Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N@:11]1[CH2:13][CH:12]1[C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:18][CH2:17]1)=[O:15])(=[O:10])=[O:9].[I-].[Na+].[O:34]1[CH2:39][CH2:38][CH:37]([N:40]=[C:41]=[O:42])[CH2:36][CH2:35]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:13][C@@H:12]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([C:28]([F:30])([F:29])[F:31])=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])[N:40]([CH:37]2[CH2:38][CH2:39][O:34][CH2:35][CH2:36]2)[C:41]1=[O:42])(=[O:10])=[O:9]
Reactant: O=C=NC1CCOCC1
Reactant: O=C(C1C[N@@]1S(=O)(=O)c1ccccc1Cl)N1CCN(c2ncccc2C(F)(F)F)CC1
Agent: [I-]
Agent: [Na+]
Product: O=C([C@@H]1CN(S(=O)(=O)c2ccccc2Cl)C(=O)N1C1CCOCC1)N1CCN(c2ncccc2C(F)(F)F)CC1

Procedure:
In analogy to example 2, [(S)-1-(2-chloro-benzenesulfonyl)-aziridin-2-yl]-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone (example 72, step 3) was reacted with sodium iodide and tetrahydropyran-4-yl-isocyanate to give the title compound as a light yellow solid. MS: 601.9 ([M+H]+)
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH:25]=[CH:24][N:23]=[C:22](Cl)[N:21]=3)[CH:15]=2)[CH2:9]1)=O)(C)(C)C.[NH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1>>[NH:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]2[CH:15]=[C:16]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:27][CH2:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=4)[N:21]=3)[CH:17]=[CH:18][CH:19]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccc(-c3ccnc(Cl)n3)c2)C1
Reactant: NCCc1ccc(O)cc1
Product: Oc1ccc(CCNc2nccc(-c3cccc(NC4CCNC4)c3)n2)cc1

