Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([O:24][CH2:25][C@@H:26]4[C@@H:30]([OH:31])[CH2:29][CH2:28][NH:27]4)=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[N:34]=2)[N:4]=1)[CH3:2].C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:44](C)=O.[Na+]>CO>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([O:24][CH2:25][C@@H:26]4[C@@H:30]([OH:31])[CH2:29][CH2:28][N:27]4[CH3:44])=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[N:34]=2)[N:4]=1)[CH3:2]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(OC[C@H]5NCC[C@@H]5O)ccn34)c12
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(OC[C@@H]5[C@@H](O)CCN5C)ccn34)c12
Reaction time: 0.5 h

Procedure:
To N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(((2R,3S)-3-hydroxypyrrolidin-2-yl)methoxy)imidazo[1,2-a]pyridine-3-carboxamide (5 mg, 0.0095 mmol; Example 38 in MeOH (1 mL) was added HCHO (as a 35% aqueous solution) (7.7 mg, 0.095 mmol) and NaBH(OAc)3 (10 mg, 0.048 mmol). The reaction mixture was stirred for 30 minutes and concentrated under reduced pressure. Purification by silica gel chromatography (DCM/MeOH/NH4OH 10:1:0.1) provided the final product (3 mg). MS (ES+APCI) m/z=540 (M+H).
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]([CH2:16][CH3:17])[CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Se](=O)=[O:19].O>ClC1C=CC=CC=1>[CH2:1]([O:8][N:9]=[C:10]([CH2:16][CH3:17])[C:11](=[O:19])[C:12]([O:14][CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(CC(=O)OC)=NOCc1ccccc1
Reactant: O=[Se]=O
Solvent: O
Solvent: Clc1ccccc1
Product: CCC(=NOCc1ccccc1)C(=O)C(=O)OC
Temperature: 120 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
To a solution of 47.06 g (0.2 mol) of methyl 3-benzyloxyiminovalerate in 150 ml of chlorbenzene, 24.41 g (0.22 mol) of selenium dioxide was added and the mixture was stirred for 8 hours at 120° C. After adding 200 ml of water and filtering through Celite, the filtrate was extracted three times with 200 ml of diethylether. After washing with water and a saturated aqueous sodium chloride followed by drying over with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a residue, which was purified by a column chromatography on a silica gel (n-hexanelethyl acetate) to obtain 31.15 g (yield 62%) of methyl 3-benzyloxyimino-2-oxovalerate as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][C:11](=O)[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1.[N:21]1([C:26]2[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=2)[CH:25]=[CH:24][N:23]=[CH:22]1>C(O)C.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Zn+2]>[N:21]1([C:26]2[CH:27]=[CH:28][C:29]([N:32]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=4)=[CH:9][CH:10]=[C:11]3[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:30][CH:31]=2)[CH:25]=[CH:24][N:23]=[CH:22]1
Reactant: Nc1ccc(-n2ccnc2)cn1
Reactant: CCOC(=O)CCC(=O)CCC(=O)c1ccc(Br)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Zn+2]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(-c2ccc(Br)cc2)n1-c1ccc(-n2ccnc2)cn1
Yield: 7.2 %

Procedure:
To a solution of ethyl 7-(4-bromophenyl)-4,7-dioxoheptanoate (5B) (2.56 g, 7.5 mmol) and 5-(1H-imidazol-1-yl)pyridin-2-amine (1.20 g, 7.5 mmol) in 15 mL of ethanol was added Zn(OTf)2 (8.18 g, 22.5 mmol). The resultant mixture was heated at 120° C. for 4 h under microwave irradiation and then concentrated to dryness. The resultant residue was dissolved in EA, washed with water and brine, dried over MgSO4, concentrated and purified by silica gel column chromatography (PE:EA=6:1) to afford ethyl 3-(1-(5-(1H-imidazol-1-yl)pyridin-2-yl)-5-(4-bromophenyl)-1H-pyrrol-2-yl)propanoate as a brown oil (250 mg, 7.1%).
Reaction SMILES: S(Cl)(Cl)=O.[NH:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.C(Cl)Cl.[Cl:13][C:14]1[CH:32]=[CH:31][C:17]([CH2:18][O:19][C:20]2[CH:30]=[CH:29][CH:28]=[CH:27][C:21]=2[C:22]([NH:24][O:25][CH3:26])=O)=[CH:16][CH:15]=1>O>[CH3:26][O:25][N:24]=[C:22]([N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)[C:21]1[CH:27]=[CH:28][CH:29]=[CH:30][C:20]=1[O:19][CH2:18][C:17]1[CH:31]=[CH:32][C:14]([Cl:13])=[CH:15][CH:16]=1
Reactant: c1c[nH]cn1
Reactant: CONC(=O)c1ccccc1OCc1ccc(Cl)cc1
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CON=C(c1ccccc1OCc1ccc(Cl)cc1)n1ccnc1
Yield: 1.9 %

