Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[O:8][C:9](=O)[C:10]1[CH:15]=[C:14]([C:16]#[N:17])[CH:13]=[CH:12][C:11]=1[CH2:18][N:19]([CH2:28][C:29]1[C:34]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:32]=[CH:31][N:30]=1)[CH2:20][C:21]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=1.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1COCC1>[NH2:17][CH2:16][C:14]1[CH:13]=[CH:12][C:11]([CH2:18][N:19]([CH2:20][C:21]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:28][C:29]2[C:34]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:32]=[CH:31][N:30]=2)=[C:10]([CH2:9][OH:8])[CH:15]=1
Reactant: COC(=O)c1cc(C#N)ccc1CN(Cc1ncccc1C)Cc1ncccc1C(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1cccnc1CN(Cc1ccc(CN)cc1CO)Cc1ncccc1C(C)C
Yield: 17.6 %

Procedure:
To a cold (0° C.) mixture of LiAlH4 (226 mg, 5.94 mmol) in dry THF (6 mL) was added 5-cyano-2-{[(3-isopropyl-pyridin-2-ylmethyl)-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-benzoic acid methyl ester (0.253 g, 0.59 mmol) as a solution in THF (5 mL). The resultant mixture was stirred at room temperature for 4 hours then cooled in an ice water bath. The mixture was treated with saturated aqueous sodium-potassium tartrate (5 mL) and diluted with THF (10 mL). The phases were separated and the aqueous phase was extracted with THF (2×10 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2-MeOH—NH4OH) followed by radial chromatography on silica gel (1 mm plate, 50:1:1 CH2Cl2-MeOH—NH4OH) gave COMPOUND 386 (42 mg, 17%) as a white solid. 1H NMR (CDCl3) δ 1.04 (d, 6H, J=6.0 Hz), 2.10 (s, 3H), 2.97 (septet, 1H), 3.73 (s, 2H), 3.76 (s, 2H), 3.82 (s, 2H), 3.90 (s, 2H), 4.24 (s, 2H), 6.38 (br s, 1H), 7.05-7.17 (m, 3H), 7.20-7.28 (m, 2H), 7.39 (d, 1H, J=7.2 Hz), 7.52 (dd, 1H, J=1.5, 7.8 Hz), 8.35-8.38 (m, 2H); 13C NMR (CDCl3) δ 18.53, 23.46 (2 carbons), 27.99, 46.54, 56.73, 58.03, 59.15, 63.42, 122.81, 123.13, 126.37, 130.24, 132.05, 133.62, 135.75, 138.55, 142.41, 143.66, 143.76, 146.32, 146.51, 155.10, 156.35; ES-MS m/z 405 (M+H). Anal. Calcd. for C25H32N4O.0.9H2O: C, 71.36; H, 8.10; N, 13.32. Found: C, 71.58; H, 7.93; N, 12.95.
Reaction SMILES: C(=S)([S-])[S-:2].[Na+].[Na+].[C:7]([O:11][CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])[CH:8]=[CH2:9]>Cl>[CH2:12]([O:11][C:7](=[O:10])[CH:8]([SH:2])[CH3:9])[CH:13]([CH3:15])[CH3:14]
Reactant: S=C([S-])[S-]
Reactant: C=CC(=O)OCC(C)C
Agent: Cl
Agent: [Na+]
Product: CC(C)COC(=O)C(C)S
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 78.9 %

Procedure:
There were present in a stirring apparatus 577.5 grams of a 40% sodium trithiocarbonate solution (corresponding to 1.5 moles). Under stirring at -10° C. there were dropped in 128 grams of isobutyl acrylate (1.0 mole). Post stirring was continued for a further 10 minutes and then the mixture was acidified with 350 ml of 32% hydrochloric acid. After the phase separation the organic phase was fractionally distilled. There were obtained 128 grams of mercaptopropionic acid isobutyl ester (corresponding to a yield of 79%).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.CN(C)[C:15]1[CH:23]=CC(C(Cl)=O)=C[CH:16]=1.C(Cl)C=C.CN(C)C1C=CC(C([O-])=O)=CC=1.[Na+]>CN(C)C=O>[CH2:23]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([N:2]([CH3:12])[CH3:1])=[CH:4][CH:5]=1)[CH:15]=[CH2:16]
Reactant: CN(C)c1ccc(C(=O)Cl)cc1
Reactant: CN(C)c1ccc(C(=O)O)cc1
Agent: CN(C)c1ccc(C(=O)[O-])cc1
Agent: [Na+]
Solvent: C=CCCl
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1ccc(N(C)C)cc1
Yield: 60 %

