Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][O:12][CH:13]=[CH:14][C:15](=[O:17])[CH3:16].[CH3:18][C:19]1([C:22](Cl)=[O:23])[CH2:21][CH2:20]1>C1COCC1>[OH:23][C:22]([C:19]1([CH3:18])[CH2:21][CH2:20]1)=[CH:16][C:15](=[O:17])[CH:14]=[CH:13][O:12][CH3:11]
Reactant: CC1(C(=O)Cl)CC1
Reactant: COC=CC(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC=CC(=O)C=C(O)C1(C)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 70.8 %

Procedure:
LiHMDS (1M in THF, 88 mL, 2 eq) is added dropwise to a cold (−78° C.) solution of 4-methoxy-3-buten-2-one (8.8 mL, 88 mmol, 2 eq) in THF (300 mL). After a 30 min stirring at −78° C., a solution of 1-methyl-cyclopropanecarbonyl chloride (Step 40.8) (5.19 g, 44 mmol) in THF (100 mL) is added. The resulting mixture is allowed to warm to rt over 2 h and quenched by addition of a saturated solution of NH4Cl. THF is removed under vacuum. The concentrated mixture is extracted with Et2O. The organic phase is washed with brine (2×150 mL), dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (Hex/EtOAc, 1:0→95:5) to afford 5.68 g of the title compound as a yellow oil: ESI-MS: 183.1 [M+H]+; TLC: Rf=0.32 (Hex/EtOAc, 9:1).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13]2[N:14]=[N:15][C:16]([C:20]([CH3:26])([CH3:25])[C:21]([O:23]C)=O)=[C:17](O)[N:18]=2)=[N:6]1.P(Cl)(Cl)(Cl)=O.[NH3:36]>C(#N)C>[F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13]2[N:14]=[N:15][C:16]3[C:20]([CH3:26])([CH3:25])[C:21](=[O:23])[NH:36][C:17]=3[N:18]=2)=[N:6]1
Reactant: N
Reactant: COC(=O)C(C)(C)c1nnc(-c2nn(Cc3ccccc3F)c3c2CCC3)nc1O
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4c3CCC4)nnc21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
48 mg (0.06 mmol, purity 54%) of methyl 2-{3-[1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl]-5-hydroxy-1,2,4-triazin-6-yl}-2-methylpropanoate were admixed with 0.5 ml (5.36 mmol) of phosphoryl chloride and the mixture was stirred at RT for 2.5 h. The reaction solution was diluted with 10 ml of dry acetonitrile and gradually added dropwise while cooling with ice to 5 ml of a 25% aqueous ammonia solution, and the mixture was stirred at RT for 8 h. The reaction mixture was concentrated on a rotary evaporator and the residue was partitioned between dichloromethane/water. The organic phase was dried over sodium sulphate and concentrated on a rotary evaporator. The residue was purified by means of preparative HPLC (eluent: acetonitrile/water with 0.1% hydrochloric acid, gradient 20:80→100:0). 4.5 mg of the target compound were obtained (18% of theory).
Reaction SMILES: [CH2:1]([N:8]1[C@H:13]([CH3:14])[CH2:12][NH:11][CH2:10][C@@H:9]1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25](Br)[CH:26]=2)[CH2:21][CH2:20]1)(=[O:18])[CH3:17]>>[C:16]([N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([N:11]3[CH2:12][C@H:13]([CH3:14])[N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C@H:9]([CH3:15])[CH2:10]3)[CH:26]=2)[CH2:21][CH2:20]1)(=[O:18])[CH3:17]
Reactant: CC(=O)N1CCc2ccc(Br)cc21
Reactant: C[C@@H]1CNC[C@H](C)N1Cc1ccccc1
Product: CC(=O)N1CCc2ccc(N3C[C@@H](C)N(Cc4ccccc4)[C@@H](C)C3)cc21

Procedure:
The title compound was prepared from cis-1-benzyl-2,6-dimethylpiperazine (Org. Prep. Proc. 1976, 8, 19) and 1-acetyl-6-bromoindoline (Heterocycles 1987, 26, 2817) using a similar procedure to Description 2 as an off-white solid (53%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.[Cl:32][C:33]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[C:35]([Cl:48])[C:34]=1[OH:49]>>[Cl:32][C:33]1[CH:38]=[C:37]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:5]3[NH:17][C@H:18]2[CH2:19][CH2:20][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:28])[CH3:29])[CH2:22][CH2:23]2)[CH:36]=[C:35]([Cl:48])[C:34]=1[OH:49]
Reactant: CC(C)C(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CC(C)C(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1

