Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C@H:14]2[CH2:17][CH2:16][O:15]2)(=O)=O)=CC=1.[N-:18]=[N+:19]=[N-:20].[Na+].O>CS(C)=O>[N:18]([CH2:12][CH2:13][C@H:14]1[CH2:17][CH2:16][O:15]1)=[N+:19]=[N-:20]
Reactant: Cc1ccc(S(=O)(=O)OCC[C@H]2CCO2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=NCC[C@H]1CCO1
Temperature: 55 °C
Reaction time: 18 h

Procedure:
The mixture of (R)-2-(oxetan-2-yl)ethyl 4-methylbenzenesulfonate (80 mg, 0.31 mmol), NaN3 (30 m2, 0.465 mmol) and KI (5 mg) in DMSO (1 mL) was heated to 55° C. and stirred for 18 h. Then the mixture was cooled to RT, then it was poured into 20 mL of water, then extracted with MTBE (20 mL×3), the organic layers was washed with 1-120 (10 mL), brine (10 mL), and dried over Na2SO4. After filtration, the filtrate was concentrated under the reduced pressure. to give the titled compound which was used to the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([Br:20])[C:17]([OH:19])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)(Cl)C(=N)O[C:25]([CH3:28])([CH3:27])[CH3:26].B(F)(F)F.CCOCC.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([Br:20])[C:17]([O:19][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCCCC[C@H](Br)C(=O)O)OCc1ccccc1
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)C(Br)CCCCNC(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
(S)-6-{[(Benzyl-oxy)carbonyl]amino}-2-bromohexanoic acid, 10.0 g (0.029 mole), was dissolved in chloroform, 20 mL. To this was added a solution of t-butyl trichloroacetimidate, 12.7 g (0.058 mole), dissolved in chloroform, 50 mL, drop-wise over 30 minutes. The mixture was allowed to stir an additional 5 minutes and boron trifluoride etherate, 100 μL, was added. The reaction mixture was allowed to stir overnight. Sodium bicarbonate, 5 g, was added. After stirring 10 minutes, hexanes, 50 mL, was added and the mixture filtered to remove the solids present. The filtrate was evaporated and the residue purified by flash chromatography, ethyl acetate-hexanes, to give a clear-colorless oil. The yield was 8.5 g, 73% based on starting (S)-6-{[(benzyloxy)carbonyl]amino}-2-bromohexanoic acid. NMR is consistent with structure.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:22](=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][C:8]=2[N:9](C(OC(C)(C)C)=O)[CH:10]=1)=[O:5])[CH3:2].[CH3:24][N:25](C(N(C)C)N(C)C)C.Cl.NO>CCO>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:22]3[O:23][N:25]=[CH:24][C:21]=3[CH2:20][CH2:19][CH2:18][C:8]=2[NH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)CCCC2
Reactant: CN(C)C(N(C)C)N(C)C
Agent: Cl
Agent: NO
Solvent: CCO
Product: CCOC(=O)c1c[nH]c2c1-c1oncc1CCC2
Temperature: 60 °C
Yield: 76 %

Procedure:
In a sealed tube, 4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (2.6 mmol) and tris(dimethylamino)methane (5.2 mmol) are combined and heated at 60° C. for 3 hours. After cooling to RT the volatile material is removed in vacuo. To the residue were added hydroxylamine hydrochloride (7.8 mmol) and 7 mL EtOH. The mixture is heated at 100° C. for 16 hours. The solvent is evaporated in vacuo and the residue is taken up in CH2Cl2 and washed two times with NaHCO3 (aq). The organic layer is dried over Na2SO4 and evaporated in vacuo and the residue chromatographed using 10% MeOH in CH2Cl2 as mobile phase to yield 4,5,6,7-tetrahydro-1-oxa-2,7-diaza-cyclopenta[e]azulene-9-carboxylic acid ethyl ester as a white solid (76%). 1H NMR (CDCl3) 1.19 (t, 3H), 1.95-2.07 (m, 2H), 2.78 (t, 2H), 2.95 (t, 2H), 4.38 (q, 2H), 7.26 (s, 1H), 8.03 (s, 1H), 8.77 (s, 1H).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.O>CN(C=O)C>[N:21]1[CH:22]=[CH:23][C:18]([CH2:17][CH2:16][CH2:15][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])=[CH:19][CH:20]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: ClCCCc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCCc1ccncc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 465.9 %

