Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH:21]([C:30](=[N:43][O:44]C)[C:31]#[C:32][CH:33]1[CH2:36][CH:35]([CH2:37][CH:38]([CH2:41][CH3:42])[CH2:39][CH3:40])[CH2:34]1)[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(#N)C.[I:49]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)(=O)C>[Si:1]([O:18][CH2:19][CH2:20][CH:21]([C:30]1[C:31]([I:49])=[C:32]([CH:33]2[CH2:36][CH:35]([CH2:37][CH:38]([CH2:41][CH3:42])[CH2:39][CH3:40])[CH2:34]2)[O:44][N:43]=1)[CH2:22][C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: II
Reactant: CCC(CC)CC1CC(C#CC(=NOC)C(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC(=O)OC(C)(C)C)C1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCC(CC)CC1CC(c2onc(C(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC(=O)OC(C)(C)C)c2I)C1
Reaction time: 4.5 h
Yield: 80.4 %

Procedure:
tert-Butyl 3-[2-(tert-butyldiphenylsilanyloxy)ethyl]-6-[3-(2-ethylbutyl)cyclobutyl]-4-methoxyimino-5-hexynoate (7.50 g) and acetonitrile (60 mL) were mixed. To the mixture was added iodine (7.54 g) was added at ice temperature. The mixture was stirred for 4.5 hr, and then to the mixture were added aqueous 5 w/v % sodium thiosulfate (50 mL), ethyl acetate (200 mL) and aqueous 5 w/v % sodium thiosulfate (75 mL, 150 mL) at ice temperature. The aqueous layer was removed, and the organic layer was washed with saturated aqueous sodium bicarbonate/brine=1/1 (100 mL) and brine (50 mL), then dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated in vacuo. The resultant residue was purified twice by silica gel column chromatography (Eluent: ethyl acetate/hexane=1/50→1/40→1/20) to give the title compound (7.1 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17][CH2:16]3)[C:5]([Cl:28])=[CH:4][N:3]=1.[H-].[Na+].I[CH3:32]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:32])[CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17][CH2:16]3)[C:5]([Cl:28])=[CH:4][N:3]=1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCNc3nc(Cl)ncc3Cl)ccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCN(C)c3nc(Cl)ncc3Cl)ccc21
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a solution of Example 441 (520 mg, 1.23 mmol) in DMF (15 mL) at 0° C. was added portionwise NaH (95 mg, 2.45 mmol, 60% dispersion in mineral oil) [H2 evolution]. The heterogeneous mixture was stirred for 30 min, then iodomethane (0.31 mL, 4.90 mmol) was added. After 18 h of agitation at rt, the excess NaH was quenched by the slow addition of NH4Cl (10% solution in water) [H2 evolution]. The resulting mixture was concentrated under reduced pressure, brought to basic pH using a saturated solution of NaHCO3, and the product was extracted with EtOAc. The combined organic layers were washed with water and brine, after which they were dried (Na2SO4), filtered, and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (4:1 hexanes/EtOAc) to yield the product (442 mg, 82%). 1H NMR (400 MHz, CDCl3): δ 1.30 (t, 3H), 1.75-1.82 (m, 1H), 2.12-2.20 (m, 2H), 2.30-2.45 (m, 2H), 2.70 (dd, 1H), 2.72-2.90 (m, 2H), 3.30 (s, 3H), 3.44-3.54 (m, 1H), 3.84 (t, 2H), 3.95 (t, 2H), 4.16 (q, 2H), 6.65 (d, 1H), 6.75 (s, 1H), 7.05 (d, 1H), 8.15 (s, 1H).
