Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([NH2:10])=[C:5]([CH3:11])[CH:4]=1.[N:12]([O-])=O.[Na+].[Sn](Cl)Cl>O>[Br:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([NH:10][NH2:12])=[C:5]([CH3:11])[CH:4]=1
Reactant: O=N[O-]
Reactant: Cc1cc(Br)cc(C)c1N
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: Cc1cc(Br)cc(C)c1NN
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 70.6 %

Procedure:
In a 3 L 3-neck round bottom flask equipped with a mechanical stirrer was added concentrated hydrochloric acid (125 mL) and water (250 mL). 4-Bromo-2,6-dimethylbenzenamine (100 g, 500 mmol) was added slowly at 0° C. Stirring was continued for an additional 15 minutes, resulting in a thick white slurry. A freshly prepared solution of sodium nitrite (34.5 g, 500 mmol) in water (100 mL) was added to the slurry dropwise maintaining the internal temperature below 5° C. After stirring for 30 minutes, a deep orange solution was formed. Tin(II) chloride dehydrate (282 g, 1250 mmol) in 1:1 concentrated hydrochloric acid:water (300 mL) was added dropwise while maintaining the internal temperature between 0-5° C. The resulting mixture was stirred at 0° C. for 1 hour and then warmed to room temperature and stirred for 15 hours. The reaction mixture was filtered and washed with diethyl ether. The solid was slowly added to an aqueous 10 M solution of sodium hydroxide (1 L) between 0-10° C. and extracted with ethyl acetate (3×800 mL). The organic layer was washed with brine twice, dried over anhydrous sodium sulfate, and concentrated to give 1-(4-bromo-2,6-dimethylphenyl)hydrazine (76.0 g, 353 mmol). The hydrazine was dissolved in ethyl acetate (800 mL) to which hydrochloric acid/methanol (88.2 mL) was added. The mixture was stirred for 25 minutes. The reaction was filtered, washed with ethyl acetate until the solid is white. The white solid was dried in vacuo to afford 1-(4-bromo-2,6-dimethylphenyl)hydrazine hydrochloride (80.0 g, 64%). 1H NMR (400 MHz, DMSO-d6, δ): 9.71 (s, 3H), 7.32 (s, 2H), 6.78 (s, 1H), 2.37 (s, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.C(NC(C)C)(C)C.[C:38]1([CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[Cl-].[NH4+]>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:18])[CH:44]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:45]([O:47][CH2:48][CH3:49])=[O:46])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccccc1
Reactant: O=C(O)CCCCNC(=O)OCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C(=O)CCCCNC(=O)OCc1ccccc1)c1ccccc1
Yield: 42.6 %

Procedure:
The target compound was prepared as a pale yellow oil in an amount 3.8 g at a yield of 42.6% in the same manner as in Example 1 except that 5.7 g (22 mmol) of 5-(N-benzyloxycarbonylamino)pentanoic acid was dissolved in 23 ml of THF and 5.35 g (33 mmol) of CDI was dividedly added several times; 5.8 ml (44 mmol) of diisopropylamine and 10 ml of THF were added and 27.5 ml (44 mmol) of 1.63N BA solution was added dropwise; 6.6 ml (44 mmol) of ethyl phenylacetate instead of methyl phenylacetate was dissolved in 10 ml of THF; and 30 ml of saturated aqueous ammonium chloride solution was added to the reaction solution, the reaction was terminated, 50 g of 4N hydrochloric acid was added, and 100 ml of ethyl acetate was further added. The analytical results on the target compound are given below.
Reaction SMILES: [C:1]([C:5]1[CH:29]=[CH:28][C:8]([C:9]([NH:11][C@H:12]([C:24]([O:26][CH3:27])=[O:25])[CH2:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].Cl>O1CCOCC1.O>[C:1]([C:5]1[CH:29]=[CH:28][C:8]([C:9]([NH:11][C@H:12]([C:24]([O:26][CH3:27])=[O:25])[CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:22][CH:23]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(C[C@H](NC(=O)c2ccc(C(C)(C)C)cc2)C(=O)OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)[C@H](Cc1ccc(C(=O)O)cc1)NC(=O)c1ccc(C(C)(C)C)cc1
Reaction time: 2 h
Yield: 68.7 %