Procedure:
Intermediate 8b was coupled with tyramine following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 376. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.2 (d, 1H) 7.0-7.5 (m, 4H) 6.9 (d, 1H) 6.68 (d, 2H) 5.05 (m, 1H) 4.28 (m, 1H) 3.8 (m, 2H) 3.2-3.6 (m, 4H) 2.9 (m, 2H) 2.0-2.6 (m, 2H).
Reaction SMILES: [N:1]([C@@H:4]([CH:20]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:5](N1[C@@H](CC2C=CC=CC=2)COC1=O)=[O:6])=[N+:2]=[N-:3].OO.O[Li].O.[O-:40]S([O-])=O.[Na+].[Na+]>C1COCC1.O>[N:1]([C@@H:4]([CH:20]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:5]([OH:6])=[O:40])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=N[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Li]O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: [N-]=[N+]=N[C@H](C(=O)O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a solution of 3-[2-(S)-azido-3,3-bis-(4-chloro-phenyl)-propionyl]-4-(S)-benzyl-oxazolidin-2-one (1.53 g, 3.1 mmol) in 3:1 THF/water (60 mL) at 0° C. was added 30% aq. H2O2 (1.4 mL, 12.3 mmol) and LiOH.H2O (259 mg, 6.2 mmol). The mixture was stirred for 1 h at 0° C. Na2SO3 (2.52 g, 20 mmol) was added, and the mixture was stirred for 30 min at 0° C., then warmed to rt, and stirred for 1 h. The mixture was concentrated without external heating, and the residue was diluted with water and extracted with DCM (3×). The aqueous layer was acidified with conc. HCl and extracted with EtOAc (4×). The combined EtOAc extracts were dried (Na2SO4) and concentrated to provide the desired azidoacid as a colorless solid (0.98 g, 94%). 1H NMR (500 MHz, CDCl3): 7.33-7.24 (m, 6H), 7.21-7.18 (m, 2H), 4.52 (d, J=8.3, 1H), 4.49 (d, J=8.3, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]1[CH:15]([C:16]([OH:18])=[O:17])[CH2:14][C:13](=[O:19])[O:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.[C:32](O)([CH3:35])([CH3:34])[CH3:33].Cl>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[O:19]=[C:13]1[O:12][CH:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH:15]([C:16]([O:18][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:17])[CH2:14]1
Reactant: O=C1CC(C(=O)O)C(C(=O)OCc2ccccc2)O1
Reactant: CC(C)(C)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)C1CC(=O)OC1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
6.53 g of (2RS,3SR)-2-benzyloxycarbonyl-5-oxotetrahydrofuran-3-carboxylic acid was dissolved in 70 ml of chloroform, and 4.53 g of 4-dimethylaminopyridine, 7.11 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 4.70 ml of tert-butyl alcohol were sequentially added thereto, followed by stirring at room temperature for 14 hours. The reaction solution was poured into 1N hydrochloric acid cooled with ice and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the drying agent was filtered off. Then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1), to obtain 5.16 g of the above-identified compound as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:7][C:6]=1[C:22]1[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.[C:35](Cl)(=[O:41])[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>ClCCl>[C:35]([NH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:7][C:6]=1[C:22]1[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=1)(=[O:41])[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CCCCCC(=O)Cl
Reactant: COc1cccc(C(=O)Nc2ccc(OCCN)c(-c3ccnn3C)c2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCC(=O)NCCOc1ccc(NC(=O)c2cccc(OC)c2)cc1-c1ccnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
To a mixture of N-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide (0.020 g, 0.15 mmol) and triethylamine (0.038 mL, 0.27 mmol) in dichloromethane was added hexanoyl chloride (50 mg, 0.14 mmol), dropwise at room temperature. The mixture was stirred at room temperature overnight. The reaction was quenched with water, extracted with dichloromethane (3×20 mL) and dried over anhydrous MgSO4. The crude product was purified by flash column chromatography. (EtOAc/Hexane=50-90%). N-[4-(2-Hexanoylamino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide was obtained as white solid in 43% yield. LCMS m/z (%)=465 (M+H, 100). 1H NMR (400 MHz, CDCl3) δ ppm 0.9 (t, J=7.1 Hz, 3 H), 1.3 (m, 4 H), 1.6 (m, 2 H), 2.1 (m, 2 H), 3.5 (q, J=5.4 Hz, 2 H), 3.8 (s, 3 H), 3.9 (s, 3 H), 4.0 (t, J=5.1 Hz, 2 H), 5.5 (m, 1 H), 6.3 (d, J=2.0 Hz, 1 H), 7.0 (d, J=9.1 Hz, 1 H), 7.1 (m, 1 H), 7.4 (m, 2 H), 7.4 (d, J=2.0 Hz, 1 H), 7.6 (d, J=2.0 Hz, 1 H), 7.6 (d, J=3.0 Hz, 1 H), 7.7 (dd, J=8.8, 2.8 Hz, 1 H), 7.8 (s, 1 H).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[C:21]1([C:29](OCC)=[O:30])([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:23][CH2:22]1.[Cl-].[NH4+]>CCOCC>[CH2:27]([O:26][C:24]([C:21]1([C:29](=[O:30])[CH2:14][C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:23][CH2:22]1)=[O:25])[CH3:28]
Reactant: CC(=O)OC(C)(C)C
Reactant: CCOC(=O)C1(C(=O)OCC)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C1(C(=O)CC(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 45.6 %

Procedure:
A solution of n-butyllithium (2.5M in hexane, 40 ml) was added dropwise with stirring to a cooled solution of diisopropylamine (10.1 g) in anhydrous ether (100 ml) in an atmosphere of nitrogen, whilst maintaining the temperature below -70° C. The mixture was stirred at -78° C. for 0.5 hour and a solution of t-butyl acetate (11.6 g) in anhydrous ether (20 ml) was added dropwise, whilst maintaining the temperature below -70° C. The mixture was stirred at -78° C. for 1 hour and a solution of diethyl cyclopropane-1,1-dicarboxylate (18.6 g) in anhydrous ether (20 ml) was added dropwise whilst maintaining the temperature below -70° C. The mixture was stirred at -78° C. for 0.5 hour and the temperature was allowed to rise to room temperature. A saturated solution of ammonium chloride (150 ml) was added cautiously and the layers were separated. The organic extract was washed with water (2×50 ml) hydrochloric acid (2M, 2×50 ml) and water (2×50 ml). The solution was dried (anhydrous sodium sulphate) and filtered. The filtrate was evaporated to dryness and the residue was distilled to give t-butyl 3-(1-ethoxycarbonylcyclopropyl)-3-oxopropionate (11.66 g) as a clear oil bp 89°-90° C./0.5 mmHg.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:10]([CH2:21][CH2:22][OH:23])[CH2:9]1)C1C=CC=CC=1>C(O)C.[Pd]>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH:10]1[CH2:21][CH2:22][OH:23])=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)CC1CCO
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCNCC1CCO
Yield: 91.7 %

