Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:23])[C@@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])=[CH:11][C:10]1=[O:22])[CH2:5][CH2:6][O:7][CH3:8].O.[OH-].[Li+].Cl>O1CCCC1.O>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][C:12]1[CH2:13][N:9]([C@@H:4]([CH2:5][CH2:6][O:7][CH3:8])[C:3]([OH:23])=[O:2])[C:10](=[O:22])[CH:11]=1
Reactant: COCC[C@@H](C(=O)OC)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COCC[C@@H](C(=O)O)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 46.8 %

Procedure:
In a flask was placed (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methoxy-butyric acid methyl ester (71 mg, 0.21 mmol) in tetrahydrofuran (3 mL). To this mixture at 25° C. was added a solution of lithium hydroxide monohydrate (18 mg, 0.42 mmol) in water (3 mL) and stirred for 1.5 h at 25° C. The mixture was then treated with a 1N aqueous hydrochloric acid solution to pH=2 and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to afford (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methoxy-butyric acid (32 mg, 98%) as a light yellow solid.
Reaction SMILES: Cl[C:2]1[C:7]([Br:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[O:9]1[C:13]2([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[O:12][CH2:11][CH2:10]1>>[Br:8][C:7]1[C:2]([N:16]2[CH2:17][CH2:18][C:13]3([O:12][CH2:11][CH2:10][O:9]3)[CH2:14][CH2:15]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1ncccc1Br
Reactant: C1CC2(CCN1)OCCO2
Product: Brc1cccnc1N1CCC2(CC1)OCCO2

Procedure:
The title compound was prepared from 2-chloro-3-bromopyridine and 1,4-dioxa-8-azaspiro[4,5]decane in a manner similar to that of Description 10.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[C:13]4[CH:26]=[CH:25][S:24][C:14]=4[C:15](=[O:23])[NH:16][C:17]=3[CH:18]=[CH:19][C:20]=2[O:21]C)=[CH:7][CH:6]=1.BrB(Br)Br>>[CH3:27][N:2]([CH3:1])[CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]3[C:13]4[CH:26]=[CH:25][S:24][C:14]=4[C:15](=[O:23])[NH:16][C:17]=3[CH:18]=[CH:19][C:20]=2[OH:21])=[CH:9][CH:10]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(CCN(C)C)cc1
Agent: BrB(Br)Br
Product: CN(C)CCc1ccc(-c2c(O)ccc3[nH]c(=O)c4sccc4c23)cc1
Yield: 91.5 %

Procedure:
Following General Procedure F, 9-{4-[2-(dimethylamino)ethyl]phenyl}-8-methoxythieno[2,3-c]quinolin-4(5H)-one (25 mg, 0.060 mmol) was reacted with tribromoborane (1.0 M in methylene chloride, 0.20 mL, 0.18 mmol) to afford the desired product (20 mg, 89%) as a yellow solid: 1H NMR (500 MHz, CD3CN+D2O) δ 7.55 (d, J=5.4 Hz, 1H), 7.43-7.41 (m, 3H), 7.22-7.18 (m, 3H), 5.99 (d, J=5.4 Hz, 1H), 3.00 (s, 4H), 2.56 (s, 6H); ESI MS m/z 365 [C21H20N2O2S+H]+; HPLC 98.3% (AUC), tR=9.24 min.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[C:12]([O:19][CH3:20])=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[C:12]([O:19][CH3:20])=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: COc1ccc(N)c(OC)n1
Reactant: Fc1cnc(Cl)nc1Cl
Product: COc1ccc(Nc2nc(Cl)ncc2F)c(OC)n1

Procedure:
In like manner to the preparation of 2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 3-amino-2.6-dimethoxypyridine gave 2-chloro-N4-(2,6-dimethoxypyridin-3-yl)-5-fluoro-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.57 (d, 1H, J=8.7 Hz), 8.02 (d, 1H, J=2.7 Hz), 6. 40 (d, 1H, J=8.1 Hz), 4.03 (s, 3H), 3.98 (s, 3H); 19F NMR (CDCl3): −44640; LCMS: purity: 90%; MS (m/e): 285 (M+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=[O:19])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21](O)([CH3:24])([CH3:23])[CH3:22].CC(C)N=C=NC(C)C>C(Cl)Cl.CN(C=O)C.CN(C1C=CN=CC=1)C>[C:21]([O:19][C:18]([CH:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:13][CH2:14]1)=[O:20])([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C(NC1CCC(C(=O)O)CC1)OCc1ccccc1
Reactant: CC(C)(C)O
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C1CCC(NC(=O)OCc2ccccc2)CC1
Yield: 54.2 %

