Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[CH:4]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[N:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:15]=1)[O:5][P:6]([CH:9]([NH2:13])[CH:10]([CH3:12])[CH3:11])([OH:8])=[O:7].CCN(C(C)C)C(C)C.[C:48]1([CH:54]=[CH:55][S:56](Cl)(=[O:58])=[O:57])[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>C(Cl)Cl>[C:26]([O:25][C:23]([N:22]=[C:21]([NH:30][C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[NH:20][C:16]1[CH:15]=[C:14]([CH:4]([O:5][P:6]([CH:9]([NH:13][S:56]([CH:55]=[CH:54][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)(=[O:58])=[O:57])[CH:10]([CH3:12])[CH3:11])([OH:8])=[O:7])[C:3]([O:2][CH3:1])=[O:38])[CH:19]=[CH:18][CH:17]=1)=[O:24])([CH3:28])([CH3:29])[CH3:27]
Reactant: O=S(=O)(Cl)C=Cc1ccccc1
Reactant: COC(=O)C(OP(=O)(O)C(N)C(C)C)c1cccc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(OP(=O)(O)C(NS(=O)(=O)C=Cc1ccccc1)C(C)C)c1cccc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1
Temperature: 0 °C
Yield: 57.3 %

Procedure:
To a solution of 2-(3-(N′,N″-di(t-butoxycarbonyl)guanidino)phenyl)-2-((1-amino-2-methylpropyl)(hydroxy)phosphinoyloxy)ethanoic acid methyl ester (300 mg, 0.53 mmol) in 8 mL methylene chloride was added DIEA (0.44 mL, 1.06 mmol), which was cooled to 0° C. by an ice-water bath. Then a solution of 2-phenylethenylsulfonyl chloride (120 mg, 0.59 mmol) in 1 mL methylene chloride was added dropwise. The resulting mixture was stirred at ambient temperature for thirty minutes. The mixture was washed with water, 2N NaHSO4, and brine. The organic phase was dried over sodium sulfate and concentrated to afford a yellow solid. Purification by chromatograph on silica gel afforded a yellow solid, 2-(3-(N′,N″-di(t-butoxycarbonyl)guanidino)phenyl)-2-((1-(2-phenylethenylsulfonyl)amino-2-methylpropyl)(hydroxy)phosphinoyloxy)ethanoic acid, methyl ester, (220 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[CH:20][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClCCl.[CH2:33]([S:35](Cl)(=[O:37])=[O:36])[CH3:34]>C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27]([S:35]([CH2:33][CH3:34])(=[O:37])=[O:36])[CH2:26][CH2:25]3)=[CH:20][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N3CCNCC3)cn2)c2ccccc21
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N1CCN(c2ccc(N3CCN(C(=O)OC(C)(C)C)c4ccccc43)nc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.8 g of 4-(5-(piperazin-1-yl)pyridin-2-yl)-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester is placed in a 25 ml round-bottomed flask. 10 ml of dichloromethane are added, followed by 0.37 ml of triethylamine and finally 0.23 ml of ethylsulphonyl chloride. The reaction mixture is stirred at ambient temperature for 3 h, then washed twice with water and once with a saturated sodium chloride solution and then evaporated under reduced pressure. 0.98 g of 4-[5-(4-(ethanesulphonyl)piperazin-1-yl)pyridin-2-yl]-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester is obtained.
Reaction SMILES: [F:1][CH:2]([F:38])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]5[C:35]([OH:36])=[CH:34][CH:33]=[CH:32][C:31]=5[Cl:37])[O:27][N:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:45](Br)[CH:46]=[CH2:47].O>CC(C)=O>[CH2:47]([O:36][C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:37])[C:30]=1[CH:28]1[O:27][N:26]=[C:25]([C:23]2[N:24]=[C:20]([CH:17]3[CH2:18][CH2:19][N:14]([C:12](=[O:13])[CH2:11][N:5]4[C:6]([CH:8]([F:10])[F:9])=[CH:7][C:3]([CH:2]([F:1])[F:38])=[N:4]4)[CH2:15][CH2:16]3)[S:21][CH:22]=2)[CH2:29]1)[CH:46]=[CH2:45]
Reactant: C=CCBr
Reactant: O=C(Cn1nc(C(F)F)cc1C(F)F)N1CCC(c2nc(C3=NOC(c4c(O)cccc4Cl)C3)cs2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C=CCOc1cccc(Cl)c1C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)F)cc4C(F)F)CC3)n2)=NO1
Yield: 62.3 %