Procedure:
Esters of p-dimethylaminobenzoic acid can be prepared by several methods. U.S. Pat. No. 2,202,865 describes the preparation of esters by reacting p-dimethylaminobenzoyl chloride with alcohols. Another method is by reacting an alkali salt of p-dimethylaminobenzoic acid with an alkene halide. Either method can be used but the latter is preferred. For example, if allyl chloride is added to sodium p-dimethylaminobenzoate in a suitable solvent such as dimethylformamide using a quaternary ammonium salt catalyst, allyl-p-dimethylaminobenzoate is obtained in yield of about 60%.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([OH:10])=[O:9])[C:5](=[S:18])[NH:4][CH2:3]1.[F:19][C:20]([F:36])([F:35])[O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[S:32][C:31]([CH:33]=O)=[CH:30][CH:29]=2)=[CH:24][CH:23]=1.NCCC(O)=O.CO.C(Cl)Cl>C(O)(=O)C>[F:36][C:20]([F:19])([F:35])[O:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[S:32][C:31]([CH:33]=[C:3]3[C:2](=[O:1])[N:6]([CH:7]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([OH:10])=[O:9])[C:5](=[S:18])[NH:4]3)=[CH:30][CH:29]=2)=[CH:26][CH:27]=1
Reactant: O=C(O)C(Cc1ccccc1)N1C(=O)CNC1=S
Reactant: O=Cc1ccc(-c2ccc(OC(F)(F)F)cc2)s1
Agent: NCCC(=O)O
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)C(Cc1ccccc1)N1C(=O)C(=Cc2ccc(-c3ccc(OC(F)(F)F)cc3)s2)NC1=S
Temperature: 170 °C

Procedure:
To a mixture of 2-(5-oxo-2-thioxoimidazolidin-1-yl)-3-phenylpropanoic acid (0.031 g, 0.117 mmol) and 5-(4-trifluoromethoxy-phenyl)thiophene-2-carbaldehyde (0.030 g, 0.117 mmol) in acetic acid 5 mL is added β-alanine (1.042 mg, 0.012 mmol) and heat to 170° C. for 30 min under microwave irradiation. The resulting reaction mixture is cooled down and the solvent is removed. The pure product (0.035 g, 0.069 mmol, red solid) is obtained by column chromatography using MeOH/DCM, 2-7% ration solvent system. 1H-NMR (CD3OD/300 MHz): 7.91 (m, 2H), 7.32 (d, J=9.0 Hz, 2H), 7.14 (m, 5H), 7.02 (m, 2H), 6.47 (s, 1H), 5.64 (dd, J=11.1, 5.4 Hz, 11H), 3.70 (dd, J=14.1, 12.6 Hz, 1H), 3.53 (dd, J=14.1, 5.1 Hz, 1H). MS (ES−, m/z): 501.4 (M−, 100.0).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH:10]1[CH2:15][CH2:14][O:13][C:11]1=[O:12].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:13][CH2:14][CH2:15][CH:10]1[C:11](=[O:12])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8]1
Reactant: Nc1ccccc1O
Reactant: O=C1OCCC1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2OC1CCO
Temperature: 75 °C
Reaction time: 6 h
Yield: 40 %

Procedure:
2.18 g of 2-aminophenol and 1.1 equivalents of 2-bromo-γ-butyrolactone are mixed in 25 ml of DMF with 4 g of potassium carbonate. After 6 hours, it is heated to 75° C., poured onto water, extracted with ethyl acetate, the organic phase is dried with sodium sulfate and concentrated by evaporation. 40% yield results.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:17])=[CH:4][C:5]([N+:14]([O-])=O)=[C:6]([CH2:8][C:9](OCC)=[O:10])[CH:7]=1>[Fe].CC(O)=O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[F:17])[NH:14][C:9](=[O:10])[CH2:8]2
Reactant: CCOC(=O)Cc1cc(Br)c(F)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: O=C1Cc2cc(Br)c(F)cc2N1
Temperature: 60 °C
Yield: 86.9 %

