoluble materials are filtered off. The filtrate is washed with an aqueous sodium bicarbonate solution and an aqueous sodium chloride solution and dried, and then concentrated to remove solvent. The residue is purified by silica gel column chromatography (solvent; chloroform:methanol=9:1) and crystallized with ether to give N-(N-tert-butoxycarbonyl-L-phenylalanyl L-phenylalanyl)histamine (1.88 g) as white crystals. Yield ; 74.3%
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:5][CH2:4]1.CO.Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].[OH-].[Na+]>C1(C)C=CC=CC=1>[N:3]1([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:8][CH2:7][CH:6]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:5][CH2:4]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C1CC(C2CCNCC2)CCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)N1CCC(C2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.6 %

Procedure:
4,4′-Bipiperidine dihydrochloride (2.95 g) was mixed with MeOH (25 ml), and a mixture of benzyl chloroformate (2.2 g) and toluene (5 ml) was added dropwise thereto over 1 hour while keeping the solution neutral by adding a 6 M aqueous NaOH solution at the same time. The reaction mixture was stirred at room temperature for 30 minutes and then concentrated under reduced pressure. CHCl3, and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain benzyl 4,4′-bipiperidine-1-carboxylate (1.5 g).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[CH3:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[N:20]=[C:19](Cl)[CH:18]=[C:17]([Cl:22])[N:16]=1.[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:19]1[CH:18]=[C:17]([Cl:22])[N:16]=[C:15]([Cl:14])[N:20]=1)[CH3:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](OC(C)(C)C)[C@H]1COC(=O)N1
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](OC(C)(C)C)[C@H]1COC(=O)N1c1cc(Cl)nc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.5 %

Procedure:
A solution of (R)-4-((R)-1-tert-butoxyethyl)oxazolidin-2-one (0.830 g, 4.43 mmol) and 2,4,6-trichloropyrimidine (0.894 g, 4.88 mmol, 1.10 equiv) in DMF (15 mL) was treated with NaH (60%, 0.248 g, 6.21 mmol, 1.40 equiv), then the resulting mixture (yellow) was stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc (100 mL) and quenched with saturated aqueous NaCl (100 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 0 to 40%) provided (R)-4-((R)-1-tert-butoxyethyl)-3-(2,6-dichloropyrimidin-4-yl)oxazolidin-2-one (1.0 g, white solid) in 69% yield. 1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 4.70-4.66 (m, 2H), 4.45-4.40 (m, 2H), 1.26 (s, 9H), 1.04 (d, J=6.6 Hz, 3H); MS m/z 334.0 (M+H)+; Rt-1.10 min.
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[Cl-].[OH:14][NH3+:15]>C(O)C>[CH3:1][CH:2]([CH3:12])[CH2:3][C:4](=[N:15][OH:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [NH3+]O
Reactant: CC(C)CC(=O)c1ccccc1
Agent: [Cl-]
Solvent: CCO
Product: CC(C)CC(=NO)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.5 %

Procedure:
A mixture of the above ketone (20.6 g, 127 mmol), hydroxylammonium chloride (17.7 g, 254 mmol) and absolute ethanol (200 ml) was heated at reflux for 1 h and then stirred at ambient temperature for 16 h. The solvent was evaporated in vacuo. The residue was suspended in water (200 ml) and the resulting mixture was extracted with dichloromethane (2×100 ml). The combined organic phases were washed with water (50 ml) and brine (10 ml) and dried (MgSO4). The solvent was evaporated in vacuo to give 20.6 g of 3-methylbutyrophenone oxime.
Reaction SMILES: Cl[CH2:2][C:3]1[C:7]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=2[Cl:16])=[CH:6][S:5][CH:4]=1.[C-:17]#[N:18].[Na+]>CS(C)=O>[Cl:16][C:10]1[C:11]([CH3:15])=[CH:12][CH:13]=[CH:14][C:9]=1[NH:8][C:7]1[C:3]([CH2:2][C:17]#[N:18])=[CH:4][S:5][CH:6]=1
Reactant: [C-]#N
Reactant: Cc1cccc(Nc2cscc2CCl)c1Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cccc(Nc2cscc2CC#N)c1Cl
Reaction time: 3 h

