Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:79])[C@H:7]([CH2:70][CH2:71][C:72]([O:74]C(C)(C)C)=[O:73])[NH:8][C:9](=[O:69])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:68])[CH2:18][CH2:19][S:20][CH2:21][CH:22]([O:46][C:47](=[O:67])[NH:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])[CH2:23][O:24][C:25](=[O:45])[NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[CH:12][CH:11]=1)(C)(C)C.ClCCl>FC(F)(F)C(O)=O>[CH2:49]([NH:48][C:47]([O:46][CH:22]([CH2:23][O:24][C:25](=[O:45])[NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:21][S:20][CH2:19][CH2:18][C:17]([NH:16][C:13]1[CH:12]=[CH:11][C:10]([C:9]([NH:8][C@H:7]([C:6]([OH:79])=[O:5])[CH2:70][CH2:71][C:72]([OH:74])=[O:73])=[O:69])=[CH:15][CH:14]=1)=[O:68])=[O:67])[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CSCCC(=O)Nc1ccc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1)OC(=O)NCCCCCCCCCCCCCCCCCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CSCCC(=O)Nc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)OC(=O)NCCCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of 4-[6,7-bis(octadecylcarbamoyloxy)-4-thiaheptanoylamino]benzoyl-glutamic acid di-t-butyl ester as obtained in Example 31 (100 mg) in trifiuoroacetic acid (2 ml)-dichloromethane (0.5 ml) was stirred at room temperature for 1 hour. After solvent concentration under reduced pressure, the resulting residue was crystallized from chloroform-methanolwater to yield the title compound (99 mg, yield 100%) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:18]2[C:23](=[O:24])[NH:22][C:21](=[O:25])[CH:20]=[N:19]2)[CH:5]=[C:6]([Cl:17])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:38](O)=[O:39]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:18]2[C:23](=[O:24])[NH:22][C:21](=[O:25])[CH:20]=[N:19]2)[CH:5]=[C:6]([Cl:17])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH:38]=[O:39])[CH:10]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(Oc2c(Cl)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)cc1
Agent: C1N2CN3CN1CN(C2)C3
Product: COc1ccc(Oc2c(Cl)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)cc1C=O
Reaction time: 0.5 h

Procedure:
A solution of 2-[3,5-dichloro-4-(4-methoxy-phenoxy)-phenyl]-2H-[1,2,4]triazine-3,5-dione (1 g) and hexamethylenetetraamine (0.6 g) in trifluoroacetic acid (8 mL) was stirred at 70° C. for 18 h. The trifluoroacetic acid was removed in vacuo, water added and the resulting mixture was stirred for 30 min. The residue was extracted with ethyl acetate, the organic phase washed with water, brine, dried (Na2SO4), concentrated in vacuo and flash chromatographed on silica gel (35% acetone/hexanes) to afford the title compound of Step A as an off-white solid, 1.0 g (m.p. 184-187° C.).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1.[C:26]([O-])([O-])=[O:27].[K+].[K+]>CO>[CH3:26][O:27][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1nc(Nc2ccc(OC)c(Cl)c2)nc(NC2CCCCCC2)n1

Procedure:
To 6-chloro-N-(3-chloro-4-methoxyphenyl)-N′-cycloheptyl-[1,3,5] triazine-2,4-diamine (5 g) dissolved in methanol was added K2CO3 (3.2 g) and refluxed for about 6-8 h. TLC was monitored. After the completion of the reaction, the reaction mass was filtered through vacuum and the filtrate was evaporated to yield the title compound. (Wt. 4.7 g Y: 95%)
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:20])=[C:12](C([O-])=O)[CH:13]=[N:14]3)=[CH:9][CH:8]=2)=[C:5]([CH3:21])[O:4][N:3]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>CCCCCC>[CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:20])=[CH:12][CH:13]=[N:14]3)=[CH:9][CH:8]=2)=[C:5]([CH3:21])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1ccc2c(O)c(C(=O)[O-])cnc2c1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: Cc1noc(C)c1-c1ccc2c(O)ccnc2c1
Yield: 86 %

