Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:16]2[CH2:21][C:20](=[O:22])[C:19]([C:23](=O)[CH2:24][CH3:25])=[C:18]([OH:27])[CH2:17]2)=[C:4]2[C:9](=[C:10]([CH3:14])[C:11]=1[O:12][CH3:13])[C:8](=[O:15])[CH2:7][CH2:6][CH2:5]2.Cl.[CH2:29]([O:31][NH2:32])[CH3:30].C([O-])(=O)C.[Na+].Cl>>[CH3:1][C:2]1[C:3]([CH:16]2[CH2:21][C:20](=[O:22])[C:19]([C:23](=[N:32][O:31][CH2:29][CH3:30])[CH2:24][CH3:25])=[C:18]([OH:27])[CH2:17]2)=[C:4]2[C:9](=[C:10]([CH3:14])[C:11]=1[O:12][CH3:13])[C:8](=[O:15])[CH2:7][CH2:6][CH2:5]2
Reactant: CCON
Reactant: CCC(=O)C1=C(O)CC(c2c(C)c(OC)c(C)c3c2CCCC3=O)CC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: CCON=C(CC)C1=C(O)CC(c2c(C)c(OC)c(C)c3c2CCCC3=O)CC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 5-(6,8-dimethyl-7-methoxy-1-oxo-1,2,3,4-tetrahydronaphth-5-yl)-3-hydroxy-2-propionylcyclohex-2-en-1-one (0.48 g), ethoxyamine hydrochloride (1 equiv), anhydrous sodium acetate (1 equiv) and absolute alcohol (30 ml) was stirred at room temperature for 1 hr. The mixture was poured into a very dilute aqueous hydrochloric acid solution which was then immediately extracted with diethyl ether. The dried (MgSO4) organic fraction was evaporated to give 5-(6,8-dimethyl-7-methoxy-1-oxo-1,2,3,4-tetrahydronaphth-5-yl)-2[1-(ethoxyimino)propyl]-3-hydroxycyclohex-2-en-1-one (6) as a pale yellow oil. Pmr spectrum (CDCl3 ; δ in ppm): 1.11-1.42 (6H,2xt); 1.9-3.8 (15H,m); 2.41 (3H,s); 2.52 (3H,s); 3.66 (3H,s); 4.14 (2H, q); OH not observed.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:11][CH:12]([C:14](=[O:16])[CH3:15])[CH3:13].C(B(CC)CC)C.[O:24]([C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34]Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1.O>[CH3:11][CH:12]([C:14](=[O:16])[CH2:15][CH2:34][C:33]1[CH:36]=[CH:37][CH:38]=[C:31]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:32]=1)[CH3:13]
Reactant: CC(=O)C(C)C
Reactant: BrCc1cccc(Oc2ccccc2)c1
Agent: CCB(CC)CC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(=O)CCc1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.6 %

Procedure:
To a solution of potassium bis (trimethylsilyl) amide (20.9 g, 0.105 mol) in 200 ml tetrahydrofuran at 0° C. was added 2-methyl-3-butanone (12 ml, 0.112 mol). After 15 minutes, triethylborane (100 ml of a 1.0M solution in hexanes) was added, followed by 24.8 g (0.094 mole) 3-phenoxybenzyl bromide. The mixture was stirred at 25° C. for 18 hours, poured into 300 ml water and extracted with ether. The organic phase was dried, filtered and concentrated, leaving a yellow oil. The crude ketone product was purified by chromatography over silica gel using 5% ethyl acetate in hexanes, producing 16.8 g of product, a light yellow oil.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:13][C:14]([N:16]2[C@H:21]([C:22](=[O:36])[NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:33])[F:32])[C:25]=3[F:35])[CH2:20][C@:19]3([CH2:37][O:38]C(=O)CN4C5C(=CC=CC=5)C(C(=O)N)=N4)[C@H:17]2[CH2:18]3)=[O:15])[N:5]=1)(=[O:3])[NH2:2].[OH-].[Na+].CCOC(C)=O>C1COCC1.O>[F:35][C:25]1[C:26]([O:30][C:31]([F:33])([F:34])[F:32])=[CH:27][CH:28]=[CH:29][C:24]=1[NH:23][C:22]([C@@H:21]1[CH2:20][C@:19]2([CH2:37][OH:38])[C@@H:17]([CH2:18]2)[N:16]1[C:14](=[O:15])[CH2:13][N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([C:1]([NH2:2])=[O:3])=[N:5]1)=[O:36]
Reactant: NC(=O)c1nn(CC(=O)OC[C@@]23C[C@@H](C(=O)Nc4cccc(OC(F)(F)F)c4F)N(C(=O)Cn4nc(C(N)=O)c5ccccc54)[C@@H]2C3)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)c1nn(CC(=O)N2[C@H](C(=O)Nc3cccc(OC(F)(F)F)c3F)C[C@@]3(CO)C[C@@H]23)c2ccccc12