Reaction SMILES: [C:1]1([CH:7]([CH3:10])C=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.N[OH:13].[N:14]1[CH:19]=CC=CC=1>CCO>[C:1]1([CH2:7][CH2:10][CH:19]=[N:14][OH:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NO
Reactant: c1ccncc1
Reactant: CC(C=O)c1ccccc1
Agent: Cl
Solvent: CCO
Product: ON=CCCc1ccccc1
Reaction time: 4 h
Yield: 24 %

Procedure:
Phenylpropionaldehyde (3.35 g, 3.3 ml, 25 mmol) was dissolved in EtOH (90 ml) and mixed successively with hydroxylamine hydrochloride (2.6 g, 37.5 mmol) and abs. pyridine (2.42 ml, 30 mmol) while stirring. After stirring for 4 h, the solvent was removed under vacuum, the residue taken up in toluene (1×50 ml) and the solvent removed again under vacuum. The oily residue was stirred with EtOAc (50 ml) and water (30 ml) for 15 min. Subsequently, the phases were separated. The organic phase was washed with water (2×20 ml), dried and concentrated. The oil obtained (4.71 g) was highly contaminated and crystallised only in part. The oil was dissolved in n-hexane (20 ml) and stored for 18 h at 5° C. The precipitated plates were removed by suction-filtration. Compound Z was obtained as a white solid in a yield of 24% (892 mg) having a melting point of 85-93° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]3[CH:29]=[CH:28][C:27]([C:30]4[CH:31]=[C:32]([CH:42]=[CH:43][CH:44]=4)[C:33]([NH:35][C:36]([CH3:41])([CH3:40])[C:37]([OH:39])=O)=[O:34])=[CH:26][C:20]=3[C:21]=2[C:22](=[O:25])[NH:23][CH3:24])=[CH:13][CH:12]=1.[CH3:45][C:46]1[O:50][N:49]=[C:48]([NH2:51])[CH:47]=1.[H-].[Na+]>CN(C=O)C.CO>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[O:18][C:19]3[CH:29]=[CH:28][C:27]([C:30]4[CH:44]=[CH:43][CH:42]=[C:32]([C:33](=[O:34])[NH:35][C:36]([CH3:40])([CH3:41])[C:37]([NH:51][C:48]5[CH:47]=[C:46]([CH3:45])[O:50][N:49]=5)=[O:39])[CH:31]=4)=[CH:26][C:20]=3[C:21]=2[C:22]([NH:23][CH3:24])=[O:25])=[CH:15][CH:16]=1
Reactant: Cc1cc(N)no1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NC(C)(C)C(=O)O)c3)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NC(C)(C)C(=O)Nc4cc(C)on4)c3)cc12
Reaction time: 0.5 h
Yield: 9.5 %

Procedure:
DIEA (28 μL, 0.158 mmol) was added to a stirring solution of 2-(3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzamido)-2-methylpropanoic acid (25 mg, 0.053 mmol), 5-methylisoxazol-3-amine (11 mg, 0.105 mmol) in DMF (527 μL) at rt. It was allowed to stir for 30 min. NaH (11 mg, 0.263 mmol) was added and the reaction was allowed to stir overnight. The mixture was treated with a drop of MeOH and was purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (2.8 mg, 9%). 1H NMR (500 MHz, CD3OD) δ ppm 8.17-8.25 (1 H, m), 7.92-8.00 (3 H, m), 7.83-7.91 (2 H, m), 7.66-7.76 (2 H, m), 7.58 (1 H, t, J=7.78 Hz), 7.27 (2 H, t, J=8.85 Hz), 6.63 (1 H, s), 2.98 (3 H, s), 2.39 (3 H, s), 1.65 (6 H, s). LC-MS retention time: 1.69 min; m/z (MH+): 555. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10 u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 mm, Rt=12.20 min, purity=95%; Column: Waters Xbridge Phenyl column 4 6×150 mm, 3.5 mm, Rt=11.30 min, purity=90%.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[C:14]([F:20])[CH:13]=2)=[CH:8][CH:7]=1.[CH3:21][N:22]([CH3:28])[C@@H:23]1[CH2:27][CH2:26][NH:25][CH2:24]1>>[CH3:21][N:22]([CH3:28])[C@@H:23]1[CH2:27][CH2:26][N:25]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[C:14]([F:20])[CH:13]=3)=[CH:8][CH:7]=2)[CH2:24]1
Reactant: CN(C)[C@@H]1CCNC1
Reactant: N#Cc1ccc(-c2ccc(OCCCCl)cc2)cc1F
Product: CN(C)[C@@H]1CCN(CCCOc2ccc(-c3ccc(C#N)c(F)c3)cc2)C1
Yield: 63 %

Procedure:
The product from Example 166C and (3R)-N,N-dimethyl-3-pyrrolidinamine were processed as described in Example 164D to provide the title compound (63% yield). 1HNMR (300 MHz, CDCl3) δ1.68 (m, 2H), 2.15 (m 4H), 2.23 (s, 6H), 2.30-2.95 (m, 5H), 4.15 (m, 2H), 7.00-7.63 (m, 7H); MS (ESI) m/z 368 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:12]1([CH:18]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[CH2:19][NH2:20])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[C:21]1[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=1)=[O:6]
Reactant: NCC(c1ccncc1)N1CCOCC1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: O=C(NCC(c1ccncc1)N1CCOCC1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and (2-morpholin-4-yl-2-pyridin-4-ylethyl)amine.