Procedure:
Prepared using General Procedure 4: To a stirred solution of (S)-methyl 4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoate (316.6 mg, 0.79 mmol) in dioxane (15 mL) and water (1 mL) at 0° C. was added lithium hydroxide monohydrate (93.52 mg, 2.23 mmol). After 2 h, the solution was neutralized with 1 M HCl to pH 7.0. The mixture was partitioned between DCM (15 mL) and saturated aqueous NaHCO3 (10 mL). The organic layer was washed with saturated aqueous NaHCO3 (3×10 mL) and brine (10 mL). The organic layer was dried over MgSO4 and concentrated to afford 208 mg (69%) of (S)-4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoic acid INT-1. LCMS-ESI (m/z) calculated for C22H25NO5: 383.2; found 384.1 [M+H]+, tR=2.13 min. (Method 1). 1H NMR (400 MHz, DMSO) δ 12.86 (s, 1H), 8.80 (d, J=8.0 Hz, 1H), 7.87-7.78 (m, 2H), 7.75-7.65 (m, 2H), 7.50-7.35 (m, 4H), 4.72 (ddd, J=10.3, 8.0, 5.1 Hz, 1H), 3.65 (s, 3H), 3.28-3.05 (m, 2H), 1.29 (s, 9H). 13C NMR (101 MHz, DMSO) δ 173.00, 167.21, 166.29, 154.39, 143.10, 130.85, 129.34, 129.27, 129.21, 129.03, 127.21, 125.39, 125.10, 53.75, 52.04, 34.64, 30.92, 30.88.
Reaction SMILES: [C:1]([C:3]1(O[Si](C)(C)C)[CH2:8][CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1)#[N:2].COCCN(S(F)(F)[F:31])CCOC.[O-][Mn](=O)(=O)=O.[K+]>C(Cl)Cl>[F:31][C:3]1([C:1]#[N:2])[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCCC(C#N)(O[Si](C)(C)C)C1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Product: N#CC1(F)CCCNC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 156.1 %

Procedure:
To a mixture of tert-butyl 3-cyano-3-(trimethylsilyloxy)piperidine-1-carboxylate (300 mg, 1.005 mmol) in DCM (10 mL) was added [bis(2-methoxyethyl)amino]sulfur trifluoride (0.222 mL, 1.206 mmol). The reaction mixture was stirred for 2 hours at room temperature. TLC (1:1 EtAOc/hexanes) shows a new higher Rf spot when stained with KMnO4 and no starting material. The reaction mixture was diluted with DCM (10 mL) and washed with H2O. The organic layer was dried with MgSO4, filtered, and concentrated. Solids were purified on a silica gel cartridge using a 0-100% gradient of EtOAc/hexanes, concentrated, and then treated with TFA/DCM for 1 hour. Solvent was removed in vacuo and the solids were dried to give 201 mg of 3-fluoropiperidine-3-carbonitrile as a TFA salt. 1H NMR (400 MHz, chloroform-d) δ ppm 3.82-4.01 (1H, m), 3.68(1H, br. s.), 3.45-3.61 (1H, m), 3.37(1H, br. s.), 2.06-2.31 (2H, m), 1.79-1.94(1H, m), 1.63-1.76 (1H, m); 19F NMR (400 MHz, chloroform-d) δ ppm −157.4 (alpha-F); −156.5 (TFA).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.ClC1C=CC=C(C(OO)=[O:29])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:29])[CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][C:11]=2[N:12]=1
Reactant: FC(F)(F)c1ccc2oc(-c3ccncc3Cl)nc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: [O-][n+]1ccc(-c2nc3cc(C(F)(F)F)ccc3o2)c(Cl)c1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 52.7 %