Procedure:
A solution of (3-carbamoyl-indazol-1-yl)-acetic acid (1R,3S,5S)-2-[2-(3-carbamoyl-indazol-1-yl)-acetyl]-3-(2-fluoro-3-trifluoromethoxy-phenylcarbamoyl)-2-aza-bicyclo[3.1.0]hex-5-ylmethyl ester (69.2 mg, 0.085 mmol) and NaOH (1N, 188 μL, 0.19 mmol) in THF (0.45 mL) and water (43 μL) was stirred at RT 1 h. Water and EtOAc were added, the layers were separated and the aqueous one extracted with EtOAc (×2). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude residue was purified by preparative HPLC (Waters Sunfire C18-OBD, 5 μm, 30×100 mm, eluent: 20% to 100% CH3CN in H2O in 25 min, CH3CN and H2O containing 0.1% TFA, flow: 40 mL/min). Rf, TLC (CH2Cl2/MeOH 9:1)=0.45; MS (UPLC/MS): 536.4 [M+H]+, 553.3 [M+NH4]+, 558.2 [M+Na]+, 534.3 [M−H]−, 580.3 [M+HCOO]−; tR (HPLC conditions f): 1.82 min.
Reaction SMILES: [C:1]1(=[O:23])[N:5]([C:6]2[CH:15]=[C:14]3[C:9]([C:10]([CH3:17])=[CH:11][C:12]([CH3:16])=[N:13]3)=[CH:8][CH:7]=2)[C:4](=[O:18])[C:3]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:2]12.ClC1C=CC=C(C(OO)=[O:32])C=1>C(Cl)Cl>[C:4]1(=[O:18])[N:5]([C:6]2[CH:15]=[C:14]3[C:9]([C:10]([CH3:17])=[CH:11][C:12]([CH3:16])=[N+:13]3[O-:32])=[CH:8][CH:7]=2)[C:1](=[O:23])[C:2]2=[CH:22][CH:21]=[CH:20][CH:19]=[C:3]12
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(C)c2ccc(N3C(=O)c4ccccc4C3=O)cc2n1
Solvent: ClCCl
Product: Cc1cc(C)[n+]([O-])c2cc(N3C(=O)c4ccccc4C3=O)ccc12
Temperature: 25 °C

Procedure:
4.25 g (14 mmol) of 7-phthalimido-2,4-dimethyl-quinoline are dissolved in 500 ml of boiling methylene chloride. After cooling to ambient temperature, 4.80 g of 3-chloroperbenzoic acid (about 50% strength) are added. After 3 hours at ambient temperature the reaction solution is washed 1 x with sodium hydrogen carbonate solution and saline solution, dried over sodium sulphate, concentrated by evaporation and recrystallised from ethanol.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])=[C:9]([O:23][CH3:24])[C:8]([Cl:25])=[C:7]([CH3:26])[C:6]=1[C:27](=[O:29])[CH3:28].Br.BrC[C:33]1[CH:38]=[CH:37][CH:36]=C[N:34]=1>>[Cl:25][C:8]1[C:7]([CH3:26])=[C:6]([C:27](=[O:29])[CH3:28])[C:5]([O:4][CH2:3][C:2]2[CH:36]=[CH:37][CH:38]=[CH:33][N:34]=2)=[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])[C:9]=1[O:23][CH3:24]
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(OCCBr)c1OCCC(C)c1ccc(F)cc1
Reactant: BrCc1ccccn1
Agent: Br
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCc2ccccn2)c1OCCC(C)c1ccc(F)cc1
Yield: 49 %