Reaction SMILES: [OH-].[K+].[C:3]1([CH2:9][C:10]#[N:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([O-:14])=O.C(O)(=O)C>CO.O>[OH:14][N:12]=[C:15]1[CH:20]=[CH:19][C:18](=[C:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:10]#[N:11])[CH:17]=[CH:16]1
Reactant: O=[N+]([O-])c1ccccc1
Reactant: N#CCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: N#CC(=C1C=CC(=NO)C=C1)c1ccccc1
Temperature: 55 °C
Reaction time: 4 h
Yield: 76.7 %

Procedure:
60 g of KOH are dissolved in 300 ml of methanol and heated up to 55° C. To the solution are added 32.2 g (0.27 mol) of phenylacetonitrile followed by 30.8 g (0.25 mol) of nitrobenzene. The reaction mixture is stirred at 55° C. for 4 hrs. After cooling, 400 ml of water are added with stirring. The resulting solution is acidified by addition of 110 ml of acetic acid in 100 ml of water, leading to a yellow-orange precipitate. The mixture is then filtered, and the yellow solid is washed with a mixture of methanol and water. The crude product is dried in air, boiled with 150 ml of benzene for 15 min., cooled, filtered and dried under vacuum. 42.6 g (77%) of (4-Hydroxyimino-cyclohexa-2,5-dienylidene)-phenyl-acetonitrile are obtained in the form of a yellow solid having a melting point of 159-163° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[C:21]([CH3:24])[S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[N:28]1([CH2:33][C:34]2[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=2)[CH:32]=[CH:31][CH:30]=[N:29]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)Cl.N.CN(C=O)C>[N:28]1([CH2:33][C:34]2[CH:41]=[CH:40][C:37]([C:38]3[NH:8][C:5]4=[N:6][CH:7]=[C:2]([Br:1])[C:3]([N:12]5[CH2:17][CH2:16][N:15]([CH2:18][C:19]6[N:20]=[C:21]([CH3:24])[S:22][CH:23]=6)[CH2:14][CH2:13]5)=[C:4]4[N:9]=3)=[CH:36][CH:35]=2)[CH:32]=[CH:31][CH:30]=[N:29]1
Reactant: O=Cc1ccc(Cn2cccn2)cc1
Reactant: Cc1nc(CN2CCN(c3c(Br)cnc(N)c3[N+](=O)[O-])CC2)cs1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: ClCCl
Product: Cc1nc(CN2CCN(c3c(Br)cnc4[nH]c(-c5ccc(Cn6cccn6)cc5)nc34)CC2)cs1
Temperature: 85 °C

Procedure:
To a mixture of 5-bromo-4-(4-((2-methylthiazol-4-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.050 g, 0.12 mmol), EtOH (2.3 mL) and DMF (0.2 mL), 4-(1H-pyrazol-1-ylmethyl)-benzaldehyde (0.025 g, 0.13 mmol) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.36 mL, 0.36 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 96:4). The title compound was obtained after trituration with ether as a white solid (0.033 g, 49%); 1H-NMR (500 Mz, DMSO-d6): δ 2.62-2.70 (m, 7H), 3.64 (s, 2H, NCH2), 3.65-3.70 (m, 4H), 5.42 (s, 2H, NCH2), 6.30 (t, J=2.5 Hz, 1H), 7.32 (s, 1H, thiazole 5-H), 7.34 (d, J=8.0 Hz, 1H), 7.48-7.51 (m, 1H), 7.86 (d, J=2.0 Hz, 1H), 8.13 (d, J=8.0 Hz, 2H), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.49 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z) 3.17 min—549/551 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 549.1176, calculated for C25H26N8SBr (M+H)+: 549.1185.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([CH3:14])([CH3:13])[C:10](Cl)=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:15]([N:22]1[CH2:26][C@@H:25]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[C@H:24]([NH:34][CH3:35])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:15]([N:22]1[CH2:26][C@@H:25]([C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)[C@H:24]([N:34]([CH3:35])[C:10](=[O:11])[C:9]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)([CH3:14])[CH3:13])[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CN[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(F)cc1