Procedure:
7-(3,5-dimethyl-4-isoxazolyl)-4-hydroxy-3-quinolinecarboxylate (for a preparation see Intermediate 9, 10 g, 35.21 mmol) was suspended by small portions to boiling diphenyl ether (200 ml) and allowed to reflux for 2 h. The reaction mixture was poured into hexane (500 ml) at 0° C., the precipitate was filtered and washed several times with hexane to give the title compound as a white solid (6.8 g, 86%). [APCI-MS] m/z: 240 MH+, Rt 1.89 min. 1H NMR (300 MHz, CDCl3, ppm) δ: 12.44 (brs, 1H), 8.67 (d, J=8.5 Hz, 1H), 8.10 (d, J=7.2 Hz, 1H), 7.80 (s, 1H), 7.62-7.55 (m, 1H), 7.25 (d, J=8.5 Hz, 1H), 6.61 (d, J=7.4 Hz, 1H), 2.64 (s, 3H), 2.49 (s, 3H).
Reaction SMILES: [C:1]1([CH2:7][O:8][CH2:9][CH:10]2[CH2:15][N:14]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH:12]([CH2:23][OH:24])[O:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:26][C:27]([N:29]([CH2:33][CH2:34][CH3:35])[CH2:30][CH2:31][CH3:32])=[O:28].[H-].[Na+].O>CS(C)=O>[C:1]1([CH2:7][O:8][CH2:9][CH:10]2[CH2:15][N:14]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH:12]([CH2:23][O:24][CH2:26][C:27]([N:29]([CH2:33][CH2:34][CH3:35])[CH2:30][CH2:31][CH3:32])=[O:28])[O:11]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCN(CCC)C(=O)CCl
Reactant: OCC1CN(Cc2ccccc2)CC(COCc2ccccc2)O1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCN(CCC)C(=O)COCC1CN(Cc2ccccc2)CC(COCc2ccccc2)O1
Temperature: 25 °C
Yield: 65.4 %

Procedure:
A mixture of 4.9 g (0.015 mole) of 6-[(phenylmethoxy)methyl]-4-(phenylmethyl)-2-morpholinemethanol and 2.84 g (0.016 mole) of 2-chloro-N,N-dipropylacetamide are dissolved in 100 ml of dry DMSO and the mixture stirred at room temperature under nitrogen. Slowly, 0.88 g of sodium hydride (0.0183 mole, 50% oil dispersion) is added to the DMSO mixture and the reaction allowed to stir at ambient temperature (22°). After stirring for 10 minutes, an exothermic reaction begins to take place and an ice-bath is used to maintain the reaction temperature below 30°. After stirring for 1/2 hour, the ice-bath is removed and the reaction allowed to stir at room temperature for 18 hours. The excess NaH is destroyed by adding 5 ml of methanol and the entire reaction mixture is then poured into 400 ml of water. The product is extracted and washed with 6×300 ml portions of water. The product is then extracted with 3×125 ml portions of chloroform. The CHCl3 extracts are combined and washed with 6×300 ml portions of water. The CHCl3 layer is separated and dried over anhydrous Na2SO4 overnight. The CHCl3 is removed in vacuo yielding the crude product as a dark oil. The resulting oil is purified on a neutral Alumina III column (200 g), eluting with 2% methanol/chloroform, yielding 4.6 g (69%) of the desired product, 2-[[6-[(phenylmethoxy)methyl]-4-(phenylmethyl)-2-morpholinyl]methoxy]-N,N-dipropylacetamide.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].CS(O[CH2:11][C@@H:12]([NH:17][C:18]1[C:23]([F:24])=[CH:22][N:21]=[C:20]([Cl:25])[N:19]=1)[C:13]([CH3:16])([CH3:15])[CH3:14])(=O)=O.O>CN(C=O)C>[C:1](=[O:4])([S:3][CH2:11][C@@H:12]([NH:17][C:18]1[C:23]([F:24])=[CH:22][N:21]=[C:20]([Cl:25])[N:19]=1)[C:13]([CH3:16])([CH3:14])[CH3:15])[CH3:2]
Reactant: CC([O-])=S
Reactant: CC(C)(C)[C@@H](COS(C)(=O)=O)Nc1nc(Cl)ncc1F
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)SC[C@@H](Nc1nc(Cl)ncc1F)C(C)(C)C
Temperature: 78 °C
Reaction time: 1 h