Procedure:
A solution of (RS)-4-benzyl-1-(tert-butyloxycarbonyl)-2-(2-hydroxyethyl)piperazine (D5) (2.5 g, 7.81 mmol) in ethanol (150 ml) was hydrogenated at atmospheric pressure and room temperature in the presence of 10% palladium on charcoal (2.07 g, 54% paste with water) for 3.5 h. The mixture was filtered through Kieselguhr and the filtrate evaporated in vacuo to give the title compound as a colourless oil (1.65 g, 92%). Mass spectrum (AP+): Found 231 (MH+). C11H22N2O3 requires 230.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH2:15])=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].CS[C:24]1[NH:25][CH:26]=[C:27]([CH2:31][C:32]2[CH:33]=[N:34][C:35](=[O:38])[NH:36][CH:37]=2)[C:28](=[O:30])[N:29]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][C:24]3[NH:25][CH:26]=[C:27]([CH2:31][C:32]4[CH:33]=[N:34][C:35](=[O:38])[NH:36][CH:37]=4)[C:28](=[O:30])[N:29]=3)=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:18]([F:19])([F:20])[F:21]
Reactant: NCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: CSc1nc(=O)c(Cc2cnc(=O)[nH]c2)c[nH]1
Solvent: c1ccncc1
Product: O=c1ncc(Cc2c[nH]c(NCCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)c[nH]1
Temperature: 150 °C
Reaction time: 8 h
Yield: 17.1 %

Procedure:
2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-ethylamine (0.380 mmol, 1.00 eq) and 2-methylsulfanyl-5-(2-oxo-1,2-dihydro-pyrimidin-5-ylmethyl)-1H-pyrimidin-4-one (0.240 mmol, 0.63 eq) were dissolved in dry pyridine (300 μL) and stirred at 150° C. overnight. Solvent was evaporated and crude product was purified on Biotage SP 1 Snap Si 10; 15 ml/min in the gradient of MeOH in DCM: 0-10% in 25CV. The appropriate fractions were combined and evaporated in vacuo to give the required product 2-{2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]ethylamino}-5-(2-oxo-1,2-dihydro-pyrimidin-5-ylmethyl)-1H-pyrimidin-4-one (0.041 mmol, yield: 11%, HPLC-MS/UV:[M+H]+=518.047; rt: 10.97 mins; purity: 85%). 1H NMR (300 MHz; CDCl3) δ/ppm 2.80 (t, J=6.50, 2H), 3.19-3.22 (m, 2H), 3.41-3.52 (m, 2H), 5.39 (br.s., 1H), 6.33-6.64 (m, 1H), 6.99-7.10 (m, 2H), 7.22 (dd, J=9.24, J=3.42, 1H), 7.26-7.32 (m, 2H), 7.38-7.43 (m, 1H), 7.58-7.72 (m, 2H), 8.11 (br.s., 1H), 10.93 (br.s., 1H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].[CH2:18]([O:20][CH:21](OCC)OCC)[CH3:19].C(OC(=O)C)(=O)C>>[CH2:18]([O:20][CH:21]=[C:11]([C:10](=[O:17])[C:3]1[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=1[F:1])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:19]
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)cc1F
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)cc1F
Temperature: 115 °C

Procedure:
A solution of 7.88 g of 2,4,5-trifluoro-β-oxobenzenepropanoic acid, ethyl ester, 8.15 ml of 98% triethoxymethane and 7.5 ml of acetic anhydride in a 50 ml of flask was connected through a short distillation head to a 160 mm vacuum source and heated at 115° C. for 3 hours. The solution was then evaporated in vacuo at 45° C. giving 9.67 g of α-(ethoxymethylene)-2,4,5-trifluoro-β-oxobenzenepropanoic acid, ethyl ester as a yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=O)=[C:9]1[Cl:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][S:21]([CH2:24][C:25]#[N:26])(=[O:23])=[O:22].C(N(CC)CC)C>C1COCC1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=[C:24]([S:21]([CH3:20])(=[O:23])=[O:22])[C:25]#[N:26])=[C:9]1[Cl:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1c(Cl)n(Cc2ccccc2)c2ccccc12
Reactant: CS(=O)(=O)CC#N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)C(C#N)=Cc1c(Cl)n(Cc2ccccc2)c2ccccc12
Reaction time: 144 h