Reactant: CC(C)(C(=O)Cl)c1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)C(C)(C)c1cc(Cl)cc(Cl)c1)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(F)cc1
Reaction time: 2 h
Yield: 68 %

Procedure:
A solution of 2-(3,5-dichloro-phenyl)-2-methyl-propionyl chloride (the preparation of which is described in WO2005002577) (0.146 g, 0.58 mmol) in CH2Cl2 (4 ml) was added drop wise to a stirred solution of rac-[(3S,4R)-1-benzyl-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-methyl-amine (the preparation of which is described herein above) (0.15 g, 0.52 mmol) and ethyl-diisopropyl-amine (0.13 ml, 0.79 mmol) in CH2Cl2 (5 ml). The reaction mixture was stirred 2 h, concentrated under vacuo and purification by flash chromatography (SiO2, EtOAc/H, 1:4) yielded 0.18 g (68%) of the title product as light brown oil.
Reaction SMILES: C(O)(C)(C)C.[C:6]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C@H:19]([CH3:20])[CH2:18][N:17]([C:21]([NH:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26](C(O)=O)[CH:25]=3)=[O:22])[C@@H:16]([CH3:33])[CH2:15]2)=[CH:10][C:9]=1[C:34]([F:37])([F:36])[F:35])#[N:7].C1C=CC(P([N:52]=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1>C(N(CC)CC)C>[NH2:52][C:26]1[CH:25]=[C:24]([NH:23][C:21]([N:17]2[CH2:18][C@@H:19]([CH3:20])[N:14]([C:11]3[CH:12]=[CH:13][C:8]([C:6]#[N:7])=[C:9]([C:34]([F:35])([F:37])[F:36])[CH:10]=3)[CH2:15][C@@H:16]2[CH3:33])=[O:22])[CH:29]=[CH:28][N:27]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: C[C@@H]1CN(C(=O)Nc2ccnc(C(=O)O)c2)[C@@H](C)CN1c1ccc(C#N)c(C(F)(F)F)c1
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(C(=O)Nc2ccnc(N)c2)[C@@H](C)CN1c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 50 ml portion of t-butanol solution containing 1.38 g of (+/−)-trans-4-{[4-(4-cyano-3-trifluoromethylphenyl)-2,5-dimethylpiperazine-1-carbonyl]amino}pyridine-2-carboxylic acid synthesized in the same manner as described in Example 12-1, 1.5 ml of DPPA and 1.5 ml of triethylamine was heated under reflux for 8 hours, and then the solvent was evaporated under reduced pressure. This was mixed with 30 ml of trifluoroacetic acid and stirred at room temperature for 1 hour, the solvent was evaporated under reduced pressure, and then the resulting residue was alkalified with saturated sodium bicarbonate solution. Next, this was extracted with ethyl acetate, the organic layer was washed with purified water and then with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by a silica gel column chromatography to obtain 0.94 g of the title compound from chloroform-methanol (10:1, v/v) eluate. Thereafter, this was crystallized from ethyl acetate-hexane to obtain 0.72 g of the title compound as white crystals.