Procedure:
To a solution of 2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[5-(2-chloro-6-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone (39 mg) and potassium carbonate (47 mg) in acetone (5 ml) is added, at room temperature, allyl bromide (33 mg). The reaction mixture is stirred at reflux for 5 h. Then the mixture is admixed with water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated. Purification by column chromatography gives 1-[4-(4-{5-[2-(allyloxy)-6-chlorophenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]-2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]ethanone (26 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:14](=[S:16])[NH2:15])=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=1.Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O>C(#N)C>[Br:1][C:2]1[C:3]([C:14]2[S:16][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:15]=2)=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=1
Reactant: CCNC(=O)Nc1cc(C(N)=S)c(Br)cn1
Reactant: O=C(CBr)c1ccccc1
Solvent: CC#N
Product: CCNC(=O)Nc1cc(-c2nc(-c3ccccc3)cs2)c(Br)cn1
Temperature: 25 °C
Yield: 84.7 %

Procedure:
To a mixture of 5-bromo-2-(3-ethylureido)pyridine-4-carbothioamide (Intermediate 42, 0.146 g, 0.48 mmol) in acetonitrile (3 mL), 2-bromo-1-phenylethanone (0.105 g, 0.53 mmol) was added and the reaction mixture was heated to 80° for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting solids were filtered and washed with acetonitrile to yield 164 mg of the title compound as an off-white solid.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C@@H:13]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH3:14])=[CH:7][CH:6]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][C@@H:13]([NH:15][C:16](=[O:17])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])[CH3:14])=[CH:9][CH:10]=1
Reactant: CC(=O)Oc1ccc(OC[C@H](C)NC(=O)OC(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C[C@@H](COc1ccc(O)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 67 %

Procedure:
A mixture of 4-({(2S)-2-[(tert-butoxycarbonyl)amino]propyl}oxy)phenyl acetate (70 g), potassium carbonate (156 g) and methanol (800 mL) was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, and the obtained residue was neutralized with aqueous citric acid solution, and diluted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (40.5 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[S:14][CH:13]=[N:12][CH:11]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.Cl[C:16]1[N:17]=[CH:18][C:19]2[CH:24]=[C:23]([C:25]3[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH:30]=3)[NH:22][C:20]=2[N:21]=1.CN(C=O)C>C(O)CCC>[CH3:8][N:6]1[C:5](=[O:9])[C:4]([C:10]2[S:14][CH:13]=[N:12][CH:11]=2)=[CH:3][C:2]([NH:1][C:18]2[C:19]3[CH:24]=[C:23]([C:25]4[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH:30]=4)[NH:22][C:20]=3[N:21]=[CH:16][N:17]=2)=[CH:7]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3cnc(Cl)nc3[nH]2)CC1
Reactant: Cn1cc(N)cc(-c2cncs2)c1=O
Solvent: CCCCO
Solvent: CN(C)C=O
Product: Cn1cc(Nc2ncnc3[nH]c(C4=CCN(C(=O)OC(C)(C)C)CC4)cc23)cc(-c2cncs2)c1=O
Temperature: 120 °C
Reaction time: 15 h