Procedure:
To a solution of 4-benzyloxycarbonylamino-cyclohexanecarboxylic acid (8.0 g, 28.78 mmol) in DCM (35 mL) and DMF (35 mL) is added t-butanol (10 mL, 105.4 mmol) and DMAP (1.4 g, 11.50 mmol). DIPC (10 mL) is added portionwise over 1 h. The resulting mixtures stirs 18 h. The mixture is mounted onto SiO2 and purified by flash chromatography (gradient elution: 0-60% EtOAc/Hep) which affords 5.2 g of 4-benzyloxycarbonylamino-cyclohexanecarboxylic acid tert-butyl ester. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.14 (m, 2 H) 1.30 (m, 2 H) 1.38 (m, 9 H) 1.82 (m, 4 H) 2.07 (m, 1 H) 3.20 (m, 1 H) 3.47 (m, 3 H) 4.99 (m, 2 H) 7.27 (m, 5 H).
Reaction SMILES: C(O[C:4](=[O:9])[CH2:5][C:6]([CH3:8])=[O:7])C.[F:10][C:11]([F:20])([F:19])[C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>C1(C)C(C)=CC=CC=1>[O:7]=[C:6]([CH3:8])[CH2:5][C:4]([NH:16][C:15]1[CH:17]=[CH:18][C:12]([C:11]([F:10])([F:19])[F:20])=[CH:13][CH:14]=1)=[O:9]
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: Cc1ccccc1C
Product: CC(=O)CC(=O)Nc1ccc(C(F)(F)F)cc1

Procedure:
Ethylacetoacetate (10 g) and 4-(trifluoromethyl) aniline (12.38 g) in xylene (250 ml) was refluxed for 48 hours. Reaction mixture was concentrated and purified by column chromatography to give pure (9.7 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>>[N:11]1([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=2)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: Clc1ccc2nccn2n1
Reactant: C1CNCCN1
Product: c1cn2nc(N3CCNCC3)ccc2n1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
An intimate mixture of 6-chloro-imidazo[1,2-b]pyridazine [6775-88-6] (4.1 g, 26.5 mmol and piperazine [110-85-0] (11.4 g, 132.8 mmol) was heated to 120° C. and stirred as a melt under N2 blanket for 2 h. The cooled reaction was partitioned between water and ethyl acetate, the extract dried (MgSO4), and evaporated to yield 5.6 g of 6-piperazin-1-yl-imidazo[1,2-b]pyridazine which, without purification, was suspended in ethyl acetate (250 mL). To this stirred mixture was added Hunig's base [7087-68-5] (9.6 mL, 55.1 mmol) and di-tert-butyl pyrocarbonate [24424-99-5] (7.2 g, 33.2 mmol). The N2 blanketed mixture was stirred overnight at ambient temperature then partitioned between brine and ethyl acetate. The phase separated extract was dried (CaSO4), evaporated, and crystallized from ethyl acetate/heptane to provide a white crystalline powder, mp. 122-123° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43 (s, 9H) 3.46 (s, 8H) 7.16 (d, J=10.11 Hz, 1H) 7.50 (s, 1H) 7.81-7.94 (m, 2H). 13C NMR (100 MHz, DMSO-d6) δ ppm 28.03, 42.66, 45.42, 79.07, 110.58, 116.43, 125.91, 131.62, 135.77, 153.88, 154.71. LRMS (ESI) m/z 304.2 [(M+H)]+, calc'd for C15H21N5O2: 303.37.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:15]([O:19][C:20](=[O:24])[C@H:21]([CH3:23])[NH2:22])[CH:16]([CH3:18])[CH3:17]>>[CH2:15]([O:19][C:20](=[O:24])[C@H:21]([CH3:23])[NH:22][C:11](=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH:16]([CH3:18])[CH3:17]
Reactant: O=C(O)CCCCc1ccccc1
Reactant: CC(C)COC(=O)[C@H](C)N
Agent: Cl
Product: CC(C)COC(=O)[C@H](C)NC(=O)CCCCc1ccccc1