Procedure:
To a suspension of NaH (0.4 g) in DMF (8 mL) was added diethyl malonate (0.16 g) at 0° C. The mixture was stirred at RT for 30 min. To the mixture was added a solution of 4-(3-chloropropyl)pyridine (1.2 g) prepared in (1) in DMF (4 mL). The reaction mixture was stirred at 80° C. for 10 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over Na2SO4. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (Developing solvent: hexane/ethyl acetate=1/1) to give the title compound (1.3 g, 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9](=O)[C:10]([N:15]1C(=O)C2C(=CC=CC=2)C1=O)=[CH:11][N:12](C)[CH3:13].C[NH:28]N>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[C:10]([NH2:15])=[CH:11][N:12]([CH3:13])[N:28]=1
Reactant: CNN
Reactant: CN(C)C=C(C(=O)c1cc(Cl)ccc1Cl)N1C(=O)c2ccccc2C1=O
Solvent: CCO
Product: Cn1cc(N)c(-c2cc(Cl)ccc2Cl)n1
Temperature: 0 °C
Yield: 38.1 %

Procedure:
To an ice-cooled solution of 2-(3-(2,5-Dichlorophenyl)-1-(dimethylamino)-3-oxoprop-1-en-2-yl)isoindoline-1,3-dione (0.050 g, 0.13 mmol) in ethanol (6 mL) was added 40% aqueous methylhydrazine solution (45 mg, 0.39 mmol). The mixture was then heated at reflux for 3 hours. The reaction mixture was then concentrated and purified by flash column chromatography to afford 3-(2,5-dichlorophenyl)-1-methyl-1H-pyrazol-4-amine as a solid (12 mg, 38% yield). 1H NMR (400 MHz, CDCl3): 7.50 (d, J=3.6 Hz, 1H), 7.38 (d, J=8.8 Hz, 1H), 7.28 (m, 1H), 7.06 (s, 1H), 3.86 (s, 3H), 2.98 (s, 2H).
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[O:17]1[CH2:21][CH2:20][CH2:19][C@@H:18]1[C:22](O)=[O:23].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.C(N=C=NCCCN(C)C)C.Cl>ClCCl>[O:17]1[CH2:21][CH2:20][CH2:19][C@@H:18]1[C:22]([N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:23]
Reactant: O=C(O)[C@H]1CCCO1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)[C@H]1CCCO1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred suspension of (S)-benzyl pyrrolidine-2-carboxylate hydrochloride (5.63 g, 23.3 mmol), (R)-tetrahydrofuran-2-carboxylic acid (2.24 mL, 23.3 mmol), DIPEA (10.2 mL, 58.3 mmol), and HOBt (3.15 g, 23.3 mmol) in dry dichloromethane (100 mL) at 25° C. was added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (4.45 g, 23.3 mmol) in one portion. The mixture was stirred at 25° C. for 16 h then 1N HCl (50 mL) was added. The organic phase was separated, washed with saturated sodium bicarbonate solution, dried with Na2SO4, filtered and concentrated to afford intermediate (S)-benzyl 1-((R)-tetrahydrofuran-2-carbonyl)pyrrolidine-2-carboxylate as a yellow oil which was carried forward directly.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1N.C(O)(C)C.S(=O)(=O)(O)O.N([O-])=O.[Na+]>O>[Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][CH:3]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1Cl
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: O=[N+]([O-])c1cccc(Cl)c1
Yield: 90 %

Procedure:
172.5 parts of 2-chloro-4-nitro-aniline are introduced into 180 parts of isopropanol and 300 parts of water, and 200 parts of concentrated sulfuric acid (98 percent strength by weight) are then added to the mixture. A solution of 125 parts of NaNO2 in 175 parts of water is run in at 50° C., as described in Example 1. The mixture is cooled, 400 parts of water are added and the product is filtered off. 142 parts (90% of theory) of 3-chloro-nitro-benzene, of melting point 40°-42° C., are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14](Cl)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1)=[O:5])[CH3:2].[Br:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([O:24][C:21]2[CH:22]=[CH:23][C:18]([Br:17])=[CH:19][CH:20]=2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: Oc1ccc(Br)cc1
Reactant: CCOC(=O)c1cc(Cl)c2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(Oc2ccc(Br)cc2)c2ccccc2n1
Temperature: 60 °C
Yield: 42.3 %