Procedure:
Following general procedure D, tert-butyl trans-4-(6-bromo-3-isobutyrylquinolin-4-ylamino)cyclohexylcarbamate (49 mg, 0.100 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (73 mg, 0.253 mmol) to afford the crude product (60 mg) as an off-white solid: ESI MS m/z 572 [C30H35Cl2N3O4+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][NH:10][C:11](=O)[C:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:21].C1(O)C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][N:10]=[C:11]([Cl:21])[C:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC(C)(C)C(=O)NNc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: Oc1ccccc1
Product: CC(C)(C)C(Cl)=NNc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Temperature: 20 °C
Yield: 63.6 %

Procedure:
A suspension of 1-(4,5-dichloro-2-nitrophenyl)-2-trimethylacetyl-hydrazine (739 g.) and phosphorus pentachloride (517 g.) in carbon tetrachloride (4.8 liters) is heated until the evolution of gas ceases, the reaction mixture being taken progressively to the reflux temperature. To the solution obtained there is added, after cooling to 20°C., a solution of phenol in carbon tetrachloride (3.36 liters) containing 2.36 moles of phenol per liter. The reaction mixture is then heated at the reflux temperature until the evolution of gas finishes. It is then cooled to 20°C., filtered and the resulting solution is concentrated under reduced pressure (20 mm. Hg.) at 60°C. The residue is purified by chromatography on "Kieselgel", elution being effected with a mixture of heptane and diethyl ether (9.5 - 0.5 by volume). After recrystallisation from isopropanol and then heptane, there is obtained 1-(4,5-dichloro-2-nitrophenyl-hydrazono)-1-chloro-2,2-dimethylpropane (498 g.) melting at 99° - 100°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:17]3[C:16]([CH:18](O)[CH2:19][CH3:20])=[CH:15][C:14]([F:22])=[CH:13][C:12]=3[N:11]3[CH2:23][CH2:24][CH:25]([CH2:26][C:27]([OH:29])=[O:28])[C:10]=23)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:17]3[C:16]([CH2:18][CH2:19][CH3:20])=[CH:15][C:14]([F:22])=[CH:13][C:12]=3[N:11]3[CH2:23][CH2:24][CH:25]([CH2:26][C:27]([OH:29])=[O:28])[C:10]=23)=[CH:4][CH:3]=1
Reactant: CCC(O)c1cc(F)cc2c1c(Sc1ccc(Cl)cc1)c1n2CCC1CC(=O)O
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1cc(F)cc2c1c(Sc1ccc(Cl)cc1)c1n2CCC1CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.9 %

Procedure:
To a solution of [9-[(4-chlorophenyl)thio]-6-fluoro-8-(1-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetic acid (Example 19, 36 mg, 0.08 mmol) in CH2Cl2 were added trifluoroacetic acid (0.5 mL) and triethylsilane (0.2 mL). The mixture was stirred for 1 hour at r.t. and solvent was removed. The residue was purified by silica gel chromatography eluted with 40% EtOAc/hexane containing 1% of AcOH to give 10 mg the title compound as a white foam.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:28])([CH3:27])[O:6][CH2:7][CH2:8][C:9]1(OS(C)(=O)=O)[CH2:12][CH:11](CO[Si](C(C)(C)C)(C)C)[CH2:10]1)([CH3:4])[CH3:3].[N-:29]=[N+:30]=[N-:31].[Li+]>CN(C=O)C>[CH3:4][C:2]([Si:5]([CH3:27])([CH3:28])[O:6][CH2:7][CH2:8][CH:9]1[CH:10]([CH2:7][O:6][Si:5]([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:28])[CH3:27])[CH2:11][CH:12]1[N:29]=[N+:30]=[N-:31])([CH3:1])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCCC1(OS(C)(=O)=O)CC(CO[Si](C)(C)C(C)(C)C)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCC1C(CO[Si](C)(C)C(C)(C)C)CC1N=[N+]=[N-]
Temperature: 80 °C
Yield: 146.4 %

