Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].N1C=CC=CC=1>ClCCl>[Cl:15][C:16]1[CH:17]=[C:18]([NH:19][S:2]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9](=[O:14])[CH2:8]3)(=[O:4])=[O:3])[CH:20]=[CH:21][CH:22]=1
Reactant: Nc1cccc(Cl)c1
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C1Cc2cc(S(=O)(=O)Nc3cccc(Cl)c3)ccc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
A suspension of 5-chlorosulfonyl-2-oxindole (5 g), 3-chloroaniline (2.74 mL) and pyridine (3.5 mL) in dichloromethane (30 mL) was stirred at room temperature for overnight. The precipitate was filtered, washed with dichloromethane and dried to give 5.2 g (74%) 2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid (3-chloro-phenyl)-amide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9].[Na+].[S:25]1[CH2:30][CH2:29][N:28]([C:31]2([C:34]([O-])=[O:35])[CH2:33][CH2:32]2)[CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:34]([C:31]2([N:28]3[CH2:27][CH2:26][S:25][CH2:30][CH2:29]3)[CH2:33][CH2:32]2)=[O:35])[C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Reactant: O=C([O-])C1(N2CCSCC2)CC1
Agent: [Na+]
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2C(=O)C2(N3CCSCC3)CC2)CC1
Yield: 46 %

Procedure:
The reaction of (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 7H with 1-thiomorpholinocyclopropanecarboxylic acid sodium salt 16C carried out according to the general procedure L yielded (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-thiomorpholinocyclopropanecarbonyl)pyrrolidine-2-carboxamide as a light brown solid (46%). MS ISP (m/e): 523.3 (100) [(M+H)]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([N:20]3[CH2:25][CH2:24][CH:23]([CH:26](OC)[O:27]C)[CH2:22][CH2:21]3)(=[O:19])=[O:18])=[CH:13][CH:12]=2)[N:7]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:12]=[CH:13][C:14]([S:17]([N:20]3[CH2:25][CH2:24][CH:23]([CH:26]=[O:27])[CH2:22][CH2:21]3)(=[O:18])=[O:19])=[CH:15][CH:16]=2)[N:7]=1
Reactant: COC(=O)CCc1nc(-c2ccc(S(=O)(=O)N3CCC(C(OC)OC)CC3)cc2)no1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CCc1nc(-c2ccc(S(=O)(=O)N3CCC(C=O)CC3)cc2)no1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 223.1 %

Procedure:
The intermediate 3-[3-(4-{[4-(dimethoxymethyl)-1-piperidinyl]sulfonyl}-phenyl)-1,2,4-oxadiazol-5-yl]propanoic acid methyl ester(0.13 g, 0.22 mmol) was dissolved in 10 mL of CH2Cl2 containing 1 mL of TFA and stirred at ambient temperature for 45 minutes. The reaction mixture was concentrated in vacuo to an oil. The residue was partitioned with CH2Cl2 and sat'd NaHCO3. The organic base was dried (Na2SO4) and concentrated in vacuo to give the product (0.2 g) as a clear oil which was used as is.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.OOS([O-])=O.[K+].O>CN(C=O)C>[Br:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:14]=2)=[CH:18][CH:17]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: Nc1ccccc1Nc1ccccc1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 35.5 %

Procedure:
N-Phenyl-o-phenylenediamine (50 g, 0.27 mol) is dissolved in anhydrous DMF (400 ml) under N2, and 4-bromobenzaldehyde (45.5 g, 0.25 mol) is added dropwise. The reaction mixture is warmed to 40° C., and Oxone (potassium hydrogen monopersulfate, 98.1 g, 0.16 mol) is added in portions. After the mixture has been stirred at room temperature for 120 min., 1 l of water is added. The precipitated product is filtered off, washed with water and dried in vacuo. Recrystallisation from acetonitrile gives a cream-coloured solid (31 g, 35%).
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:12]([O-])=[O:13].[Na+]>O>[N:12]([N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][C:9]([OH:11])=[O:10])=[O:13]
Reactant: O=C(O)CNc1ccccc1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=NN(CC(=O)O)c1ccccc1