Procedure:
To a solution of 4-chloro-quinoline-2-carboxylic acid ethyl ester (910 mg, 3.87 mmol) in DMF (15 ml) was added 4-bromophenol (737 mg, 4.26 mmol), followed by Cs2CO3 (1.89 g, 5.81 mmol). The reaction mixture was then heated to 60° C. for 16 hrs. On the second day the mixture was cooled to r.t. and concentrated down. The residue was partitioned between EtOAc (10 ml) and water (20 ml). The EtOAc layer was separated, dried over MgSO4, filtrated, concentrated, and purified by Biotage with EtOAc/Hexane (15%, 4 CV) to afford 4-(4-bromo-phenoxy)-quinoline-2-carboxylic acid ethyl ester (609 mg, 42.3%). 1H NMR (300 MHz, DMSO-d6): δ 8.36 (m, 1H), 8.18 (m, 1H), 7.93 (m, 1H), 7.80 (m, 1H). 7.75 (m, 2H), 7.34 (m, 2H), 7.14 (s, 1H), 4.34 (m, 2H), 1.30 (m, 3H). LC-MS m/z=373 [C18H14BrNO3+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:8].C([O-])([O-])=O.[K+].[K+].Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([B:23]2[O:31][C:28]([CH3:30])([CH3:29])[C:25]([CH3:27])([CH3:26])[O:24]2)=[CH:19][CH:18]=1>CN(C=O)C>[CH3:29][C:28]1([CH3:30])[C:25]([CH3:26])([CH3:27])[O:24][B:23]([C:20]2[CH:19]=[CH:18][C:17]([CH2:16][O:8][N:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]3=[O:1])=[CH:22][CH:21]=2)[O:31]1
Reactant: [O-][n+]1ccccc1O
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)OB(c2ccc(COn3ccccc3=O)cc2)OC1(C)C
Temperature: 80 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
2-hydroxypyridine-1-oxide (0.04 g, 0.34 mmol) was dissolved in 5 mL of anhydrous DMF. To this was added K2CO3 (0.14 g, 1.02 mmol) and 4-bromomethylphenyl boronic acid pinacol ester (0.10 g, 0.34 mmol). The reaction was heated to 80° C. and allowed to stir under nitrogen overnight. After cooling to room temperature, the solvent was evaporated and the resulting residue was brought up in dichloromethane and washed twice with water. The organic layer was dried over MgSO4, filtered and concentrated for purification via silica gel chromatography eluting with 2% MeOH in DCM. The protected B19 was collected as an off-white solid in 87% yield (98 mg, 0.3 mmol). 1H NMR (400 MHz, CDCl3) δ=7.79 (d, J=8.0 Hz, 2H), 7.38 (d, J=8.0 Hz, 2H), 7.24 (td, J=7.2 Hz, J2=2.0 Hz, 1H), 7.05 (dd, J=7.2 Hz, J2=2.0 Hz, 1H), 6.67 (dd, J=9.2 Hz, J2=1.2 Hz, 1H), 5.89 (td, J=6.8 Hz, J2=1.6 Hz, 1H), 5.29 (s, 2H), 1.35 (s, 12H). 13C NMR (100 MHz, CDCl3) δ=159.2, 138.9, 137.0, 136.8, 135.3, 129.5, 122.9, 104.7, 84.3, 78.4, 25.1. ESI-MS(+): m/z 328.18 [M+H]+. Anal. calcd. for C18H22BNO4. 0.4 CH3OH: C, 65.26; H, 6.94; N, 4.16. Found: C, 65.54; H, 7.20; N, 3.76.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:21]=3)[CH2:16][NH:15]2)=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2].[CH3:38][O:39][C:40]([NH:42][CH:43]([C:47]([CH3:50])([CH3:49])[CH3:48])[C:44](O)=[O:45])=[O:41].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC#N>[CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:21]=3)[CH2:16][N:15]2[C:44](=[O:45])[CH:43]([NH:42][C:40]([O:39][CH3:38])=[O:41])[C:47]([CH3:50])([CH3:49])[CH3:48])=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]
Reactant: COC(=O)NC(C(=O)O)C(C)(C)C
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1)C(=O)OCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)C(NC(=O)OC)C(C)(C)C)C(=O)OCC
Temperature: 25 °C
Yield: 47 %