Procedure:
2-(2-(((1,1-Dimethylethyl)dimethylsilyl)oxy)ethyl-3-(((1,1-dimethylethyl)dimethyl-silyl)oxymethyl)-1-O-methanesulfonylcyclobutanol (180 mg, 0.41 mmol) was mixed with 200 mg (4.1 mmol) of lithium azide in 4 mL of DMF. The reaction mixture was heated at 80° C. for 2 h then concentrated in vacuo. The residue was purified on a silica gel column eluted with 5% ethyl acetate in hexane to give 120 mg (73% yield) of the title compound; MS DCI-NH3M/Z: 400 (M+H)+, 417 (M+NH4)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])/[CH:4]=[CH:5]\[C:6]([OH:8])=[O:7].C(N(CC)CC)C.[CH3:17][N:18]([CH3:23])[CH2:19][CH2:20][CH2:21][NH2:22]>CC(C)=O>[CH3:1][O:2][C:3](=[O:9])[CH2:4][C@@H:5]([C:6]([OH:8])=[O:7])[NH:22][CH2:21][CH2:20][CH2:19][N:18]([CH3:23])[CH3:17]
Reactant: CN(C)CCCN
Reactant: COC(=O)/C=C\C(=O)O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COC(=O)C[C@H](NCCCN(C)C)C(=O)O
Temperature: 25 °C

Procedure:
286 g (2.0 mols+10% excess) of maleic acid-monomethyl ester are placed into a glass flask fitted with a blade stirrer, thermometer, reflux condenser and dropping funnel, and, with ice-water cooling, 400 ml of triethylamine are added dropwise at 6°-11° C. internal temperature within 1 hour and 35 minutes. The cooling is subsequently removed, 204 g (2.0 mols) of 3-dimethylaminopropylamine are quickly added, and the mixture is reacted for 10 minutes at 87°-90° C. and is then cooled to room temperature; the crystalline crude product is mixed with 1 liter of acetone, the suspension is filtered, and the filter residue is washed with acetone. The yield after drying at 80° C. in vacuo is 296 g (63.7% of theory) of a crystalline aspartic acid derivative, which melts at 171°-172° C.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH:10]([CH3:11])[CH2:9][C:8]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N+:18]([O-])=O)=[CH:7][CH:6]1[NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])(=[O:3])[CH3:2]>CO.CCOC(C)=O.[Pd]>[C:1]([O:4][CH:5]1[CH:10]([CH3:11])[CH2:9][CH:8]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[NH2:18])[CH2:7][CH:6]1[NH:21][C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])(=[O:3])[CH3:2]
Reactant: CC(=O)OC1C(C)CC(c2ccncc2[N+](=O)[O-])=CC1NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)OC1C(C)CC(c2ccncc2N)CC1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 59 %

Procedure:
To a degassed solution of (+/−)-2-(tert-butoxycarbonylamino)-6-methyl-4-(3-nitropyridin-4-yl)cyclohex-3-enyl acetate (1.0 equiv.) in MeOH and EtOAc (1:1, 0.1 M) was added 10% Pd/C (0.1 equiv.) and the reaction was stirred at room temperature under a hydrogen balloon for 3 days. Upon completion, the solution was filtered through a pad of Celite, the pad was washed with ethyl acetate and the filtrate was concentrated. The crude material contained about 10% of the undesired isomer. The crude was dissolved in ethyl acetate (˜20%) and hexanes and heated until all dissolved. The solution was allowed to sit at room temperature for 2 days. The precipitate was then collected to give (+/−)-4-(3-aminopyridin-4-yl)-2-(tert-butoxycarbonylamino)-6-methylcyclohexyl acetate as the pure product in 59% yield. LC/MS=364.3 (M+H), Rt=0.63 min. The racemic material was resolved using an AD-H chiral column (20% i-PrOH/80% n-heptanes, 20 mL/min flow rate) to (1S,2S,4S,6R)-4-(3-aminopyridin-4-yl)-2-((tert-butoxycarbonyl)amino)-6-methylcyclohexyl acetate (peak#1, Rt=3.76 min on AD-H chiral analytical column, 20% i-PrOH/80% n-heptanes, 1 mL/min) and (1R,2R,4R,6S)-4-(3-aminopyridin-4-yl)-2-((tert-butoxycarbonyl)amino)-6-methylcyclohexyl acetate (peak#2, Rt=6.79 min on AD-H chiral analytical column, 20% i-PrOH/80% n-heptanes, 1 mL/min)
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][NH2:5].[OH-].[Na+].Cl[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].O>O1CCOCC1>[Br:2][CH2:3][CH2:4][NH:5][C:9](=[O:10])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCCBr
Reactant: O=C(Cl)OCc1ccccc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(NCCBr)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 183 %

