Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])=[O:17])[CH:11]=[CH:12][C:13]=1[OH:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:46][N:47]([CH3:52])[CH2:48][CH2:49][CH2:50]O.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])=[O:17])[CH:11]=[CH:12][C:13]=1[O:14][CH2:50][CH2:49][CH2:48][N:47]([CH3:52])[CH3:46]
Reactant: Cn1ncc(Cl)c1-c1cc(NC(=O)Nc2ccc(F)cc2F)ccc1O
Reactant: CN(C)CCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)CCCOc1ccc(NC(=O)Nc2ccc(F)cc2F)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.4 %

Procedure:
To a solution of 1-[3-(4-chloro-2-methyl-2H-pyrazol-3yl)-4-hydroxy-phenyl]-3-(2,4-difluoro-phenyl)urea (see above) (0.035 g, 0.09 mmol) in THF (3 mL), triphenyl phosphine (0.071 g, 0.27 mmol) and 3-dimethylamino propanol (31.6 μL, 0.27 mmol) were added followed by dropwise addition of diisopropyl azodicarboxylate (DIAD) (52.3 μL, 0.27 mmol). The reaction mixture was stirred at room temperature for 2 hours, concentrated to give a crude product that was purified via preparative HPLC. The corresponding fractions were collected, neutralized with 1N NaOH and extracted with EtOAc four times. A second purification by flash chromatography (SiO2, CH2Cl2/MeOH gradient elution) afforded Compound 133 as an off-white solid in 25.4% yield. LCMS m/z (%)=464 (M+H 35Cl, 100), 466 (M+H 37Cl, 39). 1H NMR (400 MHz, DMSO-d6) δ: 9.02 (s, 1H), 8.47 (s, 1H), 8.07-8.01 (m, 1H), 7.62 (s, 1H), 7.51 (d, J=8.90 Hz, 1H), 7.38 (s, 1H), 7.33-7.28 (m, 1H), 7.15 (d, J=9.02 Hz, 1H), 7.03-6.97 (m, 1H), 4.11-3.94 (m, 2H), 3.63 (s, 3H), 2.28-2.18 (m, 2H), 2.11 (s, 6H), 1.78-1.69 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11][C:12]1[NH:13][C:14]2[C:19]([N:20]=1)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=2.Br[CH2:23][CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=1>>[F:32][C:31]([F:33])([F:34])[C:29]1[CH:30]=[C:25]([CH2:24][CH2:23][N:13]2[C:12]([S:11][C:4]3[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=3[O:2][CH3:1])=[N:20][C:19]3[C:14]2=[N:15][CH:16]=[N:17][C:18]=3[NH2:21])[CH:26]=[C:27]([C:35]([F:36])([F:37])[F:38])[CH:28]=1
Reactant: FC(F)(F)c1cc(CCBr)cc(C(F)(F)F)c1
Reactant: COc1ccc(OC)c(Sc2nc3c(N)ncnc3[nH]2)c1
Product: COc1ccc(OC)c(Sc2nc3c(N)ncnc3n2CCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1