Procedure:
Potassium thioacetate (1.30 g, 11.51 mmol) was added to a stirring solution of (S)-2-(2-chloro-5-fluoropyrimidin-4-ylamino)-3,3-dimethylbutyl methanesulfonate, 75a, (2.50 g, 7.67 mmol) in dry DMF (50 mL). The resulting brown solution was heated with stirring at 78° C. for 1 hour. The brown suspension was poured into water and extracted with EtOAc (3×100 mL). The combined organic phases were dried (MgSO4), filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0-30% EtOAc/Hexanes gradient) to afford 2.1 g of compound 76a as a pale brown solid: 1H NMR (400 MHz, CDCl3) δ 7.81 (s, 1H), 5.12 (m, 1H), 4.21 (t, J=9.1 Hz, 1H), 3.15-2.90 (m, 2H), 2.23 (s, 3H), 0.95 (m, 9H); LC/MS (10-90% ACN/water 5 min with 0.9% FA) m/z 306.02 (M+H) RT=3.32 min.
Reaction SMILES: [CH3:1][NH2:2].[Br:3][C:4]1[C:13]([S:14](Cl)(=[O:16])=[O:15])=[CH:12][C:11]([C:18]([OH:20])=[O:19])=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][O:9]2.[OH-].[Na+]>O>[Br:3][C:4]1[C:13]([S:14](=[O:16])(=[O:15])[NH:2][CH3:1])=[CH:12][C:11]([C:18]([OH:20])=[O:19])=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][O:9]2
Reactant: CN
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)c(Br)c2c1OCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CNS(=O)(=O)c1cc(C(=O)O)c2c(c1Br)CCCO2
Temperature: 0 °C

Procedure:
70 g of methylamine in a 40% aqueous solution and 70 ml of water were introduced into a 1-liter round-bottomed flask. The contents were cooled to 0° C. and 160 g of 5-bromo-6-chlorosulphonylchroman-8-carboxylic acid were added in 16 g portions, the introduction of each portion of acid being followed by the addition of 18 ml of a solution containing 90 ml of 30% sodium hydroxide in 90 ml of water. The temperature was maintained between 0° and 5° C. during the entire period of introduction and for a further period of one hour. The temperature was then allowed to rise. The solution obtained was taken up with 1 liter of water, filtered with charcoal and acidified with concentrated hydrochloric acid until a color change of Congo red was observed.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:5][N:6]=1.ClC1C=CC=C(C(OO)=[O:22])C=1>C(Cl)(Cl)Cl.CN(C)C=O>[NH2:1][C:2]1[S:3][C:4]([S:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[O:22])=[CH:5][N:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Nc1ncc(Sc2ccncc2)s1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Nc1ncc(S(=O)c2ccncc2)s1
Yield: 58.1 %

Procedure:
To a mixture of 2-amino-5-(4-pyridylthio)thiazole (4.0 g) in a mixture of chloroform (300 ml) and N,N-dimethylformamide (10 ml) was added dropwise the solution of 3-chloroperbenzoic acid (4.5 g) in chloroform (100 ml) at 5° C. with stirring. The mixture was stirred at 5° C. for 26 hours under ice cooling. The reaction mixture was washed with aqueous sodium bicarbonate and water and dried over magnesium sulfate. The solvent was concentrated under reduced pressure to give solid. The solid was subject to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 250 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the objective compound were combined and concentrated under reduced pressure to give 2-amino-5-(4-pyridylsulfinyl)thiazole (2.5 g, yield: 58.1%). mp: 193°-195° C.
Reaction SMILES: [F:1][C:2](=[C:7]([F:9])[F:8])[CH2:3][C:4](Cl)=[O:5].[NH2:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=[O:15].C(=O)(O)[O-].[Na+].ClCCl>C(OCC)(=O)C.O>[F:1][C:2](=[C:7]([F:9])[F:8])[CH2:3][C:4]([NH:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=[O:15])=[O:5]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: O=C(Cl)CC(F)=C(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(CC(F)=C(F)F)Nc1cccc(C(=O)O)c1
Temperature: 0 °C
Yield: 69.4 %