Procedure:
To a mixture of 0.45 g of 2-(3-chloropyridin-4-yl)-5-(trifluoromethyl)benzoxazole and 5 ml of chloroform, 0.53 g of 65% m-chloroperbenzoic acid was added while ice-cooling. The reaction mixture was stirred at room temperature for 5.5 hours, and was then diluted with chloroform, and washed with 5% aqueous solution of sodium hydroxide and a saturated sodium chloride solution, sequentially. Organic layers were dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.25 g of 3-chloro-4-[5-(trifluoromethyl)benzoxazole-2-yl]pyridine N-oxide (hereinafter, referred to as “active compound 19”).
Reaction SMILES: I.I[C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)=[C:12]([CH3:24])[CH:11]=2)[C:4]=1[NH2:25].[C:26]([C:28]1[CH:29]=[C:30]([CH:40]=[CH:41][CH:42]=1)[CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])#[CH:27]>C(#N)C.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:25][C:4]1[C:3]([C:27]#[C:26][C:28]2[CH:29]=[C:30]([CH:40]=[CH:41][CH:42]=2)[CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:36])[CH3:37])=[N:8][CH:7]=[N:6][C:5]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=2)=[C:12]([CH3:24])[CH:11]=1
Reactant: C#Cc1cccc(CNC(=O)OC(C)(C)C)c1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc(I)c3N)cc2C)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(Oc2ccc(Nc3ncnc(C#Cc4cccc(CNC(=O)OC(C)(C)C)c4)c3N)cc2C)cn1
Yield: 78.6 %

Procedure:
6-Iodo-N4-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}pyrimidine-4,5-diamine hydroiodide (500 mg) was dissolved in a mixed solvent of acetonitrile (14.8 mL)/triethylamine (11.0 mL), and tert-butyl 3-ethynylbenzylcarbamate (247 mg), trans-dichlorobis(triphenylphosphine)palladium(II) (31.3 mg) and copper(I) iodide (10.2 mg) were sequentially added. The title compound (376 mg) was obtained as a powder by the reaction in the same manner as in Example 9 (iv).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([NH2:10])=[CH:5][C:4]=1[C:11]1[NH:12][C:13]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[C:14]([CH3:16])[N:15]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>C(OCC)(=O)C.O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([NH:10][C:23](=[O:25])[CH3:24])=[CH:5][C:4]=1[C:11]1[NH:12][C:13]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[C:14]([CH3:16])[N:15]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(Cl)c(N)cc1-c1nc(C)c(-c2cccnc2)[nH]1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(Cl)c(NC(C)=O)cc1-c1nc(C)c(-c2cccnc2)[nH]1
Temperature: 0 °C

Procedure:
A solution of 2-(2-methoxy-4-chloro-5-aminophenyl)-4-methyl-5-(3-pyridyl)imidazole (1.0 g) and acetic anhydride (2 ml) in a mixture of ethyl acetate (20 ml) and tetrahydrofuran (10 ml) was refluxed for 2 hours. The reaction mixture was cooled with ice-water and the crystalline residue was collected by filtration to give 2-(2-methoxy-4-chloro-5-acetamidophenyl)-4-methyl-5-(3-pyridyl)imidazole (0.7 g).
Reaction SMILES: [CH:1]1[C:6]2[C:7]#[C:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[CH2:11][CH:12]([OH:13])[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)=[O:20].N1C=CC=CC=1>C(Cl)Cl>[N+:28]([C:25]1[CH:24]=[CH:23][C:22]([O:21][C:19](=[O:20])[O:13][CH:12]2[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:6]=3[C:7]#[C:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[CH2:11]2)=[CH:27][CH:26]=1)([O-:30])=[O:29]
Reactant: OC1Cc2ccccc2C#Cc2ccccc21
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1Cc2ccccc2C#Cc2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.2 %