Procedure:
The precursor N-nitrosophenylglycine was prepared according to the method described in Organic Syntheses, Coll. Vol. 5, p. 962 (1973); Vol. 45, p. 96 (1965). N-phenyl glycine (50 g) was dissolved in water (600 ml) with stirring, and the solution was cooled to below 0° C. in a salt/ice bath mixture. To this was slowly added a cooled solution of sodium nitrite (25 g) in water (150 ml) so that the temperature of the mixture never rose above 0° C. After addition was complete, the mixture was stirred below 0° C. for 40 minutes after which a red-brown solution was obtained with a small amount of brown solid residue. The residue was removed by filtering the solution under vacuum, and the clear liquid was decolorised by treating with charcoal (5 g) for 5 minutes. After filtering off the charcoal, the solution was cooled again and acidified with concentrated hydrochloric acid (50 ml), whereupon a slightly reddish-brown precipitate formed. The mixture was stirred for 10 minutes and then the precipitate was filtered off. This was allowed to dry in air to give a tan coloured powder (48 g).
Reaction SMILES: [CH:1]1([N:4]2[C:8]([NH2:9])=[C:7]([I:10])[CH:6]=[N:5]2)[CH2:3][CH2:2]1.C(NC(C)C)(C)C.[C:18](Cl)(=[O:20])[CH3:19]>ClCCl>[CH:1]1([N:4]2[C:8]([NH:9][C:18](=[O:20])[CH3:19])=[C:7]([I:10])[CH:6]=[N:5]2)[CH2:3][CH2:2]1
Reactant: CC(=O)Cl
Reactant: Nc1c(I)cnn1C1CC1
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: CC(=O)Nc1c(I)cnn1C1CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 103.1 %

Procedure:
A 100-mL round-bottom flask was charged with 1-cyclopropyl-4-iodo-1H-pyrazol-5-amine (0.250 g, 1.00 mmol), N,N-diisopropylamine (0.52 mL, 2.99 mmol) and dichloromethane (8 mL), and the solution was cooled to 0° C. A solution of acetyl chloride (0.085 mL, 1.19 mmol) in dichloromethane (2 mL) was added dropwise, and the resulting solution stirred for 1 h at 0° C. The reaction mixture was concentrated under vacuum, and the residue was purified via column chromatography on silica gel (gradient elution with 0.5-50% ethyl acetate/petroleum ether) to afford N-(1-cyclopropyl-4-iodo-1H-pyrazol-5-yl)acetamide (0.300 g, 92%) as yellow oil. MS (ESI, pos. ion) m/z 292 [M+H]+.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH2:14]([NH:21][CH:10]1[CH2:11][CH2:12][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1CCN(c2ccccc2)CC1
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: c1ccc(CNC2CCN(c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-Phenylpiperidin-4-one (2.0 g, 11.4 mmol) (from Example 123) and benzylamine (1.33 g, 12.5 mmol) were dissolved in 1,2-dichloroethane (35 mL) and acetic acid (1.36 g, 22.6 mmol) was added. The mixture was stirred for 2 hrs at room temperature, then cooled to 0° C. (ice-water) and sodium triacetoxyborohydride (3.14 g, 14.8 mmol) was added, then the reaction mixture was stirred at room temperature for 18 hrs. Sat. NaHCO3 (aq) (30 mL) was added, and the organic layer was extracted. The aqueous phase was extracted with dichloromethane (2×50 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with hexane--30% ethyl acetate to give the product as a white solid.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[F:23][C:24]([F:28])([F:27])[CH2:25][NH2:26].[Cl:29][C:30]1[CH:35]=[CH:34][N:33]=[C:32]([C:36](O)=[O:37])[CH:31]=1>O.ClCCl>[F:23][C:24]([F:28])([F:27])[CH2:25][NH:26][C:36]([C:32]1[CH:31]=[C:30]([Cl:29])[CH:35]=[CH:34][N:33]=1)=[O:37]
Reactant: NCC(F)(F)F
Reactant: O=C(O)c1cc(Cl)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: O=C(NCC(F)(F)F)c1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
1-hydroxybenzotriazole (0.53 g, 3.5 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSC) (0.67 g, 3.5 mmol) and 2,2,2-trifluoroethyl amine (0.51 ml. 6.35 mmol) were added to a dichloromethane solution (5 ml) of 4-chloropyridine-2-carboxylic acid (0.5 g, 3.17 mmol) and the mixture was stirred at room temperature for one hour. Water was added to the reaction solution, which was then extracted with ethyl acetate. The extraction solution with ethyl acetate was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=11:1→5:1). The purified product was concentrated to dryness under reduced pressure to obtain N-(2,2,2-trifluoroethyl)-4-chloropyridine-2-carboxamide (435 mg) as white powder.
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=O)=[O:3].C(N(CC)CC)C.[C:17]1([CH2:23][C@H:24]([NH2:27])[CH:25]=[CH2:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[CH3:1][S:2]([NH:27][C@H:24]([CH:25]=[CH2:26])[CH2:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:5])=[O:3]
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: C=C[C@@H](N)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C[C@H](Cc1ccccc1)NS(C)(=O)=O
Reaction time: 1 h