Procedure:
5-Amino-1-methyl-3-thiazol-5-yl-1H-pyridin-2-one (99.0 mg, 0.478 mmol) was added to a solution of tert-butyl 4-(chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (133 mg, 0.398 mmol) in 1-butanol (2.0 L). The reaction was stirred at 120° C. for 15 h. DMF (1.5 mL) was added and the mixture was filtered. The filtrate was purified by HPLC to yield the title compound. 1H-NMR (CD3OD, 400 MHz): δ=1.50 (s, 9H), 2.57 (m, 2H), 3.67 (m, 2H), 3.73 (s, 3H), 4.13 (m, 2H), 6.30 (s, br, 1H), 6.62 (s, 1H), 8.21 (s, 1H), 8.33 (d, J=2.4 Hz, 1H), 8.34 (d, J=2.4 Hz, 1H), 8.47 (s, 1H), 8.99 (s, 1H). MS (ES+): m/z 506.08 [MH+]. HPLC: tR=2.62 min (ZQ2000, polar—5 min).
Reaction SMILES: [CH3:1][Si:2]([CH:5]=[N+:6]=[N-:7])([CH3:4])[CH3:3].C([Li])CCC.[C:13]([C:15]1[CH:16]=[C:17]([C:21]2([CH3:34])[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:23][CH:22]2[CH3:33])[CH:18]=[CH:19][CH:20]=1)#[N:14]>O1CCCC1>[CH2:27]([N:24]1[CH2:25][CH2:26][C:21]([CH3:34])([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:13]3[N:14]=[N:7][NH:6][C:5]=3[Si:2]([CH3:4])([CH3:3])[CH3:1])[CH:16]=2)[CH:22]([CH3:33])[CH2:23]1)[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CCCCCCN1CCC(C)(c2cccc(C#N)c2)C(C)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCN1CCC(C)(c2cccc(-c3nn[nH]c3[Si](C)(C)C)c2)C(C)C1
Reaction time: 0.33 h

Procedure:
To a solution of (trimethylsilyl)diazomethane (2.0 M in hexane, 400 μL, 0.80 mmol) in tetrahydrofuran (10 mL) at 0° C. under an atmosphere of nitrogen was added n-butyllithium (2.5 M in diethyl ether, 320 μL, 0.80 mmol) dropwise. After 20 min, a solution of 4-(3-cyanophenyl)-1-hexyl-3,4-dimethylpiperidine (Preparation 6, 200 mg, 0.67 mmol) in tetrahydrofuran (5 mL) was added such that the internal temperature remained at 0° C. After stirring overnight, the reaction was quenched with saturated aqueous sodium hydrogencarbonate (25 mL) and the mixture was extracted with diethyl ether (3×25 mL). The extracts were washed with water and brine (10 mL each), dried over MgSO4, filtered and concentrated in vacuo to give the title compound as a white foam which was used without further purification (266 mg, 96%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C@@H:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][NH:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:16]([OH:17])[CH2:18][N:21]([CH3:20])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H]1CO1
Product: CN(CCc1ccccc1)C[C@H](O)[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
Using general procedure 1 with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.30 g, 1.14 mmol) and N-methyl-phenethylamine (0.166 mL, 1.14 mmol) gives the title compound.
Reaction SMILES: [CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=C.[O:26]=[O+][O-].[BH4-].[Na+]>C(Cl)Cl>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]2[CH2:6][CH2:5][C@:4]([CH2:1][CH2:2][OH:26])([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[O:9][C:8]2=[O:10])[CH3:12])=[CH:14][CH:15]=1
Reactant: C=CC[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Reactant: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCO)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
To a solution of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (3 g, 7.5 mmol) in CH2Cl2 (50 mL) was treated with O3 at −78° C. till the mixture turned blue. Then NaBH4 (285 mg, 75 mmol) was added to the solution at 0° C., and the reaction solution was stirred at room temperature for 3 hours. The reaction was quenched by H2O, and the mixture was extracted with EtOAc. The combined organic phase was concentrated to give the crude product, which was purified by preparative TLC to give (S)-3-((S)-1-(4-bromo-phenyl)ethyl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one (2.5 g, 84%). 1H NMR (CDCl3): 1.48 (t, 3H), 2.05-2.41 (m, 4H), 2.71-2.92 (m, 2H), 3.51 (m, 1H), 3.71 (m, 1H), 5.58 (m, 1H), 6.73 (d, 2H), 7.12 (m, 2H), 7.23-7.45 (m, 6H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[C:12]=1[C:13]([NH2:15])=[O:14].C1(C)C=CC(S(O)(=O)=O)=CC=1.OS([O-])=O.[Na+]>CC(N(C)C)=O>[Br:1][C:2]1[N:7]=[C:6]([C:8]2[NH:15][C:13](=[O:14])[C:12]3[C:11](=[CH:19][C:18]([F:20])=[CH:17][C:16]=3[F:21])[N:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1c(N)cc(F)cc1F
Reactant: O=Cc1cccc(Br)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=c1[nH]c(-c2cccc(Br)n2)nc2cc(F)cc(F)c12
Temperature: 110 °C
Yield: 14.8 %

