Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[S:2]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[CH2:12][C:13]([O:15][CH3:16])=[O:14])(=[O:4])=[O:3].[NH2:17][C:18]1[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]2[C:21]([CH:22]3[CH2:32][CH:23]3[CH2:24][O:25]2)=[CH:20][CH:19]=1>N1C=CC=CC=1.C(Cl)Cl>[F:11][C:8]1[CH:9]=[CH:10][C:5]([S:2]([NH:17][C:18]2[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]3[C:21]([CH:22]4[CH2:32][CH:23]4[CH2:24][O:25]3)=[CH:20][CH:19]=2)(=[O:4])=[O:3])=[C:6]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:7]=1
Reactant: COC(=O)c1c(N)ccc2c1OCC1CC21
Reactant: COC(=O)Cc1cc(F)ccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)Cc1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCC1CC21
Reaction time: 96 h
Yield: 97.6 %

Procedure:
A solution of methyl (2-chlorosulfonyl-5-fluorophenyl)acetate (Intermediate 85, 0.293 g) and methyl (1aRS,7bSR)-5-amino-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate (Intermediate 42, 0.219 g) in pyridine (1 mL) and DCM (3 mL) was left to stand at room temperature for 4 days. The mixture was diluted with DCM, washed with 2M hydrochloric acid and filtered through a phase separator. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-40% to give methyl (1aRS,7bSR)-5-[4-fluoro-2-(methoxycarbonylmethyl)-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.438 g) as a colourless gum.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][C:14]1[N:15]=[CH:16][NH:17][C:18]=1[C:19]([O:21][CH3:22])=[O:20])=O)C1C=CC=CC=1.C(O)(=O)C.[BrH:27]>>[BrH:27].[BrH:27].[NH2:11][CH2:12][CH2:13][C:14]1[N:15]=[CH:16][NH:17][C:18]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1[nH]cnc1CCNC(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: COC(=O)c1[nH]cnc1CCN
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-[2-(N-Benzyloxycarbonylamino)ethyl]5-methoxycarbonylimidazole (1.2 g) is dissolved in 30% hydrogenbromide acetic acid solution (20 ml) and the solution is stirred at room temperature for 30 minutes. The reaction mixture is concentrated under reduced pressure and the residue is triturated with ether to give 4-(2-aminoethyl)-5-methoxycarbonylimidazole dihydrobromide. To the thus-obtained product are added dimethylformamide (20 ml), N-tert-butoxycarbonyl-L-phenylalanyl-L-phenylalanine (1.65 g) and 1-hydroxybenzotriazole (0.54 g). Dicyclohexylcarbodiimide (0.83 g) is added to the mixture under ice-cooling and the mixture is stirred for 10 minutes. Triethylamine (1.4 ml) is added to the mixture and the mixture is stirred at room temperature overnight. Ethyl acetate is added to the reaction mixture, and insoluble materials are filtered off. The filtrate is washed with an aqueous sodium bicarbonate solution and an aqueous sodium chloride solution, dried, and then concentrated to remove solvent. The residue is purified by silica gel column chromatography (solvent; chloroform:methanol=12:1) and crystallized with ether to give 4-{2-[N-(N-tert-butoxycarbonyl-L-phenylalanyl-L-phenylalanyl) amino]ethyl}-5 -methoxycarbonylimidazole (1.4 g) as colorless crystals. Yield ; 62.2%
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)C=O)[CH:5]=[CH:4][N:3]=1.Cl.O1CCOCC1.[CH3:23][O:24][CH:25](OC)[O:26][CH3:27]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[CH:10][CH:13]=[C:14]([CH:25]([O:26][CH3:27])[O:24][CH3:23])[CH:15]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COC(OC)OC
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Agent: Cl
Solvent: C1COCCO1
Product: COC(OC)c1cccc(-c2ccnc(Cl)n2)c1