Procedure:
2.36 g (13.6 mmol) of methansulfonic acid anhydride and 1.88 ml (13.6 mmol) of triethylamine are added at 0° C. to a solution of 1 g (6.8 mmol) of 1-phenyl-3-buten-2(S)-amine from Example 16b) in 10 ml methylene chloride and the mixture is stirred for 1 h. The reaction mixture is washed with water and saturated sodium hydrogen carbonate solution and the organic phase is filtered through cotton wadding and concentrated by evaporation to yield 2(S)-methylsulfonylamino-1-phenyl-3-butene. 1 g (4.4 mmol) of that crude product is dissolved in 30 ml of methylene chloride, 3.05 g (17.7 mmol) of 4-chloroperbenzoic acid are added at RT and stirring is carried out for 18 h. The reaction solution is washed 5 times with 10% aqueous sodium sulfite solution, filtered through cotton wadding and fully concentrated by evaporation. According to 1H-NMR the crude product contains both the (2R)- and the (2S)-epimer in a ratio of 4:1. 1 H-NMR (200 MHz, CD3OD): 2.30 and 2.52 (2 s, together 3H), 2.6 to 3.2 (m, 5H), 3.55 (m, 1H) 7.32 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[NH:11][C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([N:11]1[C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=[C:2]1[Cl:1])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: Cn1c(=O)c2[nH]c(Cl)nc2n(C)c1=O
Product: Cn1c(=O)c2c(nc(Cl)n2Cc2ccccc2)n(C)c1=O

Procedure:
From 8-Chlorotheophylline (50 g, 233 mmol) and benzyl bromide.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[CH:5]=[C:4]([CH3:12])[N:3]=1.[I:13]N1C(=O)CCC1=O.S([O-])(O)=O.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[C:5]([I:13])=[C:4]([CH3:12])[N:3]=1
Reactant: CCCNc1cc(C)nc(Cl)n1
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCCNc1nc(Cl)nc(C)c1I
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
To a suspension of 2-chloro-6-methyl-N-propylpyrimidin-4-amine (T1, 200 mg) in acetic acid (4 mL), N-iodosuccinimide (485 mg) was added at room temperature, and the mixture was stirred at 80° C. for 30 minutes. The reaction mixture was cooled to room temperature, and then saturated aqueous sodium hydrogensulfite, saturated aqueous sodium hydrogencarbonate and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 90-75% hexane in ethyl acetate) to obtain 2-chloro-5-iodo-6-methyl-N-propylpyrimidin-4-amine (T2, 252 mg).
Reaction SMILES: [OH-].[K+].[C:3]1([SH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19]>CN(C)C=O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([S:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[C:12]([N+:18]([O-:20])=[O:19])[CH:13]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Reactant: Sc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cl)ccc1Sc1ccccc1
Reaction time: 3 h
Yield: 57 %

Procedure:
Potassium hydroxide (6.15 g; 87%) was added to a stirred solution of thiophenol (10.0 g) in N,N-dimethylformamide (170 mL) at room temperature. When most of the potassium hydroxide appeared to have dissolved, 2,5-dichloronitrobenzene (17.4 g) was added, and the initially dark solution turned bright yellow with some precipitate. The reaction was placed in an oil bath at 70° C. for three hours, and then evaporated in vacuo. The residue was partitioned between chloroform and 1N NaOH and the layers were separated. The aqueous layer was extracted once more with chloroform. The chloroform solutions were combined, washed with 1N NaOH, H2O, 1N HCl, H2O and brine, dried over MgSO4, and evaporated in vacuo. The resulting oil was treated with cyclohexane, and the product crystallized. The crystalline product was collected by filtration, washed with hexane, and dried in vacuo at 56° C. to yield 13.73 g (57%) of yellow crystals. mp: 84°-86° C.
Reaction SMILES: Cl.Cl.[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[O:12][C:13]1[CH:21]=[C:20]2[C:16]([C:17]([CH2:22][N:23]3[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]3)=[CH:18][NH:19]2)=[CH:15][CH:14]=1.CCN(CC)CC.[C:37](OC(=O)C)(=[O:39])[CH3:38]>C(Cl)Cl>[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[O:12][C:13]1[CH:21]=[C:20]2[C:16]([C:17]([CH2:22][N:23]3[CH2:28][CH2:27][CH:26]([NH:29][C:37](=[O:39])[CH3:38])[CH2:25][CH2:24]3)=[CH:18][NH:19]2)=[CH:15][CH:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: NC1CCN(Cc2c[nH]c3cc(Oc4nc5ccccc5s4)ccc23)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC1CCN(Cc2c[nH]c3cc(Oc4nc5ccccc5s4)ccc23)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60 %