Procedure:
Following General Procedure B and using 5-phenylpentanoic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example B above), the title compound was prepared as an oil. The reaction was monitored by tlc on silica gel and purification was by extraction with Et2O followed by washes with aqueous K2CO3 and aqueous HCl.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:27])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH:18]([OH:25])[C:19]4[S:23][CH:22]=[N:21][C:20]=4[CH3:24])=[C:13]([C:15](O)=[O:16])[N:14]=[C:7]3[C:6]=2[CH:26]=1.[Cl-].[NH4+:29]>>[Br:1][C:2]1[C:3]([F:27])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH:18]([OH:25])[C:19]4[S:23][CH:22]=[N:21][C:20]=4[CH3:24])=[C:13]([C:15]([NH2:29])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:26]=1
Reactant: [NH4+]
Reactant: Cc1ncsc1C(O)c1c(C(=O)O)nc2n1CCOc1cc(F)c(Br)cc1-2
Agent: [Cl-]
Product: Cc1ncsc1C(O)c1c(C(N)=O)nc2n1CCOc1cc(F)c(Br)cc1-2
Yield: 15 %

Procedure:
10-bromo-9-fluoro-3-[hydroxy-(4-methylthiazol-5-yl)methyl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxylic acid was reacted with ammonium chloride and purified by flash chromatography to afford 30.4 mg (15% yield) of the title compound.
Reaction SMILES: Cl.N1[CH:7]=[CH:6][CH:5]=[N:4][C:3]=1[CH2:8][C:9]([OH:11])=O.[CH2:12](N(CC)CC)C.C(N1C=CN=C1)(N1C=CN=C1)=O.[F:31][C:32]([F:46])([F:45])[C:33]1[C:38]([CH:39]([NH:43][CH3:44])[CH:40]([CH3:42])[CH3:41])=[CH:37][N:36]=[CH:35][N:34]=1>O1CCCC1.O>[CH3:44][N:43]([CH:39]([C:38]1[C:33]([C:32]([F:31])([F:45])[F:46])=[N:34][CH:35]=[N:36][CH:37]=1)[CH:40]([CH3:42])[CH3:41])[C:9](=[O:11])[CH2:8][C:3]1[CH:12]=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CNC(c1cncnc1C(F)(F)F)C(C)C
Reactant: O=C(O)Cc1ncccn1
Reactant: CCN(CC)CC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(c1cncnc1C(F)(F)F)N(C)C(=O)Cc1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.4 %

Procedure:
0.3 g (1.7 mmol) of 2-pyrimidinylacetate hydrochloride and 0.18 g (1.8 mmol) of triethylamine were dissolved in 30 ml of tetrahydrofuran, and 0.28 g (1.7 mmol) of 1,1′-carbonylbis-1H-imidazole was added, followed by stirring at room temperature for 1 hour. Then, 0.4 g (1.7 mmol) of 4-trifluoromethyl-5-[1-(N-methylamino)-2-methylpropyl]pyrimidine was added, followed by heating and refluxing for further 3 hours. To the reaction solution, 100 ml of water was added, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and then dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (developing solvent/n-hexane:ethyl acetate:methanol=4.5:4.5:1) to obtain 0.2 g (yield: 33%) of N-methyl-N-[2-methyl-1-(4-trifluoromethylpyrimidin-5-yl)propyl]-2-pyridylacetamide as colorless transparent crystals (melting point: 99-100° C.).
Reaction SMILES: [C:1](O)(C(F)(F)F)=O.[Cl:8][C:9]1[C:13]([CH3:14])=[C:12]([C:15]2[C:16]([CH3:25])=[CH:17][C:18]([CH3:24])=[C:19]([CH:23]=2)[C:20]([O-:22])=[O:21])[N:11](COCC[Si](C)(C)C)[N:10]=1>C(Cl)Cl>[Cl:8][C:9]1[C:13]([CH3:14])=[C:12]([C:15]2[C:16]([CH3:25])=[CH:17][C:18]([CH3:24])=[C:19]([CH:23]=2)[C:20]([O:22][CH3:1])=[O:21])[NH:11][N:10]=1
Reactant: Cc1cc(C)c(-c2c(C)c(Cl)nn2COCC[Si](C)(C)C)cc1C(=O)[O-]
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc(-c2[nH]nc(Cl)c2C)c(C)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
TFA (10 mL) was carefully added to a solution of 5-(3-chloro-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-2,4-dimethylbenzoate (compound 250.4, 2.0 g, 4.90 mmol) in CH2Cl2 (10 mL). The mixture was stirred at room temperature for 2 hours, then the solvents were removed under reduced pressure. The residue was dissolved in EtOAc (200 mL) and washed with sat. NaHCO3 (50 mL), brine (50 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexanes:EtOAc, 4:1) to yield the title compound as white foam (1.13 g, 83%) m/z (ES+) 279 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1.[OH:30]O.O.C1(C)C=CC=CC=1>C(O)(=O)C.O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>[CH3:29][O:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([S:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:10][CH:11]=2)=[O:30])=[CH:17][CH:18]=1
Reactant: OO
Reactant: COCCOCCOc1ccc(Sc2ccc(OCCOCCOC)cc2)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COCCOCCOc1ccc(S(=O)c2ccc(OCCOCCOC)cc2)cc1
Reaction time: 12 h
Yield: 95 %

