Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][N:6]([CH2:15][CH2:16][CH3:17])[C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)=[O:22]>>[CH:21]([C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:20]=[CH:19][CH:18]=[C:4]([CH2:5][N:6]([CH2:15][CH2:16][CH3:17])[C:7](=[O:14])[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:3]=2)=[CH:25][CH:24]=1)=[O:22]
Reactant: CCCN(Cc1cccc(Br)c1)C(=O)c1ccccc1
Reactant: O=Cc1ccc(B(O)O)cc1
Product: CCCN(Cc1cccc(-c2ccc(C=O)cc2)c1)C(=O)c1ccccc1
Yield: 52 %

Procedure:
In a manner similar to that of Example 1(e), by reacting 1.4 g (4.2 mmol) of N-(3-bromo benzyl)-N-propylbenzamide with 940 mg (6.2 mmol) of 4-formylbenzene boronic acid, 780 mg (53%) of the expected product are obtained.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([N:14]1[C:20](=[O:21])[CH2:19][CH2:18][N:17]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH2:16][CH2:15]1)[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32]I.[H-].[Na+]>CN(C=O)C>[CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([N:14]1[C:20](=[O:21])[CH2:19][CH2:18][N:17]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:31])[F:29])[CH:23]=2)[CH2:16][CH2:15]1)[CH2:12][O:13][CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(c2cccc(C(F)(F)F)c2)CCN1[C@H](CO)CCOCc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC[C@H](CCOCc1ccccc1)N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Reaction time: 3 h

Procedure:
0.40 g (0.92 mmol) of the above prepared 4-((S)-3-benzyloxy-1-hydroxymethyl-propyl)-1-(3-trifluoromethyl-phenyl)-[1,4]diazepan-5-one and 0.29 ml (4.58 mmol) of methyl iodide were dissolved in 1.6 ml of DMF. After cooling (0° C.), 0.048 g (1.10 mmol) of NaH (55% dispersion in oil) was added. The reaction was stirred for 3 h at this temperature, then poured onto crashed ice/aq. 10% KHSO4 solution and extracted with Et2O (3×). The organic layers were washed with aq. 10% KHSO4 solution and aq. 10% NaCl solution, dried over Na2SO4, evaporated and purified by flash silica gel column (n-heptane:EtOAc 1:1) to yield 0.42 g (quantitative) of the title compound as light yellow oil. MS: 451.2 (MH+, 1Cl).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[C:6]([N+:19]([O-])=O)[CH:5]=1)([O-])=O.[H][H].CCOCC>C(O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[C:6]([NH2:19])[CH:5]=1
Reactant: Cc1ccc(C=Cc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOCC
Solvent: CCO
Product: Cc1ccc(CCc2ccc(N)cc2N)cc1

Procedure:
1.4 g of 1,3-dinitro-4-[2-(4-methylphenyl)ethenyl]benzene prepared as described by S. Saravanan and P. Srinivasan, Synth. Commun. 31(6), pages 823-826 (2001) was dissolved in 50 mL of ethanol and hydrogenated using 0.2 g of Pd/C 10% for 4 hours at 8 bar of hydrogen pressure. The catalyst was then filtered off, and the filtrate was evaporated to dryness. This gave a brownish oil which upon addition of 10 mL of ether crystallized. Yield: 1.1 g of yellowish oil.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C@@H:15]([CH3:16])[C@@H:14]([CH2:17][OH:18])[O:13][C:12]2=[O:19])=[CH:7][CH:6]=1.F[C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1>CN(C)C=O>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C@@H:15]([CH3:16])[C@@H:14]([CH2:17][O:18][C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=3)[O:13][C:12]2=[O:19])=[CH:9][CH:10]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: COc1ccc(N2C(=O)O[C@H](CO)[C@@H]2C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(N2C(=O)O[C@H](COc3ccc(C#N)cc3)[C@@H]2C)cc1
Temperature: 50 °C
Reaction time: 0.42 h
Yield: 70.2 %