Procedure:
Treat a 0° C. solution of 2-bromoethylamine hydrobromide (50 g, 0.246 mol) in dioxane (500 mL) with aqueous NaOH (1 M, 492 mL, 0.492 mol), add benzyl chloroformate (21.6 g, 0.127 mol) dropwise, warm to RT and stir overnight. Pour the mixture into H2O, extract with EtOAc (3×), wash the combined organics with brine, dry over Na2SO4, concentrate to dryness and purify via silica gel chromatography (EtOAc/Petroleum ether) to afford the title compound (60 g, 95%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.37-7.33 (m, 5H), 5.12 (s, 2H), 3.61 (t, J=5.6 Hz, 2H), 3.47 (t, J=5.6 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10](=[O:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14].S(=O)(=O)(O)O.[CH2:22](O)[CH3:23]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10](=[O:16])[CH2:11][CH2:12][C:13]([O:15][CH2:22][CH3:23])=[O:14]
Reactant: O=C(O)CCC(=O)Cc1ccc(Cl)cc1Cl
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)CCC(=O)Cc1ccc(Cl)cc1Cl
Yield: 46 %

Procedure:
A 1-liter R.B. flask was equipped with a magnetic stirrer and charged with 104.13 g (0.400 mol) of 5-(2',4'-dichlorophenyl)-4-ketopentanoic acid dissolved in 250 ml of ethanol and 250 ml of toluene. To this solution was added 5 ml of concentrated sulfuric acid, and the reaction mixture was refluxed through a Soxhlet extractor containing 300 g of Type 3A molecular sieves for 24 hours. The mixture was cooled and 300 ml of the solvent removed on the Rotary Evaporator. The residue was taken up in 300 ml of ether and washed once with water. The mixture was extracted twice with 150 ml portions of 10% K2CO3 solution, then washed with saturated salt solution, and dried (MgSO4). The solvent was removed on the Rotary Evaporator, and the residue vacuum distilled. The product (52.97 g, 46% yield) was obtained as a slightly yellow viscous oil, b.p. 124°-165° C./0.10-0.30 mm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[CH:18][C:11]=12)[NH2:5].[CH2:19]([O:21][C:22](=[O:32])[CH2:23][C:24]1[CH:29]=[C:28](Cl)[N:27]=[C:26]([NH2:31])[N:25]=1)[CH3:20]>>[CH2:19]([O:21][C:22](=[O:32])[CH2:23][C:24]1[CH:29]=[C:28]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([O:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]4[NH:16][CH:17]=[CH:18][C:11]=34)=[C:2]([F:1])[CH:3]=2)[N:27]=[C:26]([NH2:31])[N:25]=1)[CH3:20]
Reactant: Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Reactant: CCOC(=O)Cc1cc(Cl)nc(N)n1
Product: CCOC(=O)Cc1cc(Nc2ccc(Oc3ccnc4[nH]ccc34)c(F)c2)nc(N)n1

Procedure:
The title compound is synthesized analogously to example 25 from 220 mg (0.908 mmol) of 3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)aniline (from example XIX) and 195 mg (0.908 mmol) of ethyl(2-amino-6-chloropyrimidin-4-yl)acetate (from example LXIX).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[N:26]1[CH:31]=[C:30]([C:32]2[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=2)[CH:29]=[N:28][CH:27]=1>>[CH3:24][CH:23]([CH3:25])[C@H:18]([N:13]1[CH2:12][C:11]2[C:15](=[CH:16][C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:36](=[O:37])[C:35]4[CH:34]=[CH:33][C:32]([C:30]5[CH:29]=[N:28][CH:27]=[N:26][CH:31]=5)=[CH:40][CH:39]=4)=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[C:14]1=[O:17])[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: O=C(Cl)c1ccc(-c2cncnc2)cc1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(-c5cncnc5)cc4)cc3)cc2C1=O
Yield: 37 %