Procedure:
2.2 g (0.0139 mole) 3,4,4-trifluoro-3-butenoyl chloride is added to a mixture of 3-aminobenzoic acid (1.37 g, 0.01 mole), sodium bicarbonate (0.84 g, 0.01 mole), water (20 mL) and dichloromethane (20 mL) with stirring at 0° C. After stirring for 15 min at room temperature, the mixture is diluted with ethyl acetate (100 mL) and water (50 mL). The organic layer is washed with 2N HCl and brine, and dried. The residue obtained after evaporation of the solvent is triturated with dry ether and filtered to give 1.8 g of the title compound as a light pink solid, a 69% yield. m.p. 252°-255° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[N:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:23][CH:22]=2)=[CH:15][CH:14]=1.[CH3:39][N:40]([CH3:44])[CH2:41][CH2:42][OH:43].O1CCCC1>CO>[Br-:1].[CH2:27]([C:24]1[CH:25]=[CH:26][C:21]([N:20]=[N:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N+:40]([CH2:41][CH2:42][OH:43])([CH3:44])[CH3:39])=[CH:14][CH:15]=2)=[CH:22][CH:23]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCCCCCCc1ccc(N=Nc2ccc(OCCCCCCCCCCBr)cc2)cc1
Reactant: CN(C)CCO
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCCCCCCc1ccc(N=Nc2ccc(OCCCCCCCCCC[N+](C)(C)CCO)cc2)cc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 3000 ml three-necked round bottom flask was equipped with magnetic stirring, a heating mantle, a reflux condenser, and a nitrogen atmosphere. The flask was charged with 4-(10-bromodecyloxy)-4'-dodecylazobenzene (40 g, 0.068 mol), dimethylethanolamine (95.2 g, 1.068 mole) and 1050 ml of tetrahydrofuran. The reaction mixture was allowed to reflux for 24 hours. During the course of the reaction mixture. After 24 hours, the reaction mixture was cooled to room temperature, and then chilled in an ice-water bath. The crystalline solid was isolated by suction filtration. The crude product was dissolved in hot methanol and filtered to remove insoluble impurities. The methanol was removed by evaporation at reduced pressure. The crude product was recrystallized from tetrahydrofuran. Yield 28.0 g, 61.0%.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16](Cl)=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[OH:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[OH:19][CH:20]1[CH2:25][CH2:24][N:23]([C:16]([C:13]2[S:14][CH:15]=[C:11]([C:7]3[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=3[CH3:10])[N:12]=2)=[O:17])[CH2:22][CH2:21]1
Reactant: CC(=O)Nc1nc(C)c(-c2csc(C(=O)Cl)n2)s1
Reactant: OC1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2csc(C(=O)N3CCC(O)CC3)n2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
2′-Acetylamino-4′-methyl-[4,5′]bithiazolyl-2-carbonyl chloride, prepared as in Step I of Example 13, described above, (166.6 mg, 0.55 mmol, 1 eq.), is dissolved in THF (8 ml) and DCM (4 ml). 4-Hydroxypiperidine (Fluka)(55.8 mg; 0.55 mmol; 1 eq.) and triethylamine (0.15 ml; 1.10 mmol; 2 eq.) are added and the mixture is stirred overnight at rt. Solvents are evaporated and the crude product is crystallized in MeOH, affording Compound (29) as a brown solid (80.3 mg; 40%). 1H NMR (DMSO-d6, 300 MHz) δ 1.44 (m, 2H), 1.82 (m, 2H), 2.14 (s, 3H), 2.50 (s, 3H), 3.35 (m, 2H), 3.80 (m, 2H), 4 (m, 1H), 4.60 (m, 1H), 7.98 (s, 1H), 12.16 (br s, 1H). M− (ESI): 365; M+ (ESI): 367. HPLC (method A), Rt: 2.31 min (purity: 91.1%).
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.Cl.[Cl:17][C:18]1[CH:19]=[C:20]([O:27][CH3:28])[CH:21]=[C:22]2[C:26]=1[NH:25][CH2:24][CH2:23]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:25]2[C:26]3[C:22](=[CH:21][C:20]([O:27][CH3:28])=[CH:19][C:18]=3[Cl:17])[CH2:23][CH2:24]2)[C:3](=[O:15])[N:4]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=1
Reactant: CC[C@H](COC)n1cc(Cl)nc(Cl)c1=O
Reactant: COc1cc(Cl)c2c(c1)CCN2
Agent: Cl
Product: CC[C@H](COC)n1cc(Cl)nc(N2CCc3cc(OC)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 7-chloro-5-methoxyindoline hydrochloride as the starting materials. mp 126-128° C.; 1H NMR (300 MHz, CDCl3): δ 6.99 (s, 1 H), 6.74 (s, 2 H), 5.00-4.90 (m, 1 H), 4.35 (t, J=8.0 Hz, 2 H), 3.78 (s, 3H), 3.67 (dd, J=10.6, 5.5 Hz, 1 H), 3.56 (dd, J=10.6, 3.7 Hz, 1 H), 3.35 (s, 3 H), 3.09 (t, J=7.7 Hz, 2 H), 1.92-1.72 (m, 2 H), 0.93 (t, J=7.4 Hz, 3 H); HRMS (ESI) calcd for C18H22N3O3Cl2 (M+H)+: 398.1038; Found m/z 398.1064.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:7]2[CH2:12][CH2:11][CH:10]([NH:13][CH2:14][CH2:15][OH:16])[CH2:9][CH2:8]2)[S:5][CH:6]=1.[CH3:17][C:18]1([CH3:36])[C:26]2[C:21](=[CH:22][CH:23]=[C:24](B3OC(C)(C)C(C)(C)O3)[CH:25]=2)[CH2:20][CH2:19]1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O>[CH3:17][C:18]1([CH3:36])[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:2]3[N:3]=[C:4]([N:7]4[CH2:12][CH2:11][CH:10]([NH:13][CH2:14][CH2:15][OH:16])[CH2:9][CH2:8]4)[S:5][CH:6]=3)[CH:25]=2)[CH2:20][CH2:19]1
Reactant: CC1(C)CCc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: OCCNC1CCN(c2nc(Br)cs2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)CCc2ccc(-c3csc(N4CCC(NCCO)CC4)n3)cc21
Temperature: 120 °C