Procedure:
To a suspension of 200 mg of 60% sodium hydride in anhydrous N,N-dimethylformamide (1 ml) was added dropwise an N,N-dimethylformamide (7 ml) solution of 0.98 g of (4S, 5S)-(-)-3-(4-methoxyphenyl)-4-methyl-2-oxooxazolidin-5-ylmethyl alcohol obtained in Reference Example 11 at room temperature in a stream of nitrogen, and the mixture was stirred at 50° C. for 25 minutes. A solution of 500 mg of p-fluorobenzonitrile in anhydrous N,N-dimethylformamide (2 ml) was added thereto at the same temperature and the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure and the obtained residue was extracted with ethyl acetate. The extract was washed with water, dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and purified by hexane-ethyl acetate gradient elution to give 0.98 g of the title compound (yield 70%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([N:11]2[CH:16]=[CH:15][C:14](=[O:17])[NH:13][C:12]2=[O:18])[CH:5]=[C:6]([I:10])[C:7]=1[O:8][CH3:9].Br[C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[C:25]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[CH:24]=[CH:23]2.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[O:18]=[C:12]1[NH:13][C:14](=[O:17])[CH:15]=[CH:16][N:11]1[C:4]1[CH:5]=[C:6]([I:10])[C:7]([O:8][CH3:9])=[C:2]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[C:25]([NH:30][S:31]([CH3:34])(=[O:32])=[O:33])[CH:24]=[CH:23]3)[CH:3]=1
Reactant: CS(=O)(=O)Nc1ccc2cc(Br)ccc2c1
Reactant: COc1c(I)cc(-n2ccc(=O)[nH]c2=O)cc1I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1c(I)cc(-n2ccc(=O)[nH]c2=O)cc1-c1ccc2cc(NS(C)(=O)=O)ccc2c1
Yield: 11 %

Procedure:
A mixture of the product from Part B 1-(3,5-diiodo-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione (118 mg, 0.25 mmol), the product from Example 2A, Part B (87 mg, 0.25 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride CH2Cl2 complex (10.21 mg, 0.013 mmol) and sodium carbonate (0.250 ml, 0.25 mmol) in toluene (1.0 ml) and ethanol (1.0 ml) was sparged with nitrogen for 5 min and microwaved at 100° C. for 30 min. The mixture was cooled and partitioned with ethyl acetate and 1M HCl. The organic layer was washed with saturated sodium bicarbonate, brine, dried with sodium sulfate, filtered and evaporated. The residue was chromatographed on silica eluting with ethyl acetate/hexane (2:3 to 4:1) to give the title compound (16 mg, 11%). 1H NMR (300 MHz, DMSO-D6) δ ppm 3.08 (s, 3 H) 3.35 (s, 3 H) 5.67 (d, J=8.09 Hz, 1 H) 7.42 (dd, J=8.82, 2.21 Hz, 1 H) 7.59 (d, J=2.57 Hz, 1 H) 7.73 (m, 2 H) 7.81 (d, J=8.09 Hz, 1 H) 7.95 (m, 3 H) 8.09 (s, 1 H) 10.06 (s, 1 H) 11.47 (s, 1 H). MS (ESI−) m/z 562 (M−H)+.
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[N:15][C:14]([CH2:17][CH3:18])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[F:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[C:29]1[O:33][CH:32]=[N:31][CH:30]=1)[C:23](O)=[O:24]>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[N:15][C:14]([CH2:17][CH3:18])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:28]([C:29]3[O:33][CH:32]=[N:31][CH:30]=3)=[C:20]([F:19])[CH:21]=2)[CH2:2][CH2:3]1
Reactant: CCc1cnc(N2CCC(NC3CC3)CC2)cn1
Reactant: O=C(O)c1ccc(-c2cnco2)c(F)c1
Product: CCc1cnc(N2CCC(N(C(=O)c3ccc(-c4cnco4)c(F)c3)C3CC3)CC2)cn1