Procedure:
To 1 g of 1-benzyl-2-chloroindole-3-carbaldehyde, dissolved in 25 ml of THF, was added 930 mg of methylsulfonylacetonitril and 1.6 g of triethylamine. After 24 hours another 1 g of methylsulfonylacetonitril and 0.3 g of triethylamine was added, and the mixture was stirred for 6 days. The precipitate was collected by filtration to give (4a). Yield 1.1 g of (4a), m.p. 206° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][NH:4][N:3]=1.[CH:10]1([NH2:13])[CH2:12][CH2:11]1>>[CH:10]1([NH:13][C:7]([C:6]2[C:2]([CH3:1])=[N:3][NH:4][CH:5]=2)=[O:9])[CH2:12][CH2:11]1
Reactant: NC1CC1
Reactant: Cc1n[nH]cc1C(=O)O
Product: Cc1n[nH]cc1C(=O)NC1CC1
Yield: 93.8 %

Procedure:
Following the same procedure in Example 29 (Step B and C in Method B), using 3-methyl-1H-pyrazole-4-carboxylic acid (252 mg, 2.0 mmol) and cyclopropylamine (285 mg, 5.0 mmol), provided the desired crude compound (310 mg, 94%), which was used in Step A directly.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][C:9]([CH3:33])([CH3:32])[C@H:10]([NH:19][C:20](=[O:31])[C@@H:21]([CH2:26][N:27]([CH:29]=[O:30])[OH:28])[CH2:22][CH2:23][CH2:24][CH3:25])[C:11](C1N(C)C=CN=1)=[O:12]>>[CH3:32][C:9]([CH3:8])([CH3:33])[C@H:10]([NH:19][C:20](=[O:31])[C@@H:21]([CH2:26][N:27]([CH:29]=[O:30])[OH:28])[CH2:22][CH2:23][CH2:24][CH3:25])[C:11]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)=[O:12]
Reactant: Brc1ccccn1
Reactant: CCCC[C@H](CN(O)C=O)C(=O)N[C@H](C(=O)c1nccn1C)C(C)(C)C
Product: CCCC[C@H](CN(O)C=O)C(=O)N[C@H](C(=O)c1ccccn1)C(C)(C)C

Procedure:
The title compound was prepared from 2-bromopyridine as outlined in Scheme 2, in an analogous manner to 2(R)-[(N-formyl-N-hydroxyamino)-methyl]-hexanoic acid-[2,2-dimethyl-1(S)-(1-methyl-1H-imidazole-2-carbonyl)-propyl]-amide. The relevant spectroscopic data are described below.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C:4]([C:6]1[C:18]2[CH:17]=[N:16][C:15]([Cl:19])=[CH:14][C:13]=2[N:12]2[C:7]=1[CH2:8][CH2:9][CH:10]([N:20]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH3:21])[CH2:11]2)=O.C(O)(C(F)(F)F)=O.[SiH](CC)(CC)CC>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:32])[CH2:4][C:6]1[C:18]2[CH:17]=[N:16][C:15]([Cl:19])=[CH:14][C:13]=2[N:12]2[C:7]=1[CH2:8][CH2:9][CH:10]([N:20]([S:22]([C:25]1[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=1)(=[O:24])=[O:23])[CH3:21])[CH2:11]2
Reactant: COC(=O)C(=O)c1c2n(c3cc(Cl)ncc13)CC(N(C)S(=O)(=O)c1ccc(F)cc1)CC2
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cc1c2n(c3cc(Cl)ncc13)CC(N(C)S(=O)(=O)c1ccc(F)cc1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
To a solution of (±)-{3-chloro-6-[(4-fluoro-benzenesulfonyl)-methyl-amino]-5,6,7,8-tetrahydro-2,4b-diaza-fluoren-9-yl}-oxo-acetic acid methyl ester (0.006 g) in 0.2 mL of CH2Cl2 were added 0.2 mL of TFA and 0.2 mL of Et3SiH. The reaction mixture was stirred overnight at r.t. and concentrated under vacuum. The residue was purified by silica gel chromatography eluted with 50% EtOAc/hexane to give 0.005 g desired product as a white solid. MS (ESI): 466.1. (M+1).
Reaction SMILES: [NH:1]1[C:8]2[N:4]([N:5]=[CH:6][C:7]=2[CH2:9][CH2:10][NH:11][CH:12]=[O:13])[CH2:3][CH2:2]1.[C:14]1([C:20](Cl)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1>[C:20]([N:1]1[C:8]2[N:4]([N:5]=[CH:6][C:7]=2[CH2:9][CH2:10][NH:11][CH:12]=[O:13])[CH2:3][CH2:2]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CNCCc1cnn2c1NCC2
Solvent: c1ccncc1
Product: O=CNCCc1cnn2c1N(C(c1ccccc1)(c1ccccc1)c1ccccc1)CC2
Temperature: 60 °C
Reaction time: 5.5 h
Yield: 15.6 %