Procedure:
Thionyl chloride (0.16 ml) was added to a suspension of imidazole (0.63 g) and methylene chloride (6 ml) under ice-cooling, and the mixture was stirred under ice-cooling for 30 minutes. Then 2-(4-chlorobenzyloxy)-N-methoxybenzamide (0.44 g) was added, and the mixture was stirred under reflux for 2 hours. After completion of the reaction, water (100 ml) was added, and the mixture was extracted with methylene chloride (50 ml) twice, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel chromatography to give 2-(4-chlorobenzyloxy)-α-(1-imidazolyl)benzaldehyde O-methyloxime (0.01 g) as colorless crystals. mp. 92.5°-93.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:6]([CH:7]=[O:8])[C:5]=1[OH:12])[CH3:2].[C:13](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]1[C:5]([O:12][CH3:13])=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOc1cccc(C=O)c1O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: CCOc1cccc(C=O)c1OC
Temperature: 60 °C
Reaction time: 5 h
Yield: 101.4 %

Procedure:
To a suspension of 3-ethoxysalicylaldehyde (1.00 g, 6.02 mmol) and potassium carbonate (3.33 g, 24.1 mmol) in N,N-dimethylformamide (10 mL) was added dimethyl sulfate (0.91 g, 7.22 mmol), and the mixture was stirred at 60° C. for 5 hours. The reaction mixture was diluted with ethyl acetate, filtered, and the filtrate was washed with water, and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=7:3) to give the title compound (1.10 g, yield 99%) as an oily matter.
Reaction SMILES: [C:1]([CH:3]([C:12]#[N:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)#[N:2].[H-].[Na+].[CH3:16]I.O>CN(C=O)C>[C:1]([C:3]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)([C:12]#[N:13])[CH3:16])#[N:2]
Reactant: CI
Reactant: COc1ccc(C(C#N)C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(C)(C#N)C#N)cc1
Reaction time: 22 h
Yield: 268.5 %

Procedure:
To a mixture of Compound 35 (1.0 g, 6.0 mmol) and NaH (280 mg, 7.0 mmol) in DMF (12 ml) was added MeI (1.0 g, 7.0 mmol) at room temperature. After the mixture was stirred for 22 hours, the mixture was poured into H2O (30 ml), and extracted with CH2Cl2. The combined extracts were dried (Na2SO4), and concentrated to give a yellow oil (3 g), which was purified by a column chromatography on silica gel to give Compound 35 as a colorless solid (900 mg, 81%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[CH3:25][C:26]1[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29].C(NC1C=CC(N2C(=O)CC(=O)NC3C4C(C=CC2=3)=CC=CC=4)=CC=1)(=O)C1C=CC=CC=1>>[CH3:25][C:26]1[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[O:29]
Reactant: Cc1cccc(C(=O)Cl)c1C
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: O=C1CC(=O)N(c2ccc(NC(=O)c3ccccc3)cc2)c2ccc3ccccc3c2N1
Product: Cc1cccc(C(=O)Nc2ccc(N3C(=O)CC(=O)Nc4c3ccc3ccccc43)cc2)c1C
Yield: 10.5 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30 mg, 0.095 mmol) obtained in Example 1, (3), and 2,3-dimethylbenzoyl chloride (0.143 mmol), the title compound (4.5 mg, yield 11%) was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:18])[C:5]([NH2:17])=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16].C1N=CN([C:24](N2C=NC=C2)=[O:25])C=1>C(OCC)(=O)C>[Br:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])=[CH:6][C:5]2[NH:17][C:24](=[O:25])[NH:18][C:4]=2[CH:3]=1
Reactant: Nc1cc(Br)c(Oc2ccc(F)cc2F)cc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Product: O=c1[nH]c2cc(Br)c(Oc3ccc(F)cc3F)cc2[nH]1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 38.8 %