Procedure:
A mixture of 6-bromopicolinaldehyde (2.8 g, 15 mmol), 2-amino-4,6-difluorobenzamide (2.5 g, 10 mmol), p-toluenesulfonic acid (4.2 g, 22 mmol), NaHSO3 (2.6 g, 25 mmol) and DMA (40 mL) was heated at 110° C. for 48 h in a sealed tube. The reaction mixture was cooled to room temperature and partitioned between water and EtOAc (25 mL). The aqueous phase was extracted with EtOAc (2×25 mL). The organic layers were combined, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The product was purified by crystallization (EtOAc) to provide the title compound (500 mg, 15%): 1H NMR (500 MHz, DMSO-d6) δ 11.97 (s, 1H), 8.32 (d, J=7.7, 0.7 Hz, 1H), 8.05-7.96 (m, 1H), 7.91 (dd, J=7.7, 0.7 Hz, 1H), 7.46-7.29 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-])=O)=[C:6]([NH:8][CH:9]([CH3:11])[CH3:10])[CH:7]=1.[C:15](N1C=CN=C1)(N1C=CN=C1)=[O:16].C1COCC1>CO.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:12][C:15](=[O:16])[N:8]([CH:9]([CH3:11])[CH3:10])[C:6]=2[CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)Nc1cc(F)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)n1c(=O)[nH]c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 63.8 %

Procedure:
A mixture of (5-fluoro-2-nitrophenyl)isopropylamine (Step 1 of Example 9, 5.85 g, 30 mmol) and 10% Pd—C (600 mg) in MeOH was stirred under atmosphere of hydrogen gas at room temperature for 12 h. The catalyst was filtered off on a pad of Celite, and the filtrate was evaporated under reduced pressure. To the residue was added 1,1′-carbonyldiimidazole (4.5 g, 28 mmol) and THF (100 μL) and then stirred at 100° C. for 10 h. After cooling, the volatile materials were removed under reduced pressure and the residue was partitioned between ethylacetate and H2O. After extraction with ethylacetate (3 times), the combined organic phase was washed with brine, dried over MgSO4 and concentrated. The residue was chromatographed on a column of silica gel eluting with hexane/ethyl acetate (2:1) to give 3.47 g (60%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][NH2:12].C(N(CC)CC)C.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][NH:12][C:33](=[O:34])[C:32]1[CH:36]=[CH:37][C:29]([C:28]([F:27])([F:38])[F:39])=[CH:30][CH:31]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: NCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)c1ccc(C(F)(F)F)cc1
Yield: 79.4 %

