Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.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.[N+:52]([C:55]1[CH:56]=[C:57]([C:61]2[N:62]=[C:63]([NH2:66])[S:64][CH:65]=2)[CH:58]=[CH:59][CH:60]=1)([O-:54])=[O:53]>CN(C=O)C>[CH2:12]([O:11][C:9]([N:1]1[CH2:8][CH2:7][CH2:6][CH:2]1[C:3](=[O:5])[NH:66][C:63]1[S:64][CH:65]=[C:61]([C:57]2[CH:58]=[CH:59][CH:60]=[C:55]([N+:52]([O-:54])=[O:53])[CH:56]=2)[N:62]=1)=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
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: CN(C)C=O
Product: O=C(Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1)C1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Z-Pro-OH (1.5 g, 6.15 mmol) and HATU (2.3 g, 6.15 mmol) were combined in 30 mL of dry DMF. To this solution was added DIEA (1.5 mL, 8.8 mmol). This solution was stirred at room temperature for 1 hour. To this solution was added 4-(3-nitro-phenyl)-thiazol-2-ylamine (0.9, 4.1 mmol). Reaction mixture was stirred at room temperature overnight. The crude material was purified using reverse phase HPLC to yield 2-[4-(3-Nitro-phenyl)-thiazol-2-ylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester. MS: 453.1 (M+H+).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:17]1[O:18][C:19]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:20]=2[N:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(C(C)=O)C.O>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)[C:17]1[O:18][C:19]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:20]=2[N:21]=1
Reactant: CNc1ccc(O)cc1
Reactant: Clc1ccc2oc(Cl)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCC(C)=O
Product: CN(c1ccc(O)cc1)c1nc2cc(Cl)ccc2o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of the sulfate salt of 4-(N-methylamino)phenol (0.008 mol, 2.76 g) in methyl ethyl ketone (25 ml) containing pure potassium carbonate (0.008 mol, 1.1 g) was warmed to reflux and a solution of 2,5-dichlorobenzoxazole (0.016 mol, 3.0 g) in methyl ethyl ketone (25 ml) was added dropwise over 2 hours. The resulting mixture was heated at reflux for a further hour, stood overnight, then stirred at room temperature for a further 8 hours. The solvent was then evaporated leaving a white solid. This was treated with a mixture of water (25 ml) and saturated aqueous sodium carbonate solution (25 ml). The solid was collected, washed with water, dried by suction and recrystallised three times from boiling toluene. Yield 1.4 g, mp 216°-217° C.; ir and pmr spectra and analysis consistent with assigned structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:32][CH2:31][C:14]2([C:18](=[O:19])[N:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][OH:30])=[NH:28])=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:10])=[O:9].[C:33](OC(=O)C)(=O)[CH3:34]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:12][CH2:13][C:14]2([C:18](=[O:19])[N:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]4[N:28]=[C:33]([CH3:34])[O:30][N:29]=4)=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)[CH2:31][CH2:32]1)(=[O:10])=[O:9]
Reactant: N=C(Cc1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4Cl)CC3)C2=O)cc1)NO
Reactant: CC(=O)OC(C)=O
Product: Cc1nc(Cc2ccc(N3CCC4(CCN(S(=O)(=O)c5ccccc5Cl)CC4)C3=O)cc2)no1