Procedure:
In 200 g of acetic acid was dissolved 26.6 g of bis[4-[2-(2-methoxyethoxy)ethoxy]phenyl]sulfide obtained in Synthesis Example 1-42. While the solution was maintained at an internal temperature of 30° C., 6.4 g of 35 wt % aqueous hydrogen peroxide was added dropwise. The reaction solution was aged at room temperature for 12 hours, after which under ice cooling, a mixture of 0.5 g sodium thiosulfate pentahydrate and 20 g water was added dropwise to quench the reaction. The solution was combined with 200 g of toluene and 100 g of water. The organic layer was separated, washed with water, and concentrated in vacuum, obtaining 26.1 g of the target compound, bis[4-[2-(2-methoxyethoxy)ethoxy]phenyl]sulfoxide as oily matter. Yield 95%.
Reaction SMILES: [CH3:1][C:2]([S:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[CH3:8][C:9]1[N:14]=[C:13]([CH:15]=O)[CH:12]=[CH:11][CH:10]=1>C(Cl)Cl.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:1][C:2]([S:5](/[N:7]=[CH:15]/[C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:8])[N:14]=1)=[O:6])([CH3:4])[CH3:3]
Reactant: Cc1cccc(C=O)n1
Reactant: CC(C)(C)S(N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: Cc1cccc(/C=N/S(=O)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-methylpropane-2-sulfinamide (0.18 g, 1.49 mmol) in methylene chloride (3 mL) was added copper sulfate (0.24 g, 1.49 mmol) followed by 6-methylpyridine-2-carbaldehyde (0.2 g, 1.63 mmol). The reaction was stirred at ambient temperature for 16 hours, then filtered through a pad of celite (washing with methylene chloride) and evaporated in vacuo to give crude 2-methyl-N-[(1E)-(6-methylpyridin-2-yl)methylene]propane-2-sulfinamide. LC-MS EIMS: m/z 225.1 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Cl[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=1>>[CH3:18][C:14]1[N:13]=[C:12]([N:4]([C:1](=[O:3])[CH3:2])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cccc(Cl)n1
Reactant: CC(=O)Nc1ccccc1
Product: CC(=O)N(c1ccccc1)c1cccc(C)n1
Yield: 7 %