Procedure:
130 mg (0.30 mmol) of 2-[1-(4-bromothiazol-2-yl]piperidin-4-ylamino]ethanol from step b, 92 mg (0.29 mmol) of 2-(3,3-dimethylindan-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 92 mg (0.03 mmol) of tetrakis(triphenlyphosphine)palladium(0) and 125 mg (1.18 mmol) of sodium carbonate were weighed out, placed under nitrogen. 2.5 ml of dioxane and 0.5 ml of water were added with stirring. The mixture was degassed, homogenised in an ultrasound bath and heated at 120° C. in the microwave for 30 min, diluted with about 20 ml of EA and 20 ml of water and filtered off. The phases were separated, and the water phase was extracted a further once with EA. The organic phases were combined, dried over sodium sulfate, filtered and evaporated. The oily residue was purified by means of preparative HPLC. The product is in the form of the hydrochloride.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[O:13]=[C:14]1[NH:18][C:17](=[O:19])[C:16]2([CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]2)[NH:15]1.[CH:32]1(O)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1>>[CH:32]1([N:18]2[C:17](=[O:19])[C:16]3([CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]3)[NH:15][C:14]2=[O:13])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: OC1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCCC2(C1)NC(=O)NC2=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC2(C1)NC(=O)N(C1CCCCC1)C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diethyl azodicarboxylate (0.315 mL, 0.00200 mol) was added to a mixture of tert-butyl 2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-carboxylate (269.3 mg, 0.001000 mol), cyclohexanol (0.156 mL, 0.00150 mol), and triphenylphosphine (524 mg, 0.00200 mol) in tetrahydrofuran (6 mL, 0.08 mol). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by Combiflash with ethyl acetatehexane. LC-MS: 296.2 (M−Bu+2H)+.
Reaction SMILES: C([O:4][C:5]1[C:14]([CH3:15])=[C:13]2[C:8]([CH2:9][CH2:10][C:11]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH:26](Cl)[C:27](OCC)=[O:28])=[CH:21][CH:20]=3)([CH3:16])[O:12]2)=[CH:7][CH:6]=1)(=O)C.[NH2:33][C:34](N)=[S:35].S1(CCCC1)(=O)=[O:38].Cl>COCCO>[OH:4][C:5]1[C:14]([CH3:15])=[C:13]2[C:8]([CH2:9][CH2:10][C:11]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH:26]4[S:35][C:34](=[O:38])[NH:33][C:27]4=[O:28])=[CH:21][CH:20]=3)([CH3:16])[O:12]2)=[CH:7][CH:6]=1
Reactant: O=S1(=O)CCCC1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(Cl)Cc1ccc(OCC2(C)CCc3ccc(OC(C)=O)c(C)c3O2)cc1
Agent: Cl
Solvent: COCCO
Product: Cc1c(O)ccc2c1OC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)CC2