Procedure:
The title compound was prepared from 8-(2,5-dimethoxy-phenylsulfanyl)-9H-purin-6-ylamine and 1-(2-bromo-ethyl)-3,5-bis-trifluoromethyl-benzene by a procedure similar to examples 1 and 2. The compound was purified by preparative HPLC. 9-[2-(3,5-Bistrifluoromethyl-phenyl)-ethyl]-8-(2,5-dimethoxy-phenylsulfanyl)-9H-purin-6-ylamine: 1H NMR (DMSO-d6) δ 8.10 (s, 1H), 7.86 (s, 1H), 7.54 (s, 2H), 7.01 (d, J=9.0 Hz, 1H), 6.83 (dd, J=11.0, 3.0 Hz, 1H), 6.40 (d, J=2.9 Hz, 1H), 4.50 (t, J=7.2 Hz, 2H), 3.75 (s, 3H), 3.59 (s, 3H), 3.24 (t, J=7.2 Hz, 2H); LC-MS [M+H]+ 544.1.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.Cl[C:12]([CH3:15])([CH3:14])[CH3:13].[Cl-].[Al+3].[Cl-].[Cl-].O>C(Cl)Cl>[C:12]([C:5]1[S:1][C:2]([C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)=[CH:3][CH:4]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)Cl
Reactant: c1csc(-c2cccs2)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1ccc(-c2cccs2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
2,2′-bithiophene (10 g, 60.1 mmol) was dissolved in DCM (300 mL) and 2-chloro-2-methylpropane (7.95 g, 72.2 mmol) was added. Aluminum chloride (8.82 g, 66.2 mmol) was added in one portion, and the colourless solution turned a green/brown colour immediately. The reaction mixture was stirred at room temperature for 30 minutes, then was poured into water (500 mL), mixed well and separated. The aqueous portion was extracted with DCM (200 mL) and the combined organics were washed with brine (2×400 mL), dried over MgSO4, filtered and solvent removed by rotary evaporation to afford a clear, green oil (13.3 g, 99%) that was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 7.17 (dd, J=5.1, 1.1 Hz, 1H), 7.10 (dd, J=3.6, 1.1 Hz, 1H), (dd, J=5.1, 3.6 Hz, 1H), 6.98 (d, J=3.6 Hz, 1H), 6.73 (d, J=3.7 Hz, 1H), 1.40 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[Cl:26][C:27]1[CH:35]=[CH:34][C:30]2[O:31][CH2:32][O:33][C:29]=2[C:28]=1[NH2:36]>>[Cl:26][C:27]1[CH:35]=[CH:34][C:30]2[O:31][CH2:32][O:33][C:29]=2[C:28]=1[NH:36][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccc(OCCN3CCOCC3)cc12
Reactant: Nc1c(Cl)ccc2c1OCO2
Product: O=c1[nH]c2nccc(Nc3c(Cl)ccc4c3OCO4)c2c2ccc(OCCN3CCOCC3)cc12
Yield: 6.5 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 212 using 222 (90 mg, 0.25 mmol) and 5-chloro-benzo[1,3]dioxol-4-ylamine (56 mg, 0.33 mmol) to provide 225 (8 mg, 6% yield) as a white solid. LC-MS (M+H=568, obsd.=568).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10](Cl)(=[O:12])=[O:11])=[C:5]([O:14][CH3:15])[CH:4]=1)#[N:2].[Br:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19]>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[Br:16])(=[O:12])=[O:11])=[C:5]([O:14][CH3:15])[CH:4]=1)#[N:2]
Reactant: COc1cc(C#N)ccc1NS(=O)(=O)Cl
Reactant: Nc1ccccc1Br
Solvent: CN(C)C=O
Product: COc1cc(C#N)ccc1NS(=O)(=O)Nc1ccccc1Br

Procedure:
To a solution of N-(4-cyano-2-methoxyphenyl)-sulfamoyl chloride (1 mmol) in DMF (1 mL) is added 2-bromoaniline (1 mmol). Upon completion of the reaction, an aqueous work up is performed. The crude material will be purified by either recrystalization or chromatography to give N-(4-Cyano-2-methoxyphenyl)-N′-(2-bromophenyl) sulfamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[CH:16]=2)=[CH:12][C:13]#[N:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H][H]>C(OCC)(=O)C.[Pd]>[NH2:21][C:17]1[CH:16]=[C:15]([C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:12][C:13]#[N:14])[CH:20]=[CH:19][CH:18]=1
Reactant: [H][H]
Reactant: COc1ccc(C(=CC#N)c2cccc([N+](=O)[O-])c2)cc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(C(=CC#N)c2cccc(N)c2)cc1OC
Yield: 38.8 %