Procedure:
Using acetanilide (9.16 g) and 2-chloro-6-methylpyridine (17.3 g), a reaction was made in the same manner as in 1) of Production Example 14. The subsequent purification by silica gel chromatography (developing solvent, ethyl acetate:hexane=1:1, ethyl acetate) produced N-(6-methyl-2-pyridyl)acetanilide (1.07 g; yield, 7%) as a pale brown oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:21]3[S:22][C:23]4[C:29]([O:30][CH3:31])=[CH:28][C:27]([CH3:32])=[CH:26][C:24]=4[CH:25]=3)[C:9]([CH2:13][N:14]3[CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]3)=[C:10]([CH2:11][OH:12])[N:6]2[N:5]=[CH:4][N:3]=1.S(Cl)(Cl)=O.[CH2:37](O)[CH3:38].CC[O-].[Na+]>ClCCl>[NH2:1][C:2]1[C:7]2=[C:8]([C:21]3[S:22][C:23]4[C:29]([O:30][CH3:31])=[CH:28][C:27]([CH3:32])=[CH:26][C:24]=4[CH:25]=3)[C:9]([CH2:13][N:14]3[CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]3)=[C:10]([CH2:11][O:12][CH2:37][CH3:38])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: COc1cc(C)cc2cc(-c3c(CN4CCNC(=O)C4)c(CO)n4ncnc(N)c34)sc12
Reactant: CCO
Agent: CC[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCOCc1c(CN2CCNC(=O)C2)c(-c2cc3cc(C)cc(OC)c3s2)c2c(N)ncnn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
A suspension of Example 125 (100 mg, 221 μmol) in dichloromethane (10 ml) was treated with thionyl chloride (161 μl, 2.21 mmol), and the mixture was stirred at rt for 30 min. Ethanol was added, and the volatiles were evaporated under reduced pressure. The residue was dissolved in ethanol (10 ml), sodium ethylate (30 mg, 442 μmol) was added, and the mixture was stirred at rt for 1 h. The mixture was then directly separated by preparative RP-HPLC (Reprosil C18, gradient 20-40% acetonitrile/0.2% aq. trifluoroacetic acid). The product fractions were combined and alkalized by addition of sat. aq. sodium bicarbonate solution. The solution was extracted with ethyl acetate, and the organic layer was washed with brine, dried over magnesium sulfate and evaporated to yield 57 mg of the title compound (54% of th.).
Reaction SMILES: Br[C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH2:21]1[O:23][CH2:22]1>C(Cl)Cl>[CH:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:13]([C:14]=2[CH2:21][CH2:22][OH:23])=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc2cc3ccccc3cc12
Reactant: C1CO1
Agent: [Li]CCCC
Solvent: ClCCl
Product: OCCc1c2ccccc2cc2ccccc12

Procedure:
A solution in methylene chloride (20 ml) of 2-(9-anthryl)ethanol (3.5 g; 15.7 mmoles), which had been obtained by reaction between bromoanthracene and n-butyllithium and subsequent reaction with ethylene oxide was slowly added to an ice-cold solution of phosgene (20 ml; 38.4 mmoles; 20% in toluene). The reaction mixture was kept for 3 hours in an ice-bath and was then allowed to stand at room temperature during the night. Work up by vacuum evaporation of the solvent gave a crystalline residue, which was recrystallized from methylene chloride solution by precipitation with hexane to give 3.36 g (75%) of AEOC as practically colourless crystals, mp 85°-87° C. 270 MHz 1H-NMR in CDCl3 : 4.10 (t, J=8 Hz, 2 H); 4.66 (t, J=8 Hz, 2 H); 7.46-7.61 (m, 4 H); 8.03 (d, J=8 Hz, 2 H); 8.27 (d, J=8.6 Hz, 2 H); 8.43 (s, 1 H, H-10).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:52])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][N:17]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:39])=[O:38])[C@@H:16]([CH2:47][CH2:48][C:49]([OH:51])=[O:50])[CH2:15]2)=[CH:10][CH:9]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:54].S([O-])([O-])(=O)=O.[Mg+2]>CO>[CH3:54][O:50][C:49](=[O:51])[CH2:48][CH2:47][C@H:16]1[CH2:15][C@H:14]([C:11]2[CH:12]=[CH:13][C:8]([CH2:7][O:6][CH2:5][C@@H:4]([CH3:52])[CH2:3][O:2][CH3:1])=[CH:9][CH:10]=2)[C@@H:19]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]3[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=3[CH:36]=2)[CH2:18][N:17]1[S:37]([C:40]1[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=1)(=[O:38])=[O:39]
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CCC(=O)O)C[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CO
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CCC(=O)OC)C[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21

Procedure:
To a solution of 1.0 mmol of 3-[(2S,4R,5R)-4-[4-((S)-3-methoxy-2-methyl-propoxymethyl)-phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-propionic acid in 5 ml of MeOH at 0° C. are added 5.0 mmol of TMS-diazomethane (2M in hexane) until the conversion to the methyl ester is complete. The reaction mixture is treated with magnesium sulfate to destroy the excess of TMS-diazomethane. The solids are removed by filtration and the organic layer is concentrated under reduced pressure. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound which is identified based on its Rf-value.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16](=[O:18])[CH3:17])[C:7]=1[C:8]([OH:10])=[O:9]>O>[CH3:5][C:6]1[C:14]([N+:1]([O-:4])=[O:2])=[CH:13][CH:12]=[C:11]([NH:15][C:16](=[O:18])[CH3:17])[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: CC(=O)Nc1cccc(C)c1C(=O)O
Reactant: O=[N+]([O-])O
Solvent: O
Product: CC(=O)Nc1ccc([N+](=O)[O-])c(C)c1C(=O)O
Temperature: 10 °C
Reaction time: 1 h