Procedure:
To a solution of 0.21 g of 3,5-dichloro-4-(3-aminopropyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene and 0.07 g of triethylamine dissolved in 5 ml of dichloromethane was added dropwise a solution of 0.15 g of 4-trifluoromethylbenzoyl chloride dissolved in 5 ml of dichloromethane, while stirring under ice cooling. After stirring at room temperature for 6 hours, the reaction mixture was washed with water and then concentrated to give a residue. The residue was subjected to silica gel chromatography, which afforded 0.25 g of 3,5-dichloro-4-(3-(4-trifluoromethylbenzamido)propyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene (79% yield), m.p., 93.5° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:10])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Br:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2=[O:22]>>[Br:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2([OH:22])[C:2]1[CH:3]=[C:4]([CH3:10])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Reactant: COc1ccc(C)cc1Br
Product: COc1ccc(C)cc1C1(O)C(=O)Nc2ccc(Br)cc21
Yield: 90.2 %

Procedure:
With 56.3 g of 3-bromo-4-methoxy toluene and 45.2 g of 5-bromoisatin as starting materials, 62.8 g of the title compound was obtained by a similar method to Step 21-1.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=1)=[O:8].[CH2:22](C([Sn])=C(CCCC)CCCC)[CH2:23]CC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][NH:9][C:7](=[O:8])[C:6]2[CH:20]=[C:2]([CH:22]=[CH2:23])[CH:3]=[CH:4][C:5]=2[F:21])=[CH:12][C:13]=1[O:18][CH3:19]
Reactant: COc1cc(CNC(=O)c2cc(Br)ccc2F)ccc1Cl
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc(F)c(C(=O)NCc2ccc(Cl)c(OC)c2)c1
Yield: 88 %

Procedure:
To a solution of 5-bromo-N-(4-chloro-3-methoxybenzyl)-2-fluorobenzamide (2.00 g) in toluene (40 mL) were added tetrakis(triphenylphosphine)palladium (217 mg) and tributylvinyltin (1.87 g), and the mixture was heated for 4 hours under reflux. After evaporation of the solvent, the residue was partitioned between ethyl acetate and saturated potassium fluoride solution. The remaining precipitates were removed by filtration. The separated organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (3:1) to give N-(4-chloro-3-methoxybenzyl)-2-fluoro-5-vinylbenzamide as pale yellow powders (1.51 g).
Reaction SMILES: [OH2:1].[ClH:2].[NH2:3][C@H:4]([C:13]([NH:15][C@@H:16]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:22])[CH2:17][CH2:18][S:19][CH3:20])=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.OO>C(O)(=O)C>[OH2:12].[ClH:2].[NH2:3][C@H:4]([C:13]([NH:15][C@@H:16]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:22])[CH2:17][CH2:18][S:19](=[O:1])[CH3:20])=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[OH2:12].[OH2:12].[NH2:3][C@H:4]([C:13]([NH:15][C@@H:16]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:22])[CH2:17][CH2:18][S:19](=[O:1])[CH3:20])=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[ClH:2]
Reactant: CSCC[C@@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)NCCCc1ccccc1
Agent: Cl
Agent: OO
Solvent: CC(=O)O
Solvent: O
Product: CS(=O)CC[C@@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)NCCCc1ccccc1
Yield: 244.2 %