Procedure:
To a 250 mL round bottom flask was added ethyl 2-(5-bromo-4-fluoro-2-nitrophenyl)acetate (5.2 g, 17 mmol), iron (4.7 g, 85 mmol) and 50 mL of AcOH. The reaction mixture was heated at 60° C. for 1 hour. The reaction mixture was then concentrated, dissolved in 100 mL of EtOAc, filtered, and washed with 50 mL of a saturated NaHCO3 solution. The organic layer was concentrated and purified with silica gel column chromatography, eluting with 40% EtOAc/hexane to give 5-bromo-6-fluoroindolin-2-one (3.4 g, 87% yield) as a white solid. MS m/z: 230 (M+1). 1H NMR (400 MHz, CD3OD) δ ppm 3.49-3.54 (m, 2H), 6.77 (d, J=8.80 Hz, 1H), 7.45 (d, J=6.65 Hz, 1H).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:17]([NH:19][C:20]([CH2:26][CH3:27])([CH2:24][CH3:25])[C:21](O)=[O:22])=[O:18])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[CH2:3][CH2:2]1.Cl.[CH3:29][NH2:30]>>[CH2:24]([C:20]([NH:19][C:17]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[N:8]=1)=[O:18])([C:21](=[O:22])[NH:30][CH3:29])[CH2:26][CH3:27])[CH3:25]
Reactant: CN
Reactant: CCC(CC)(NC(=O)c1ccc(C2CC2)c(OCC2CCCO2)n1)C(=O)O
Agent: Cl
Product: CCC(CC)(NC(=O)c1ccc(C2CC2)c(OCC2CCCO2)n1)C(=O)NC

Procedure:
The title compound was synthesized in analogy to Example 1, using 2-(5-cyclopropyl-6-((tetrahydrofuran-2-yl)methoxy)picolinamido)-2-ethylbutanoic acid and methanamine hydrochloride as starting materials, MS (EI): m/e=390.3 [M+H]+.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]=[C:17]=[O:18])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:20][O:21][C:22](=[O:33])[C@H:23]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)[NH2:24].C(N(CC)CC)C>ClCCl>[CH3:20][O:21][C:22](=[O:33])[C@@H:23]([NH:24][C:17]([NH:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:8])=[O:9])=[O:18])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1
Reactant: O=C=Nc1ccccc1S(=O)(=O)c1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)Nc1ccccc1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
A solution of 2-benzenesulfonylphenyl isocyanate (600 mg, 2.31 mmol, prepared as described in Preparation 20) in dichloromethane (4 ml) was slowly added to a solution of L-tyrosine methyl ester hydrochloride (589 mg, 2.54 mmol) and triethylamine (0.64 ml, 4.62 mmol) in dichloromethane (4 ml) and the resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane (50 ml) and washed with hydrochloric acid 1N (2×20 ml), saturated aqueous NaHCO3 (2×20 ml) and brine (1×20 ml). The organic layer was dried (MgSO4) and concentrated under reduced pressure to yield the title compound (930 mg, 89%) as a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:30][CH3:31])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21]Cl)=[CH:15][CH:14]=3)=[CH:7][C:5]=2[CH:6]=1.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>CO>[Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:30][CH3:31])=[C:12]([C:23]3[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=3)[C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][N:36]4[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]4)=[CH:17][CH:18]=3)=[CH:7][C:5]=2[CH:6]=1
Reactant: CN1CCNCC1
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc2oc(Cl)cc2c1
Solvent: CO
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCN2CCN(C)CC2)cc1)c1ccc2oc(Cl)cc2c1
Yield: 76 %