Procedure:
To a solution of 45 (0.22 g, 1 mmol) in CH2Cl2 (30 mL) was added 4-nitro-phenyl chloroformate (0.4 g, 2 mmol) and pyridine (0.4 ml, 5 mmol). After stirring 4 hours at ambient temperature, the reacting mixture was washed with brine (2×10 mL), and the organic layer was dried (MgSO4). The solvents were evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate, 10/1, v/v) to afford 47 (0.34 g, 89%). 1H NMR (300 MHz, CDCl3): δ 8.23-8.18 (2H, aromatics), 7.56-7.54 (2H, aromatics), 7.46-7.18 (8H, aromatics), 5.5 (1H, dd, J=3.9, 15.3 Hz, CHOH), 3.2 (1H, dd, J=3.9, 15.3 Hz, CH2), 2.9 (1H, dd, J=3.9, 15.3 Hz, CH2). 13C NMR (75 MHz, CDCl3): δ 154.5, 150.7, 149.1, 148.7, 129.0, 127.4, 127.3, 126.7, 126.5, 125.5, 125.2, 124.3, 124.0, 122.6, 122.4, 120.8, 120.6, 120.2, 112.2, 108.5, 80.6, 44.8. MALDI HRMS: m/z 408.0852 [M+Na+]. Calcd for C23H15NNaO5: 408.0848.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[F:12][C:13]1[C:20]([F:21])=[CH:19][CH:18]=[C:17]([F:22])[C:14]=1[CH2:15]Br.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[N:9][N:8]([CH2:15][C:14]3[C:17]([F:22])=[CH:18][CH:19]=[C:20]([F:21])[C:13]=3[F:12])[C:5]2=[N:6][CH:7]=1
Reactant: Fc1ccc(F)c(CBr)c1F
Reactant: Fc1cnc2[nH]nc(I)c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cnc2c(c1)c(I)nn2Cc1c(F)ccc(F)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10.0 g (38.021 mmol) of the compound from Example 6A were initially charged in DMF (170 ml), and 9.41 g (41.823 mmol) of 2,3,6-trifluorobenzyl bromide and 13.62 g (41.82 mmol) of caesium carbonate were then added. The mixture was stirred at RT overnight. The reaction mixture was then added to water (200 ml) and stirred for 15 min A precipitate was filtered off with suction, washed with water and subsequently dried under high vacuum. This gave 12.1 g of the title compound (78% of theory).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[F:17][C:18]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:19]=1[C:20](O)=[O:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:20]([C:19]3[CH:23]=[C:24]([C:27]([F:28])([F:29])[F:30])[CH:25]=[CH:26][C:18]=3[F:17])=[O:21])=[CH:12][CH:11]=2)[C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: NC(=O)c1c(-c2ccc(N)cc2)csc1N
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)c1c(-c2ccc(NC(=O)c3cc(C(F)(F)F)ccc3F)cc2)csc1N
Temperature: 25 °C