Procedure:
Intermediate 1 (3.69 g) was refluxed for two hours in trimethylorthoformate containing 10 mL of 4N HCl/dioxane. The solvent was removed by rotary evaporation to give product, which showed the expected M+H+ of 265 by LC-MS.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=2)=[O:12])[CH2:7][CH2:6]1.[NH:23]1[CH:27]=[C:26]([CH2:28][C:29](O)=[O:30])[N:25]=[N:24]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][N:2]([CH2:3][CH2:4][CH:5]1[CH2:6][CH2:7][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:16]=[C:17]([Cl:22])[CH:18]=[C:19]([Cl:21])[CH:20]=2)=[O:12])[CH2:9][CH2:10]1)[C:29](=[O:30])[CH2:28][C:26]1[N:25]=[N:24][NH:23][CH:27]=1
Reactant: CNCCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Reactant: O=C(O)Cc1c[nH]nn1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(CCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1)C(=O)Cc1c[nH]nn1

Procedure:
A mixture comprising of 3,5-dichlorobenzyl 4-(2-(methylamino)ethyl)piperidine-1-carboxylate (Example 1, step 3) (100 mg, 0.290 mmol), 2-(1H-1,2,3-triazol-4-yl)acetic acid (55.2 mg, 0.434 mmol), T3P® (50% solution in DMF) (338 μl, 0.579 mmol) and Huenig's base (101 μl, 0.579 mmol) in DMF was stirred at room temperature for 18 hours. The resulting mixture was concentrated under pressure. The crude residue was diluted with water and extracted with EtOAc. The organic portion was dried over MgSO4, filtered and solvent concentrated under reduced pressure. Further purification was carried out using preparative LC-MS. The resulting product fractions were concentrated under reduced pressure to give an aqueous solution and then extracted with EtOAc. The organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]([C:17]#[N:18])=[CH:12][N:7]3[C@@H:8]([CH3:11])[CH2:9][O:10][C:5]([C:6]=23)=[C:4](F)[C:3]=1[F:20].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C@H:27]2[CH2:32][CH2:31][CH2:30][C@H:29]([NH2:33])[CH2:28]2)[CH:22]=1.C(N(C(C)C)CC)(C)C>CS(C)=O>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]([C:17]#[N:18])=[CH:12][N:7]3[C@@H:8]([CH3:11])[CH2:9][O:10][C:5]([C:6]=23)=[C:4]([NH:33][C@H:29]2[CH2:30][CH2:31][CH2:32][C@H:27]([C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)[CH2:28]2)[C:3]=1[F:20]
Reactant: C[C@H]1COc2c(F)c(F)c(N)c3c(=O)c(C#N)cn1c23
Reactant: N[C@H]1CCC[C@H](c2cccnc2)C1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1COc2c(N[C@H]3CCC[C@H](c4cccnc4)C3)c(F)c(N)c3c(=O)c(C#N)cn1c23
Temperature: 84 °C
Reaction time: 9 h
Yield: 24.7 %

Procedure:
A mixture of (3S)-8-amino-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carbonitrile (800 mg, 2.89 mmol), trans-3-(3-pyridyl)cyclohexylamine (612 mg, 3.47 mmol) and diisopropylethylamine (1.11 mL, 6.36 mmol) in anhydrous DMSO (12 mL) was stirred at 84° C. for 9 h. After cooling, the reaction mixture was poured into ice-water and then extracted with CH2Cl2-MeOH. The organic layer was washed with water and brine, and dried over anhyd Na2SO4 followed by the removal of solvent. The crude product was purified by column chromatography (EtOAc) to yield (3S)-8-amino-9-fluoro-2,3-dihydro-3-methyl-7-oxo-10-[trans-3-(3-pyridyl)cyclohexylamino]-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carbonitrile (309 mg, 24%) as a yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:15][N:14]=[C:13]([CH3:16])[C:12]=2[NH2:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:15][N:14]=[C:13]([CH3:16])[C:12]=2[NH:17][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][CH:28]=[C:20]([O:19][CH3:18])[CH:21]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: COc1ccc(-c2[nH]nc(C)c2N)cc1OC
Product: COc1cccc(C(=O)Nc2c(C)n[nH]c2-c2ccc(OC)c(OC)c2)c1