Procedure:
To a solution of 3-(3,4-dimethoxyphenyl)-3-(3′-nitrophenyl)acrylonitrile (0.7 g, 2.3 mmol) in 40 mL of ethyl acetate was added 0.1 g of 10% palladium on carbon catalyst. The mixture was hydrogenated in a Parr-Shaker apparatus at 55-60 psi of hydrogen for 2.5 hours. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to afford the crude product. The crude product was purified by flash column chromatography (silica gel, 15% ethyl acetate/methylene chloride) to afford 0.25 g (56%) of a mixture of the E and Z isomers as a yellow solid: mp 100-101° C.; 1H NMR (CDCl3) δ7.30-6.59 (m, 14 H); 5.63 (s, 1 H), 5.59 (s, 1 H), 3.94 (s, 3 H), 3.91 (s, 3 H), 3.87 (s, 3 H), 3.84 (s, 3 H); 13C NMR (CDCl3) 6 163.1, 162.9, 151.1, 150.5, 148.8, 148.7, 146.5, 146.4, 140.4, 138.2, 131.5, 129.5, 129.5, 129.4, 123.2, 122.1, 119.9, 119.0, 118.4, 118.2, 116.8, 116.6, 115.9, 115.0, 112.7, 111.0, 110.7, 93.3, 92.7, 56.1, 56.0, 55.9; Anal. Calcd for C17H16N2O3. Theoretical: C, 72.84; H, 5.75; N, 9.99. Found: C, 72.48; H, 6.05; N, 9.58.
Reaction SMILES: S([NH:11][C@H](C(O)=O)CC1N=CNC=1)(C1C=CC(C)=CC=1)(=O)=O.N[C@H:23]([C@@H:31]([OH:37])[CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[NH2:11][CH:24]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[CH2:23][C@@H:31]([OH:37])[CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35]
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](Cc2c[nH]cn2)C(=O)O)cc1
Reactant: CC(C)CC[C@H](O)[C@@H](N)CC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CC(C)CC[C@H](O)CC(N)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 108.1 %

Procedure:
To a solution of Nα -t-butoxycarbonyl-Nα -methyl-Nim -tosyl-L-histidine (2.77 g) and 2(S)-amino-1-cyclohexyl-3(S)-hydroxy-6-methylheptane (1.49 g) in dry methylene chloride (60 ml) which was cooled at 0° C., was added N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide (1.25 g). The mixture was stirred at ambient temperature for 3 hours. After evaporation of the solvent, the residue was dissolved in ethyl acetate (200 ml) and the solution was washed with 0.5% hydrochloric acid, saturated sodium bicarbonate solution and water successively, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (1% methanol in chloroform as eluent) to give 2(S)-(Nα -t-butoxycarbonyl-Nα -methyl-Nim -tosyl-L-histidyl)amino-1-cyclohexyl-3(S)-hydroxy-6-methylheptane (1.61 g) as an amorphous powder.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:19][CH2:18][C@H:17]([C:20]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])[CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[N:22]1([C:20]([C@H:17]2[CH2:18][CH2:19][NH:15][CH2:16]2)=[O:21])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C(=O)N2CCCC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C([C@H]1CCNC1)N1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
Pyrrolidine (51 μL, 1.03 mmol) was added to a solution of (S)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (200 mg, 0.93 mmol), HATU (391 mg, 1.03 mmol) and DIPEA (410 μL, 2.35 mmol) in DMF and the resulting mixture stirred at ambient temperature for 1 h, then concentrated in vacuo. The resulting oil was partitioned between EtOAc and water. The organic layer was separated, washed with water and brine, then dried (MgSO4) and concentrated in vacuo to give (S)-3-(pyrrolidine-1-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester as a colourless oil. TFA (3 mL) was added to a solution of (S)-3-(pyrrolidine-1-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester in DCM (10 mL) and the mixture stirred at ambient temperature for 1 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo to afford the title compound as a pale brown oil (110 mg, 70%). 1H NMR (CDCl3, 400 MHz) δ 4.01 (m, 3H); 3.52-3.41 (m, 3H); 3.25-3.11 (m, 2H); 3.10-2.97 (m, 2H); 2.89 (dt, J=11.4, 7.5 Hz, 1H); 2.11-1.99 (m, 1H); 2.01-1.91 (m, 2H) and 1.93-1.82 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([OH:15])=[CH:6][C:7]([N+:12]([O-:14])=[O:13])=[C:8]([CH:11]=1)[CH:9]=[O:10])[CH3:2].[N+:16]([O-])([OH:18])=[O:17]>ClCCl>[CH2:1]([O:3][C:4]1[C:5]([OH:15])=[C:6]([N+:16]([O-:18])=[O:17])[C:7]([N+:12]([O-:14])=[O:13])=[C:8]([CH:11]=1)[CH:9]=[O:10])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCOc1cc(C=O)c([N+](=O)[O-])cc1O
Solvent: ClCCl
Product: CCOc1cc(C=O)c([N+](=O)[O-])c([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5-Ethoxy-4-hydroxy-2-nitro-benzaldehyde (1.6 g) was dissolved in dichloromethane (30 ml) and a solution of nitric acid in dichloromethane (2M, 13 ml) was gradually added at a temperature under 30° C. The solution was stirred at room temperature for 10 min and then it was poured into ice-cold water. The organic phase was washed with water and then it was dried and evaporated.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[N:6]=1)[CH2:3][NH2:4].[OH:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](=O)[CH3:24])=[CH:18][CH:17]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[OH:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[N:6]=2)[CH3:24])=[CH:18][CH:17]=1
Reactant: CC(=O)Cc1ccc(OCCO)cc1
Reactant: NCC(O)c1cccc(Cl)n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(Cc1ccc(OCCO)cc1)NCC(O)c1cccc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
21.2 g (0.122 mol) of 2-hydroxy-2-(6-chloro-pyridin-2-yl)-ethanamine and 21 g (0.108 mol) of 1-(4-(2-hydroxyethoxy)-phenyl)-propan-2-one are dissolved in 500 ml of absolute methanol, mixed with 7.3 g (0.122 mol) of acetic acid and 7.2 g (0.114 mol) of sodium cyanoborohydride and stirred overnight at ambient temperature. Then 300 ml of methanol are distilled off in vacuo, diluted with 400 ml of water, acidified with hydrochloric acid and then extracted three times with 250 ml of methylene chloride. The aqueous phase is then made alkaline with ammonia and extracted with methylene chloride. The organic phase obtained is dried over sodium sulphate and concentrated by evaporation, and the oil obtained initially crystallises out after a short time.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([F:11])[C:5]([NH:12][S:13]([CH2:16][CH2:17][CH3:18])(=[O:15])=[O:14])=[CH:4][CH:3]=1>CO.[OH-].[OH-].[Pd+2]>[F:11][C:6]1[C:5]([NH:12][S:13]([CH2:16][CH2:17][CH3:18])(=[O:15])=[O:14])=[CH:4][CH:3]=[CH:2][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: CCCS(=O)(=O)Nc1ccc(Cl)c(C(=O)O)c1F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCS(=O)(=O)Nc1cccc(C(=O)O)c1F
Reaction time: 2 h