Procedure:
Following a procedure similar to that described in Example 1, but using 1 g of ethyl 3-[4-(7-acetoxy-2,8-dimethylchroman-2-ylmethoxy)phenyl]-2-chloropropionate (prepared as described in Preparation 41), 0.22 g of thiourea, 1.5 ml of sulfolane, 10 ml of ethylene glycol monomethyl ether and 4 ml of 3N aqueous hydrochloric acid, 586 mg of the title compound were obtained as a pale yellow powder, softening at 68°-71° C.
Reaction SMILES: CO[C:3](=[O:31])[C:4]([N:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:30])[CH:14]([NH:18][C:19](=[O:29])[CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]1)([CH3:6])[CH3:5].[CH2:32]([Li])[CH3:33].O1CC[CH2:37][CH2:36]1>>[CH2:36]([C:3]([OH:31])([CH2:32][CH3:33])[C:4]([N:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:30])[CH:14]([NH:18][C:19](=[O:29])[CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]1)([CH3:6])[CH3:5])[CH3:37]
Reactant: C1CCOC1
Reactant: [Li]CC
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)C(=O)OC)cn1
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)C(O)(CC)CC)cn1
Reaction time: 0.5 h

Procedure:
To a solution of 2-(4-{2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1-yl)-2-methyl-propionic acid methyl ester (1 equiv) in tetrahydrofuran at −0° C. is added ethyl lithium (5 equiv., 0.5 M benzene/cyclohexane) dropwise. The reaction is stirred for 30 min., quenched with water, and extracted with methylene chloride. The solvent is dried, concentrated, and purified by silica gel chromatography to afford the title compound: C13 NMR (100 MHz, CDCl3) 9.0, 9.3, 14.0, 18.9, 24.5, 25.2, 27.3, 27.5, 36.0, 43.0, 53.1, 65.9, 102.5, 102.8, 103.0, 107.2, 112.4, 112.6, 112.7, 133.3, 136.3, 138.6, 164.3, 164.5, 169.0, 169.1; MS m/z 465.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([O:11][C:12]1[CH:13]=[C:14]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[O:15][CH2:16][CH2:17][CH2:18][O:19][NH2:20])(=[O:10])=[O:9].Cl.[N:26]1([C:31](N)=[NH:32])C=CC=N1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([O:11][C:12]1[CH:13]=[C:14]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[O:15][CH2:16][CH2:17][CH2:18][O:19][NH:20][C:31]([NH2:32])=[NH:26])(=[O:10])=[O:9]
Reactant: Cc1cc(OCCCON)cc(OS(=O)(=O)c2ccccc2Cl)c1
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cc(OCCCONC(=N)N)cc(OS(=O)(=O)c2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
A solution of 3-[3-(2-chlorophenylsulfonyloxy)-5-methylphenoxy]propoxyamine (0.43 g, 0.0012 mol), as prepared in the preceding step, in anhydrous N,N-dimethylformamide (15 mL) was treated with 1H -pyrazole-1-carboxamidine hydrochloride (0.34 g, 0.0034 mol). The reaction mixture was stirred overnight at ambient temperature. An additional 100 mg of 1H -pyrazole-1-carboxamidine hydrochloride was added, and the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was evaporated to dryness under high vacuum. The residue was treated with acetonitrile, and the resulting crystalline material was collected by filtration and discarded. The filtrate was evaporated to dryness and partitioned between ether and water. The aqueous layer was washed with ether (4×25 mL). The aqueous layer was separated and basified with 2N sodium hydroxide, and the resultant aqueous layer was extracted with ethyl acetate (4×50 mL). The combined ethyl acetate extracts were washed with brine, dried, and evaporated to give 0.46 g of the title compound as an oil. 1H-NMR (300 MHz, CDCl3) δ7.94 (d, J=7.6 Hz, 1H), 7.54-7.62 (m, 2H), 7.34-7.40 (m, 1H), 6.57 (br s, 1H), 6.48 (m, 2H), 5.75 (br m, 2H), 3.96 (t, J=6.2 Hz, 4H), 2.21 (s, 3H), and 2.05 (pentet, J=6.2 Hz, 2H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C17H20ClN3O5S: 4.14.1 (M+H). Found: 4.14.2