Procedure:
Example 8a (91 mg, 0.24 mmol) was reacted with 2-(bromomethyl)-pyridine hydrobromide (1.6 eq.) as described under General Procedure F and the crude mixture was purified by flash chromatography (silica gel, Et2O/hexane 1:1) to afford the title compound (55 mg, 49%) as a pale yellow oil. 1H NMR (300 MHz, CDCl3) δ 8.57 (m, 1H), 7.71 (dt, J=Hz, 1.8, 7.7 Hz, 1H), 7.42 (d, J=7.8 Hz, 1H), 7.24 (m, 1H), 7.11-7.06 (m, 2H), 6.94-6.88 (m, 2H), 5.17 (s, 2H), 3.95 (t, J=6.8 Hz, 2H) 3.86 (s, 3H), 2.93 (m, 1H), 2.45 (s, 3H), 2.20 (s, 3H), 1.97-1.91 (m, 2H), 1.20 (d, J=7.2 Hz, 3H). MS (ES+) m/z 472.2 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.[NH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[N:17][C:18]([Cl:24])=[CH:19][CH:20]=2)[N:15]=1.C(#N)C>O>[Cl:24][C:18]1[N:17]=[C:16]2[C:21]([CH:22]=[CH:23][C:14]([NH:13][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][CH:11]=[C:3]([N:2]([CH3:1])[CH3:12])[CH:4]=3)=[N:15]2)=[CH:20][CH:19]=1
Reactant: CN(C)c1cccc(C(=O)O)c1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Solvent: CC#N
Solvent: O
Product: CN(C)c1cccc(C(=O)Nc2ccc3ccc(Cl)nc3n2)c1
Temperature: 4 °C
Yield: 63.1 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 3-dimethylaminobenzoic acid (6.6 g), N,N'-carbonyldiimidazole (6.5 g) and 2-amino-7-chloro-1,8-naphthyridine (5.4 g). The product produced by precipitation in water (9 g; m.p. 212° C.) is dissolved in boiling acetonitrile (400 cc). After 3 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with acetonitrile (3×20 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-(7-Chloro-1,8-naphthyridin-2-yl)-3-dimethylaminobenzamide (6.2 g) is produced, m.p. 215° C.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:21]2[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3C(C)=N[O:17][N:16]=3)[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:27]([C:31]1[N:32]=C(N2CC[C@H](OC(=O)C(F)(F)F)C2)C2N=NNC=2N=1)(C)(C)C.ClCC1N=C(C)ON=1>>[C:1]([C:5]1[N:6]=[C:7]([N:21]2[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[N:32]=[C:31]([CH3:27])[O:17][N:16]=3)[N:13]=2)[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(N2CC[C@H](OC(=O)C(F)(F)F)C2)c2nn[nH]c2n1
Reactant: Cc1nonc1Cn1nc2nc(C(C)(C)C)nc(N3CC[C@H](O)C3)c2n1
Agent: Cc1nc(CCl)no1
Product: Cc1nc(Cn2nc3nc(C(C)(C)C)nc(N4CC[C@H](O)C4)c3n2)no1

