Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:15]([CH3:18])=[N:16][N:17]=3)[C:9]=2[CH:8]=[C:7]1[C:19]([OH:21])=O.[CH:25]([N:28](CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.CN.C1COCC1>CN(C=O)C.CC#N>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:15]([CH3:18])=[N:16][N:17]=3)[C:9]=2[CH:8]=[C:7]1[C:19]([NH:28][CH3:25])=[O:21]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1nnc2ccc3c(cc(C(=O)O)n3Cc3cccc(Cl)c3)n12
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=O)c1cc2c(ccc3nnc(C)n32)n1Cc1cccc(Cl)c1
Reaction time: 0.25 h

Procedure:
To a solution of 6-(3-chlorobenzyl)-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine-7-carboxylic acid (0.034 g, 0.10 mmol, from Step 4) in DMF (2 mL) was added N,N-diisopropylethylamine (0.16 mL, 0.93 mmol, Aldrich) followed by N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.12 g, 0.32 mmol, Aldrich) and then by 2.0 M methylamine in THF (0.40 mL, 0.80 mmol, Aldrich). After stirring for 15 minutes, the reaction mixture was diluted with MeCN and purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH). Yield: (25 mg, 71%).
Reaction SMILES: [O:1]1[C:5]2[C:6]3[C:7](=[CH:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])[CH2:8][CH2:9][C:10]=3[CH:11]=[CH:12][C:4]=2[N:3]=[CH:2]1>CO.[C].[Pd]>[O:1]1[C:5]2[C:6]3[CH:7]([CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])[CH2:8][CH2:9][C:10]=3[CH:11]=[CH:12][C:4]=2[N:3]=[CH:2]1
Reactant: CC(=O)NCC=C1CCc2ccc3ncoc3c21
Agent: [Pd]
Solvent: CO
Product: CC(=O)NCCC1CCc2ccc3ncoc3c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
N-[2-(6,7-Dihydro-8H-indeno[5,4-d][1,3]oxazol-8-ylidene)ethyl]acetamide (19.0 mg, 0.0784 mmol) was dissolved in methanol (1 mL), a 10% palladium-carbon powder (10 mg) was added, and the mixture was stirred at room temperature for 1 hr under a hydrogen atmosphere. The catalyst was filtered off using celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol=90/10) to give the title compound (16.0 mg, yield 84%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[F:8][C:9]1[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:10]=1[O:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[CH3:26][N:27]([CH3:31])[C:28](Cl)=[O:29]>O.C(Cl)(Cl)Cl>[CH3:26][N:27]([C:28]([N:15]1[CH2:16][CH2:17][CH:12]([O:11][C:10]2[C:18]([F:25])=[C:19]([F:24])[C:20]([F:23])=[C:21]([F:22])[C:9]=2[F:8])[CH2:13][CH2:14]1)=[O:29])[CH3:31]
Reactant: CN(C)C(=O)Cl
Reactant: Fc1c(F)c(F)c(OC2CCNCC2)c(F)c1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CN(C)C(=O)N1CCC(Oc2c(F)c(F)c(F)c(F)c2F)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 71.1 %

Procedure:
To a stirring solution of 10 g of potassium carbonate in 50 ml of water was added 4.42 g of 4-(2,3,4,5,6-pentafluorophenoxy)piperidine hydrochloride in 50 ml of chloroform, followed by a solution of 3.23 g of dimethylcarbamoyl chloride in 20 ml of chloroform which was added, dropwise, over a period of 20 minutes. After stirring for 20 hours at room temperature, the layers were separated; the organic layer was washed with water followed by a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Filtration, followed by evaporation of the filtrate afforded an oil. The oil was purified by means of high pressure liquid chromatography (silica gel; elution with 5% methanol/dichloromethane) to afford 3.50 g (69.0%) of 1-[(N,N-dimethylamino)carbonyl]-4-(2,3,4,5,6-pentafluorophenoxy)piperidine as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]([OH:10])[CH3:9]>C1(C)C=CC=CC=1.O=[Mn]=O>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8](=[O:10])[CH3:9]
Reactant: CC(O)c1ccncc1F
Agent: O=[Mn]=O
Solvent: Cc1ccccc1
Product: CC(=O)c1ccncc1F
Yield: 70.5 %