Procedure:
According to the same procedure as example 1, step E described, 4-(2-(2-chlorobenzofuran-5-yl)-1-(4-(2-chloroethoxy)phenyl)but-1-enyl)phenol (70 mg, 1.0 eq, made by example 11, step D) was reacted with 1-methylpiperazine (1 mL) in MeOH (8 mL) under reflux to give the desired product (60 mg, 76%, Z/E=1/1.7) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.23 (s, 1H), 7.20 (d, J=8.8 Hz, 1H), 7.12 & 7.08 (d, J=8.8 Hz, 2H), 7.00 (d, J=8.8 Hz, 1H), 6.83 & 6.78 (d, J=8.8 Hz, 2H), 6.72 & 6.69 (d, J=8.8 Hz, 2H), 6.45 & 6.44 (s, 1H), 6.42 (d, J=8.8 Hz, 2H), 4.12 & 3.93 (t, J=5.6 Hz, 2H), 2.84 & 2.73 (t, J=5.6 Hz, 2H), 2.40-2.62 (m, 10H), 2.31 & 2.82 (s, 3H), 0.91 (t, J=7.2 Hz, 3H); m/z=517[M+1]+.
Reaction SMILES: [CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C@H:3]1[CH2:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][CH:10]2[CH:22]=[N:23]O.C(O)C.C(O)(=O)C.[H][H]>O=[Pt]=O.O>[NH2:23][CH2:22][CH:10]1[CH2:9][CH2:8][C@H:7]2[C@H:6]3[C@H:15]([CH2:14][CH2:13][C@:11]12[CH3:12])[C@:16]1([CH3:21])[C@H:3]([N:2]([CH3:1])[C:19](=[O:20])[CH2:18][CH2:17]1)[CH2:4][CH2:5]3
Reactant: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)C(C=NO)CC[C@H]4[C@@H]3CC[C@@H]12
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)C(CN)CC[C@H]4[C@@H]3CC[C@@H]12

Procedure:
A mixture of (46) (0.67 g, 2.0 mM), ethanol (100 mL), glacial acetic acid (8 mL) and water (4 mL) was reduced in a hydrogen atmosphere (40 p.s.i.) at room temperature in the presence of PtO2 until TLC analysis indicated complete reduction. The filtered reaction mixture was concentrated in vacuo, the residue taken up in chloroform, and the chloroform solution washed with fresh dilute sodium hydrogen carbonate solution and dried (Na2SO4). Concentration of the filtered chloroform solution followed by trituration of the residue obtained with hexane containing a small amount of ether yielded (47) as an off-white solid. MS MH+ calcd for C20H34N2O 318.49, observed m/e 319.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][N:11]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:48][CH2:49][C:50]([N:52]1[CH2:57][CH2:56][N:55]([C:58](=[O:69])[C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[C:65]([F:68])([F:67])[F:66])[CH2:54][CH2:53]1)=[O:51].C(O)(C(F)(F)F)=O>CN(C=O)C.O>[CH3:10][N:11]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:12]1[CH:13]=[CH:14][C:15]([C:16]([NH:48][CH2:49][C:50](=[O:51])[N:52]2[CH2:53][CH2:54][N:55]([C:58](=[O:69])[C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=3[C:65]([F:66])([F:68])[F:67])[CH2:56][CH2:57]2)=[O:18])=[CH:19][CH:20]=1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: CN(c1ccccc1)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1ccccc1)c1ccc(C(=O)NCC(=O)N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
DIPEA (92 mg, 0.125 mL, 0.72 mmol) was added drop wise to 4-(Methyl-phenyl-amino)-benzoic acid (55 mg, 0.24 mmol) in DMF (5 mL). EDCI (115 mg, 0.6 mmol) and HOBT (39 mg, 0.28 mmol) were added consecutively and, after 10 minutes, 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone in its TFA salt form (124 mg, 0.289 mmol) was added. The resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by Preparative HPLC [(Column-Zorbax XDB C18-21.2×150 mm, mobile phase-0.1% TFA in water (A)/acetonitrile (B), gradient: (Time): (% B)-0:20; 2:30; 8:70)]) to afford 34 mg (26% yield) of 4-(Methyl-phenyl-amino)-N-{2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-benzamide. LC-MS purity: 97.62%. 1H-NMR (CDCl3): δ 7.7 (m, 3H), 7.6 (m, 2H), 7.4 (q, 3H), 7.2 (m, 2H), 7.1 (m, 1H), 6.8 (d, 2H), 4.3 (dd, 1H), 4.2 (dd, 1H), 4.0 (m, 1H), 3.9 (m, 1H), 3.7 (m, 3H), 3.4 (m, 1H), 3.3 (s, 3H), 3.2 (m, 2H).
Reaction SMILES: [N:1]1([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3](O)=[O:4].C([N:22](CC)CC)C.ClC(OCC(C)C)=O.N>C(OCC)(=O)C>[N:1]1([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([NH2:22])=[O:4]
Reactant: CCN(CC)CC
Reactant: O=C(O)[C@H]1CCCCN1C(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: CCOC(C)=O
Product: NC(=O)[C@H]1CCCCN1C(=O)OCc1ccccc1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 87.7 %