Procedure:
In analogy to the procedure described for the synthesis of (S)-1-[5-tert-Butyl-2-(4-methyl-furazan-3-ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol (example 73), the title compound was prepared from Trifluoro-acetic acid (S)-1-(5-tert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)-pyrrolidin-3-yl-ester and 3-(chloromethyl)-5-methyl-1,2,4-oxadiazole and isolated as light yellow gum. MS (m/e): 359.5 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:25])[CH2:14][N:15]3[C:19]([CH3:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[N:16]3)[CH2:9][CH2:8]2)[S:5][CH:6]=1.C(N(C(C)C)CC)(C)C.[C:35]1([S:41](Cl)(=[O:43])=[O:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CC(N(C)C)=O>[CH3:20][C:19]1[N:15]([CH2:14][C:13]([N:10]2[CH2:11][CH2:12][CH:7]([C:4]3[S:5][CH:6]=[C:2]([NH:1][S:41]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)(=[O:43])=[O:42])[N:3]=3)[CH2:8][CH2:9]2)=[O:25])[N:16]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:18]=1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(N)cs2)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(NS(=O)(=O)c3ccccc3)cs2)CC1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1-[4-(4-amino-thiazol-2-yl)-piperidin-1-yl]-2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone (100 mg, 0.04 mmol) in dimethylacetamide (0.8 mL) is added diisopropylethylamine (8.6 μL, 0.28 mmol), followed by benzenesulfonyl chloride (8.8 mg, 0.05 mmol) at RT. After stirring 15 min at 60° C., the reaction mixture is purified directly by preparative HPLC to give N-(2-{1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperidin-4-yl}-thiazol-4-yl)-benzenesulfonamide (Compound No. I.g.025). MS: m/z=514 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:31][C:32]1[CH:37]=[C:36]([F:38])[C:35]([F:39])=[CH:34][C:33]=1[F:40])[CH2:9][C:10]([N:12]1[CH2:17][CH:16](C(=O)N)[N:15]2[C:21]([C:27]([F:30])([F:29])[F:28])=[N:22][C:23](CCC)=[C:14]2[CH2:13]1)=[O:11])(C)(C)C.FC(F)(F)[C:44]([OH:46])=O>ClCCl>[CH2:8]([NH:7][C:44]([C:23]1[N:22]=[C:21]([C:27]([F:30])([F:29])[F:28])[N:15]2[CH2:16][CH2:17][N:12]([C:10](=[O:11])[CH2:9][C@H:8]([NH2:7])[CH2:31][C:32]3[CH:37]=[C:36]([F:38])[C:35]([F:39])=[CH:34][C:33]=3[F:40])[CH2:13][C:14]=12)=[O:46])[CH2:9][CH3:10]
Reactant: CCCc1nc(C(F)(F)F)n2c1CN(C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)CC2C(N)=O
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCNC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@H](N)Cc1cc(F)c(F)cc1F)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
(R)-[3-(1-Propylcarbamoyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 44a (70 mg, 0.118 mmol) was dissolved in 10 mL of dichloromethane, and trifluoroacetic acid (270 mg, 2.37 mmol) was then added to the solution. The reaction mixture was stirred at room temperature for 1 hour and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid propylamide 44 (25 mg, yield 43.1%) as a white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:13][C@@:12]3([CH2:17][C@@H:16]([C:18]([O:20][C:21](C)(C)C)=[O:19])[N:15](C(OC(C)(C)C)=O)[CH2:14]3)[O:11][C:10]2=[O:32])[CH:6]=[CH:7][CH:8]=1>CO>[CH3:21][O:20][C:18]([C@@H:16]1[CH2:17][C@:12]2([O:11][C:10](=[O:32])[N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([Cl:2])[CH:4]=3)[CH2:13]2)[CH2:14][NH:15]1)=[O:19]
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@@]2(CN(c3cccc(Cl)c3)C(=O)O2)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@H]1C[C@]2(CN1)CN(c1cccc(Cl)c1)C(=O)O2
Reaction time: 8 h
Yield: 81.8 %