Procedure:
Into a stirred solution of 3-fluoropyridine (14 g, 144.2 mmol) in anhydrous THF (150 mL), cooled to −78° C. and under argon, 79.2 mL (158.6 mmol) of a 2N solution of lithiumdiisopropylamide (LDA) in n-heptane, THF, ethylbenzene, were slowly dropped in about 1 h. After stirring for 2.5 h a cooled solution (ca. 0° C.) of acetaldehyde (8.9 mL, 158.5 mmol) in 25 mL of anhydrous THF was slowly dropped and the reaction mixture was stirred at −78° C. for 1.5 h. The solution was warmed to −30° C. and a solution of ammonium chloride (150 g) in 700 mL of water was added. The mixture was extracted with ethylacetate (3×400 mL) and the organic layers were washed with brine (4×200 mL) and dried over sodium sulfate. After concentration, the oil was crystallized with n-hexane (40 mL) and 15.6 g (76% yield) of 1-(3-fluoropyridin-4-yl)ethanol were obtained. A mixture of 1-(3-fluoropyridin-4-yl)ethanol (10 g, 70.3 mmol) and commercial activated MnO2 (8 g, 92.1 mmol) in toluene (100 mL) were refluxed until disappearance of starting material. After cooling, the mixture was filtered on a bed of celite, the cake washed with toluene and the organic phases concentrated to give 3-fluoro-4-acetyl pyridine (6.9 g, 70%) that was used directly in the next step. To a stirred solution of 3-fluoro-4-acetylpyridine (5.3 g, 38.1 mmol) in glacial acetic acid (14 mL) and 48% hydrobromic acid (5.3 mL), bromine (2 mL, 38 mmol) in glacial acetic acid (5.3 mL) was added slowly and dropwise. After addition, the solution was stirred at 60° C. for 2.5 hour. This solution was cooled down and ethylacetate (70 mL) was added. After 30 minutes of stirring, the mixture was filtered and the solid was washed thoroughly with ethylacetate and dried. The title compound was obtained in 82% yield (9.4 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=4)=[CH:15][C:13]=3[N:14]=2)[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[CH:27]1[C:32]([C:33]([OH:35])=[O:34])=[CH:31][C:30]2[C:36]([O:38][C:39](=O)[C:29]=2[CH:28]=1)=[O:37]>>[CH3:9][O:8][C:5]1[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=4)=[CH:15][C:13]=3[N:14]=2)=[CH:3][C:2]([N:1]2[C:36](=[O:37])[C:30]3[C:29](=[CH:28][CH:27]=[C:32]([C:33]([OH:35])=[O:34])[CH:31]=3)[C:39]2=[O:38])=[CH:7][CH:6]=1
Reactant: COc1ccc(N)cc1-c1nc2cc(-c3ccc(F)c(Cl)c3)ccc2o1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: COc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(-c3ccc(F)c(Cl)c3)ccc2o1