Procedure:
271 ml of 98 percent nitric acid are initially taken at -5° C. and 106 g (0.55 mol) of the 2-methyl-6-acetamidobenzoic acid prepared in 1. are added in portions. After stirring at 10° C. for one hour, the reaction mixture is poured into a mixture of 540 g of ice and 270 ml of water. The deposited precipitate is filtered off with suction, washed withwater and dried under reduced pressure at 50° C. Yield: 75.6 g (0.317 mol)=58% of theory, m.p.: 190°-191° C.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:17])[CH2:14][CH2:15][CH3:16].[Cl:18][CH2:19][CH2:20][N:21]=[C:22]=[O:23]>>[Cl:18][CH2:19][CH2:20][NH:21][C:22]([N:17]([CH2:13][CH2:14][CH2:15][CH3:16])[CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4])=[O:23]
Reactant: O=C=NCCCl
Reactant: CCCCN
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CCCCN(C(=O)NCCCl)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 73.4 %

Procedure:
3.6 g of D-glucose, 1.7 g of n-butylamine and 2.5 g of 2-chloroethyl isocyanate are treated in the same manner as described in Example 5-(1). 5.0 g of 1-(2-chloroethyl)-3-n-butyl-3-D-glucopyranosylurea are obtained as colorless caramel.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([NH:10][CH:11]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:12]2[C:13]([C:18](O)=[O:19])=[N:14][N:15]([CH3:17])[CH:16]=2)[CH:3]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([N:10]2[CH:11]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[C:12]3[C:13](=[N:14][N:15]([CH3:17])[CH:16]=3)[C:18]2=[O:19])[CH:3]=1
Reactant: Cn1cc(C(Nc2cc(Cl)c(=O)n(C)c2)c2ccc(Cl)cc2)c(C(=O)O)n1
Solvent: CO
Solvent: ClCCl
Product: Cn1cc2c(n1)C(=O)N(c1cc(Cl)c(=O)n(C)c1)C2c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Example 1 using 4-((5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-ylamino)(4-chlorophenyl)methyl)-1-methyl-1H-pyrazole-3-carboxylic acid (Step 10.4). tR: 3.65 min (HPLC 1); tR: 0.82 min (LC-MS 2): ESI-MS: 389/391 [M+H]+ (LC-MS 2); Rf=0.56 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 3.45 (s, 3H) 3.98 (s, 3H) 6.21 (s, 1H) 7.26 (d, J=8.4 Hz, 2H) 7.38 (d, J=8.4 Hz, 2H) 7.79 (s, 1H) 7.90-8.04 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[O:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[CH3:22][N:23]([CH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=1)[CH3:24].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:24][N:23]([CH2:25][C:26]1[CH:27]=[CH:28][C:29]([C:30]([N:19]2[CH2:20][CH2:21][CH:16]([O:15][C:3]3[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([C:9]4[CH:14]=[CH:13][N:12]=[CH:11][N:10]=4)[N:4]=3)[CH2:17][CH2:18]2)=[O:31])=[CH:33][CH:34]=1)[CH3:22]
Reactant: Cn1c(OC2CCNCC2)nc(-c2ccncn2)cc1=O
Reactant: CN(C)Cc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)Cc1ccc(C(=O)N2CCC(Oc3nc(-c4ccncn4)cc(=O)n3C)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 15 %

Procedure:
To a mixture of 1-methyl-2-(piperidin-4-yloxy)-1H-[4,4′]bipyrimidinyl-6-one (290 mg, 1.0 mmol), 4-dimethylaminomethyl benzoic acid (180 mg, 1.0 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (380 mg, 2.0 mmol) and 1-hydroxybenzotriazole monohydrate (310 mg, 2.0 mmol) in N,N-dimethylformamide (10 ml) was added N,N-diisopropylethylamine (130 mg, 1.0 mmol) at room temperature. The mixture was stirred at room temperature for 3 hours. The mixture was partitioned between water and dichloromethane. The organic layer was washed with water (three times), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by NH-silica gel column chromatography (eluent; hexane/ethyl acetate=15/85) to afford 2-[1-(4-dimethylaminomethyl-benzoyl)piperidin-4-yloxy]-1-methyl-1H-[4,4′]bipyrimidinyl-6-one as a colorless solid (66 mg, 0.15 mmol, 15%).