Procedure:
Saturated HCl in MeOH (5 mL) was added to (5S,8S)-di-tert-butyl 3-(3-chlorophenyl)-2-oxo-1-oxa-3,7-diazaspiro[4.4]nonane-7,8-dicarboxylate (107 mg, 0.236 mmol) and stirred at room temp. overnight. The solution was concentrated and chromatography using DCM and 20% MeOH in DCM gave 60 mg (0.193 mmol) of (5S,8S)-methyl-3-(3-chlorophenyl)-2-oxo-1-oxa-3,7-diazaspiro[4.4]nonane-8-carboxylate (B3). 1H NMR (300 MHz, DMSO) 7.68 (s, 1H), 7.6-7.4 (m, 2H), 7.23 (m, 1H), 4.62 (m, 1H), 4.22 (m, 2H), 3.85-3.68 (m, 4H), 3.6-3.5 (m, 1H), 2.9-2.7 (m, 2H). LC MS+: 311.14 at 1.65 min (10-90%, 3-5 min, Formic Acid).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([N:18]3[C:22]4[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=4[N:20]=[C:19]3[C:28]([OH:31])([CH3:30])[CH3:29])[CH2:14][CH2:13]1)[CH2:5]2.C(N(CC)C(C)C)(C)C.[C:41](Cl)(=[O:44])[CH2:42][CH3:43]>C1COCC1>[OH:31][C:28]([C:19]1[N:18]([CH:15]2[CH2:14][CH2:13][N:12]([CH2:11][CH:6]3[CH2:5][C:4]4[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:41](=[O:44])[CH2:42][CH3:43])[CH:3]=4)[CH2:7]3)[CH2:17][CH2:16]2)[C:22]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=2[N:20]=1)([CH3:29])[CH3:30]
Reactant: Cc1ccc2c(c1)nc(C(C)(C)O)n2C1CCN(CC2Cc3ccc(N)cc3C2)CC1
Reactant: CCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)Nc1ccc2c(c1)CC(CN1CCC(n3c(C(C)(C)O)nc4cc(C)ccc43)CC1)C2
Reaction time: 8 h
Yield: 94.8 %

Procedure:
To a solution of 2-{1-[1-(5-amino-indan-2-ylmethyl)-piperidin-4-yl]-5-methyl-1H-benzoimidazol-2-yl}-propan-2-ol (50 mg, 0.12 mmol), N,N-diisopropylethylamine (46 mg, 0.36 mmol) in THF (3 mL) was added propionyl chloride (12 mg, 0.13 mmol). After stirring overnight, the reaction mixture was quenched with silica-supported diamine-3 (119 mg, Silicycle) to scavenge the excess propionyl chloride. The mixture was filtered and concentrated in vacuo, and the residue was purified by flash chromatography to afford N-(2-{4-[2-(1-hydroxy-1-methyl-ethyl)-5-methyl-benzoimidazol-1-yl]-piperidin-1-ylmethyl}-indan-5-yl)-propionamide (54 mg, 95%) as white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH2:25])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:34][CH2:35][CH2:36]N.C([O-])(=O)C.[Na+].C(OCC)(=O)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH:25][CH2:36][CH2:35][F:34])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: NCCF
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2cn(-c3cccc(F)c3)cc2NC(N)=O)C1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2cn(-c3cccc(F)c3)cc2NC(=O)NCCF)C1
Yield: 95 %