Procedure:
Above 2-{4-[8-(2-chloro-benzenesulfonyl)-1-oxo-2,8-diaza-spiro[4.5]dec-2-yl]-phenyl}-N-hydroxy-acetamidine (150 mg) were treated at RT with acetic anhydride (40 ml) and then refluxed for 30 minutes. The reaction mixture was concentrated in vacuo, the residue purified by chromatography on silica gel to give the desired 8-(2-chloro-benzenesulfonyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-ylmethyl)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one as a light yellow crystalline solid. MS (ESI): 502.1 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:15][CH3:16])=[N:5][C:6]2[N:7]([CH:10]=[C:11]([C:13]#[N:14])[N:12]=2)[C:8]=1[CH3:9])[CH3:2].Cl.[NH2:18][OH:19].[OH-].[K+]>C(O)C>[CH2:1]([C:3]1[C:4]([O:15][CH3:16])=[N:5][C:6]2[N:7]([CH:10]=[C:11]([C:13]([NH:18][OH:19])=[NH:14])[N:12]=2)[C:8]=1[CH3:9])[CH3:2]
Reactant: CCc1c(OC)nc2nc(C#N)cn2c1C
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCc1c(OC)nc2nc(C(=N)NO)cn2c1C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
A suspension of 8.0 g of 6-ethyl-7-methoxy-5-methylimidazo [1,2-a]pyrimidine-2-carbonitrile, 2.82 g of hydroxylamine hydrochloride and 2.28 g of potassium hydroxide in 100 ml of ethanol was refluxed with stirring for 2 hours and the mixture was cooled. The precipitated product was filtered, suspended in water with stirring for 15 minutes, filtered, then washed with water and ether and dried under vacuum to give 7.96 g of 6-ethyl-N-hydroxy-7-methoxy-5-methylimidazo[1,2-a]pyrimidine-2-carboxamidine (86% yield) melting at 249°-250° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][C:16]([CH3:28])([CH3:27])[CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23]>>[CH3:28][C:16]([NH:15][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])([CH3:27])[CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: CC(C)(N)CCNC(=O)OC(C)(C)C
Product: CC(C)(CCNC(=O)OC(C)(C)C)Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
This is prepared analogously to method 2a) from a total of 3.25 g (15.5 mmol) 1-fluoro-2-nitro-4-trifluoromethyl-benzene and 2.74 g (13.5 mmol) tert-butyl (3-amino-3-methyl-butyl)-carbamate. 6.1 g yellow oil. Mass spectroscopy: [M+H]+=392.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:13][N:12]=[C:11]([OH:14])[CH:10]=1.[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24]O)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24][O:14][C:11]1[CH:10]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[O:13][N:12]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: Oc1cc(-c2ccc(Cl)cc2Cl)on1
Product: CC(C)(C)OC(=O)NCCOc1cc(-c2ccc(Cl)cc2Cl)on1
Yield: 80.1 %

Procedure:
5-(2,4-Dichlorophenyl)-3-hydroxyisoxazole (0.2 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.17 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 9(a) to obtain the title compound (0.26 g, 81%) as a colorless powder.
Reaction SMILES: [CH:1]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=3)=[CH:15][CH:16]=2)[N:11]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:40](Cl)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(Cl)Cl>[CH:1]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[CH:20]=[C:21]([NH:25][C:40](=[O:47])[C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:16]=2)[N:11]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:33])[CH3:32])[N:10]=1)=[CH:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(Nc3cccc(N)c3)cc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(Nc3cccc(NC(=O)c4ccccc4)c3)cc21
Yield: 96.3 %

Procedure:
To a solution of N-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-benzene-1,3-diamine (91 mg, 0.2 mmol) and pyridine (0.081 mL, 1.0 mmol) in CH2Cl2 (0.5 mL) cooled to −5° C. under an atmosphere of argon was added benzoyl chloride (0.028 mL, 0.24 mmol). After 0.5 h the reaction was quenched with saturated NaHCO3(aq) then extracted 2×5 mL CH2Cl2. The pooled organic material was washed with brine (5 mL), dried with Na2SO4, decanted and concentrated under reduced pressure to give an oil. The crude material was purified by silica gel chromatography (eluting with hexane:EtOAc 3:2) to give N-(3-{3-Styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-ylamino}-phenyl)-benzamide (108 mg, 96% yield). Rf sm 0.35, Rf p 0.44 (ethyl acetate:hexane 1:1); FTIR (thin film) 3320, 2951, 2893, 1657, 1604, 1537, 1493, 1409, 1303, 1248, 1074 cm−1; LCMS (ESI) [M+H]/z Calc'd 561. Found 561. Anal. Calc'd: C, 72.82; H, 6.47; N, 9.99. Found: C, 72.33; H, 6.39; N, 9.81.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][CH:10]([OH:16])[CH2:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:17][C:18]([C:28]([F:31])([F:30])[F:29])=[CH:19][C@@H:20]1[C@H:22]([C:23](Cl)=[O:24])[C:21]1([CH3:27])[CH3:26].N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:17][C:18]([C:28]([F:29])([F:30])[F:31])=[CH:19][C@@H:20]1[C@H:22]([C:23]([O:16][CH:10]2[CH2:9][C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:11]2)=[O:24])[C:21]1([CH3:27])[CH3:26]
Reactant: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Reactant: OC1Cc2cccc(-c3ccccc3)c2C1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)OC1Cc2cccc(-c3ccccc3)c2C1
Yield: 61.4 %