Procedure:
The title compound is prepared from cyclopropyl-[1-(5-ethyl-pyrazin-2-yl)-piperidin-4-yl]-amine and 3-fluoro-4-oxazol-5-yl-benzoic acid following a procedure analogous to that described in Example 17. LC (method 1): tR=1.18 min; Mass spectrum (ESI+): m/z=436 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[CH3:20][C:21]([CH3:27])([CH3:26])[CH2:22][CH2:23][CH2:24][NH2:25].[BH4-].[Na+]>CO>[CH3:20][C:21]([CH3:27])([CH3:26])[CH2:22][CH2:23][CH2:24][NH:25][CH2:18][C:16]1[CH:15]=[CH:14][C:3]([O:4][C:5]2[N:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=2)=[C:2]([F:1])[CH:17]=1
Reactant: CC(C)(C)CCCN
Reactant: NC(=O)c1cnc(Oc2ccc(C=O)cc2F)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)CCCNCc1ccc(Oc2cnc(C(N)=O)cn2)c(F)c1
Reaction time: 8 h
Yield: 56.9 %

Procedure:
Place 5-(2-fluoro-4-formylphenoxy)pyrazine-2-carboxamide (Example 737, Pall E) (0.400 g, 1.53 mmol), 4,4-dimethylpentylamine (0.194 g, 1.68 mmol) (Example 97, Part B) and 3 Å molecular sieves in a vial. Add methanol (7.7 mL), cap and stir overnight. Add NaBH4 (0.058 g, 1.53 mmol) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 0% to 15% (2.0 M NH3 in methanol) in 80% (ethyl acetate in hexanes). Concentrate the fractions containing the product. Take the solid up in dichloromethane (100 mL) and wash with 1.0 N NaOH (2× 25 mL) to give the title compound (0.314 g, 57%): TOF MS ES+ 361.2 (M+H)+, HRMS calcd for C19H26N4O2F 361.2040 (M+H)+, found 361.2042, time 0.55 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=12.0 min. 100% purity.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].[O:15](S(C(F)(F)F)(=O)=O)[S:16]([C:19]([F:22])([F:21])[F:20])(=O)=[O:17]>C(Cl)Cl>[F:20][C:19]([F:22])([F:21])[S:16]([O:7][C:3]1[CH2:4][CH2:5][CH2:6][C:1](=[O:8])[CH:2]=1)(=[O:17])=[O:15]
Reactant: O=C1CCCC(=O)C1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C1C=C(OS(=O)(=O)C(F)(F)F)CCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a solution of cyclohexane-1,3-dione (1 equiv) in DCM (0.4M) was added Na2CO3 (1.0 equiv.) and cooled to 0° C. Added Tf2O (1.0 equiv.) in DCM (5M) dropwise over 1 hr at room temperature under a nitrogen atmosphere. Upon addition, the reaction was stirred for 2 hr (dark red solution). The solution was filtered and to the filtrate was added saturated NaHCO3 (carefully), then extracted the organics, dried with brine, then Na2SO4, and concentrated. The crude was purified via SiO2 column chromatography eluting with DCM and hexanes (1:1) or alternatively via a neutral alumina plug eluting with DCM to afford 3-oxocyclohex-1-enyl trifluoromethanesulfonate in 30% or 67% yield respectively. The triflate decomposes upon storage and should be used immediately for the next reaction. LC/MS=244.9/286.0 (M+H and M+CH3CN); Rt=0.88 min.
Reaction SMILES: [I:1]I.[NH2:3][C:4]1[CH:5]=[N:6][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:9]=1>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[NH2:3][C:4]1[C:5]([I:1])=[N:6][C:7]([C:10]([F:13])([F:11])[F:12])=[CH:8][CH:9]=1
Reactant: Nc1ccc(C(F)(F)F)nc1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: Nc1ccc(C(F)(F)F)nc1I
Yield: 65.8 %