Procedure:
The compound of example 652 was prepared analogous to the compound of example 640 by reaction of compound of example 6 with commercially available 4-(pyrimidin-5-yl)benzoyl chloride.
Reaction SMILES: [C:1]1([S:7]([C:10]([CH:16]2[CH2:28][CH2:27][C:26]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([Cl:29])[CH:24]=4)[NH:19][C:18]=3[CH2:17]2)([F:15])[C:11]([NH:13][CH3:14])=[O:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[O:37](C(OC(C)(C)C)=O)[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:41]([O:40][C:38]([N:19]1[C:18]2[CH2:17][CH:16]([C:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:8])=[O:9])([F:15])[C:11](=[O:12])[NH:13][CH3:14])[CH2:28][CH2:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[C:23]([Cl:29])[CH:24]=2)=[O:37])([CH3:44])([CH3:43])[CH3:42]
Reactant: CNC(=O)C(F)(C1CCc2c([nH]c3ccc(Cl)cc23)C1)S(=O)(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)C(F)(C1CCc2c(n(C(=O)OC(C)(C)C)c3ccc(Cl)cc23)C1)S(=O)(=O)c1ccccc1
Yield: 78.5 %

Procedure:
0.924 g (0.002 mol) of (RS, SR)-2-benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-2-fluoro-N-methyl-acetamide were dissolved in 20 mL CH2Cl2 at RT. Then, 0.59 mL triethylamine (0.004 mol, 2 eq), 26 mg DMAP (0.2 mmol, 0.1 eq) and 0.556 g BOC2O (0.003 mol, 1.2 eq) were added. The reaction mixture was stirred for 2H30. The reaction was quenched with a saturated NH4Cl aqueous solution, and the product extracted with CH2Cl2. The combined organic phases were dried on Na2SO4, filtered and evaporated. The crude material was precipitated in diethyl ether. The solvent was removed and the remaining solid was dried under vaccum to yield to 0.840 g (74%) of (RS, SR)-2-(benzenesulfonyl-fluoro-methylcarbamoyl-methyl)-6-chloro-1,2,3,4-tetrahydro-carbazole-9-carboxylic acid tert-butyl ester as a white solid, MS: 552 (MNH4+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:36][CH2:37][CH:38]([OH:50])[CH2:39][N:40]1[CH2:49][CH2:48][C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:41]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:36][CH2:37][CH:38]([OH:50])[CH2:39][N:40]1[CH2:49][CH2:48][C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:41]1)=[O:9]
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: Nc1ccc(F)c(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Nc1ccc(F)c(C(=O)NCC(O)CN2CCc3ccccc3C2)c1
Temperature: 17 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
The solution of 5-amino-2-fluorobenzoic acid (200 mg, 1.29 mmol) and HATU (490 mg, 1.29 mmol) in DCM (15 mL) was stirred at 17° C. for 30 min. Then 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (265 mg, 1.29 mmol) and DIPEA (333 mg, 2.58 mmol) was added and the resulting solution was stirred at 17° C. for 16 h. The solution was concentrated and the residue was purified by column chromatography to give desired product (372 mg, Yield 84%).
Reaction SMILES: [K+:1].[C:2]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10][C:11](=[CH2:15])[C:12]([O-:14])=[O:13])=[CH:4][CH:3]=1.C(OC(C)C)(=O)C.[H][H]>[Pd]>[K+:1].[C:2]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:3]=[CH:4][C:5]([CH2:8][C@@H:9]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:10][C@@H:11]([CH3:15])[C:12]([O-:14])=[O:13])=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: C=C(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)[O-]
Agent: [Pd]
Agent: [K+]
Solvent: CC(=O)OC(C)C
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)[O-]
Temperature: 25 °C