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-6-methoxyphenyl)-5-(3-chloro-4-fluorophenyl)benzoxazole (60 mg, 0.16 mmol) and 1,2,4-benzenetricarboxylic anhydride (31 mg, 0.16 mmol) the title compound was obtained (75 mg, 86%). 1H NMR (DMSO) δ 13.80(s, 1H), 8.43(d, 1H), 8.32(s, 1H), 8.21(d, 1H), 8.15(s, 1H), 8.10(d, 1H), 7.99(dd, 1H), 7.88(d, 1H), 7.75(m, 3H), 7.53(t, 1H), 7.47(d, 1H), 4.03(s, 3H). MS 542.6 m/z (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]([C:8](=[O:19])[C:9]2[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=2[N+:16]([O-:18])=[O:17])=[C:4]([CH3:20])[NH:3]1.S(Cl)([Cl:24])(=O)=O>C1C=CC=CC=1>[CH3:1][N:2]1[C:6](=[O:7])[C:5]([Cl:24])([C:8](=[O:19])[C:9]2[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=2[N+:16]([O-:18])=[O:17])[C:4]([CH3:20])=[N:3]1
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1ccc([N+](=O)[O-])c(C(=O)c2c(C)[nH]n(C)c2=O)c1
Solvent: c1ccccc1
Product: CC1=NN(C)C(=O)C1(Cl)C(=O)c1cc(C)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.1 %

Procedure:
To a suspension of 2.65 g of 1,3-dimethyl-4-(2-nitro-5-methylbenzoyl)-5-pyrazolone in 20 ml of dry benzene was added 1.62 g of sulfuryl chloride and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was treated in the same manner as in the Example 1 to give 2.0 g of the desired product melting at 110° - 111° C. (Yield 64.72%)
Reaction SMILES: [CH2:1]([N:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH2:15][CH2:14]2)[CH3:5])[CH:2]=[CH2:3].C(Cl)Cl.Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)=[O:25]>>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([O:26][C:24]([N:16]2[C:17]3[C:13](=[CH:12][C:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][N:4]([CH2:1][CH:2]=[CH2:3])[CH3:5])=[CH:19][CH:18]=3)[CH2:14][CH2:15]2)=[O:25])=[CH:28][CH:29]=1
Reactant: C=CCN(C)CCCCCc1ccc2c(c1)CCN2
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Solvent: ClCCl
Product: C=CCN(C)CCCCCc1ccc2c(c1)CCN2C(=O)Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
To 130 mg (0.5 mmol) Allyl-[5-(2,3-dihydro-1H-indol-5-yl)-pentyl]-methyl-amine in 2 ml CH2Cl2 0.34 ml (2 mmol) Huenig's base were added, followed by 0.28 ml (2 mmol) 4-chlorophenyl chloroformate. The solution was stirred at RT for 30 min, was concentrated and dissolved in 0.1 M NaOH and ether. The inorganic phase was extracted with ether. The combined organic phases were washed with water and dried over Na2SO4. Column chromatography on silica gel with CH2Cl2/MeOH 9:1 yielded 160 mg (77%) 5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carboxylic acid 4-chloro-phenyl ester as light yellow oil, MS: 413 (MH+, 1Cl).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1.[O:24]([CH2:31][C:32]#[CH:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:33]#[C:32][CH2:31][O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1
Reactant: Cc1nnc2n1-c1ccc(I)cc1C(c1ccccc1Cl)=NC2
Reactant: C#CCOc1ccccc1
Product: Cc1nnc2n1-c1ccc(C#CCOc3ccccc3)cc1C(c1ccccc1Cl)=NC2

Procedure:
This compound was obtained by coupling 6-(2-chlorophenyl)-8-iodo-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine with 1-phenoxy-2-propyne as described in example 1. Chromatographic isolation and crystallization from ethyl acetate gave colorless crystals with m.p. 160°-162° C.
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([CH3:29])=[C:13](/[CH:17]=[C:18]2/[C:19]3[CH:20]=[C:21]([F:28])[CH:22]=[CH:23][C:24]=3[NH:25][C:26]/2=[O:27])[NH:14][C:15]=1[CH3:16])=[O:10])[CH2:4][CH3:5].[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]\[C:33]([OH:35])=[O:34]>CO.ClCCl>[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([CH3:29])=[C:13](/[CH:17]=[C:18]2/[C:19]3[CH:20]=[C:21]([F:28])[CH:22]=[CH:23][C:24]=3[NH:25][C:26]/2=[O:27])[NH:14][C:15]=1[CH3:16])=[O:10])[CH2:4][CH3:5].[CH2:31]([C:30]([OH:37])=[O:36])[C@H:32]([OH:10])[C:33]([OH:35])=[O:34]
Reactant: O=C(O)/C=C\C(=O)O
Agent: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Solvent: CO
Solvent: ClCCl
Product: O=C(O)C[C@H](O)C(=O)O
Temperature: 27.5 °C
Reaction time: 1 h