Procedure:
To a solution of 1-{[4-(7-methoxy-2-phenyl-quinolin-4-yloxy)-pyrrolidine-2-carbonyl]-amino}-2-vinyl-cyclopropanecarboxylic acid ethyl ester (600 mg, 1.115 mmol) in CH3CN (20 mL) was 2-methoxycarbonylamino-3,3-dimethyl-butyric acid (317 mg, 1.673 mmol), DIEA (0.97 mL, 5.575 mmol) and the coupling reagent HOBt (256 mg, 1.673 nunol) and HBTU (634 g, 1.673 mmol). The solution was stirred at rt. overnight. Then it was concentrated, washed with water and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over MgSO4 and concentrated to give yellowish oil. It was then purified by Prep. HPLC column to give a yellowish oil as product. (410 mg, 47% yield).1H NMR (400 MHz, CD3OD) δ1.03 (s, 9H), 1.22 (t, J=7.09 Hz, 3H), 1.41 (dd, J=9.41, 5.26 Hz, 1H), 1.71 (dd, J=8.19, 5.26 Hz, 1H), 2.17 (m, 1H), 2.50 (m, 1H), 2.77 (m, 1H), 3.33 (s, 3H), 4.03 (s, 3H), 4.04–4.14 (m, 3H), 4.18 (s, 1H), 4.61–4.69 (m, 2H), 4.86 (m, 1H), 5.08 (dd, J=10.27, 1.71 Hz, 1H), 5.25 (d, J=17.11 Hz, 1H), 5.72–5.82 (m, 2H), 7.39 (dd, J=9.29, 2.20 Hz, 1H), 7.51 (m, 1H), 7.63 (m, 1H), 7.69–7.77 (m, 3H), 8.06 (m, 2H), 8.35 (d, J=9.29 Hz, 1H), 8.75 (s, 1H). LC-MS (retention time: 2.857 min.), MS m/z 673 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[CH:4]=[N:5][OH:6].[Cl:12]N1C(=O)CCC1=O>CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](=[N:5][OH:6])[Cl:12]
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=Cc1c(F)cccc1F
Solvent: CN(C)C=O
Product: ON=C(Cl)c1c(F)cccc1F
Yield: 64.9 %

Procedure:
In a fashion similar to that for preparation 14, 2,6-difluorobenzaldehyde oxime (2.00 g, 12.7 mmol), N-chlorosuccinimide (1.75 g, 13.2 mmol), and DMF (20 ml) gave 2,6-difluorobenzoylchloride oxime (1.58 g, 65%) after column chromatography (silica gel, hexanes/diethyl ether gradient).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C(O)C.[Na]>O>[NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][CH2:9][CH2:8][CH2:7]2
Reactant: Nc1cccc2cccnc12
Agent: [Na]
Solvent: CCO
Solvent: O
Product: Nc1cccc2c1NCCC2
Yield: 52.4 %