Procedure:
13.15 g (50 mmoles) of Z-D-Pip-OH (L. Balaspiri et al.: Monatsh. Chem. 101, 177/1970/) are dissolved in 100 ml of ethyl acetate, 7.0 ml (50 mmoles) of triethylamine are added, and the solution is cooled to -20° C. 6.5 ml (50 mmoles) of isobutyl chloroformate are added dropwise to the stirred solution at the same temperature, thereafter the mixture is stirred for 15 minutes, and then gaseous ammonia is introduced into the mixture at -10° C. for 1.5 hours. The separated precipitate is filtered off, the filtrate is washed with n hydrochloric acid, n sodium hydrocarbonate solution and water, dried over anhydrous sodium sulfate and evaporated. The residue is crystallized from a mixture of ethyl acetate and ether to obtain 11.5 g (88%) of Z-D-Pip-NH2 ; m.p.: 114°-115° C., Rf2 =0.50, [α]D25 =+32.0° (c=1%, in methanol).
Reaction SMILES: [Cl:1][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[N:20]1([CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][NH2:38])[CH2:32][CH2:31]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:51].Cl>>[ClH:1].[ClH:51].[N:20]1([CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][NH:38][C:2]([N:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[C:8](=[O:15])[NH:7][C:6]4[CH:16]=[CH:17][CH:18]=[N:19][C:5]3=4)=[O:3])[CH2:32][CH2:31]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NCCN1CCC(CCCCN2CCCCC2)CC1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: O=C1Nc2cccnc2N(C(=O)NCCN2CCC(CCCCN3CCCCC3)CC2)c2ccccc21
Yield: 40 %

Procedure:
Prepared analogously to Example 46 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[4-[4-(piperidin-1-yl)butyl]-piperidin-1-yl]ethanamine in a yield of 40% of theory. The colourless dihydrochloride melted at 231°-233° C.
Reaction SMILES: [CH3:1][C:2]([NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][C:11]=1[Cl:22])([CH3:7])[C:3]([O:5]C)=O.[F:23][C:24]([F:36])([F:35])[O:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1>>[CH3:7][C:2]1([CH3:1])[N:8]([CH2:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]=2[Cl:22])[C:33](=[O:34])[N:32]([C:29]2[CH:28]=[CH:27][C:26]([O:25][C:24]([F:23])([F:35])[F:36])=[CH:31][CH:30]=2)[C:3]1=[O:5]
Reactant: COC(=O)C(C)(C)NCc1c(Cl)cnc2ccc(OC)cc12
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Product: COc1ccc2ncc(Cl)c(CN3C(=O)N(c4ccc(OC(F)(F)F)cc4)C(=O)C3(C)C)c2c1

Procedure:
The product is prepared according to the procedure described in Example 59, starting with 180 mg of methyl 2-methyl-2-[(3-chloro-6-methoxyquinol-4-ylmethyl)amino]propanoate instead of methyl 2-methyl-2-[(quinol-4-ylmethyl)amino]propanoate used in Example 59 and 267 mg of 4-(trifluoromethoxy)phenyl isocyanate. After purification by flash chromatography on a column (SiO2, 80/20 cyclohexane/EtOAc by volume as eluent, Ar), 137 mg of the expected product are obtained.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]([N:8]1[C:12](=[O:13])[CH:11]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:10][C:9]1=[O:22])[CH:5]([CH3:7])[CH3:6]>Cl>[O:22]=[C:9]1[NH:10][CH:11]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12](=[O:13])[N:8]1[CH:4]([CH:5]([CH3:7])[CH3:6])[C:3]([OH:23])=[O:2]
Reactant: COC(=O)C(C(C)C)N1C(=O)NC(CCc2ccccc2)C1=O
Agent: Cl
Product: CC(C)C(C(=O)O)N1C(=O)NC(CCc2ccccc2)C1=O
Temperature: 70 °C
Reaction time: 3 h
Yield: 46 %