Procedure:
In the manner of Example 12A, the reaction of 1.5 g (0.007 mole) of (+)-4-phenyl-2-indanol (EE≥95%) and 1.77 g (0.007 mole) of (+)-cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarbonyl chloride in the presence of 0.7 g (0.009 mole) of pyridine and 20 ml of toluene gave 1.87 g of (+)-4-phenyl-2-indanyl (+)-cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate as an oil, EE≥95% (alcohol moiety). The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [Br-:1].[Li+].C1COCC1.Cl[CH2:9][C:10]1[CH:27]=[CH:26][C:13]2[N:14]([CH2:24][CH3:25])[C:15](=[O:23])[C:16]([CH3:22])([CH3:21])[C:17](=[O:20])[N:18]([CH3:19])[C:12]=2[CH:11]=1>O>[Br:1][CH2:9][C:10]1[CH:27]=[CH:26][C:13]2[N:14]([CH2:24][CH3:25])[C:15](=[O:23])[C:16]([CH3:22])([CH3:21])[C:17](=[O:20])[N:18]([CH3:19])[C:12]=2[CH:11]=1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CCl)ccc21
Reactant: [Br-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CBr)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
Lithium bromide (0.678 g) was added to an THF solution (2.3 ml) of 7-chloromethyl-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione (0.23 g), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was dried with magnesium sulfate, and was condensed under reduced pressure to give the title compound (0.24 g) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:5]([CH:6]=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[CH2:14](O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.C(OCC)C>[CH2:14]([O:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([CH:6]=[O:7])=[C:8]([O:10][CH3:11])[CH:9]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1cc(O)cc(OC)c1C=O
Reactant: OCc1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(OCc2ccccc2)cc(OC)c1C=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.3 %

Procedure:
To a solution of 4-hydroxy-2,6-dimethoxybenzaldehyde (1.0 g, 5.49 mmol), benzyl alcohol (0.65 g, 6.01 mmol) and tributylphosphine (1.5 g, 7.41 mmol) in tetrahydrofuran (120 ml) was added 1,1′-(azodicarbonyl)dipiperidine (1.8 g, 7.13 mmol) by small portions, and the mixture was stirred at room temperature for 18 hrs. Diethyl ether (120 ml) was added to the reaction mixture, the precipitated insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel chromatography (ethyl acetate:hexane=2:3-1:1) to give 4-benzyloxy-2,6-dimethoxybenzaldehyde (1.2 g) as pale-yellow crystals. Separately, a solution of ethyl diethylphosphono acetate (1.1 g, 4.91 mmol) and 60% sodium hydride (0.17 g, 4.25 mmol) in tetrahydrofuran (40 ml) was stirred under ice-cooling for 10 min. A solution of 4-benzyloxy-2,6-dimethoxybenzaldehyde (1.2 g) was added, and the mixture was stirred while elevating the temperature to room temperature for 5 hrs. The reaction solution was diluted with ethyl acetate, washed successively with aqueous citric acid solution, water and aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was washed with diethyl ether-hexane to give the title compound (1.2 g) as colorless crystals. yield 64%. MS 343.1 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:15](=[CH2:19])[CH2:16]CO)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH:20]1([OH:23])C[CH2:21]1>>[C:11]([C:9]1[CH:8]=[C:7]([C:15]2([CH:20]([OH:23])[CH3:21])[CH2:19][CH2:16]2)[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=1)([CH3:12])([CH3:13])[CH3:14]
Reactant: OC1CC1
Reactant: C=C(CCO)c1cc(C(C)(C)C)cc(C(C)(C)C)c1
Product: CC(O)C1(c2cc(C(C)(C)C)cc(C(C)(C)C)c2)CC1
Yield: 91 %