Procedure:
2.72 g (10 mmoles) of 3-chloromethyl-4-(2-chloro-3-methylanilino)thiophen in 15 ml of dimethylsulfoxide are added dropwise to a solution of 650 mg of sodium cyanide in 15 ml of dimethylsulfoxide at 40°. The mixture is stirred for a further three hours, poured onto water and extracted three times with ethyl acetate. The combined extracts are washed with 50 ml each of 6 N hydrochloric acid and water, dried and concentrated. Crude 4-(2-chloro-3-methylanilino)-3-thiophenacetonitrile is obtained as an oil.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([S:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)(=[O:13])=[O:12])[CH2:7][CH2:6]1)=[O:4].C1COCC1.[CH3:29][NH2:30]>O>[CH3:29][NH:30][CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([S:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)(=[O:13])=[O:12])[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C(CCl)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Reactant: CN
Solvent: C1CCOC1
Solvent: O
Product: CNCC(=O)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.9 %

Procedure:
To a stirred solution of 2-chloro-1-(4-(naphthalen-2-ylsulfonyl)piperazin-1-yl)ethanone (compound 5, 0.1 g, 0.85 mmol) in THF (10 mL) diisopropyl ethyl amine (81 mg, 0.62 mmol) was added at 0° C. followed by methyl amine solution (30% solution, 10 mL). The reaction mixture was allowed to stir for overnight at room temperature. The reaction mixture was poured into a large volume of water (50 mL) and the solution was extracted with ethyl acetate. The combined organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to obtain the title compound (20.0 mg, 22.90% yield) as an off-white solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([CH:10]1[O:12][CH2:11]1)[Cl:9]>>[C:2]([C:3]([O:5][CH2:11][CH:10]([OH:12])[CH2:8][Cl:9])=[O:4])([F:7])([F:6])[F:1]
Reactant: ClCC1CO1
Reactant: O=C(O)C(F)(F)F
Product: O=C(OCC(O)CCl)C(F)(F)F
Temperature: 0 °C

Procedure:
To 22.8 g (0.2 mole) of trifluoroacetic acid stirred in an ice-cooled flask was added 102 grams (1.1 moles) of epichlorohydrin at such a rate as to maintain the reaction temperature at 60°-70° C. Excess epichlorohydrin was removed under reduced pressure (35 torr) to yield the initiator CF3CO2CH2CH(CH2Cl)OH product which contained some isomeric CF3CO2CH(CH2Cl)CH2OH. SnCl4 catalyst (3.1 g) was added. The temperature was held at 70°-75° C. while an additional 275 g epichlorohydrin was added over a 90-minute period. The reaction mixture was stirred an additional 16 hours at 70° C., stripped at 70° C. and 5 torr for two hours. The stripped, blocked polyepichlorohydrin intermediate was unblocked by reacting it with a mixture of 180 g methanol, 20 g water, and 20 g concentrated ammonium hydroxide, first at a temperature of 30° C. for 30 minutes and then at 65° C. for 90 minutes. The pH of the aqueous phase was neutral (about 7). The organic phase was washed twice with a solution of 180 g of methanol and 20 g of water, then stripped at 60° C. at 5 torr to yield the desired primary hydroxyl-terminated polyepichlorohydrin polyol, having a structure like that of formula III, supra, Scheme III, where R3 is --CH(CH2Cl)--. Proton nmr analysis at 100 MHz showed the presence of 19% primary and 81% secondary hydroxyl groups.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C@@H:13]([CH2:14][OH:15])[CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]1[C@@H:13]([CH2:14][O:15][S:34]([CH3:33])(=[O:36])=[O:35])[CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1COS(C)(=O)=O
Temperature: 25 °C
Yield: 96 %