Procedure:
To a solution of 20.00 g of 8-aminoquinoline in boiling absolute ethanol (400 ml) was added 44.74 g of sodium pellets over 20 mins, with stirring, until the sodium is dissolved. The reaction mixture was poured into water (50 ml) and concentrated. The residue was diluted with sodium bicarbonate solution and the mixture was extracted with dichloromethane. The extracts were dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated. The residue was distilled under vacuum to give 10.77 g (52.3%) of product.
Reaction SMILES: [NH2:1][C@H:2]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1)[C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([CH3:15])([CH3:14])[O:12][B:11]([OH:16])[C:10]=2[CH:17]=1)=[O:4].[NH:30]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C@H:31]([C:44](O)=[O:45])[CH2:32][CH2:33][C:34](=[O:43])[O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:50]([O:49][C:47]([NH:30][C@H:31]([C:44]([NH:1][C@H:2]([CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:24][CH:25]=1)[C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([CH3:15])([CH3:14])[O:12][B:11]([OH:16])[C:10]=2[CH:17]=1)=[O:4])=[O:45])[CH2:32][CH2:33][C:34]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:43])=[O:48])([CH3:53])([CH3:52])[CH3:51]
Reactant: CC1(C)OB(O)c2cc(NC(=O)[C@H](N)CCc3ccc(C(F)(F)F)cc3)ccc21
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
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: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)N[C@H](CCc1ccc(C(F)(F)F)cc1)C(=O)Nc1ccc2c(c1)B(O)OC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
To a suspension of (R)-2-amino-N-(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-(4-(trifluoromethyl)phenyl)butanamide (CLXIX) (1.2 g, 2.71 mmol) and Boc-Glu(OBzl)-OH (CLXX) (0.915 g, 2.71 mmol) in DCM (10 mL) was added DIPEA (1.39 mL, 8.13 mmol). To this solution was added HATU (1.03 g, 2.71 mmol) and the mixture was stirred at room temperature overnight. The mixture was washed with 2 N aqueous HCl, 1 M aqueous K2CO3, brine and dried over MgSO4. The solution was evaporated to dryness under vacuum to give (S)-benzyl 4-(tert-butoxycarbonylamino)-5-((R)-1-(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-ylamino)-1-oxo-4-(4-(trifluoromethyl)phenyl)butan-2-ylamino)-5-oxopentanoate as an orange foam (1.83 g, 2.52 mmol, 93% yield). 1H NMR (DMSO-d6) δ ppm 1.33 (s, 9H), 1.4 (s, 6H), 1.8-1.88 (m, 1H), 1.9-1.96 (m, 2H), 2.08 (brs, 1H), 2.42 (brs, 2H), 2.6-2.66 (m, 1H), 2.7-2.76 (m, 1H), 3.98-4.05 (m, 1H), 4.4 (brs, 1H), 5.07 (s, 2H), 7.1 (brs, 1H), 7.28-7.34 (m, 6H), 7.37-7.44 (m, 2H), 7.55-7.63 (m, 3H), 7.89 (s, 1H), 8.34 (brs, 1H), 9.0 (s, 1H), 9.86 (s, 1H); 19F NMR (DMSO-d6) δ ppm −60.11 (s, 3F); ESIMS found for C37H43BF3N3O8 m/z 726.7 (M+H).
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]([NH2:13])=[S:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:14][CH2:15][C:16](=O)[CH2:17]Cl>C(O)C>[C:1]([O:9][CH2:10][C:11]1[S:12][CH:17]=[C:16]([CH2:15][Cl:14])[N:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=S)COC(=O)c1ccccc1
Solvent: CCO
Product: O=C(OCc1nc(CCl)cs1)c1ccccc1
Yield: 70 %

Procedure:
A mixture of 2-amino-2-thioxoethyl benzoate (7.6 g), 1,3-dichloro-2-propanone (7.6 g) and ethanol (100 mL) was heated under reflux for 4 hrs. The solvent was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:5, v/v) to give (4-chloromethyl-1,3-thiazol-2-yl)methyl benzoate as a brown oil (7.3 g, yield 45%).
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][C@H:11]1[CH2:15][CH2:14][NH:13][C:12]1=[O:16])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1>C1COCC1>[Si:3]([O:10][C@H:11]1[CH2:15][CH2:14][N:13]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[C:12]1=[O:16])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: Clc1ccc(CBr)cc1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCN(Cc2ccc(Cl)cc2)C1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 47.1 %