Procedure:
The above unsaturated alcohol 8 (930 mg, 4.55 mmol) was converted to the cyclopropyl alcohol as described in Example 1 to give 900 mg of [1-(3,4-diethyl benzene)-cyclopropyl]-ethanol (9) as a pale yellow oil in 91% yield. The above cyclopropyl alcohol (900 mg, 4.12 mmol) was oxidized as described in Example 1 to give 520 mg of 1-(3,4-diethyl benzene) cyclopropaneacetaldehyde (10) as a clear oil in 58% yield. 1H NMR (400 MHz, CDCl3) δ9.77 (t, J=2.5 Hz, 1H, aldehyde), 7.08 (m, 3H, aromatic), 2.62 (m, 4H, aliphatic 2CH2), 2.59 (d, J=2.8 Hz, 2H, aliphatic CH2), 1.20 (m, 6H, aliphatic, 2CH3), 1.02 (dd, J=6.3, 4.9 Hz, 2H, aliphatic CH2), 0.87 (dd, J=6.0, 4.4 Hz, 2H, aliphatic CH2).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.C1OCCOCCOCCOCCOCCOC1.[H-].[Na+].[Cl:31][C:32]1[CH:47]=[CH:46][C:35]([N:36]=[CH:37][C:38]2[C:43]([F:44])=[CH:42][CH:41]=[CH:40][C:39]=2[F:45])=[CH:34][CH:33]=1>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:8][CH:37]([NH:36][C:35]2[CH:46]=[CH:47][C:32]([Cl:31])=[CH:33][CH:34]=2)[C:38]2[C:43]([F:44])=[CH:42][CH:41]=[CH:40][C:39]=2[F:45])=[O:7])=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(Br)cc1
Reactant: Fc1cccc(F)c1C=Nc1ccc(Cl)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NC(Nc1ccc(Cl)cc1)c1c(F)cccc1F)c1ccc(Br)cc1
Temperature: 50 °C
Yield: 17.4 %

Procedure:
4-Bromobenzamide 117 (0.94 g, 4.56 mmol) and 18-crown-6 (1.2 g, 4.54 mmol) in DMF (6 mL) was treated with sodium hydride (0.37 g, 9.25 mmol) for 5 minutes at room temperature. 4-Chloro-N-(2,6-difluorobenzylidene)aniline 116 (0.936 g, 3.72 mmol) in DMF (4 mL) was added and the mixture was heated to 50° C. for 5 minutes. The reaction mixture was quenched with crushed ice and the product was isolated by a typical aqueous workup and extraction with ethyl acetate. Chromatographic purification (9:1 hexanes:ethyl acetate) followed by trituration (ethanol) of the material gave 4-bromo-N-((4-chlorophenylamino)(2,6-difluorophenyl)methyl)benzamide (Compound-6) as a white solid (292 mg, 17%). 1H NMR (300 MHz, CDCl3): δ=7.62-7.52 (series m, 4H), 7.38-7.28 (m, 1H), 7.19-7.15 (m, 2H), 7.14-7.08 (m, 1H), 7.02-6.96 (m, 2H), 6.88-6.85 (m, 1H), 6.76-6.72 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13](F)[C:12]([N+:16]([O-:18])=[O:17])=[CH:11][C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:19]1([CH2:25][NH2:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.CCN(C(C)C)C(C)C.Cl>CN(C=O)C>[CH:19]1([CH2:25][NH:26][C:13]2[C:12]([N+:16]([O-:18])=[O:17])=[CH:11][C:3]([NH:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[C:2]([F:1])[CH:14]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=[N+]([O-])c1cc(Nc2ccccc2)c(F)cc1F
Reactant: NCC1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(Nc2ccccc2)c(F)cc1NCC1CCCCC1
Yield: 34.9 %