Procedure:
Following general method 7, employing (S)-3-{[1-(3-fluorophenyl)-4-ureido-1H-pyrrole-3-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester and 2-fluoroethylamine hydrochloride, afforded the crude desired product (Note: 0.34 mmol of anhydrous sodium acetate was added to the reaction mixture to neutralise the amine). Column chromatography (silica, 12 g column, ISCO, 0-100% ethyl acetate in DCM) afforded the title compound as a glass (80 mg, 95%). LCMS (method B): RT=3.68 min, M+H+=492.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH:6]1[C:18](=[O:20])[NH2:19])(=[O:4])[CH:2]=[CH2:3].[ClH:21].CO>>[ClH:21].[C:1]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH:6]1[C:18]([NH2:19])=[O:20])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)N1CCN(C(=O)OC(C)(C)C)CC1C(N)=O
Agent: Cl
Solvent: CO
Product: C=CC(=O)N1CCNCC1C(N)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl 4-acryloyl-3-carbamoylpiperazine-1-carboxylate (200 mg, 0.706 mmol) in HCl/MeOH (20 mL, 2.86; N) was stirred at room temperature for 1 h. The mixture was concentrated in vacuo to yield the crude product (160 mg) as a yellow solid which was used directly in next step without further purification.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:36])[NH:10][C@@H:11]([CH2:30][C:31]2[N:32]=[CH:33][S:34][CH:35]=2)[C:12]([NH:14][CH2:15][C:16]2[N:17]=[N:18][N:19]([C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)[CH:20]=2)=[O:13])[O:7]1)=[O:5])C.[Li+].[OH-]>>[N+:27]([C:24]1[CH:25]=[CH:26][C:21]([N:19]2[CH:20]=[C:16]([CH2:15][NH:14][C:12](=[O:13])[C@@H:11]([NH:10][C:9]([C@H:8]3[O:7][C@@H:6]3[C:4]([OH:5])=[O:3])=[O:36])[CH2:30][C:31]3[N:32]=[CH:33][S:34][CH:35]=3)[N:17]=[N:18]2)=[CH:22][CH:23]=1)([O-:29])=[O:28]
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](Cc1cscn1)C(=O)NCc1cn(-c2ccc([N+](=O)[O-])cc2)nn1
Agent: [Li+]
Agent: [OH-]
Product: O=C(NCc1cn(-c2ccc([N+](=O)[O-])cc2)nn1)[C@H](Cc1cscn1)NC(=O)[C@H]1O[C@@H]1C(=O)O
Yield: 82.1 %

Procedure:
Followed general procedure using: the corresponding peptidomimetic epoxide ethyl ester 45 (27 mg, 0.05 mmol); LiOH (1.2 mg, 0.05 mmol); after extraction afforded the desired product as a white solid (20 mg, 78.3%). 1H NMR (DMSO-d6, 400 MHz): δ 9.00-8.99 (d, 1H, J=1.79 Hz); 8.74-8.71 (t, 1H); 8.59 (s, 1H); 8.48-8.47 (d, 1H, J=8.42 Hz); 8.47-8.45 (d, 2H, J=9.15 Hz); 8.21-8.19 (d, 2H, J=9.15 Hz); 7.34-7.33 (d, 1H, J=1.78 Hz); 4.69-4.66 (q, 1H); 4.42-4.41 (d, 2H, J=5.60 Hz); 3.60-3.59 (d, 1H, J=1.79 Hz); 3.50-3.10 (m, 3H). 13C NMR (DMSO-d6, 100 MHz): 170.68, 169.07, 165.75, 154.10, 153.25, 147.11, 147.05, 141.26, 126.08, 121.95, 120.94, 116.23, 53.24, 52.95, 51.85, 34.69, 33.44. HRMS-ESI: m/z [M+H+] calculated for C19H17N7O7S: 488.4543, observed: m/z 488.0986 (M+H+); m/z 486.0864 (M−H+). HPLC Method 2: Rt=20.4 min; 93.4%.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH:5]([Cl:7])[Cl:6])[CH3:2].C[C:12]1[CH:17]=[CH:16][C:15](S(O)(=O)=O)=[CH:14][CH:13]=1>C(O)CCCCCCC>[CH2:1]([O:3][CH:4]([O:8][CH2:9][CH2:10][CH2:12][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13])[CH:5]([Cl:7])[Cl:6])[CH2:2][CH2:16][CH2:17][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCOC(OCC)C(Cl)Cl
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCCCCO
Product: CCCCCCCCOC(OCCCCCCCC)C(Cl)Cl

Procedure:
A mixture of 5 g of dichloro-acetaldehyde diethyl-acetal, 25 g of octanol and 0.1 g of 4-methyl-benzene-sulphonic acid is heated on a water-bath for 5 hours, then distilled.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14](N3CCN(C(OC(C)(C)C)=O)CC3)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.NC1N=CC([C:37]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[O:38])=CC=1.BrC1C(=O)N(C)C=C(Br)C=1>>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:37]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[O:38])=[CH:15][N:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1=O
Reactant: Nc1ccc(C(=O)N2CCOCC2)cn1
Agent: Cn1cc(Br)cc(Br)c1=O
Product: Cn1cc(Br)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Yield: 21 %