Procedure:
To 6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoic acid (63, 0.69 g, 2.3 mmol) in methanol (10 mL) was added 20% palladium hydroxide on carbon (200 mg). The reaction was stirred under hydrogen at 50 psi for 2 hours. The reaction was filtered and concentrated to give the desired compound. MS (ESI) [M−H+]−=260.1.
Reaction SMILES: C(S[C:4]1[S:5][C:6](=[CH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=2[C:28]([F:31])([F:30])[F:29])[N:15]=[CH:14]3)[C:7](=[O:9])[N:8]=1)C.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][C@@H:40]1[CH2:45][OH:46])=[O:38])([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:4]2[S:5][C:6](=[CH:10][C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[N:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=3[C:28]([F:31])([F:29])[F:30])[N:15]=[CH:14]4)[C:7](=[O:9])[N:8]=2)[CH2:41][C@@H:40]1[CH2:45][OH:46])=[O:38])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1CO
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(O)cc3C(F)(F)F)c2)S1
Product: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(O)cc4C(F)(F)F)c3)S2)C[C@@H]1CO

Procedure:
(2R)2-Hydroxymethyl-4-{5-[1-(4-hydroxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperazine-1-carboxylic acid tert-butyl ester was prepared from 2-Ethylsulfanyl-5-[1-(4-hydroxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one and (2R)2-Hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure C.
Reaction SMILES: Br.[O:2]1[C:8]2[C:9]([OH:13])=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[O:21](C(OC(C)(C)C)=O)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=O>ClCCl>[OH:13][C:9]1[C:8]2[O:2][CH2:3][CH2:4][N:5]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:21])[CH2:6][C:7]=2[CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Oc1cccc2c1OCCNC2
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCOc2c(O)cccc2C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 100.9 %