Procedure:
A solution of 2,4-difluoro-5-nitro-N-phenylaniline (1.00 g, 4.00 mmol), cyclohexanemethylamine (0.57 mL, 4.40 mmol) and N,N′-diisopropylethylamine (0.77, 4.40 mmol) in DMF (40 mL) was stirred at room temperature under an inert atmosphere for 18.5 h. The reaction mixture was transferred to a separatory funnel containing 2 N HCl. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with water, brine and dried over MgSO4. The solution was filtered through diatomaceous earth and the solvent was evaporated. The resulting dark red residue was flash chromatographed (10% EtOAc/hexanes) to give N4-cyclohexylmethyl-2-fluoro-5-nitro-N1-phenyl-benzene-1,4-diamine as a dark red solid (0.48 g, 34.9% yield). M+, 344
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][CH:7]1[C:12](=O)[CH:11]=[CH:10][N:9]=[C:8]1[CH3:14].O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:12]1[CH:11]=[CH:10][N:9]=[C:8]([CH3:14])[C:7]=1[O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: COCCCOC1C(=O)C=CN=C1C
Reactant: O=P(Cl)(Cl)Cl
Product: COCCCOc1c(Cl)ccnc1C
Yield: 34 %

Procedure:
A solution of 3-(3-methoxy-1-propoxy)-2-methyl-4-pyridone (0.32 g, 1.6 mmol) in 50 ml POCl3 was refluxed for 14 h. The POCl3 was evaporated off and the residue was partitioned between methylene chloride and water. The aqueous layer was separated, treated with K2CO3 until pH=10 and extracted with methylene chloride. The organic layer was dried over Na2SO4 and evaporated. The residue was purified by chromatography on silica gel with methanol/methylene chloride (3:97) as eluent. Evaporation off the solvent afforded 0.12 g (34%) product as a red oil.
Reaction SMILES: [NH2:1][C:2](=O)[C@:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])(C)[CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.CO[CH2:23][CH2:24]O[AlH2-]OCCOC.[Na+]>C1(C)C=CC=CC=1>[CH:5]1([CH2:4][C@H:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])[CH2:2][NH:1][CH2:23][CH3:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COCCO[AlH2-]OCCOC
Reactant: CC(C)(C)OC(=O)N[C@@](C)(CC1CCCCC1)C(N)=O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCNC[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-tert-butyl 1-amino-3-cyclohexyl-2-methyl-1-oxopropan-2-ylcarbamate To a solution of (S)-tert-butyl 1-amino-3-cyclohexyl-2-methyl-1-oxopropan-2-ylcarbamate (811 mg, 2.85 mmol) in anhydrous toluene (15 mL) at 0° C. was added Red-Al (65%, 2.66 g, 2.6 mL, 8.55 mmol) within 20 min. After the addition, the reaction was allowed to be stirred at room temperature overnight. The reaction was cooled to 0° C. and quenched with Na2SO4.10H2O. The resulting mixture was stirred for 2-3 h, filtered through Celite, and washed with THF (200 mL). The filtrate was dried and concentrated to give crude product (S)-tert-butyl 1-cyclohexyl-3-(ethylamino)propan-2-ylcarbamate (860 mg). MS ESI +ve m/z 271 (M+H).
Reaction SMILES: [C:1]([N:3]=[C:4](OC1C=CC=CC=1)[NH:5][C@@H:6]1[CH2:12][CH2:11][C@@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])[CH2:9][N:8]([CH2:21][CH3:22])[C:7]1=[O:23])#[N:2].Cl.Cl.[O:33]=[C:34]1[NH:42][C:37]2=[N:38][CH:39]=[CH:40][CH:41]=[C:36]2[N:35]1[CH:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1.C(N(CC)C(C)C)(C)C>C(O)CCCC>[C:1]([N:3]=[C:4]([N:46]1[CH2:45][CH2:44][CH:43]([N:35]2[C:36]3[C:37](=[N:38][CH:39]=[CH:40][CH:41]=3)[NH:42][C:34]2=[O:33])[CH2:48][CH2:47]1)[NH:5][C@@H:6]1[CH2:12][CH2:11][C@@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])[CH2:9][N:8]([CH2:21][CH3:22])[C:7]1=[O:23])#[N:2]
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: CCN1C[C@H](c2cccc(F)c2F)CC[C@@H](NC(=NC#N)Oc2ccccc2)C1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCO
Product: CCN1C[C@H](c2cccc(F)c2F)CC[C@@H](NC(=NC#N)N2CCC(n3c(=O)[nH]c4ncccc43)CC2)C1=O
Yield: 4.6 %