Procedure:
A solution of L-tyrosyl-N-(3-phenylpropyl)-D-methioninamide monohydrochloride monohydrate (219 mg.) and aqueous hydrogen peroxide (3%, 640 μl) in acetic acid (5 ml.) was stirred at room temperature for two and one quarter hours, then concentrated under vacuum. The residue was reevaporated under vacuum once from ethyl acetate and three times from ether. A solution of the residue in water was filtered and lyophilized, affording as an amorphous white solid L-tyrosyl-N-(3-phenylpropyl)-D-methioninamide S-oxide monohydrochloride sesquihydrate (225 mg.), whose free base is the compound of Formula II wherein Q is Met(O), R1, R2 and R5 are each hydrogen and R4 is (CH2)nY wherein n is 3 and Y is phenyl.
Reaction SMILES: [F:1][C:2]1[S:6][C:5]2[C:7]3([O:22][CH2:23][CH2:24][C:4]=2[CH:3]=1)[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][CH2:8]3.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CN1CCCN(C)C1=O.[F:44][C:45]1[CH:52]=[CH:51][CH:50]=[CH:49][C:46]=1[CH2:47]Br>O1CCCC1>[F:44][C:45]1[CH:52]=[CH:51][CH:50]=[CH:49][C:46]=1[CH2:47][CH:14]([CH2:13][N:10]1[CH2:11][CH2:12][C:7]2([C:5]3[S:6][C:2]([F:1])=[CH:3][C:4]=3[CH2:24][CH2:23][O:22]2)[CH2:8][CH2:9]1)[C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16]
Reactant: CC(C)(C)OC(=O)CCN1CCC2(CC1)OCCc1cc(F)sc12
Reactant: Fc1ccccc1CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: CC(C)(C)OC(=O)C(Cc1ccccc1F)CN1CCC2(CC1)OCCc1cc(F)sc12
Reaction time: 3 h
Yield: 79.2 %

Procedure:
To a stirred solution of tert-butyl 3-(2-fluorospiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine]-1′-yl)propanoate (4.9 g, 13.78 mmol) in tetrahydrofuran (41 mL) under N2 and cooled to −78° C., lithium bis(trimethylsilyl)amide 1M (41.35 mL, 41.45 mmol) is added dropwise. The resulting mixture is stirred at that temperature for 3 hours. Then, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.33 mL, 11.03 mmol) is added, and the resulting solution is stirred at the same temperature for 30 min. To the resulting mixture, 2-fluorobenzyl bromide (2.33 mL, 19.3 mmol) in dry tetrahydrofuran (1 mL) is added and stirring is continued. The temperature is allowed to go from −78° C. to room temperature overnight. The crude reaction mixture is quenched with aqueous saturated solution of ammonium chloride and extracted with ethyl acetate. The organic layer is decanted, dried over magnesium sulfate, the solvent is evaporated and the crude obtained is purified by normal phase Isco chromatography using ethyl acetate/hexane from 5/95 to 20/80 to yield 5.06 g of the title compound obtained as colorless oil. MS (m/z): 464 (M+1).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([S:5]([C:8]2[CH:26]=[CH:25][C:11]3[N:12]([CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[C:13]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[N:14][C:10]=3[CH:9]=2)(=[O:7])=[O:6])[CH2:2]1.C(N(CC)CC)C.Cl[CH2:35][CH2:36][OH:37]>O>[CH3:23][N:22]([CH3:24])[CH2:21][CH2:20][N:12]1[C:11]2[CH:25]=[CH:26][C:8]([S:5]([CH:3]3[CH2:4][N:1]([CH2:35][CH2:36][OH:37])[CH2:2]3)(=[O:6])=[O:7])=[CH:9][C:10]=2[N:14]=[C:13]1[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: CN(C)CCn1c(CC(C)(C)C)nc2cc(S(=O)(=O)C3CNC3)ccc21
Reactant: OCCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CN(C)CCn1c(CC(C)(C)C)nc2cc(S(=O)(=O)C3CN(CCO)C3)ccc21
Temperature: 60 °C
Reaction time: 9 h
Yield: 38.6 %

Procedure:
A mixture of 2-(5-(azetidin-3-ylsulfonyl)-2-neopentyl-1H-benzo[d]imidazol-1-yl)-N,N-dimethylethanamine (prepared in STEP A of Example 22, 554 mg, 1.46 mmol), triethylamine (226 microL, 1.61 mmol) and 2-chloroethanol (3.53 g, 43.9 mmol) was stirred at 60° C. for 9 h. The resulting mixture was diluted with water (30 mL) and extracted with dichloromethane (50 mL×3). The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude product was purified by reverse phase HPLC (0.4% aqueous ammonia-acetonitrile=96:4 to 4:96) to give the title compound (238 mg, 39%) as a clear grease.