Procedure:
A suspension of 2,3,4,5-tetrahydro-1,4-benzoxazepin-9-ol. hydrobromide (Preparation 85) (55.7 g, 226 mmol) in dichloromethane (DCM) (550 ml) was treated with triethylamine (47.3 ml, 339 mmol) and stirred for 20 minutes. This mixture was cooled in ice/water to ca 5° C. and treated slowly with a solution of BOC2O (59.6 ml, 249 mmol) in dichloromethane (DCM) (200 ml) at such a rate as to keep the internal temperature below 10° C. When the addition was complete, the mixture was allowed to warm to room temperature, stirred for 2 hours and allowed to stand at room temperature overnight. The mixture was washed with 0.5M hydrochloric acid (2×250 ml) and water (250 ml), dried (sodium sulphate) and evaporated to give the title compound as a pale brown solid (60.5 g)
Reaction SMILES: [NH2:1][C:2]1[C:10]2[NH:9][C:8](=[O:11])[NH:7][C:6]=2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[F:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([F:27])[C:25]=1[F:26])[C:20](O)=[O:21]>>[F:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([F:27])[C:25]=1[F:26])[C:20]([NH:1][C:2]1[C:10]2[NH:9][C:8](=[O:11])[NH:7][C:6]=2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1)=[O:21]
Reactant: Nc1cc(C(F)(F)F)cc2[nH]c(=O)[nH]c12
Reactant: O=C(O)c1cc(F)c(F)c(F)c1
Product: O=C(Nc1cc(C(F)(F)F)cc2[nH]c(=O)[nH]c12)c1cc(F)c(F)c(F)c1

Procedure:
4-Amino-6-trifluoromethyl-1,3-dihydro-benzoimidazol-2-one (2.17 g, 10 mmol, Example 61a) and 3,4,5-trifluoro-benzoic acid (1.94 g, 11 mmol, Aldrich) reacted under the conditions of Example 65 to give the title compound as a white solid. MS (ESI, pos. ion) m/e: 376 (M+1), (ESI, neg. ion) m/z: 374 (M−1)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C@H:14]([C:16]([OH:18])=O)[CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH3:20][O:21][C:22](=[O:28])[C@H:23]([C@@H:25]([CH3:27])[OH:26])[NH2:24]>C(Cl)(Cl)Cl.CO>[CH3:20][O:21][C:22](=[O:28])[C@H:23]([C@@H:25]([CH3:27])[OH:26])[NH:24][C:16](=[O:18])[C@H:14]([CH3:15])[NH:13][C:11](=[O:12])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: C[C@H](NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)O
Reactant: COC(=O)[C@@H](N)[C@@H](C)O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)Cc1cccc([N+](=O)[O-])c1)[C@@H](C)O

Procedure:
Following General Procedure C and using N-(3-nitrophenylacetyl)-L-alanine (from Example D11 above) and L-threonine methyl ester hydrochloride (Aldrich), the title compound was prepared as a solid. The reaction was monitored by tlc (Rf=0.1 in 95:5 CHCl3/MeOH) and the product was purified by silica gel chromatography using 95:5 CHCl3/MeOH as the eluent.
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([N:8]([CH:34]([CH3:36])[CH3:35])[C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[CH:17]2[CH2:26][CH2:25][C:24]3[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=3[CH2:18]2)=O)=[CH:4][CH:3]=1.Cl[CH2:40][C:41]([N:43]([CH2:46][CH3:47])[CH2:44][CH3:45])=O>>[CH2:44]([N:43]([CH2:46][CH3:47])[CH2:41][CH2:40][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:8]([CH:34]([CH3:36])[CH3:35])[C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[CH:17]2[CH2:26][CH2:25][C:24]3[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=3[CH2:18]2)=[CH:37][CH:38]=1)[CH3:45]
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)cc2)C(C)C)c1
Reactant: CCN(CC)C(=O)CCl
Product: CCN(CC)CCOc1ccc(CN(c2cc(OC)ccc2C2CCc3cc(O)ccc3C2)C(C)C)cc1
Yield: 73.2 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (30 mg) and 2-chloro-N,N-diethyl acetamide (18 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (22 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C@@:7]23[CH2:14][C@@H:13]([OH:15])[CH2:12][N:11]2[C:10](=[O:16])[N:9]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=2)[C:8]3=[O:25])=[CH:4][CH:3]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl.CCN(C(C)C)C(C)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@:7]23[CH2:14][C@@H:13]([O:15][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:12][N:11]2[C:10](=[O:16])[N:9]([C:17]2[CH:18]=[C:19]([Cl:24])[CH:20]=[C:21]([Cl:23])[CH:22]=2)[C:8]3=[O:25])=[CH:26][CH:27]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C1N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]2(Cc3ccc(Br)cc3)C[C@@H](O)CN12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)O[C@H]1CN2C(=O)N(c3cc(Cl)cc(Cl)c3)C(=O)[C@]2(Cc2ccc(Br)cc2)C1
Reaction time: 1 h