Procedure:
The preparation took place in analogy with Example 15a), starting with 300 mg of 5-(3,4-dimethoxyphenyl)-3-methyl-1H-pyrazol-4-ylamine (44) and 242 mg of 3-methoxybenzoyl chloride. The following was obtained: 53
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH:21]1(B(O)O)[CH2:23][CH2:22]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O>[C:17]([Si:14]([CH3:16])([CH3:15])[O:13][CH2:12][CH2:11][O:10][C:5]1[CH:4]=[CH:3][C:2]([CH:21]2[CH2:23][CH2:22]2)=[CH:9][C:6]=1[CH:7]=[O:8])([CH3:20])([CH3:19])[CH3:18]
Reactant: OB(O)C1CC1
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(Br)cc1C=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(C2CC2)cc1C=O
Temperature: 100 °C
Yield: 71.8 %

Procedure:
To a solution of 5-bromo-2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-benzaldehyde (5 g, 13.9 mmol) prepared in example 130a in toluene (75 mL) and water (7.5 mL) was added cyclopropylboronic acid (1.7 g, 19.8 mmol) (Aldrich) and potassium phosphate (14.6 g, 68.9 mmol). After the reaction mixture was degassed for 5 min, dichloro-bis-(tricyclohexyl-phosphine) (1.03 g, 1.39 mmol) (Strem) was added and the reaction mixture was heated at 100° C. under nitrogen for 4 h. The reaction mixture was cooled to room temperature and diluted with water, extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over MgSO4, filtered and concentrated. The residue was purified with chromatography to give 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-cyclopropyl-benzaldehyde as yellow oil (Yield: 3.2 g, 76.2%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([C:15](Cl)=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:18][C@H:19]1[CH2:24][N:23]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([NH:32][CH3:33])=[CH:28][CH:27]=2)[CH2:22][CH2:21][N:20]1[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([C:15]([N:32]([CH3:33])[C:29]3[CH:28]=[CH:27][C:26]([CH2:25][N:23]4[CH2:22][CH2:21][N:20]([C:34]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])[C@@H:19]([CH3:18])[CH2:24]4)=[CH:31][CH:30]=3)=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Reactant: O=C(Cl)c1ccc(Oc2ccc(F)cc2)nc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Oc4ccc(F)cc4)nc3)cc2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The acid chloride from step 1 was taken up in DCM (3 mL) and added to 1,1-dimethylethyl (2S)-2-methyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazinecarboxylate (D3) (0.288 g, 0.904 mmol) in DCM (3 mL). Triethylamine (0.251 mL, 1.808 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM and washed with water. The aqueous was extracted with DCM (×2) and the combined organic layers were dried and concentrated. The crude product was purified by column chromatography. Elution with a 0-50% EtOAc/petroleum ether gradient gave the title compound as a colourless oil (0.518 g). δH (CDCl3, 400 MHz) 8.07 (1H, m), 7.65 (1H, dd), 7.24 (2H, d), 7.03 (6H, m), 6.70 (1H, d), 4.18 (1H, br.s), 3.80 (1H, d), 3.48 (3H, s), 3.46 (1H, d), 3.34 (1H, d), 3.08 (1H, td), 2.70 (1H, d), 2.50 (1H, d), 2.10 (1H, dd), 2.00 (1H, m), 1.46 (9H, s), 1.20 (3H, d). MS (ES): MH+ 535.3.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[NH:10][C:11]1[S:12][C:13](I)=[CH:14][C:15]=1[C:16]([NH2:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O>>[CH2:1]([O:8][C:9](=[O:20])[NH:10][C:11]1[S:12][C:13]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[F:21])=[CH:14][C:15]=1[C:16]([NH2:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1cc(I)sc1NC(=O)OCc1ccccc1
Reactant: OB(O)c1ccccc1F
Product: NC(=O)c1cc(-c2ccccc2F)sc1NC(=O)OCc1ccccc1