Procedure:
A solution of 4-bromo-5-(2,4-difluorophenoxy)benzene-1,2-diamine (0.371 g, 1.18 mmol) in ethyl acetate (5.20 mL) was treated with N,N-carbonyldiimidazole (0.23 g, 1.4 mmol) and stirred at 50° C. for 30 min. The reaction mixture was treated with additional N,N-carbonyldiimidazole (1.2 eq) and stirred at 50° C. for 1 h. The reaction mixture was cooled to 20° C. and the heterogeneous mixture was filtered to give the desired product (156 mg, 39%) as a light grey solid. LCMS calculated for C13H8BrF2N2O2 (M+H)+: m/z=341.0, 343.0. found: 341.0, 342.9.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[C:14]([NH:19][NH2:20])(=O)[CH2:15][CH2:16][CH3:17]>C(O)CCC>[CH2:15]([C:14]1[N:3]2[N:4]=[C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:6]=[CH:7][C:2]2=[N:20][N:19]=1)[CH2:16][CH3:17]
Reactant: CCCC(=O)NN
Reactant: Clc1ccc(-c2ccccc2)nn1
Solvent: CCCCO
Product: CCCc1nnc2ccc(-c3ccccc3)nn12

Procedure:
A mixture of 10 g. of 3-chloro-6-phenylpyridazine, 11.2 g. of butyric acid hydrazide and 100 ml. of n-butanol is heated at reflux for 40 hours. The solution is cooled and the precipitate is filtered and washed with petroleum ether and water. The filtrate is concentrated to an oil which forms a precipitate upon the addition of petroleum ether. The precipitate is collected and washed with petroleum ether and water. The solids are combined and recrystallized from 30 ml. of ethanol giving 3-n-propyl-6-phenyl-1,2,4-triazolo[4,3-b]pyridazine as crystals, m.p. 123°-125° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[C:17](=[O:27])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=1.[C:28](Cl)(=[O:30])[CH3:29]>>[C:28]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[C:17](=[O:27])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)n1c(C(=O)c2cccc([N+](=O)[O-])c2)c(N)c2ccc(Cl)cc21
Product: CCOC(=O)n1c(C(=O)c2cccc([N+](=O)[O-])c2)c(NC(C)=O)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 2 (Method A) from 3-amino-6-chloro-1-ethoxycarbonyl-2-(3-nitrobenzoyl)indole (step 1) and acetyl chloride. 1H-NMR (CDCl3) δ: 9.18 (1H, br s), 8.65-8.69 (1H, m), 8.38-8.42 (1H, m), 8.02-8.10 (1H, m), 7.98 (1H, s), 7.61-7.71 (2H, m), 7.18-7.25 (1H, m), 4.15 (2H, q, J=7.0 Hz), 2.24 (3H, s), 1.17 (3H, t, J=7.0 Hz)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12](=[S:15])[NH:13][NH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Na].[C:17](OCC)(=[O:23])[C:18](OCC)=[O:19].Cl>CO.O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]1[C:18](=[O:19])[C:17](=[O:23])[NH:14][NH:13][C:12]1=[S:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(C)(C)OC(=O)NCCNC(=S)NN
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCCn1c(=S)[nH][nH]c(=O)c1=O
Reaction time: 2 h
Yield: 43.1 %