Procedure:
The product of Example 7G (43.7 g, 125 mmol) and triethylamine (25.2 g, 250 mmol) in CH2Cl2 (600 mL) were treated with methanesulfonyl chloride (12.6 mL, 163 mmol) over 30 minutes at −10° C. The solution was allowed to warm to ambient temperature over 1 hour and was monitored by HPLC. When the reaction was completed, it was quenched with water (100 mL). The layers were separated and the aqueous phase was extracted with CH2Cl2 (2×400 mL). The combined organic phases were washed with brine (2×100 mL), dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure to provide the title compound as a brown oil (52.0 g, 0.12 mol, 97% yield). 1H NMR (CDCl3, 300 MHz) δ 1.46 (s, 9H), 2.80 (m, 1H), 3.08 (s, 3H), 3.40 (m, 2H), 3.70 (m, 2H), 4.10 (m, 1H), 4.40 (m, 2H), 4.75 (m, 1H), 5.16 (s, 2H), 7.30 m, 5H); MS (DCl/NH3) m/z 446 (M+NH4)+, 429 (M+H)+. HPLC conditions: HPLC conditions: Zorbax-XDB-C8 column 4.6×250 mm with solvents H2O (0.2 v. % HClO4)/MeCN (from v.80:20 to 10:90 within 15 min.) at 1.0 mL/Min., UV detection @220 nm. 20/80, flow rate, 1.0 mL/min; uv 220 nm; tR=13.1 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:13]=[CH:14][C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24]([C:27](O)=[O:28])[CH:25]=[CH:26][C:17]=4[C:16]=3[N:30]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:62][CH2:63][CH2:64][NH:65][C:66](=[O:72])[O:67][C:68]([CH3:71])([CH3:70])[CH3:69]>CN(C=O)C.O>[C:68]([O:67][C:66](=[O:72])[NH:65][CH2:64][CH2:63][NH:62][C:27]([C:24]1[CH:25]=[CH:26][C:17]2[C:16]3[N:30]=[C:12]([NH:11][C:5]4[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:13]=[CH:14][C:15]=3[CH2:21][C:20](=[O:22])[NH:19][C:18]=2[CH:23]=1)=[O:28])([CH3:69])([CH3:71])[CH3:70]
Reactant: COc1ccc(Nc2ncc3c(n2)-c2ccc(C(=O)O)cc2NC(=O)C3)cc1OC
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(Nc2ncc3c(n2)-c2ccc(C(=O)NCCNC(=O)OC(C)(C)C)cc2NC(=O)C3)cc1OC
Temperature: 22 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(3,4-dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-9-carboxylic acid (I-53) (75 mg, 0.18 mmol) in DMF (5 mL) was added N,N-diisopropylethylamine (0.10 mL, 0.55 mmol), TBTU (65 mg, 0.20 mmol), and tert-butyl 2-aminoethylcarbamate (35.5 mg, 0.22 mmol). The reaction stirred at 22° C. overnight. The reaction mixture was diluted with H2O, and the precipitate that formed was filtered, washed with H2O and dried to give I-71-a [MS m/z═549 (M+H)] which was carried on crude to the deprotection.
Reaction SMILES: [ClH:1].O1CCO[CH2:4][CH2:3]1.Cl.[C:9]1([C@H:19]([NH:21][CH2:22][C@@H:23]2[C@@H:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:26][N:25]([C:34](=[O:42])[CH2:35][CH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])[CH2:24]2)[CH3:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1>C(O)C>[ClH:1].[C:9]1([C@H:19]([NH:21][CH2:22][C@@H:23]2[C@@H:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:26][N:25]([C:34](=[O:42])[CH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH2:3][CH3:4])=[O:40])[CH2:24]2)[CH3:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: C1COCCO1
Reactant: C[C@@H](NC[C@H]1CN(C(=O)CCCCC(=O)O)C[C@@H]1c1ccccc1)c1cccc2ccccc12
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CCCCC(=O)N1C[C@H](CN[C@H](C)c2cccc3ccccc23)[C@@H](c2ccccc2)C1
Temperature: 25 °C

Procedure:
A 2.0 ml portion of 4 M hydrogen chloride/1,4-dioxane was added to a 5.0 ml ethanol solution of 200 mg of 6-[(3S,4S)-3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]-6-oxohexanoic acid hydrochloride and stirred at room temperature for 1Hour. By evaporating the solvent and crystallizing the residue from ethyl acetate-hexane, 154 mg of ethyl 6-[(3S,4S)-3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]-6-oxohexanoate hydrochloride was obtained as a colorless solid.