Procedure:
A 60% dispersion of sodium hydride in mineral oil (0.608 g, 13.9 mmol) was added to a stirred solution of (S)-3-((tert-butyldimethylsilyl)oxy)pyrrolidin-2-one (2.0 g, 9.29 mmol, from example 114, step A) in THF (7 mL) at 0° C. After 15 min, a solution of 1-(bromomethyl)-4-chlorobenzene (1.72 g, 8.37 mmol) in THF (7 mL) was added to the reaction mixture. The resulting mixture was stirred at RT for 6 h. The reaction was quenched with pellets of ice. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The crude reaction mixture was purified using silica gel column chromatography (0-15% EtOAc/hexanes) to afford (S)-3-((tert-butyldimethylsilyl)oxy)-1-(4-chlorobenzyl)pyrrolidin-2-one (1.34 g, 42% yield): LCMS (M+H)+ 340.2; 1H NMR (500 MHz, chloroform-d) δ 1H NMR (500 MHz, chloroform-d) δ 7.36-7.29 (m, J=8.4 Hz, 2H), 7.23-7.16 (m, J=8.4 Hz, 2H), 4.51-4.33 (m, 3H), 3.31-3.22 (m, 1H), 3.11 (dt, J=9.7, 7.4 Hz, 1H), 2.37-2.25 (m, 1H), 1.97-1.84 (m, 1H), 0.95 (s, 9H), 0.21 (s, 3H), 0.18 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][CH2:10][CH2:11][N:12]1[CH2:18][C@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:16][CH2:15][C@@H:14]([NH:25]C(=O)OC(C)(C)C)[C:13]1=[O:33]>ClCCl>[NH2:25][CH:14]1[CH2:15][CH2:16][CH:17]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:18][N:12]([CH2:11][CH2:10][O:9][CH3:8])[C:13]1=[O:33]
Reactant: COCCN1C[C@H](c2ccccc2)CC[C@@H](NC(=O)OC(C)(C)C)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCN1CC(c2ccccc2)CCC(N)C1=O
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (2.5 mL) was added to a solution of tert-butyl (3R,6S)-1-(2-methoxyethyl)-2-oxo-6-phenylazepan-3-ylcarbamate (41 mg, 0.113 mmol) in dichloromethane (5 mL). After 1 h, the solution was concentrated. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. MS 263 (M+1). 1H NMR (500 MHz, CDCl3) δ 7.32 (t, J=7.3 Hz, 2H), 7.25-7.22 (m, 1H), 7.18 (d, J=8.3 Hz, 2H), 3.83-3.76 (m, 3H), 3.56-3.49 (m, 3H), 3.35 (s, 3H), 3.34-3.30 (m, 1H), 2.77-2.72 (m, 1H), 2.13-2.10 (m, 1H), 2.03-1.94 (m, 2H), 1.74-1.68 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:11])=[N:7][NH:8]2)=[CH:4][C:3]=1[CH:12]=O.[C:14](/[CH:16]=[C:17](\[O-:19])/[CH3:18])#[N:15].[Na+]>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:11])=[N:7][NH:8]2)=[CH:4][C:3]=1/[CH:12]=[C:16](/[C:17](=[O:19])[CH3:18])\[C:14]#[N:15]
Reactant: Cc1n[nH]c2cc(F)c(C=O)cc12
Reactant: C/C([O-])=C/C#N
Agent: [Na+]
Product: CC(=O)/C(C#N)=C/c1cc2c(C)n[nH]c2cc1F

Procedure:
Following the procedure described for Example 2A, the title compound was prepared using 2.74 g (15.5 mmol) 6-fluoro-3-methyl-1H-indazole-5-carbaldehyde (Example 17A) and 2.6 g (24.8 mmol) sodium (1Z)-1-cyanoprop-1-en-2-olate to yield 1.6 g (42% of th.) of the crude product which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.CN(C)C=O.[H-].[Na+].Cl[CH2:20][CH2:21][CH2:22][N:23]1[C:31]2[C:26](=[CH:27][C:28]([N+:32]([O-:34])=[O:33])=[CH:29][CH:30]=2)[CH:25]=[CH:24]1>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:20][CH2:21][CH2:22][N:23]1[C:31]3[C:26](=[CH:27][C:28]([N+:32]([O-:34])=[O:33])=[CH:29][CH:30]=3)[CH:25]=[CH:24]1)[CH:7]=[CH:6]2
Reactant: COc1ccc2[nH]ccc2c1
Reactant: O=[N+]([O-])c1ccc2c(ccn2CCCCl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(ccn2CCCn2ccc3cc([N+](=O)[O-])ccc32)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To 926 mg of 5-methoxyindole was added 30 ml of dimethylformamide and 230 mg of sodium hydride (in oil), this mixture was stirred under nitrogen gas stream at 60° C. for 1 hour. Then 1.5 g of 1-(3-chloropropyl)-5-nitroindole was added to the reaction mixture and stirred at room temperature overnight. The reaction mixture was further stirred at 60° C. for 5.5 hours, then water was added thereto, and the crystals being separated were collected by filtration, and washed with water. The washed crystals were subjected to a silica gel column chromatography (eluent: dichloromethane), there was obtained 1.8 g of 1-[3-(5-methoxyindol-1-yl)propyl]-5-nitroindole as in the form of yellow powdery product.