Procedure:
To a solution of 2-(2,3-dihydro-1H-imidazo[1,2-b]pyrazol-7-yl)ethylformamide (1.67 g) in pyridine (15 ml) was added triphenylmethyl chloride (3.1 g) at room temperature. The mixture was stirred at 60° C. for 5.5 hours. The reaction mixture was evaporated under reduced pressure and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate to give 2-(1-trityl-2,3-dihydro-1H-imidazo[1,2-b]pyrazol-7-yl)ethylformamide (610 mg).
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[C:6]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18](=[O:25])[N:17]([CH3:26])[CH:16]=2)=[N:7][C:8](S(C)(=O)=O)=[N:9][CH:10]=1.[O:32]=[S:33]1(=[O:38])[CH2:37][CH2:36][CH2:35][NH:34]1>>[F:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[C:6]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18](=[O:25])[N:17]([CH3:26])[CH:16]=2)=[N:7][C:8]([N:34]2[CH2:35][CH2:36][CH2:37][S:33]2(=[O:38])=[O:32])=[N:9][CH:10]=1
Reactant: Cn1cc(-c2nc(S(C)(=O)=O)ncc2Oc2ccc(F)cc2F)c2ccccc2c1=O
Reactant: O=S1(=O)CCCN1
Product: Cn1cc(-c2nc(N3CCCS3(=O)=O)ncc2Oc2ccc(F)cc2F)c2ccccc2c1=O

Procedure:
The title compound of Example 151 was treated with 1,1-dioxidoisothiazolidine instead of MeSO2NH2 in a manner similar to Example 152, step 6 to give the title compound. 1H NMR (DMSO-d6, 400 MHz) δ 8.63 (s, 1H), 8.24 (d, J=8.0 Hz, 1H), 7.86 (s, 1H), 7.83 (d, J=8.0 Hz, 1H), 7.65 (t, J=7.2 Hz, 1H), 7.53 (t, J=7.2 Hz, 1H), 7.31-7.26 (m, 1H), 7.13-7.07 (m, 1H), 6.89-6.87 (m, 1H), 3.97 (t, J=6.4 Hz, 2H), 3.57 (t, J=7.2 Hz, 2H), 3.54 (s, 3H), 2.40-2.33 (m, 2H). LCMS: 485.2 (M+H)+
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[Cl:20][C:21]1[C:22]([O:29][CH:30]([F:32])[F:31])=[N:23][CH:24]=[C:25]([CH:28]=1)[CH:26]=O>>[Cl:20][C:21]1[CH:28]=[C:25]([CH2:26][N:1]2[CH:2]([C:10]3[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=3[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]2=[O:8])[CH:24]=[N:23][C:22]=1[O:29][CH:30]([F:32])[F:31]
Reactant: O=Cc1cnc(OC(F)F)c(Cl)c1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cnc(OC(F)F)c(Cl)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with 5-chloro-6-(difluoromethoxy)-nicotinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.88 min.; [M+H]+: 427.28 g/mol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[C@H:9]1[CH2:14][N:15]1[C:23]2[CH:22]=[CH:21][C:20]([C:24]#[N:25])=[CH:19][C:18]=2[C:17]2[CH2:26][C@H:27]([NH:29][C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:28][C:16]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:36][CH2:37][C:38](O)=[O:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][C:38](=[O:39])[CH2:37][Cl:36])[C@H:9]1[CH2:14][N:15]1[C:23]2[CH:22]=[CH:21][C:20]([C:24]#[N:25])=[CH:19][C:18]=2[C:17]2[CH2:26][C@H:27]([NH:29][C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:28][C:16]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N[C@H]1Cc2c(n(C[C@@H]3[C@@H](O)CCN3C(=O)OC(C)(C)C)c3ccc(C#N)cc23)C1
Reactant: O=C(O)CCl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)N[C@H]1Cc2c(n(C[C@@H]3[C@H](OC(=O)CCl)CCN3C(=O)OC(C)(C)C)c3ccc(C#N)cc23)C1
Reaction time: 8 h
Yield: 53.6 %