Procedure:
The title compound was synthesized from benzyl[3-(aminocarbonyl)-5-iodo-2-thienyl]carbamate (Intermediate 1, Step 2) (300 mg, 0.746 mmol) and 2-fluorophenyl boronic acid (157 mg, 1.12 mmol) as the starting materials as described in Intermediate 1 Step 3.
Reaction SMILES: [Na+].[C:2]([S:5][CH2:6][CH:7]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[C:8]([NH:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([O-:16])=[O:15])=[O:9])(=[O:4])[CH3:3].Cl>O>[C:2]([S:5][CH2:6][CH:7]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[C:8]([NH:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=[O:15])=[O:9])(=[O:4])[CH3:3]
Reactant: COc1ccc(CC(CSC(C)=O)C(=O)Nc2cccc(C(=O)[O-])c2)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1ccc(CC(CSC(C)=O)C(=O)Nc2cccc(C(=O)O)c2)cc1
Yield: 70.4 %

Procedure:
3-[[2-Acetylthiomethyl-3-(4-methoxyphenyl)propionyl]amino]benzoic acid sodium salt (compound of Example 36) (1.5 g) is dissolved in water (30 ml), and the mixture is adjusted to pH 3.0 with 1N hydrochloric acid with stirring under ice cooling, and the mixture is extracted with ethyl acetate (50 ml). The extract is washed with water and dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to give the title compound (1.0 g).
Reaction SMILES: [Cl:1][C:2]1[N:6]([C@@H:7]2[O:31][C@H:30]([CH2:32][O:33]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C@H:29]([F:53])[C@H:8]2[O:9]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:5]2[CH:54]=[C:55]([Cl:59])[C:56]([Cl:58])=[CH:57][C:4]=2[N:3]=1>C(O)(C(F)(F)F)=O.C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:6]([C@@H:7]2[O:31][C@H:30]([CH2:32][OH:33])[C@H:29]([F:53])[C@H:8]2[OH:9])[C:5]2[CH:54]=[C:55]([Cl:59])[C:56]([Cl:58])=[CH:57][C:4]=2[N:3]=1
Reactant: F[C@@H]1[C@@H](OC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H](n2c(Cl)nc3cc(Cl)c(Cl)cc32)O[C@@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: OC[C@H]1O[C@@H](n2c(Cl)nc3cc(Cl)c(Cl)cc32)[C@H](O)[C@H]1F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 74.7 %

Procedure:
Compound 5 (0.28 g, 0.32 mmol) was dissolved in 10% CF3COOH in CHCl3 (20 mL) and stirred at room temperature in a stoppered flask for 45 min. The reaction mixture was evaporated to dryness in vacuo, the oily residue was purified by flash chromatography (EtOAc/hexane 5:1, 2 cm×15 cm), appropriate fractions pooled, evaporated to dryness and crystallized from MeOH/H2O to give 85 mg (74%) of compound 7 as white crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH:12]1([NH2:17])[CH2:16][CH2:15][CH2:14][CH2:13]1.C(N(CC)C(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:17][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: NC1CCCC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cnc(Cl)nc1NC1CCCC1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 84.3 %