Procedure:
Crude 2-amino-4-(4-amino-phenyl)-thiophene-3-carboxylic acid amide (0.15 mmoles, 1 eq) is dissolved in 1 mL DMF and added to a solution of 2-fluoro-5-trifluoromethylbenzoic acid (0.20 mmoles, 1.3 equiv) and HBTU (0.20 mmoles, 1.3 equiv) in 1 mL DMF. To this solution is added 0.5 mL triethylamine. The solution is stirred at room temperature until the reaction is complete, as judged by TLC. The crude reaction mixture is purified by preparative HPLC, affording the desired 2-amino-4-{4-[(1-[2-fluoro-5-trifluoromethyl-phenyl]-methanoyl)-amino]-phenyl}-thiophene-3-carboxylic acid amide. Biological Data
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[CH:8][C:9](/[CH:11]=[N:12]/[OH:13])=[CH:10][C:5]=2[C:4]([CH3:15])([CH3:14])[O:3]1.C1C(=O)N(Cl)C(=O)C1.[Cl:24][C:25]1[CH:30]=[C:29]([C:31]([C:33]([F:36])([F:35])[F:34])=[CH2:32])[CH:28]=[C:27]([Cl:37])[C:26]=1[CH3:38].CCN(CC)CC>CN(C=O)C>[Cl:24][C:25]1[CH:30]=[C:29]([C:31]2([C:33]([F:36])([F:34])[F:35])[O:13][N:12]=[C:11]([C:9]3[CH:8]=[CH:7][C:6]4[B:2]([OH:1])[O:3][C:4]([CH3:15])([CH3:14])[C:5]=4[CH:10]=3)[CH2:32]2)[CH:28]=[C:27]([Cl:37])[C:26]=1[CH3:38]
Reactant: CC1(C)OB(O)c2ccc(/C=N/O)cc21
Reactant: C=C(c1cc(Cl)c(C)c(Cl)c1)C(F)(F)F
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(Cl)cc(C2(C(F)(F)F)CC(c3ccc4c(c3)C(C)(C)OB4O)=NO2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.8 %

Procedure:
The mixture of (E)-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde oxime (62 mg, 0.3 mmol) and NCS (48 mg, 0.36 mmol) in DMF (2 mL) was stirred at rt overnight. To the mixture was added 1,3-dichloro-2-methyl-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (75 mg, 0.3 mmol) and Et3N (0.1 mL) and the mixture was stirred at rt for 4 h. It was partitioned between EA and H2O. The organic layer was washed with H2O, brine, dried over Na2SO4, concentrated under vacuum. The residue was purified to give the desired product (30 mg, 21.8% yield).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9](=[O:18])[C:8]2=[CH:19][CH:20]=[CH:21][N:7]2[N:6]=1)[CH2:3][CH3:4].[C:22]1(=O)[CH2:26][CH2:25][CH2:24][CH2:23]1.C([O-])(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCOCC1>[CH2:11]([N:10]1[C:9](=[O:18])[C:8]2=[CH:19][CH:20]=[CH:21][N:7]2[N:6]=[C:5]1[CH:2]([NH:1][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:3][CH3:4])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1CCCC1
Reactant: CCC(N)c1nn2cccc2c(=O)n1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCC(NC1CCCC1)c1nn2cccc2c(=O)n1Cc1ccccc1
Reaction time: 0.67 h
Yield: 71.3 %

Procedure:
A mixture of 2-(1-amino-propyl)-3-benzyl-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (Example 26, 50 mg, 0.16 mmol), cyclopentanone (13 mg, 0.16 mmol), anhydrous sodium acetate (26 mg, 0.32 mmol), 4 Å molecular sieves (50 mg) and 1,4-dioxane (10 mL) was stirred at room temperture for 40 min. The mixture was treated with sodium triacetoxyborohydride (51 mg, 0.24 mmol) in one portion and stirred at room temperature for 40 h. Additional portions of cyclopentanone (0.16 mmol) and sodium triacetoxyborohydride (0.16 mmol) were added to the mixture which was stirred for an additional 3.5 hours then filtered. The filtrate was partitioned between ethyl acetate and saturated sodium bicarbonate, the ethyl acetate phase washed with brine, dried (MgSO4) and concentrated. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate to give the title compound (40 mg, 71%): 1H NMR (DMSO-d6) δ 0.88 (t, 3H, J=7.15 Hz), 0.95 (m, 1H), 1.05 (m, 1H), 1.20 (m, 1H), 1.31 (m, 1H), 1.33 (m, 1H), 1.50–1.72 (m, 6H), 2.72 (m, 1H), 3.53 (m, 1H), 4.95 (m, 1H), 5.58 (m, 1H), 6.54 (s, 1H), 7.08 (s, 1H) 7.16 (s 2H), 7.24–7.35 (m, 3H), 7.35 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]([CH:13]([CH3:15])[CH3:14])[C:9](=[O:12])[CH:10]=[CH2:11])([CH3:4])([CH3:3])[CH3:2].I[C:18]1[CH:19]=[C:20]([O:24][CH3:25])[CH:21]=[CH:22][CH:23]=1.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]([CH:13]([CH3:14])[CH3:15])[C:9](=[O:12])/[CH:10]=[CH:11]/[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cccc(I)c1
Reactant: C=CC(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1cccc(/C=C/C(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C)c1
Temperature: 80 °C
Reaction time: 15 h
Yield: 88.6 %