Procedure:
A mixture of (2R,3S)-2-((S)-7-cyano-2-isopropoxycarbonylamino-2,3-dihydro-1H-cyclopenta[b]indol-4-ylmethyl)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (950 mg, 1.97 mmol), chloroacetic acid (227 mg, 2.36 mmol), and triphenylphosphine (626 mg, 2.36 mmol) in tetrahydrofuran (20 mL) is treated with diethyl azodicarboxylate (374 μL, 2.36 mmol) dropwise at room temperature. The reaction mixture is stirred overnight. The reaction is diluted with ethyl acetate (50 mL) and then washed with water and brine. The organic portion is dried over sodium sulfate and concentrated. The resulting residue is purified by medium pressure liquid chromatography, eluting with ethyl acetate:hexane (1:1). Fractions containing pure product are combined and concentrated to afford 0.59 g (54%) of the title compound. LC-ES/MS m/z 581.0 [M+Na]+, TR=4.46 min.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[N:21]3[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]3)=[C:15]([Br:22])[C:14]=2[CH3:23])=[O:12])=[CH:7][C:3]=1[C:4](O)=[O:5].[NH2:24][CH2:25][C:26]([OH:28])=[O:27]>>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[N:21]3[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]3)=[C:15]([Br:22])[C:14]=2[CH3:23])=[O:12])=[CH:7][C:3]=1[C:4]([NH:24][CH2:25][C:26]([O:28][C:3]([CH3:7])([CH3:4])[CH3:2])=[O:27])=[O:5]
Reactant: Cc1c(Br)c2ccccn2c1C(=O)c1ccc(N)c(C(=O)O)c1
Reactant: NCC(=O)O
Product: Cc1c(Br)c2ccccn2c1C(=O)c1ccc(N)c(C(=O)NCC(=O)OC(C)(C)C)c1

Procedure:
Obtained according to the process described in Step 1.5, using 2-amino-5-[(1-bromo-2-methylindolizin-3-yl)carbonyl]benzoic acid and the tert-butyl ester of glycine, in the form of a yellow powder (74%).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([N:22]2[CH2:28][CH:27]3[CH2:29][CH2:30][CH:24]([CH2:25][CH2:26]3)[CH2:23]2)=[O:21])[C:3]1=[O:31].[C:32]1([CH3:41])[CH:37]=[CH:36][CH:35]=[C:34]([N:38]=[C:39]=[O:40])[CH:33]=1>ClCCl>[CH:24]12[CH2:25][CH2:26][CH:27]([CH2:29][CH2:30]1)[CH2:28][N:22]([C:20]([CH2:19][N:4]1[C:5]3[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=3[C:7]([CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:8][CH:2]([NH:1][C:39]([NH:38][C:34]3[CH:35]=[CH:36][CH:37]=[C:32]([CH3:41])[CH:33]=3)=[O:40])[C:3]1=[O:31])=[O:21])[CH2:23]2
Reactant: Cc1cccc(N=C=O)c1
Reactant: NC1N=C(C2CCCCC2)c2ccccc2N(CC(=O)N2CC3CCC(CC3)C2)C1=O
Solvent: ClCCl
Product: Cc1cccc(NC(=O)NC2N=C(C3CCCCC3)c3ccccc3N(CC(=O)N3CC4CCC(CC4)C3)C2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
To a solution of (3RS)-3-amino-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-5-cyclohexyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (0.19 g) in dichloromethane (10 ml) was added m-tolyl isocyanate (0.064 g) at room temperature. The mixture was stirred at ambient temperature overnight. The reaction mixture was concentrated in vacuo. The residue was subjected by column chromatography on silica gel with chloroform and a mixture of chloroform and ethyl acetate (5:1) to give N-[(3RS)-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-5-cyclohexyl-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea (0.075 g) as a white amorphous mass.