Procedure:
Sunitinib (2.0 g) was suspended in 10% methanol in dichloromethane at 25° C. , followed by addition of maleic acid (0.58 g) .The reaction mass was maintained under stirring at 25-30° C. for 60 minutes. The solids obtained were filtered, suck dried and dried under vacuum for a period of 10 hrs at 60° C. to obtain sunitinib maleate. (2.3 g; yield: 89%)
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([I:19])[CH:16]=[C:15]([Cl:20])[C:3]=1[C:4](Cl)=[N:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([Cl:12])[C:7]=1F.NC(N)=[S:23].N1C=CC=CC=1.C(N(CC)CC)C>C(O)(C)C>[Cl:12][C:8]1[C:7]2[S:23][C:4]([C:3]3[C:2]([Cl:1])=[CH:18][C:17]([I:19])=[CH:16][C:15]=3[Cl:20])=[N:5][C:6]=2[CH:11]=[CH:10][N:9]=1
Reactant: NC(N)=S
Reactant: Fc1c(N=C(Cl)c2c(Cl)cc(I)cc2Cl)ccnc1Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: Clc1cc(I)cc(Cl)c1-c1nc2ccnc(Cl)c2s1
Temperature: 90 °C
Yield: 83.8 %

Procedure:
A mixture of 2,6-dichloro-N-(2-chloro-3-fluoropyridin-4-yl)-4-iodobenzimidoyl chloride (2.94 g, 6.30 mmol), thiourea (1.93 g, 25.3 mmol) and pyridine (1.73 mL, 21.4 mmol) in isopropanol (25 mL) was heated to 90° C. for 3.5 hours. Triethylamine (5.3 mL, 37.8 mmol) was added and the resulting mixture was heated to 90° C. for a further 1.5 h. The reaction was cooled to room temperature and then concentrated under reduced pressure. The resultant residue was partitioned between DCM and water. The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure. The residue was triturated with MeOH and dried under reduced pressure to give the desired compound (2.33 g, 84% yield). 1H NMR (300 MHz, CDCl3): δ 8.52 (d, J=5.6 Hz, 1H), 7.98 (d, J=5.6 Hz, 1H), 7.90-7.81 (s, 2H).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH:10]([C:12]([OH:14])=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[CH3:15][N:16]([CH3:34])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1>>[CH3:15][N:16]([CH3:34])[C:17]1[CH:18]=[CH:19][C:20]([CH2:23][N:24]([C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:32])[CH3:33])=[CH:27][CH:26]=2)[C:12]([CH:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2](=[O:1])[CH2:11]2)=[O:14])=[CH:21][CH:22]=1
Reactant: O=C1CC(C(=O)O)c2ccccc2N1
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CC(=O)Nc3ccccc32)cc1
Yield: 52.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 1 using 2-oxo-1,2,3,4-tetrahydroquinoline-4-carboxylic acid (0.5 g) and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.7 g) as starting materials, N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-4-carboxamide (0.6 g) was obtained. melting point: 170° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[O:18][CH3:19])=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31](=[O:33])[CH3:32])[CH2:27][CH2:26]1>>[NH2:1][C:2]1[C:7]([C:8](=[O:9])[C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[O:18][CH3:19])=[CH:6][N:5]=[C:4]([NH:24][CH:25]2[CH2:30][CH2:29][N:28]([C:31](=[O:33])[CH3:32])[CH2:27][CH2:26]2)[N:3]=1
Reactant: CC(=O)N1CCC(N)CC1
Reactant: CCS(=O)c1ncc(C(=O)c2cc(OC)ccc2OC)c(N)n1
Product: COc1ccc(OC)c(C(=O)c2cnc(NC3CCN(C(C)=O)CC3)nc2N)c1