Procedure:
100 mg (R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid potassium salt (2-a, R1=Boc, R2=H, R3=CO2K) (prepared according to procedure in Example 42) is added to isopropyl acetate (1 ml). 10% Palladium on carbon (10 mg, 50% water wet, Degussa type E101 NE/W) is then added. Hydrogen gas at ambient pressure is applied to the mixture. The mixture is stirred at ambient temperature and pressure overnight. The mixture is then filtered over Celite and washed with isopropyl acetate (2×1 ml). The mixture is then concentrated in vacuo to give (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid potassium salt (1-a, R1=Boc, R2=H, R3=CO2K) and (2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid potassium salt (1-b, R1=Boc, R2=H, R3=CO2K). Spectroscopic data as in Example 42, Method 1.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[C:11]([CH3:20])=[CH:10][CH:9]=2)[C:4]([SH:7])=[N:5][N:6]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[NH:31][C:32](=[O:35])[CH2:33]Cl)[C:25]([OH:27])=[O:26].O>CN(C=O)C>[NH2:1][C:2]1[N:3]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[C:11]([CH3:20])=[CH:10][CH:9]=2)[C:4]([S:7][CH2:33][C:32]([NH:31][C:30]2[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=2[Cl:21])=[O:35])=[N:5][N:6]=1
Reactant: O=C(CCl)Nc1ccc(C(=O)O)cc1Cl
Reactant: COc1ccc2c(C)ccc(-n3c(N)nnc3S)c2c1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(C)ccc(-n3c(N)nnc3SCC(=O)Nc3ccc(C(=O)O)cc3Cl)c2c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 87.2 %

Procedure:
Compound 8 (200 mg, 0.7 mmol) and 3-chloro-4-(2-chloroacetamido)benzoic acid (9) (174 mg, 0.7 mmol) were dissolved in DMF (3 mL) and the mixture was stirred at 50° C. for 18 hours. Water was then added and the mixture extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate and concentrated to give 304 mg of 4-[2-(5-amino-4-[7-methoxy-4-methylnaphthalen-1-yl]-4H-1,2,4-triazol-3-ylthio)acetamido]-3-chlorobenzoic acid (10) which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=O)[C:9](=[CH:18][N:19](C)C)[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1.O.[NH2:24]N>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:10](=[O:11])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:18][NH:19][N:24]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=C(C(=O)c1ccccc1)C(=O)c1cccc(Cl)c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=C(c1ccccc1)c1c[nH]nc1-c1cccc(Cl)c1

Procedure:
1-(3-Chlorophenyl)-2-(N,N-dimethylaminomethylene)-3-phenyl-1,3-propanedione (11.25 g) synthesized in accordance with Example 1 was dissolved in ethanol (150 ml) and added with hydrazine hydrate (1.98 g). After heating at reflux temperature for 3 hours, the solvent was distilled off, and then the resulting residue was added with diisopropyl ether and stirred. The resulting solid was then filtered off, recrystallized from acetonitrile to give the compound of interest (3.0 g). M.P.: 161.3-164.1° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C@@:6]12[CH2:17][CH2:16][CH2:15][C:13]3[C:14]1=[C:9]([CH:10]=[CH:11][CH:12]=3)[NH:8][C:7]2=[O:18].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][CH2:5][C@@:6]23[CH2:17][CH2:16][CH2:15][C:13]4[C:14]2=[C:9]([CH:10]=[CH:11][CH:12]=4)[NH:8][C:7]3=[O:18])[CH2:29][CH2:28]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=C1Nc2cccc3c2[C@@]1(CCCCBr)CCC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccccc1N1CCN(CCCC[C@@]23CCCc4cccc(c42)NC3=O)CC1
Yield: 83.4 %

Procedure:
(S)-2a-(4-bromobutyl)-2a,3,4,5-tetrahydro-1H-benz[cd]indol-2-one (308 mg, 1.0 mmol), 4-(2-methoxyphenyl)piperazine (415 mg, 2.1 mmol) and potassium carbonate (280 mg, 2.0 mmol) in anhydrous N,N-dimethylformamide (10 ml) were stirred at room temperature for 18 hours. Then, ethyl acetate (80 ml) was added to the resulting reaction mixture, which was washed with water and saturated saline solution, successively dried over anhydrous sodium sulfate, followed by evaporating the solvent under reduced pressure. The resulting product was separated and purified by means of silica gel column chromatography, whereby 350 mg (yield 84%) of the above-described object compound could be obtained.