Procedure:
A mixture of the compound obtained in step d above (482 mg, 1.52 mmol) and 6 N HCl (20 mL) was stirred at 70° C. for 3 h. The reaction mixture was cooled to room temperature and extracted with CH2Cl2. The combined organic phases were washed with brine, dried and concentrated. The residue was purified by silica gel column chromatography to afford the title compound as a colorless oil (210 mg, 46% yield) with a recover of starting material (200 mg).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[CH2:3]1.C([O-])([O-])=O.[Na+].[Na+].[O:16](S(C(F)(F)F)(=O)=O)[S:17]([C:20]([F:23])([F:22])[F:21])(=O)=[O:18]>C(Cl)Cl>[F:21][C:20]([F:23])([F:22])[S:17]([O:8][C:6]1[CH2:7][CH:2]([CH3:1])[CH2:3][C:4](=[O:9])[CH:5]=1)(=[O:18])=[O:16]
Reactant: CC1CC(=O)CC(=O)C1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1CC(=O)C=C(OS(=O)(=O)C(F)(F)F)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of 5-methylcyclohexane-1,3-dione (1.0 equiv.) in DCM (0.5M) was added Na2CO3 (1.1 equiv.) and cooled to 0° C. Added Tf2O (1.0 equiv.) in DCM (5.0 M) dropwise over 1 hr at 0° C. under a nitrogen atmosphere. Upon addition, the reaction was stirred for 1 hr at room temperature (dark red solution). The solution was filtered and the filtrate was quenched by careful addition of saturated NaHCO3 with vigorous stirring until pH=7. The solution was transferred to a separatory funnel and the layers were separated. The organic layer was washed with brine, dried with Na2SO4, filtered, concentrated under vacuo and dried under high vacuum for 15 min to yield 5-methyl-3-oxocyclohex-1-enyl trifluoromethanesulfonate as light yellow oil in 78% yield. The triflate decomposes upon storage and should be used immediately for the next reaction. LC/MS=259.1/300.1 (M+H and M+CH3CN); Rt=0.86 min, LC=3.84 min. 1H-NMR (400 MHz, CDCl3) δ ppm: 6.05 (s, 1H), 2.70 (dd, J=17.2, 4.3, 1H), 2.53 (dd, J=16.6, 3.7, 1H), 2.48-2.31 (m, 2H), 2.16 (dd, J=16.4, 11.7, 1H), 1.16 (d, J=5.9, 3H).
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([NH2:16])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[C:17]([C:19]1[CH:20]=[CH:21][C:22]([NH:25][C:26]([CH2:28][CH:29]([CH3:34])[CH2:30][C:31](O)=[O:32])=[O:27])=[N:23][CH:24]=1)#[N:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:17]([C:19]1[CH:20]=[CH:21][C:22]([NH:25][C:26](=[O:27])[CH2:28][CH:29]([CH3:34])[CH2:30][C:31]([NH:16][C:12]2[CH:13]=[CH:14][C:15]3[N:3]([CH2:1][CH3:2])[C:4]4[C:9]([C:10]=3[CH:11]=2)=[CH:8][CH:7]=[CH:6][CH:5]=4)=[O:32])=[N:23][CH:24]=1)#[N:18]
Reactant: CC(CC(=O)O)CC(=O)Nc1ccc(C#N)cn1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c2ccccc2c2cc(NC(=O)CC(C)CC(=O)Nc3ccc(C#N)cn3)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.2 %

Procedure:
To a solution of 9-ethyl-9H-carbazol-3-ylamine (306.5 mg, 1.457 mmol) in DMF (7 mL) were added the compound obtained in Step 1 (300 mg, 1.215 mmol), HATU (554.14 mg, 1.457 mmol) and DIPEA (0.632 mL, 3.644 mmol) at room temperature, and the mixture was stirred at room temperature for 16 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate (2×50 mL). The organic layer was dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by preparative HPLC to give the title compound (220 mg, 41.21%) as a colorless powder.