Procedure:
The same procedure as described in Example 326 was used, starting with (4-amino-2-ethanesulfinyl-pyrimidin-5-yl)-(2,5-dimethoxyphenyl)-methanone (Example 329) and 1-(4-amino-piperidin-1-yl)-ethanone to give 1-[4-[4-amino-5-(2,5-dimethoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-ethanone as a white solid. MS (M+H)+, 400.
Reaction SMILES: [CH:1]1([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+]>C(O)C>[CH:1]1([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCC1CCCCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCC1CCCCCCC1
Temperature: 25 °C

Procedure:
To a solution of the crude cyclooctanepropanoic acid, ethyl ester in ethanol (200 mL) was added KOH (20 g). The resulting mixture was heated to reflux for 1.25 h, cooled to room temperature, and concentrated to remove the bulk of the ethanol. To the residue was added water (250 mL) and the solution was washed with CH2Cl2 (2×200 mL, discarded). The aqueous solution was made acidic with concentrated HCl (30 mL), with ice added to keep the mixture near room temperature. The solution was extracted with CH2Cl2 (3×200 mL), and the extracts were washed with brine, dried over MgSO4, and concentrated to give crude cyclooctanepropanoic acid (11.45 g) as a colorless oil. An 0.72-g portion was evaporatively distilled to give 0.69 g of pure acid, bp 165° C./0.5 torr.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][CH2:28][O:29][C:22]=3[CH:21]=2)[C:11]2[CH:16]=[C:15]([Cl:17])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][CH2:28][O:29][C:22]=4[CH:21]=3)[C:11]3[CH:16]=[C:15]([Cl:17])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Clc1nc(NCc2ccc3c(c2)OCCO3)c2cc(Cl)sc2n1
Reactant: Cc1ncc[nH]1
Product: Cc1nccn1-c1nc(NCc2ccc3c(c2)OCCO3)c2cc(Cl)sc2n1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2,6-dichloro-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-chloro-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C@H:15]([C@@H:16]([C@@H:18]([CH2:20][OH:21])[OH:19])[OH:17])[O:14][C@:8]([O:12][CH3:13])([C:9]([OH:11])=[O:10])[CH2:7][C@@H:6]1[OH:22])(=[O:3])[CH3:2].C(O[C:27](=[O:29])[CH3:28])(=O)C>N1C=CC=CC=1>[C:1]([NH:4][C@H:5]1[C@H:15]([C@@H:16]([C@@H:18]([CH2:20][O:21][C:15](=[O:14])[CH3:5])[O:19][C:9](=[O:10])[CH3:8])[O:17][C:1](=[O:3])[CH3:2])[O:14][C@:8]([O:12][CH3:13])([C:9]([OH:11])=[O:10])[CH2:7][C@@H:6]1[O:22][C:27](=[O:29])[CH3:28])(=[O:3])[CH3:2]
Reactant: CO[C@@]1(C(=O)O)C[C@H](O)[C@@H](NC(C)=O)[C@H]([C@H](O)[C@H](O)CO)O1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CO[C@@]1(C(=O)O)C[C@H](OC(C)=O)[C@@H](NC(C)=O)[C@H]([C@H](OC(C)=O)[C@@H](COC(C)=O)OC(C)=O)O1
Temperature: 25 °C
Reaction time: 7 h
Yield: 96 %