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:10][C:9](=[O:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19]/[C:20](=[CH:24]\[CH2:25][CH3:26])/[C:21]([OH:23])=O.[CH3:27]COC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1.[Li+].[Cl-]>CCOC(C)=O>[CH3:19]/[C:20](=[CH:24]\[CH2:25][CH2:26][CH3:27])/[C:21]([N:8]1[C@@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@@H:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:10][C:9]1=[O:18])=[O:23]
Reactant: CC/C=C(\C)C(=O)O
Reactant: O=C1N[C@@H](c2ccccc2)[C@@H](c2ccccc2)O1
Reactant: CCOC(=O)N1c2ccccc2C=CC1OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Product: CCC/C=C(\C)C(=O)N1C(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Temperature: 65 °C
Reaction time: 3.33 h
Yield: 94.7 %

Procedure:
A 20 L jacketed reactor was fitted with a reflux condenser. To the reactor was charged 1100 g (4.597 mol) of (4S,5R)-4,5-diphenyl-oxazolidin-2-one, 884 g (6.896 mol) (E)-2-methyl-2-pentenoic acid, 1705 g (6.896 mol) of EEDQ, 48 g (1.149 mol) of LiCl and 16 L of EtOAc. The reaction mixture was heated to 65° C. and was held for 200 minutes. The reaction mixture was cooled to room temperature and was extracted 3× with 3.5 L aliquots of 1N HCl. The combined aqueous extracts were filtered to give a white solid. The recovered white solid was added back to the organic layer. The 20 L reactor was fitted with a distillation head and the organic layer was distilled to remove in succession: 13.5 L of EtOAc, after which 5 L of heptane was added to the reactor; 5 L of EtOAc/heptane, after which 5 L of heptane was added to the reactor; and 2.7 L of EtOAc/heptane, after which 2.7L of heptane was added to the reactor. The contents of the reactor were cooled to 25° C. and the resulting mixture was filtered under 5 psig nitrogen while washing with 4 L of heptane. The wet cake was dried under nitrogen pressure overnight to give 1521 g of the titled compound: 1H NMR (DMSO) 7.12-6.94 (m, 8H), 6.834 (dd, 2H, J=7.813, 1.709), 6.060 (d, 1H, J=8.057), 6.050 (td, 1H, J=7.447, 1.221), 5.795 (d, 1H, J=8.057), 2.119-2.064 (m, 2H), 1.778 (d, 3H, J=0.997), 1.394 (m, 2H), 0.874 (t, 3H, J=7.324); Anal Calc'd for C22H23N1O3: C, 75.62; H, 6.63; N, 4.01. Found: C, 75.26; H, 6.72; N, 3.95.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17](O)=[O:18])[CH:15]=3)[N:10]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.Cl.[CH2:40]([NH:47][C:48]1([CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[F:62])[CH2:53][CH2:52][CH2:51][CH:50]([NH2:54])[CH2:49]1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.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>CC(N(C)C)=O>[CH2:40]([NH:47][C:48]1([CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[F:62])[CH2:53][CH2:52][CH2:51][CH:50]([NH:54][C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]([C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:9]=[C:8]3[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)=[O:18])[CH2:49]1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)O)cc23)ccn1