Procedure:
A solution of phenyl N′-cyano-N-[(3R,6S)-6-(2,3-difluorophenyl)-1-ethyl-2-oxoazepan-3-yl]imidocarbamate (166 mg, 0.402 mmol) and 2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine dihydrochloride (116 mg, 0.402 mmol), in 1-pentanol (10 mL) was treated with N,N-diisopropylethylamine (52 mg, 0.402 mmol). This mixture was heated to reflux for 24 h. Concentration and purification by silica gel chromatography (0%→10% methanol/dichloromethane) followed by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (10 mg). MS 537.5 (M+1).
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:11][O:12][CH2:13][O:14][C:15]1[CH:24]=[C:23]2[C:18]([CH:19]([CH2:36][CH:37]=[CH2:38])[CH:20]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][O:34][CH3:35])=[CH:28][CH:27]=3)[C:21](=[O:25])[O:22]2)=[CH:17][CH:16]=1.[CH3:39]I>O1CCCC1>[CH3:11][O:12][CH2:13][O:14][C:15]1[CH:24]=[C:23]2[C:18]([CH:19]([CH2:36][CH:37]=[CH2:38])[C:20]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][O:34][CH3:35])=[CH:28][CH:27]=3)([CH3:39])[C:21](=[O:25])[O:22]2)=[CH:17][CH:16]=1
Reactant: CI
Reactant: C=CCC1c2ccc(OCOC)cc2OC(=O)C1c1ccc(OCOC)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC1c2ccc(OCOC)cc2OC(=O)C1(C)c1ccc(OCOC)cc1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 90.8 %

Procedure:
A 1M solution of lithium hexamethyl-disilazide in tetrahydrofuran (170 ml) was added dropwise to a solution of 7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-4-(2-propenyl)chroman-2-one (32.70 g) in anhydrous tetrahydrofuran (400 ml) at −73° C. over 15 minutes under nitrogen atmosphere, followed by stirring for 30 minutes at −10° C. The reaction mixture was cooled to −75° C. and methyl iodide (10.6 ml) was added dropwise thereto over 10 minutes, followed by stirring for 10 minutes at −75° C., for 1 hour at −10° C. and then for 1 hour at 0° C. The reaction mixture was quenched with saturated aqueous ammonium chloride and partitioned between ethyl acetate and water. The organic layer was washed twice with water and dried over sodium sulfate. After concentration under reduced pressure, the resulting oil was purified by flash column chromatography (silica gel: Merck Kieselgel 60, eluent: hexane/ethyl acetate=9/1) to give (3RS,4RS)-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-3-methyl-4-(2-propenyl)chroman-2-one (30.74 g, Yield 90.8%) as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:10])[CH:4]=[C:5]([CH2:8][OH:9])[O:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1>CN(C=O)C>[OH:9][CH2:8][C:5]1[O:6][CH:7]=[C:2]([O:1][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:3](=[O:10])[CH:4]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=c1cc(CO)occ1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2coc(CO)cc2=O)cc1
Temperature: 80 °C

Procedure:
To a solution of 5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one (Alfa Aesar, 5.11 g, 35.96 mmol) in DMF (70 mL) at room temperature was added potassium carbonate (9.94 g, 71.92 mmol) and 1-(chloromethyl)-4-methoxybenzene (5.86 mL, 43.15 mmol) dropwise. The reaction mixture was heated at 80° C. for 1 hour then concentrated. To the resulting slurry was added ice water. The precipitate was collected by filtration then triturated with ethyl acetate and filtered again. The title compound was obtained as a tan solid (6.44 g, 68%).