Procedure:
4-(2-tert.-Butoxycarbonylamino-ethyl)-thiosemicarbazide (9.37 g) is added to a solution of sodium (0.92 g) in methanol (40 cc) at 20° C., and diethyl oxalate (5.4 g) is then introduced dropwise in the course of 10 minutes. The mixture is heated under reflux for 3 hours. It is allowed to cool, water (100 cc) is added, concentrated hydrochloric acid (3 cc) is introduced dropwise, the mixture is extracted with ethyl acetate (2×100 cc) and the extract is washed with a saturated sodium chloride solution (2×50 cc), dried ocer sodium sulphate, filtered and concentrated to dryness at 20° C. under 20 mm Hg (2.7 kPa). The residue is taken up in methylene chloride (65 cc), the crystallisation is started, the batch is left for 2 hours at 20° C. and then filtered, and white crystals (4.59 g) of 4-(2-tert.-butoxycarbonylamino-ethyl)-5,6-dioxo-3-thioxoperhydro-1,2,4-triazine, melting at 160° C., are obtained.
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.[CH2:11]([CH:13]1[O:15][CH2:14]1)Cl>[OH-].[Na+]>[O:15]1[CH:13]([CH2:11][O:10][C:3]2[CH:4]=[CH:5][C:6]([N+:7]([O-:9])=[O:8])=[CH:1][CH:2]=2)[CH2:14]1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1ccc(OCC2CO2)cc1
Reaction time: 8 h

Procedure:
p-Nitrophenol (139 g, 1.0 mol) was dissolved in 1.5 l 0.8M sodium hydroxide. Epichlorohydrin, IX, (117 ml, 1.5 mol) was added and the mixture stirred vigorously overnight. The homogenous solution was then extracted three times with 300 ml chloroform and the organic fractions combined and dried over magnesium sulfate. After removal of the drying agent by filtration, evaporation of the filtrate gave a yellow oil which crystallized on standing. The oily crystals were triturated with methanol and filtered to yield 55.6 g of the desired compound as white crystals shown to be homogenous by thin layer chromatography (60:40 ethyl acetate/hexanes, Rf =0.77) m.p. 62°-65° C.
Reaction SMILES: [OH:1][C@@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@H:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.[CH3:34][N:35]([CH3:41])[CH:36]1[CH2:40][CH2:39][NH:38][CH2:37]1>>[OH:1][C@@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:38]4[CH2:39][CH2:40][CH:36]([N:35]([CH3:41])[CH3:34])[CH2:37]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@H:4]([CH3:8])[CH2:3]1
Reactant: CN(C)C1CCNC1
Reactant: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(N4CCC(N(C)C)C4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid ((1S,3S)-1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and 3-dimethylamino-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.16 (s, 1H), 4.00 (t, 2H), 3.80 (t, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.22 (s, 6H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27 (t, 1H), 1.07 (t, 1H), 0.83 (d, 3H). m/z: 446 [M+H]
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[C@H:9]([C:10]([O:12][CH3:13])=[O:11])[O:8][C:7]([CH2:24][CH3:25])([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:16][CH:15]=2)[O:6]1)=[O:4].[BrH:26].BrBr>ClCCCl>[CH3:1][O:2][C:3]([C@H:5]1[C@H:9]([C:10]([O:12][CH3:13])=[O:11])[O:8][C:7]([CH:24]([Br:26])[CH3:25])([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH:21]([CH3:22])[CH3:23])=[CH:18][CH:19]=2)[O:6]1)=[O:4]
Reactant: CCC1(c2ccc(CC(C)C)cc2)O[C@@H](C(=O)OC)[C@H](C(=O)OC)O1
Reactant: Br
Agent: BrBr
Solvent: ClCCCl
Product: COC(=O)[C@@H]1OC(c2ccc(CC(C)C)cc2)(C(C)Br)O[C@H]1C(=O)OC

Procedure:
To a solution in 1,2-dichloroethane (70 ml) of 2-ethyl-2-[4-(2-methylpropyl)-phenyl]-1,3-dioxolane-4(R),5(R)-dicarboxylic acid dimethylester (7.0 g; 20 mmoles obtained according to ex. 29), deoxygenated and added with hydrobromic acid (0.324 g; 4 mmoles), it is added dropwise in 1 h under inert atmosphere at +15° C., a solution of bromine (3.20 g; 20 mmoles) in 1,2-dichloroethane (7.0 ml) previously deoxygenated.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.Cl[C:11](=[O:16])[C:12]([O:14][CH3:15])=[O:13]>>[CH3:15][O:14][C:12](=[O:13])[C:11]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][C:4]=1[F:9])=[O:16]
Reactant: Nc1ccc(Cl)cc1F
Reactant: COC(=O)C(=O)Cl
Product: COC(=O)C(=O)Nc1ccc(Cl)cc1F