Procedure:
1.56 g (6.17 mmol) of iodine is added, in several portions, to a mixture, stirred under argon at 20° C., of 1 g (6.17 mmol) of 3-amino-6-trifluoromethylpyridine and 1.25 g (6.17 mmol) of silver sulfate in 40 mL of ethanol. Stirring is maintained for 18 hours. The insoluble matter is removed by filtration and is washed with ethanol, the filtrate is concentrated at reduced pressure, and the residue is taken up in 100 mL of dichloromethane. The organic phase is washed successively with 20 mL of 5% aqueous solution of sodium hydroxide, 40 mL of water and 20 mL of saturated aqueous solution of sodium chloride, dried over sodium sulfate, concentrated at reduced pressure, and then purified by chromatography on a silica column (eluents: heptane-ethyl acetate). In this way we isolate 1.17 g of the expected product, which is used as it is in the rest of the synthesis.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]#[N:8].Br[CH2:10][CH2:11]Br>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([CH2:7][NH2:8])[CH2:11][CH2:10]1
Reactant: BrCCBr
Reactant: N#CCc1cccs1
Product: NCC1(c2cccs2)CC1

Procedure:
(1-Thien-2-ylcyclopropyl)methylamine is prepared from 2-thienyl acetonitrile and 1,2-dibromoethane as described in Example 1 in 57% overall yield.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[S:6]1(=[O:23])=[O:22].[CH:24]1([NH2:27])[CH2:26][CH2:25]1.Cl>>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N:7]1[C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:27][CH:24]2[CH2:26][CH2:25]2)[S:6]1(=[O:23])=[O:22]
Reactant: NC1CC1
Reactant: O=S1(=O)N(CCCBr)Cc2ccccc2N1c1ccccc1F
Agent: Cl
Product: O=S1(=O)N(CCCNC2CC2)Cc2ccccc2N1c1ccccc1F
Yield: 94 %

Procedure:
In an analogous manner to Example 11 step 5, 3-(3-bromopropyl)-1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.1 g, 0.25 mmol) was reacted to cyclopropylamine and then treated with HCl to provide N-{3-[1-(2-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]propyl}cyclopropanamine (0.089 g, 94%) as a white solid:
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][NH:4][N:3]=1.[CH2:15](O)[CH2:16][CH2:17][CH3:18]>>[CH3:18][C:17]1[CH:16]=[C:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]2[N:4]=[CH:5][C:6]([C:7]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)=[O:8])=[C:2]2[N:1]=1
Reactant: Nc1n[nH]cc1C(=O)c1ccccc1
Reactant: CCCCO
Product: Cc1cc(-c2ccccc2)n2ncc(C(=O)c3ccccc3)c2n1

Procedure:
A mixture of 0.01 mole of 1-(3-phenyl)butan-1,3-dione and 0.01 mole of (3-amino-1H-pyrazol-4-yl)phenyl-methanone in 25 ml of n-butanol was refluxed for 8 hours. The solvent was removed and the product isolated as described in Example 1, giving the desired product as crystals, mp 165°-166° C.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.[C:11]1([NH:17][NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:19][C:20]([CH3:27])([CH3:26])[C:21](=O)[CH2:22][C:23]#[N:24]>C(O)C>[C:20]([C:21]1[CH:22]=[C:23]([NH2:24])[N:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:18]=1)([CH3:27])([CH3:26])[CH3:19]
Reactant: NNc1ccccc1
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(-c2ccccc2)n1
Yield: 70 %

Procedure:
N,N-Diisopropylethylamine (1.7 mL, 7.99 mmol) was added to a mixture of phenyl hydrazine hydrochloride (1.5 g, 10.39 mmol) and 4,4-dimethyl-3-oxopentane nitrile (1.0 g, 7.99 mmol) in ethanol (15 mL) and the mixture was heated under reflux for 18 hours. The cooled mixture was then concentrated to low volume and partitioned between ethyl acetate and saturated sodium hydrogen carbonate solution. The organic layer was separated, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with heptanes:ethyl acetate, 75:25, to afford the title compound as a pale orange oil that crystallised on standing (1.21 g, 70% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:20]3[CH2:24][CH2:23][CH2:22][N:21]3[CH:25]3[C:34]4[C:29](=[C:30]([OH:35])[CH:31]=[CH:32][CH:33]=4)[CH2:28][CH2:27][CH2:26]3)[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.Br[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:20]3[CH2:24][CH2:23][CH2:22][N:21]3[CH:25]3[C:34]4[C:29](=[C:30]([O:35][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:31]=[CH:32][CH:33]=4)[CH2:28][CH2:27][CH2:26]3)[O:11][C:12]=2[C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2nc(C3CCCN3C3CCCc4c(O)cccc43)oc2-c2ccc(C)cc2)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc2c1CCCC2N1CCCC1c1nc(-c2ccc(C)cc2)c(-c2ccc(C)cc2)o1
Temperature: 25 °C
Reaction time: 48 h
Yield: 84.4 %