Procedure:
To a solution of ((R)-1-Isopropyl-2-oxo-but-3-enyl)-carbamic acid tert-butyl ester (13.54 g, 59.6 mmol) in dry acetonitrile (150 mL) under argon, was added 3-iodoanisole (13.96 g, 59.6 mmol), triethylamine (9.1 mL, 65.6 mmol) followed by palladium (II) acetate (335 mg, 1.49 mmol). The resulting clear yellow solution was heated to 80° C. Upon heating, the reaction darkened and the precipitation of palladium black occurred. After 15 h, the reaction mixture was allowed to cool to room temperature, quenched with water (150 mL) and diluted with ether (150 mL). The ether layer was washed with brine (100 mL) and the combined aqueous layers were extracted with ether (two 50 mL portions). The extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was immediately purified by silica gel chromatography (9:1 hexanes/EtOAc) to provide 17.6 g (88%) of [(R)-(E)-1-Isopropyl-4-(3-methoxy-phenyl)-2-oxo-but-3-enyl]-carbamic acid tert-butyl ester as a yellow oil. MS(ES+) m/e 334.0 [M+H]+.
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[CH2:27]([O:26][C:23]1[CH:24]=[CH:25][C:20]([N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([NH:2][OH:1])=[O:5])=[N:21][CH:22]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: NO
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1ccc(OCc2ccccc2)cn1
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(CCCCCCN(c1ccccn1)c1ccc(OCc2ccccc2)cn1)NO
Reaction time: 72 h
Yield: 74 %

Procedure:
HONH2 (50% aqueous, 0.5 mL) was added to III (26 mg, 0.06 mmol) in DMF (0.2 mL) and MeOH (0.5 mL) at rt. The reaction mixture was stirred for 72 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×10 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:4 to 100:8) to furnish IV as a colourless oil (18.66 mg, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH:21][CH2:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Cl)(=[O:28])=[O:27]>C(N(C(C)C)C(C)C)C>[OH:21][CH2:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:12]1[CH2:11][CH2:10][N:9]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:14][CH2:13]1)(=[O:28])=[O:27]
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=S(=O)(CCCCCCl)NCCCO
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(CCCCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1)NCCCO
Yield: 95.1 %

Procedure:
1-[(4-Chlorophenyl)phenylmethyl]piperazine (573.6 mg, 2.00 mmol) and N-(3-hydroxypropyl)-5-chloropentanesulfonamide (487.5 mg, 2.00 mmol) were refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (20:1), to give N-(3-hydroxypropyl)-5-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]pentanesulfonamide (940.0 mg) as a pale yellow oil (yield: 95.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:25]=[CH:24][C:11]3[CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][CH2:15][O:16][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.C(OCC)(=O)C.Cl>C(OCC)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:25]=[CH:24][C:11]3[CH2:12][NH:13][CH2:14][CH2:15][O:16][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2cc(-c3ccc(Cl)cc3)ccc2C1
Agent: Cl
Solvent: CCOC(C)=O
Product: Clc1ccc(-c2ccc3c(c2)OCCNC3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 167.7 %

Procedure:
A mixture of tert-butyl 8-(4-chlorophenyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (210 mg, 0.584 mmol), ethyl acetate (1 ml) and 4N hydrogen chloride-ethyl acetate solution (4 ml) was stirred for 1 hr at room temperature, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (145 mg, 83.8%) as a solid.