Procedure:
In a manner similar to that employed in Referential Example 242, the title compound was prepared from 4-chloro-2-fluoroaniline and methyl chlorooxoacetate.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[NH:9][C:8](=[O:13])[CH:7]=1.[CH2:19](Br)[C:20]#[CH:21]>>[F:1][C:2]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]([CH2:21][C:20]#[CH:19])[C:8](=[O:13])[CH:7]=1
Reactant: Cc1cc(OCc2ccc(F)cc2F)cc(=O)[nH]1
Reactant: C#CCBr
Product: C#CCn1c(C)cc(OCc2ccc(F)cc2F)cc1=O

Procedure:
The title compound was prepared by alkylation of 4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (2.5 g, 10 mmol) with propargyl bromide (1.3 ml, 11.0 mmol) as described above to give 1.39 (44%) of the desired product. 1H-NMR (DMSOd6/300 MHz) δ 7.60 (app q, J=8.4 hz, 1H), 7.35-7.27 (m, 1H); 7.16-7.10 (m, 1H); 5.94 (d, J=2.1 Hz, 1H), 5.88 (d, J=3.0 Hz, 1H), 5.03 (s, 2H), 4.76 (d, J=2.4, Hz, 2H), 3.31 (s, 3H), 3.24 (t, J=2.4 Hz, 1H), 2.39 (s, 3H); ES-HRMS m/z 290.0994 (M+H calcd for C16H14F2NO2=290.0993).
Reaction SMILES: C1(C)C=CC(S([N:10]2[CH2:18][CH2:17][CH2:16][C@@H:15]3[C@H:11]2[CH2:12][C:13]([P:27]([O:32]CC)(=[O:31])[O:28]CC)([P:19]([O:24]CC)(=[O:23])[O:20]CC)[CH2:14]3)(=O)=O)=CC=1.[ClH:36]>>[ClH:36].[C@@H:11]12[CH2:12][C:13]([P:27]([OH:32])(=[O:28])[OH:31])([P:19]([OH:23])(=[O:20])[OH:24])[CH2:14][C@@H:15]1[CH2:16][CH2:17][CH2:18][NH:10]2
Reactant: CCOP(=O)(OCC)C1(P(=O)(OCC)OCC)C[C@@H]2CCCN(S(=O)(=O)c3ccc(C)cc3)[C@@H]2C1
Agent: Cl
Product: O=P(O)(O)C1(P(=O)(O)O)C[C@@H]2CCCN[C@@H]2C1
Temperature: 25 °C
Yield: 71 %

Procedure:
A solution of 10 (6.50 g, 11.8 mmol) in conc. HCl (100 mL) is heated to reflux for 18 h. The mixture is cooled to room temperature, washed with EtOAc (2×20 mL) and the aqueous solution is concentrated in vacuo to a brown residue (10 mL). The crude material is loaded on a Amberlite IRA-400 (Cl) resin column (150 mL), wherein the column is preeluted with 6 M HCl (600 mL) and rinsed with H2O (1 L) to pH 6˜7. The column is eluted with water (3 L) and concentrated in vacuo to give a brown solid, which is dissolved in 6 M HCl (40 mL) and added with activated carbon (1.5 g) and heated to reflux for 5 min, cooled to 50° C., filtered through Celite and the filtrate is concentrated in vacuo to give 1 as a pale yellow solid (2.68 g 71%).
Reaction SMILES: C(Cl)(=O)CCCCC([Cl:8])=O.OCCCCCCCCCCCCCCC[C:27]([O:29][CH:30]([O:32][C:33](=[O:50])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]CCCCCCCCCO)C)=[O:28]>C(Cl)(Cl)Cl>[Cl:8][C:27]([O:29][CH2:30][O:32][C:33](=[O:50])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:28]
Reactant: CC(OC(=O)CCCCCCCCCCCCCCCO)OC(=O)CCCCCCCCCCCCCCCO
Reactant: O=C(Cl)CCCCC(=O)Cl
Solvent: ClC(Cl)Cl
Product: O=C(Cl)OCOC(=O)c1ccccc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 415.4 %