Procedure:
To a solution of 1-[2-[4,5-bis(4-methylphenyl)oxazol-2-yl]pyrrolidin-1-yl]-1,2,3,4-tetrahydro-5-hydroxynaphthalene (0.13 g) and ethyl bromoacetate (0.10 g) in DMF (5 ml) was added K2CO3 (0.13 g). After being stirred for 2 days at room temperature, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine. The dried solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel to give 1-[2-[4,5-bis(4-methylphenyl)oxazol-2-yl]pyrrolidin-1-yl]-1,2,3,4-tetrahydro-5-ethoxycarbonylmethoxynaphthalene (0.13 g).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].Cl.[NH2:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:22]([O:21][C:19](=[O:20])[CH2:18][NH:17][CH2:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)c1cccc(CCl)c1
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CNCc1cccc(C(=O)OC(C)(C)C)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 64.1 %

Procedure:
To a solution of tert-butyl 3-(chloromethyl)benzoate (25.3 g) in N,N-dimethylformamide (250 mL) were added tert-butyl glycinate hydrochloride (37.4 g) and potassium carbonate (61.7 g), followed by stirring at 60° C. overnight. To the reaction suspension was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl 3-{[(2-tert-butoxy-2-oxoethyl)amino]methyl}benzoate (23.0 g).
Reaction SMILES: [S:1]([C:5]1[S:9][C:8]([C:10]#[N:11])=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].Cl.[NH2:13][OH:14].C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[OH:14][NH:13][C:10]([C:8]1[S:9][C:5]([S:1](=[O:4])(=[O:3])[NH2:2])=[CH:6][CH:7]=1)=[NH:11]
Reactant: NO
Reactant: N#Cc1ccc(S(N)(=O)=O)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N=C(NO)c1ccc(S(N)(=O)=O)s1
Yield: 57.5 %

Procedure:
A stirred mixture of 5-sulfamoyl-thiophene-2-carbonitrile [CAS-No. 519055-65-3] (0.31 g, 1.65 mmol), hydroxylamine hydrochloride (0.23 g, 3.31 mmol) and sodium carbonate (0.175 g, 1.65 mmol) in water (4.6 ml) and ethanol (1 ml) was heated under reflux conditions for 1.5 h. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with brine (100 ml), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (ethyl acetate/MeOH/hexane) to yield the title compound (0.21 g, 58%) as a white solid. MS (ISN) 220.1 [(M−H)−]; mp 189° C.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]2[N:6]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.C([Li])CCC.[F:24][C:25]([F:39])([F:38])[C:26]([C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]([CH3:37])[CH:29]=1)=[O:27]>COCCOCCOC.CCOCC>[F:16][C:13]1[CH:14]=[CH:15][C:10]([N:6]2[C:5]3[CH:17]=[CH:18][C:2]([C:26]([OH:27])([C:28]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]([CH3:37])[CH:29]=4)[C:25]([F:24])([F:39])[F:38])=[CH:3][C:4]=3[NH:8][C:7]2=[O:9])=[CH:11][CH:12]=1
Reactant: Cn1cc(C(=O)C(F)(F)F)c2ccccc21
Reactant: O=c1[nH]c2cc(Br)ccc2n1-c1ccc(F)cc1
Agent: [Li]CCCC
Solvent: COCCOCCOC
Solvent: CCOCC
Product: Cn1cc(C(O)(c2ccc3c(c2)[nH]c(=O)n3-c2ccc(F)cc2)C(F)(F)F)c2ccccc21
Reaction time: 0.5 h