Procedure:
To a suspension of 1-[6-(benzothiazol-2-yloxy)-1H-indol-3-ylmethyl]-piperidin-4-ylamine 2HCl (200 mg, 0.44 mmol) in DCM (4 mL) was added Et3N (0.37 mL, 270 mg, 2.7 mmol) and acetic anhydride (0.067 mL, 68 mg, 0.66 mmol) and the resulting reaction mixture was stirred (rt, 24 h). The reaction mixture was partitioned with EtOAc (50 mL) and brine (50 mL) and the organic layer was dried, filtered and concentrated in vacuo. The resulting residue was purified silica gel flash column chromatography using MeOH (0.2 M NH3):DCM (0-15%) to provide the title compound as a white solid (111 mg, 60%). MS (ESI): mass calcd. for C23H24N4O2S, 420.5; m/z found, 421.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 9.00 (s, 1H), 7.73 (d, J=6.0, 1H), 7.71 (d, J=5.2, 1H), 7.63 (d, J=7.5, 1H), 7.39-7.36 (m, 1H), 7.31 (br s, 1H), 7.26-7.24 (m, 1H), 7.10 (br s, 1H), 7.07 (dd, J=8.6, 2.1, 1H), 5.55 (br d, 1H), 3.80-3.70 (m, 1H), 3.68 (s, 2H), 2.89 (d, J=11.7, 2H), 2.17-2.13 (m, 2H), 1.96 (s, 3H), 1.89 (d, J=11.0, 2H), 1.48-1.40 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20])[C:8]([CH2:21][NH2:22])=[CH:7]2.Br[C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[NH:26][CH:27]=[N:28]2.C(O)CCC>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20])[C:8]([CH2:21][NH:22][C:24]1[N:32]=[CH:31][N:30]=[C:29]3[C:25]=1[N:26]=[CH:27][NH:28]3)=[CH:7]2
Reactant: Brc1ncnc2nc[nH]c12
Reactant: COc1ccc(F)cc1-c1nc2c(Cl)cccc2cc1CN
Solvent: CCCCO
Product: COc1ccc(F)cc1-c1nc2c(Cl)cccc2cc1CNc1ncnc2[nH]cnc12
Temperature: 100 °C

Procedure:
To a stirred mixture of (8-chloro-2-(5-fluoro-2-methoxyphenyl)quinolin-3 yl)-methanamine (190.4 mg, 0.601 mmol) and 6-bromopurine (126 mg, 0.631 mmol) in 1-butanol (3.300 mL, 36.1 mmol) was added N,N-ethyldiisopropylamine (0.209 mL, 1.20 mmol). The mixture was heated to 100° C. overnight. The solvents were removed and the residue subjected to chromatography: gradient/isocratic 1H NMR (500 MHz, DMSO-d6) δ ppm 12.93 (1H, br. s.), 8.28 (1H, br. s.), 8.09 (2H, s), 7.96 (1H, d, J=8.1 Hz), 7.91 (1H, d, J=7.3 Hz), 7.55 (1H, t, J=7.8 Hz), 7.26-7.33 (1H, m), 7.21 (1H, dd, J=8.6, 3.2 Hz), 7.15 (1H, br. s.), 3.77 (3H, s), 3.32 (2H, s) Mass Spectrum (ESI) m/e=335.1 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.N[CH2:10][C@@H:11]1CC[CH2:13][N:12]1CC.C(=O)C>>[CH3:1][N:2]([CH3:8])[C@@H:3]1[CH2:7][CH2:6][N:5]([CH2:10][CH2:11][NH:12][CH3:13])[CH2:4]1
Reactant: CN(C)[C@@H]1CCNC1
Reactant: CCN1CCC[C@H]1CN
Agent: CC=O
Product: CNCCN1CC[C@@H](N(C)C)C1