Reactant: NC1CCCC(Cc2ccccc2F)(NCc2ccccc2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)NC4CCCC(Cc5ccccc5F)(NCc5ccccc5)C4)cc23)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction mixture of 3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxylic acid (0.15 mmol, 75 mg), HCl salt of N1-benzyl-1-(2-fluorobenzyl)cyclohexane-1,3-diamine (0.15 mmol, 52 mg), HATU (0.15 mmol, 57 mg) and DIEA (0.1 mL) in DMA (0.5 mL) was stirred at room temperature for overnight. The product, N-(3-(benzylamino)-3-(2-fluorobenzyl)cyclohexyl)-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxamide, was purified by column chromatography on silica gel.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=1)[C:10]1[CH:9]=[N:8][C:7]([C:23](OCC)=[O:24])=[CH:6][C:5]2=1.[OH-:28].[Na+].[NH2:30]O>CO.O>[NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=1)[C:10]1[CH:9]=[N:8][C:7]([C:23]([NH:30][OH:28])=[O:24])=[CH:6][C:5]2=1
Reactant: [OH-]
Reactant: CCOC(=O)c1cc2c3cc(N)ccc3n(Cc3cccc(Cl)c3)c2cn1
Reactant: NO
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1ccc2c(c1)c1cc(C(=O)NO)ncc1n2Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 168 h
Yield: 27 %

Procedure:
To a stirred solution of ethyl 6-amino-9-(3-chlorobenzyl)-9H-β-carboline-3-carboxylate (139 mg, 0.37 mmol) in methanol (15 mL) under a nitrogen atmosphere were added NaOH (2N, 0.7 mL) and H2NOH (15 mL, 50 wt. % solution in H2O, 0.23 mol). The suspension was stirred for 7 days at ambient temperature and then diluted with H2O (10 mL). The mixture was filtered, and the solid was boiled in methanol (20 mL). After filtration, the title compound (36 mg, 27%) was obtained. 1H NMR (400 MHz, DMSO-d6): δ 11.17 (1H, s), 8.90–8.95 (2H, m), 8.55 (1H, s), 6.96–7.51 (7H, m), 5.72 (2H, s), 5.03 (2H, br, s). HRMS (M+H)+ found: 367.0961. Calcd for C19H16ClN4O2: 367.0962.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.CN(C)C=O.C1([O:16][C:17](=O)[NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[C:35]4[C:30](=[CH:31][C:32]([O:38][CH2:39][C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)=[C:33]([C:36]#[N:37])[CH:34]=4)[N:29]=[CH:28][CH:27]=3)=[C:21]([CH3:46])[C:20]=2[CH3:47])C=CC=CC=1.O>C(OCC)(=O)C>[CH2:39]([O:38][C:32]1[CH:31]=[C:30]2[C:35]([C:26]([O:25][C:22]3[CH:23]=[CH:24][C:19]([NH:18][C:17]([NH:4][CH:1]4[CH2:3][CH2:2]4)=[O:16])=[C:20]([CH3:47])[C:21]=3[CH3:46])=[CH:27][CH:28]=[N:29]2)=[CH:34][C:33]=1[C:36]#[N:37])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: Cc1c(NC(=O)Oc2ccccc2)ccc(Oc2ccnc3cc(OCc4ccccc4)c(C#N)cc23)c1C
Reactant: NC1CC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(NC(=O)NC2CC2)ccc(Oc2ccnc3cc(OCc4ccccc4)c(C#N)cc23)c1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Cyclopropylamine (1 ml) was added to dimethylformamide (10 ml), and then (4-(7-benzyloxy-6-cyano-quinolin-4-yloxy)-2,3-dimethylphenyl)carbamic acid phenyl ester (1.99 g) was added thereto and the mixture was stirred at room temperature for 10 minutes. Water (30 ml) and ethyl acetate (30 ml) were added, and the precipitated crystals were filtered out and washed with ethyl acetate to obtain the title compound (1660 mg).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CCN(CC)CC.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccccc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
To a solution of 4-fluoro-3-nitroaniline (2.00 g, 12.8 mmol) and Et3N (1.98 mL, 14.1 mmol) in THF (40 mL) was added benzoyl chloride (1.58 ml, 13.5 mmol) dropwise at 5° C. The mixture was stirred at 5° C. for 1 hour, warmed to room temperature, and then evaporated. The residue was suspended in H2O (100 ml), adjusted to pH 2, and then extracted with EtOAc. The extract was washed with H2O, 10% NaHCO3 and brine, dried over MgSO4, and concentrated under vacuum to give the crude product, which was purified by washing with i-Pr2O to give the title compound as pale brown crystal (2.70 g, 81%).