Procedure:
In a three-necked round bottomed flask equipped with a reflux condenser, a glass gas inlet tube and a pressure equalizing dropping funnel was placed freshly distilled adipoyl chloride (2.60 ml, 17.50 mmol) dissolved in absolute chloroform (15 ml). The temperature was raised to ca. 50° C. and under a gentle stream of nitrogen through the solution, a solution of ethylidene bis(16-hydroxyhexadecanoate) (1.0 g, 1.75 mmol) in absolute chloroform (30 ml) was added dropwise and left at this temperature a further 3 hours after addition. The mixture was then cooled to room temperature and quickly transferred into a 50 ml round bottomed flask equipped for distillation under reduced pressure. Chloroform was first distilled off at normal pressure, then oil-pump vacuum was established and excess adipoyl chloride distilled off at ca. 75° C., 5 mbar pressure, leaving the residual title compound (1.56 g).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])([OH:3])=[O:2].O.[C:15]1(C)C=CC(S(O)(=O)=O)=C[CH:16]=1>C(O)C>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])([O:3][CH2:15][CH3:16])=[O:2]
Reactant: O=C(O)CCCCC1CCCC1=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCCCC1CCCC1=O

Procedure:
A stirred solution of 124 g. (0.673 mole) of 2-(4-carboxybutyl)cyclopentan-1-one (Example 2), 800 ml. of ethanol and 1 g. of p-toluenesulfonic acid monohydrate is heated at reflux for 18 hours. The solvent is evaporated and the residue is dissolved in ether. The ether solution is washed with saline, dilute sodium bicarbonate solution and again with saline, dried over magnesium sulfate and evaporated. The oil is distilled under reduced pressure to give 149 g. of a colorless oil, b.p. 106°-109° C. (0.23 mm).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.Cl[CH2:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:16][CH2:15]1)=[O:13].C(OC(C)C)(C)C>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][CH:17]2[CH2:18][CH2:19][N:14]([C:12](=[O:13])[CH2:11][NH:7][C:6]3[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:15][CH2:16]2)=[CH:22][CH:23]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C(CCl)N1CCC(Cc2ccc(F)cc2)CC1
Solvent: CC(C)OC(C)C
Product: COc1ccc(NCC(=O)N2CCC(Cc3ccc(F)cc3)CC2)cc1

Procedure:
The title compound is prepared from 4-methoxy-aniline (Aldrich) and 2-chloro-1-[4-(4-fluoro-benzyl)-piperidin-1-yl]-ethanone (Example 197a) according to the method described in Example 206. Melting Point: 141-143° C. (diisopropylether)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:20]([NH:23][C:24](=[O:37])[C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[CH:27][CH:26]=2)(=[O:22])=[O:21])[CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH2:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O-:3])=[O:2].[CH2:38]([N:46]=[C:47]=[O:48])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN1C(=O)CCC1.O>[N+:1]([C:4]1[CH:5]=[C:6]([S:20]([NH:23][C:24]([C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][N:34]([C:47]([NH:46][CH2:38][CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[O:48])[CH2:33][CH2:32]3)=[CH:27][CH:26]=2)=[O:37])(=[O:21])=[O:22])[CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH2:12][S:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([O-:3])=[O:2]
Reactant: O=C(NS(=O)(=O)c1ccc(NCCSc2ccccc2)c([N+](=O)[O-])c1)c1ccc(N2CCNCC2)cc1
Reactant: O=C=NCCc1ccccc1
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(NS(=O)(=O)c1ccc(NCCSc2ccccc2)c([N+](=O)[O-])c1)c1ccc(N2CCN(C(=O)NCCc3ccccc3)CC2)cc1
Reaction time: 18 h

Procedure:
A solution of Example 173A (54.1 mg, 0.1 mmol) in NMP (2 mL) at room temperature was treated with phenethylisocyanate (0.2mmol), stirred for 18 hours, diluted with water, and centrifuged. The solid was purified by flash column chromatography on silica gel with 0-5% methanol/dichloromethane to provide the desired product. MS (ESI(−)) m/e 687 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 8.75 (t, 1H), 8.58 (d, 1H), 7.90 (dd, 1H), 7.75 (d, 2H), 7.39-7.34 (m, 2H), 7.31-7.14 (m, 9H), 6.94 (d, 2H), 6.71 (t, 1H), 3.66 (q, 2H), 3.42-3.39 (m, 4H), 3.30-3.21 (m, 8H), 2.72 (dd, 2H).