Procedure:
By using (3R)-(+)-3-(dimethylamino)pyrrolidine (200 mg) as a starting material, the title compound (123 mg) was obtained in the same manners as those of Reference Example 1, (1) and Reference Example 19, (3).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:68])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:64]([CH3:67])[CH2:65][CH3:66])[C@H:24]([O:62][CH3:63])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:60][CH3:61])[C@@H:34]([CH3:59])[C:35]([NH:37][C@@H:38]([CH2:49][C:50]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[NH:52][CH:51]=1)[C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])(O)=[O:2].[O:69]=[C:70]1[CH:74]=[CH:73][C:72](=[O:75])[N:71]1[CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][C:81]([NH:83][NH2:84])=[O:82].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[O:75]=[C:72]1[CH:73]=[CH:74][C:70](=[O:69])[N:71]1[CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][C:81]([NH:83][NH:84][C:1](=[O:2])[CH2:4][CH2:5][CH2:6][N:7]([CH3:68])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:64]([CH3:67])[CH2:65][CH3:66])[C@H:24]([O:62][CH3:63])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:60][CH3:61])[C@@H:34]([CH3:59])[C:35]([NH:37][C@@H:38]([CH2:49][C:50]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[NH:52][CH:51]=1)[C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:17])[CH3:18])=[O:13])[CH:9]([CH3:10])[CH3:11])=[O:82]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Reactant: NNC(=O)CCCCCN1C(=O)C=CC1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)NNC(=O)CCCCCN1C(=O)C=CC1=O)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9 mg (9.5 μmol) of N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-(benzyloxy)-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (Intermediate 72) were dissolved in 1000 μl of DMF and then admixed with 10 mg (38 μmol) of commercially available 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanehydrazide, 7.2 mg (19 μmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate and 8 μl of N,N-diisopropylethylamine, and the reaction mixture was stirred at RT for 1 h. Subsequently, the solvent was removed under reduced pressure and the remaining residue was purified by means of preparative HPLC. The corresponding fractions were concentrated and, by lyophilization, 6.4 mg (58% of theory) of the title compound were obtained as a colourless foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[CH:13](Cl)Cl.S(=O)(=O)(O)[OH:17]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[CH:13]=[O:17]
Reactant: O=S(=O)(O)O
Reactant: Clc1cnc2c(C(Cl)Cl)c(Cl)ccc2c1
Product: O=Cc1c(Cl)ccc2cc(Cl)cnc12

Procedure:
56 parts of 3,7-dichloro-8-dichloromethylquinoline in 250 parts of 90% strength sulfuric acid were stirred at 100° C. for 6 hours. After cooling, the solution was poured onto ice and the precipitated solid was filtered off with suction, washed neutral with water and dried. 195 parts of 3,7-dichloroquinoline-8-carbaldehyde of melting point 208° C. were obtained. The yield corresponds to 87% of theory.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH:12]2[O:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]3[O:37][CH2:36][C:35](=O)[N:34]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[C:33]=3[CH:44]=2)=[CH:7][CH:6]=1)=O.B1C2CCCC1CCC2.C(CN)O>O1CCCC1>[OH:2][CH2:3][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])[CH2:13][CH:12]2[O:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]3[O:37][CH2:36][CH2:35][N:34]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[C:33]=3[CH:44]=2)=[CH:9][CH:10]=1
Reactant: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(C(=O)OC)cc3)cc21
Agent: B1C2CCCC1CCC2
Solvent: NCCO
Solvent: C1CCOC1
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(CO)cc3)cc21
Temperature: 25 °C

Procedure:
The solution of 2.0 g of benzyl 4-(4-methoxycarbonylphenyl)-3-[4-(3-methoxypropyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate (Example 235d) in 16 ml of tetrahydrofuran is admixed with 52.1 ml of 9-BBN and stirred at reflux over 24 hours. The reaction mixture is cooled to room temperature, admixed with 1.58 ml of ethanolamine and concentrated by evaporation. The residue is stirred in 50 ml of ethyl acetate-hexane (1:1) over 1 hour and clarified by filtration, and the filtrate is concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.20 (3:1 EtOAc-heptane); Rt=4.74.
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16]Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(#N)C.C([O-])(=O)C.[Ag+]>[C:1]([O:9][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:8])[CH3:2]
Reactant: O=C(OCCOCCOCCl)c1ccccc1
Agent: [Ag+]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: CC(=O)OCOCCOCCOC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 194.6 %

Procedure:
Silver acetate (3.34 g) was added with cooling and stirring to a solution of 2-(2-benzoyloxyethoxy)ethoxymethyl chloride (5.18 g) in dry acetonitrile (15 ml). The reaction mixture was stirred overnight at room temperature. The precipitate was removed by filtration and the filtrated evaporated under reduced pressure at 35° C. to give 2-(2-benzoyloxyethoxy)ethoxymethyl acetate (5.5 g) as a pale yellow oil. NMR and IR spectra were consistent with this structure.