Procedure:
Following the procedure described for synthesis of 101i, intermediate 111a and 3,5-dibromo-1-methylpyridin-2(1H)-one were reacted to give 111b in 21% yield. LCMS: (M+H)+ 394. 1H NMR (500 MHz, MeOD) δ 8.84 (d, J=2.5, 1H), 8.42 (d, J=2, 1H), 7.72 (m, 1H), 7.42 (d, J=2, 1H), 7.11 (d, J=8.5, 1H), 3.72 (m, 8H), 3.63 (s, 3H).
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH3:17])[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=[O:3])[CH3:2].[N+](=[CH2:20])=[N-]>>[CH3:20][O:12][C:11](=[O:13])[C@@H:10]1[CH2:14][CH2:15][CH2:16][N:9]1[C:7](=[O:8])[CH:6]([CH3:17])[CH2:5][S:4][C:1](=[O:3])[CH3:2]
Reactant: CC(=O)SCC(C)C(=O)N1CCC[C@H]1C(=O)O
Reactant: C=[N+]=[N-]
Product: COC(=O)[C@@H]1CCCN1C(=O)C(C)CSC(C)=O

Procedure:
1-(3-Acetylthio-2-methylpropanoyl)-L-proline is reacted with an ethereal solution of diazomethane according to the procedure described in Example 3 to obtain 1-(3-acetylthio-2-methylpropanoyl)-L-proline methyl ester.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([O-:9])=[O:8].[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Br>CC(C)=O>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:16][C:13]1[CH:14]=[CH:15][C:10]([N+:7]([O-:9])=[O:8])=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: BrCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(OCCCCCCCCBr)cc1
Temperature: 25 °C
Yield: 88.7 %

Procedure:
Anhydrous K2CO3 (5.50 g, 39.8 mmol) was added to a stirred solution of 4-nitrophenol (3.69 g, 26.5 mmol) and 1,8-dibromooctane (36.00 g, 132.1 mmol) in acetone. The reaction mixture was heated at reflux 12 h, then cooled to ambient temperature and filtered. The residue was washed with acetone (3×15 mL) and the combined organic layers evaporated in vacuo. The residue was dissolved in EtOAc (50 mL), the solution washed with water (2×20 mL), brine, dried over Na2SO4, filtered, volatiles evaporated in vacuo, and the residue subjected to column chromatography on silica gel (230-400 mesh) using hexanes as elutant to afford 7.75 g (23.5 mmol, 89%) of product as a low melting solid, mp 39-40° C. 1H NMR (500 MHz, CDCl3) δ 1.35-1.50 (m, 8H), 1.79-1.89 (m, 4H), 3.41 (t, J=6.5 Hz, 2H), 4.04 (t, J=6.5 Hz, 2H), 6.93 (d, J=10 Hz, 2H), 8.18 (d, J=9.5, 2H); 13C NMR (125 MHz, CDCl3) δ 27.9, 28.5, 28.8, 29.0, 29.2, 32.6, 33.9, 68.7, 114.3, 125.8, 129.3, 141.2, 164.1; HRMS (EI) calculated for C14H20BrNO3 [M]+0 329.6027, observed 329.6040.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:24](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(=O)(O)[O-].[Na+]>[CH2:1]([C@H:8]1[CH2:9][N:10]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([Br:21])=[CH:19][CH:20]=2)[CH2:11][CH2:12][N:13]1[CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Brc1ccc(CN2CCN[C@@H](Cc3ccccc3)C2)cc1
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: CN1CCN(Cc2ccc(Br)cc2)C[C@@H]1Cc1ccccc1
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of 369 mg of 3-(S)-benzyl-1-(4-bromobenzyl)-piperazine in 3 mL of tetrahydrofuran was added 0.8 mL of formaldehyde and 0.15 mL acetic acid. After 2 h, 453 mg of sodium triacetoxyborohydride was added and the reaction was stirred overnight. Diluted carefully with aqueous saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organics were washed with brine, dried with sodium sulfate, filtered and concentrated in vacuo. Used crude in subsequent reactions. 82% yield. ES MS (+)m/z 361