Procedure:
2,4-Dichloro-5-nitropyrimidine (10.31 mmol, 2 g) and cyclopentylamine (10.31 mmol, 1.02 mL) were dissolved in THF (60 mL) and cooled to −78° C. N,N-diisopropylethylamine (10.31 mmol, 1.8 mL) was added dropwise. The reaction mixture was stirred at −78° C. for about 45 minutes. The cooling bath was removed and the reaction mixture was stirred at room temperature for about 16 hours. After removal of the solvent the residue was redissolved in EtOAc and washed with water and brine. The organic phase was dried over MgSO4 and the solvent evaporated. The residue was purified using column chromatography (SiO2, 9:1 n-hexanes/ethyl acetate) to give the desired product (2.11 g, 84% yield). ES-MS: 242 (M+1). When the hydrochloride salt of an amine is used in place of the cyclopentylamine described above, 2 to 3 equivalents of N,N-diisopropylethylamine and dichloromethane are used as solvent.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([N:26]3[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NC1CCNCC1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3CCC(N)CC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and piperidin-4-amine. MS obsd. (ESI+) [(M+H)+] 437, 1H NMR (400 MHz, CD3OD) δ ppm 8.10-8.08 (m, 1 H), 7.84-7.71 (m, 3 H), 7.62-7.59 (m, 3 H), 6.50 (s, 1 H), 5.34 (s, 2 H), 4.57-4.55 (m, 2 H), 3.96-3.86 (m, 2 H), 3.78-3.76 (m, 2 H), 3.48-3.45 (m, 1 H), 3.13-3.08 (m, 2 H), 2.48 (s, 3 H), 2.27-2.23 (m, 2 H), 2.02-1.92 (m, 2 H).
Reaction SMILES: C(=O)([O-])[OH:2].[Na+].[Cl:6][C:7]1[CH:29]=[CH:28][C:10]([CH2:11][NH:12][C:13](=[O:27])[CH2:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[O:21][C:20]([CH3:26])([CH3:25])[CH:19]=[CH:18]3)=[CH:9][CH:8]=1.C1C=C(Cl)C=C(C(OO)=O)C=1>ClCCl>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][NH:12][C:13](=[O:27])[CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[O:21][C:20]([CH3:26])([CH3:25])[CH:19]4[O:2][CH:18]4[C:17]=3[CH:16]=2)=[CH:28][CH:29]=1
Reactant: CC1(C)C=Cc2cc(CC(=O)NCc3ccc(Cl)cc3)ccc2O1
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)Oc2ccc(CC(=O)NCc3ccc(Cl)cc3)cc2C2OC21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
700 ml of a saturated aqueous sodium hydrogen carbonate solution was added to a solution of 21.92 g of the N-4-chlorobenzyl-2-(2,2-dimethyl-2H-chromen-6-yl) acetamide obtained above in 600 ml dichloromethane. A total of 31.6 g MCPBA (72%) was added in portions to this receiving solution and stirred for 16 hours at room temperature. The organic phase was separated, washed twice with a 5%-strength aqueous sodium hydrogen carbonate solution, dried over sodium sulfate and substantially completely evaporated at reduced pressure. Drying in an oil pump vacuum yielded N-(4-chlorobenzyl)-2-(2,2-dimethyl-1a,7b-dihydro-2H-oxireno[c]chromen-6-yl)acetamide as crude oil, which was used without further purification or characterization for the subsequent reaction.
Reaction SMILES: C(NC(C)C)(C)C.[Br:8][C@H:9]([CH:13]([CH3:15])[CH3:14])[C:10](O)=[O:11].Cl.C[O:18][C:19](=[O:26])[C:20]1([CH2:25][CH2:24][CH2:23][CH2:22]1)[NH2:21]>>[Br:8][C@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([NH:21][C:20]1([C:19]([OH:26])=[O:18])[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:11]
Reactant: CC(C)[C@@H](Br)C(=O)O
Reactant: COC(=O)C1(N)CCCC1
Agent: Cl
Solvent: CC(C)NC(C)C
Product: CC(C)[C@@H](Br)C(=O)NC1(C(=O)O)CCCC1

Procedure:
The 1-[(R)-2-bromo-3-methylbutanoylamino]cyclopentanecarboxylic acid starting material is prepared essentially by methodology described in WO 99/55726 by condensation of (R)-2-bromo-3-methylbutanoic acid diisopropylamine salt (prepared from L-valine) with cycloleucine methyl ester hydrochloride.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:18][CH3:19])[C:5]2[C:10](=[O:11])[CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[N:7]=1.[Cl:20][C:21]1[N:22]=[CH:23][N:24]([C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][C:27]=2[O:33][CH3:34])[CH:25]=1.S(=O)(=O)(O)O>C1COCC1>[Cl:20][C:21]1[N:22]=[CH:23][N:24]([C:26]2[CH:32]=[CH:31][C:29]([NH:30][C:2]3[N:3]=[C:4]([NH:18][CH3:19])[C:5]4[C:10](=[O:11])[CH2:9][CH:8]([C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=5)[C:6]=4[N:7]=3)=[CH:28][C:27]=2[O:33][CH3:34])[CH:25]=1
Reactant: COc1cc(N)ccc1-n1cnc(Cl)c1
Reactant: CNc1nc(Cl)nc2c1C(=O)CC2c1ccccc1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: CNc1nc(Nc2ccc(-n3cnc(Cl)c3)c(OC)c2)nc2c1C(=O)CC2c1ccccc1