Procedure:
After a mixture of methyl 5-acetamido-3,5-dideoxy-D-glycero-β-D-galacto-2-nonulopyranosidonic acid [Chem. Ber., 99, 611 (1966)] (150 mg; 0.464 mmol), acetic anhydride (2.3 ml) and pyridine (2.3 ml) was stirred at room temperature for 7 h, the reaction solution was evaporated to dryness in vacuo. The residue was dissolved in chloroform, and treated with Amberist-15 (H type) to obtain the title compound (218 mg, 96%) as white powder.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[Cl:10].Cl/[CH:15]=[CH:16]\[CH2:17][CH2:18]Cl.O>CS(C)=O>[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2([C:12]#[N:13])[CH2:18][CH:17]=[CH:16][CH2:15]2)[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: Cl/C=C\CCCl
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CC1(c2ccc(Cl)c(Cl)c2)CC=CC1
Temperature: 25 °C
Yield: 43 %

Procedure:
To ice-cold DMSO (100 mL) was added 60% NaH (1.0 g, 2.3 eq) in portions. The cooling bath was removed and the solution was stirred at ambient temperature for ten minutes. A solution of 2-(3,4-dichlorophenyl)acetonitrile (2.0 g, 10.75 mmol) in DMSO (50 mL) was added. The brown solution was stirred for 15 minutes before cis-1,4-dichlorobutene (1.0 mL, 0.9 eq) was added. The reaction mixture was stirred overnight and was then poured into water. The product was extracted with DCM. The organic layer was washed with brine, evaporated, diluted with 50% ethyl acetate in hexanes, washed with water, and evaporated. The residual oil was separated on silica to give the nitrile (966 mg, 43%) as a pale-brown oil. GCMS Rt=10.8 min m/z=237 (M+). 1H NMR (CDCl3, δ): 7.51 (d, J=2.3 Hz, 1H), 7.39 (d, J=8.5 Hz, 1H), 7.28 (dd, J=2.3, 8.5 Hz, 1H), 5.79 (s, 2H), 3.27 (d, J=14.7 Hz, 2H), 2.87 (d, J=14.7 Hz, 2H). 13C NMR (CDCl3, δ): 141.9, 133.2, 132.1, 131.0, 128.5, 127.6, 125.0, 124.0, 48.4.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:16]([Cl:17])[C:15]([OH:22])([C:18]([F:21])([F:20])[F:19])[O:14][N:13]=2)=[CH:8][CH:7]=1>S(=O)(=O)(O)O>[Cl:17][CH:16]1[C:15]([OH:22])([C:18]([F:19])([F:20])[F:21])[O:14][N:13]=[C:12]1[C:9]1[CH:10]=[CH:11][C:6]([Cl:5])=[C:7]([N+:1]([O-:4])=[O:2])[CH:8]=1
Reactant: OC1(C(F)(F)F)ON=C(c2ccc(Cl)cc2)C1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(C2=NOC(O)(C(F)(F)F)C2Cl)ccc1Cl
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
At 5° C., 1.81 ml of a mixture of 0.46 ml of 98% strength nitric acid and 1.35 ml of concentrated sulfuric acid were added dropwise to 2.4 g of 3-(4'-chlorophenyl)-4-chloro-5-hydroxy-5-trifluoromethylisoxazoline in 20 ml of concentrated sulfuric acid. The reaction mixture was stirred at 5° C. for 1.5 hours and then poured into 300 ml of ice-water. The organic phase was subsequently separated off, dried over sodium sulfate and finally concentrated. Yield: 2.5 g.