Procedure:
To a solution of (5S,7R)-5-(4-bromobenzyl)-3-(3,5-dichlorophenyl)-7-hydroxy-1,3-diazabicyclo[3.3.0]octane-2,4-dione (0.81 g) in CH2Cl2 (5 mL) and DIEA (0.50 mL) at 0° C. was added methanesulfonyl chloride (0.19 mL). After 1 hour at 0° C., the mixture was diluted with CH2Cl2, washed with satd. NaHCO3 and brine, dried (Na2SO4) and concentrated to give (5S, 7R)-5-(4-bromobenzyl)-3-(3,5-dichlorophenyl)-7-methylsulfonyloxy-1,3-diazabicyclo[3.3.0]octane-2,4-dione. MS (m/z) 494 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:15](=[O:17])[CH3:16])[N:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH:6]=1.[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:18]([NH:1][C:2]1[CH:3]=[C:4]([C:15](=[O:17])[CH3:16])[N:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH:6]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)c1cc(N)cn1Cc1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)c1cc(NCc2ccccc2)cn1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 100 mL round bottomed flask with a stirring bar, addition funnel and an argon inlet was added 1-[4-amino-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]ethanone AVI-2-1 (1.00 g, 4.31 mmol), MeOH (20 mL), benzaldehyde (0.875 mL, 8.61 mmol) and sodium cyanoborohydride (0.541 g, 8.61 mmol). The addition funnel was charged with a solution of glacial acetic acid (0.246 mL, 4.31 mmol) in MeOH (20 mL). The acetic acid solution was added dropwise to the reaction mixture over 1.5 h. When the addition was complete, the resulting mixture was stirred at ambient temperature 18 h. The solvents were removed in vacuo and the residue was partitioned between EtOAc (100 mL) and water. The layers were separated and the organic phase was washed with saturated aqueous NaHCO3, aqueous sodium potassium tartrate and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo gave an oil. This material was chromatographed on silica gel using 30% EtOAc in hexanes as eluant to give 1-[4-Benzylamino-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]ethanone AVIII-1-1 as a crystalline solid. 1H NMR (CDCl3) δ 2.34 (3H, s), 3.35 (1H, br s), 4.16 (2H, s), 5.41 (2H, s), 6.36 (1H, d, j=2.2 Hz), 6.49 (1H, d, j=2.2 Hz), 6.93 (2H, m), 7.06 (2H, m), 7.30 to 7.37 (5H, complex multiplet).
Reaction SMILES: Cl.Cl[C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH:5](OC1CNC1)[C:6]1C=CC=CC=1Cl.[N-]=C=O.[Cl:25][C:26]1[CH:51]=[CH:50][CH:49]=[CH:48][C:27]=1[CH:28]([O:36][CH:37]1[CH2:40][N:39]([C:41]([NH:43]C(C)(C)C)=[O:42])[CH2:38]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:35]>>[Cl:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH:28]([O:36][CH:37]1[CH2:38][N:39]([C:41]([NH:43][CH2:6][CH2:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:3]=2)=[O:42])[CH2:40]1)[C:27]1[CH:48]=[CH:49][CH:50]=[CH:51][C:26]=1[Cl:25]
Reactant: CC(C)(C)NC(=O)N1CC(OC(c2ccccc2Cl)c2ccccc2Cl)C1
Reactant: Clc1ccccc1C(OC1CNC1)c1ccccc1Cl
Agent: Cl
Agent: [N-]=C=O
Product: O=C(NCCc1ccccc1)N1CC(OC(c2ccccc2Cl)c2ccccc2Cl)C1

Procedure:
This material was prepared from 3-(2,2′-dichlorobenzhydryloxy)azetidine hydrochloride (68) and the corresponding commercially available isocyanate using the procedure described for compound (69).