Procedure:
A solution of 2-chloro-4-(methylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-5-one (Preparation AN) (7 mg) and 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) (7 mg) in THF (0.2 mL) and sulfuric acid (4 mg) was heated at 85° C. for 12 h. THF was removed in vacuo, and the residue was purified by reverse phase preparative to give the title compound (as its TFA salt) as a yellowish oil (9 mg). LC-MS (M+H)+=461.12. 1HNMR (500 MHz, CD3OD) δ ppm 7.80 (m), 7.1-7.4 (m), 4.50 (1H, m), 3.25 (1H, m), 2.56 (1H, m), 3.50 (3H, s), and 3.19 (3H, s).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]([C:15]2[C:16]([CH3:27])=[N:17][O:18][C:19]=2[C:20]2[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=2)[OH:14])[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][CH:37]=2)[CH2:35][CH2:34]1)=[O:32])[CH3:29]>>[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39]([C:23]3[CH:24]=[CH:25][C:20]([C:19]4[O:18][N:17]=[C:16]([CH3:27])[C:15]=4[CH:13]([C:11]4[N:10]=[N:9][N:8]([CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH:12]=4)[OH:14])=[CH:21][CH:22]=3)=[CH:38][CH:37]=2)[CH2:34][CH2:35]1)=[O:32])[CH3:29]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1cn(Cc2ccccc2)nn1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4cn(Cc5ccccc5)nn4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using (1-benzyl-1H-[1,2,3]triazol-4-yl)-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-methanol (Enantiomer B) and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.Cl[CH:7]([C:9]1[CH:21]=[CH:20][C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][C:11]=2[CH:10]=1)[CH3:8]>O>[CH:10]1[C:11]2[CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:19]=2[CH:20]=[CH:21][C:9]=1[CH:7]([N:1]1[CH:5]=[CH:4][N:3]=[N:2]1)[CH3:8]
Reactant: CC(Cl)c1ccc2c(c1)Cc1ccccc1-2
Reactant: c1c[nH]nn1
Solvent: O
Product: CC(c1ccc2c(c1)Cc1ccccc1-2)n1ccnn1
Temperature: 120 °C
Yield: 49.3 %

Procedure:
1H-1,2,3-Triazole (1.64 g) was added to 2-(1-chloroethyl)-9H-fluorene (1.1 g), followed by heating at 120° C. for 30 minutes. After cooling, water was added and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated and then the thus obtained residue was subjected to silica gel column chromatography. Crude crystals obtained from the chloroform eluent were recrystallized from ethyl acetate to obtain 0.62 g of 1-[1-(9H-fluoren-2-yl)ethyl]-1H-1,2,3-triazole.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH3:9])=[N:5][O:6][C:7]=1[CH3:8].[C:10]1(=[O:20])[NH:14][C:13](=[O:15])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:9][C:4]1[C:3]([CH2:2][N:14]2[C:10](=[O:20])[C:11]3[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:13]2=[O:15])=[C:7]([CH3:8])[O:6][N:5]=1
Reactant: Cc1noc(C)c1CCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1noc(C)c1CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 114.8 %

Procedure:
4-Chloromethyl-3,5-dimethyl-isoxazole (500 μL, 3.40 mmol) was added to a mixture of phthalimide (500 mg, 3.40 mmol) and K2CO3 (500 mg, 3.62 mmol) in DMF (5 mL) and stirred at ambient temperature overnight. The reaction was then heated to 70° C. for 5 hours and subsequently cooled and partitioned between ethyl acetate and water. The organic layer was washed several times with water and concentrated to give 1.0 g of the sub-title compound as a white solid. MS: ESI (positive): 257 (M+H).