Reaction SMILES: [N+:1]([C:4]1[CH:42]=[CH:41][C:7]([C:8]([O:10][C@@:11]([C:18]2[N:19]=[N:20][N:21]([CH2:23][C:24]3[CH:33]=[C:32]4[C:27]([C:28]([C:36]([O:38]CC)=[CH2:37])=[CH:29][C:30]([C:34]#[N:35])=[N:31]4)=[CH:26][CH:25]=3)[CH:22]=2)([C:14]([F:17])([F:16])[F:15])[CH2:12][CH3:13])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1C(=O)N([Br:50])C(=O)C1>C1COCC1.O>[N+:1]([C:4]1[CH:42]=[CH:41][C:7]([C:8]([O:10][C@@:11]([C:18]2[N:19]=[N:20][N:21]([CH2:23][C:24]3[CH:33]=[C:32]4[C:27]([C:28]([C:36](=[O:37])[CH2:38][Br:50])=[CH:29][C:30]([C:34]#[N:35])=[N:31]4)=[CH:26][CH:25]=3)[CH:22]=2)([C:14]([F:17])([F:16])[F:15])[CH2:12][CH3:13])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(OCC)c1cc(C#N)nc2cc(Cn3cc([C@](CC)(OC(=O)c4ccc([N+](=O)[O-])cc4)C(F)(F)F)nn3)ccc12
Solvent: C1CCOC1
Solvent: O
Product: CC[C@](OC(=O)c1ccc([N+](=O)[O-])cc1)(c1cn(Cc2ccc3c(C(=O)CBr)cc(C#N)nc3c2)nn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-1-(1-{[2-cyano-4-(1-ethoxyvinyl)quinolin-7-yl]methyl}-1H-1,2,3-triazol-4-yl)-1-(trifluoromethyl)propyl 4-nitrobenzoate (593 mg, 1.05 mmol) in THF (4 ml) and water (0.25 ml) was added NBS (205 mg, 1.16 mmol). The mixture was stirred at room temperature for 30 min. The solution was then evaporated to dryness and purified by flash chromatography (eluting solvent: 3% acetone in dichloromethane) to afford the title compound. 1H NMR (400 MHz, acetone-d6): δ 8.55 (s, 1H), 8.50 (s, 1H), 8.40 (d, 2H), 8.37 (d, 1H), 8.30 (d, 2H), 8.07 (s, 1H), 7.85 (d, 1H), 6.05 (s, 2H), 5.05 (s, 2H), 3.05 (m, 1H), 2.85 (m, 1H), 1.15 (t, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][C:20]([C:22]([N:24]([CH3:41])[CH:25]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([C:38](=[NH:40])[NH2:39])=[CH:34][CH:33]=4)[C:26]([O:28]CC)=[O:27])=[O:23])=[CH:21][C:14]=3[N:13]=2)=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].[CH:42]([O-:44])=[O:43]>ClCCl.CO>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][C:20]([C:22]([N:24]([CH3:41])[CH:25]([CH2:31][C:32]4[CH:33]=[CH:34][C:35]([C:38](=[NH:39])[NH2:40])=[CH:36][CH:37]=4)[C:26]([OH:28])=[O:27])=[O:23])=[CH:21][C:14]=3[N:13]=2)=[CH:6][CH:5]=1)(=[NH:2])[NH2:3].[CH:42]([O-:44])=[O:43]
Reactant: CCOC(=O)C(Cc1ccc(C(=N)N)cc1)N(C)C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C
Agent: O=C[O-]
Solvent: CO
Solvent: ClCCl
Product: CN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)C(Cc1ccc(C(=N)N)cc1)C(=O)O
Yield: 90 %

Procedure:
The reaction takes place analogously to the procedure described in Example 30 starting from ethyl 2-{2-[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazol-5-yl-carbonyl-(methylamino)}-3-(4-amidinophenyl)-propionate (Example 29, 1.7 mmol). The product is obtained by crystallisation from dichloromethane/methanol. Yield: >90%; melting point: 255° C.; mass: calc.: [525], found: [M+H]+ 526; 1H-NMR (250 MHz, DMSO-d6): δ [ppm]=10.20 (1H, s, COOH); 8.61 (1H, s, HCOOH); 8.09-6.77 (17H, m, 2 C(═NH)NH2, aryl-H); 5.37 (1H, m, N—CH—); 3.78 (3H, s, aryl-N—CH3); 3.33 (4H, s, aryl-CH2—CH2—); 2.98 (3H, s, CO—N—CH3).