Procedure:
To a chilled (−78° C.) solution of 5-bromo-1-(4-fluorophenyl)-1,3-dihydrobenzimidazol-2-one (152 mg, 0.5 mmol) in anhydrous bis(2-methoxyethyl)ether (10 mL) was added 0.5 mL (1.25 mmol) of a solution of 2.5 M n-butyllithium in hexanes. After 30 minutes, a solution of 2,2,2-trifluoro-1-(1-methyl-1H-indol-3-yl)ethanone (114 mg) in bis(2-methoxyethyl) in 1 mL of ether was added. The mixture stirred for 1 hour and was quenched with ammonium chloride solution. The resulting precipitate was filtered, washed with water, and dried to afford the title compound as an off-white solid. MS m/z 456 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:15][C:16]([OH:18])=O)[CH:7]=[CH:8][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:2].[CH3:19][CH:20]([CH3:36])[CH2:21][C@H:22]([NH2:35])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:15][C:16]([NH:35][C@H:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N:29]2[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]2)[CH2:21][CH:20]([CH3:36])[CH3:19])=[O:18])[CH:7]=[CH:8][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:2]
Reactant: CCOC(=O)c1ccc(CC(=O)O)cc1OCC
Reactant: CC(C)C[C@H](N)c1ccccc1N1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(CC(=O)N[C@@H](CC(C)C)c2ccccc2N2CCCCC2)cc1OCC

Procedure:
2.77 g (11 mMol) of 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid are added at ambient temperature to a solution of 2.71 g (11 mMol) of anhydrous (S)-3-methyl-1-(2-piperidino-phenyl)-1-butylamine (ee=98.5%) in 30 ml of absolute toluene and the mixture is stirred until dissolved. Then 2.38 g (11.55 mMol) of N,N'-dicyclohexyl-carbodiimide are added and the mixture is stirred at ambient temperature. After 24 hours a further 0.54 g (2.14 mMol) of 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid and 0.48 g (2.33 mMol) of N,N'-dicyclohexylcarbodiimide are added and the mixture is stirred overnight. It is then cooled to an internal temperature of +5° C. and suction filtered to separate the precipitate, which is washed once with 5 ml of toluene. The combined toluene filtrates are evaporated down in vacuo to a volume of about 10 ml. The resulting solution is heated over the steam bath and petroleum ether is added in batches thereto (total of 55 ml) until the turbidity remains. It is cooled in ice, whereupon crystallisation takes place. It is suction filtered and dried at 75° C./4 torr. The product obtained (4.57 g; melting point 111-112° C.; ee=98.9%) is suspended in 50 ml of petroleum ether. The mixture is heated over the steam bath and sufficient toluene is added in batches (8 ml in total) until a solution is obtained. This is then cooled in ice and suction filtered to separate the crystals, which are dried at 75° C./4 torr.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:17]([C@@H:19]([NH2:41])[CH:20]([OH:40])[CH:21]([NH:23][S:24]([C:27]1[CH:39]=[CH:38][C:30]2[O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:29]=2[CH:28]=1)(=[O:26])=[O:25])[CH3:22])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[C:1]([NH:11][C@H:12]([C:17]([C@H:19]([NH2:41])[C:20](=[O:40])[CH:21]([NH:23][S:24]([C:27]1[CH:39]=[CH:38][C:30]2[O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:29]=2[CH:28]=1)(=[O:25])=[O:26])[CH3:22])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)[C@@H](N)C(O)C(C)NS(=O)(=O)c1ccc2oc3ccccc3c2c1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)[C@H](N)C(=O)C(C)NS(=O)(=O)c1ccc2oc3ccccc3c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.2 %

Procedure:
1-(Cbz-leucinyl)-amino-3-(2-dibenzofuransulfonamido)-(S)-butan-2-ol (240 mg, 0.4 mmol) was dissolved in acetone (2 ml). Jones reagent (0.5 ml, 1.5 M) was added dropwise and the reaction was stirred at RT overnight. The excess Jones reagent was then quenched with isopropanol (1.0 ml), then the reaction was diluted with EtOAc (20 ml) and was extracted with water (2×20 ml) to remove the inorganic salts. The combined organics were dried with magnesium sulfate, filtered, concentrated, and chromatographed (silica gel, 2-5% MeOH/methylene chloride) to give the tide compound as a white solid (70 mg, 29%). MS(ES) M−H−=578.