Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].Br[CH2:3][C:4]1[C:5]([CH2:10]Br)=[CH:6][CH:7]=[CH:8][CH:9]=1.[C:12](#[N:17])[CH2:13][C:14]([CH3:16])=[O:15].O>C(O)C.CCOCC>[C:14]([C:13]1([C:12]#[N:17])[CH2:10][C:5]2[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:3]1)(=[O:15])[CH3:16]
Reactant: CC(=O)CC#N
Reactant: BrCc1ccccc1CBr
Agent: [Na]
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: CC(=O)C1(C#N)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium (13.2 g) was dissolved in dry ethanol (220 ml). Dry diethyl ether (270 ml) was added. To the solution were simultaneously added α,α'-dibromo-o-xylene (85.2 g), dry ether (250 ml) and acetoacetonitrile (45.6 g) in dry ether (160 ml) over a period of one hour. (Acetoacetonitrile had been prepared by the method described in U.S. Pat. No. 4,152,336.) After the addition, the mixture was stirred for 1 hour at room temperature and then refluxed for 2 hours. The cooled reaction mixture wa poured into water. The ether layer was separated and the water layer was extracted once more with ether. The combined ether solutions were washed with water, dried (MgSO4) and evaporated. The yield of crude product was 73.8 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:19])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[C:17]#[N:18].[NH2:20][C:21]1[CH:22]=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2>>[C:17]([C:10]1[CH:11]=[C:12]([C:14]([NH:20][C:21]2[CH:22]=[N:23][C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:16])[S:13][C:9]=1[S:8][C:7]1[C:6]([Cl:19])=[CH:5][N:4]=[CH:3][C:2]=1[Cl:1])#[N:18]
Reactant: Nc1cnc2ccccc2c1
Reactant: N#Cc1cc(C(=O)O)sc1Sc1c(Cl)cncc1Cl
Product: N#Cc1cc(C(=O)Nc2cnc3ccccc3c2)sc1Sc1c(Cl)cncc1Cl

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-cyano-thiophene-2-carboxylic acid (47 mg, 0.14 mmol) from step C of example 203 and 3-amino-quinoline (40 mg, 0.15 mmol). The crude material was purified by reverse phase HPLC and the title compound was obtained as a yellow solid (14.9 mg, 23% yield). MS m/z: 456.98, 458.97 [M+H]+.
Reaction SMILES: Br.C(OC(=O)[NH:11][C:12]([C:28]1[NH:29][CH:30]=[C:31]([CH2:33][C:34]([CH3:38])([CH3:37])[CH2:35][CH3:36])[N:32]=1)([CH3:27])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=2)=[CH:16][CH:15]=1)C1C=CC=CC=1>C(Cl)Cl>[CH3:37][C:34]([CH3:38])([CH2:35][CH3:36])[CH2:33][C:31]1[N:32]=[C:28]([C:12]([NH2:11])([CH3:27])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=3)=[CH:16][CH:15]=2)[NH:29][CH:30]=1
Reactant: CCC(C)(C)Cc1c[nH]c(C(C)(Cc2ccc(-c3ccc(F)cn3)cc2)NC(=O)OCc2ccccc2)n1
Agent: Br
Solvent: ClCCl
Product: CCC(C)(C)Cc1c[nH]c(C(C)(N)Cc2ccc(-c3ccc(F)cn3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Hydrogen bromide (37 wt % in acetic acid) (1 mL) was added to a solution of benzyl {1-[4-(2,2-dimethylbutyl)-1H-imidazol-2-yl]-2-[4-(5-fluoropyridin-2-yl)phenyl]-1-methylethyl}carbamate (Example 58) (10 mg, 0.02 mmol) in methylene chloride (0.5 mL). After stirring at ambient temperature for 1 h, volatiles were removed in vacuo, azeotroping with toluene. The residue was diluted with 1 N aqueous sodium hydroxide and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (sodium sulfate) and concentrated in vacuo to afford the title compound. (M+H) found: 381.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:10][CH:9]([CH3:11])[O:8][C:7]([CH3:13])([CH3:12])[C:6]=2[CH:14]=1.[C:15]([O:19][C:20]([N:22]1[CH:26]=[CH:25][CH:24]=[C:23]1B(O)O)=[O:21])([CH3:18])([CH3:17])[CH3:16].[CH3:30][N:31](C=O)C.S([O-])([O-])(=O)=O.[NH4+].[NH4+]>C1COCC1.C(OCC)(=O)C>[C:15]([O:19][C:20]([N:22]1[C:26]([C:2]2[CH:3]=[CH:4][C:5]3[NH:10][CH:9]([CH3:11])[O:8][C:7]([CH3:13])([CH3:12])[C:6]=3[CH:14]=2)=[CH:25][CH:24]=[CH:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17].[C:30]([C:23]1[N:22]([C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])[C:26]([C:2]2[CH:3]=[CH:4][C:5]3[NH:10][CH:9]([CH3:11])[O:8][C:7]([CH3:13])([CH3:12])[C:6]=3[CH:14]=2)=[CH:25][CH:24]=1)#[N:31]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: CC1Nc2ccc(Br)cc2C(C)(C)O1
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1Nc2ccc(-c3ccc(C#N)n3C(=O)OC(C)(C)C)cc2C(C)(C)O1
Product: CC1Nc2ccc(-c3cccn3C(=O)OC(C)(C)C)cc2C(C)(C)O1
Temperature: -78 °C
Reaction time: 2 h
Yield: 1.78 %

Procedure:
tert-Butyl-5-(2,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1 H-pyrrole-1-carboxylate was prepared according to the coupling procedure for Example 17 from 6-bromo-2,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazine and 1-t-butoxycarbonylpyrrol-2-yl boronic acid. To a solution of tert-butyl-5-(2,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazim-6-yl)-1H-pyrrole-l-carboxylate (1 g, 2.9 mmol) in anhydrous THF (20 mL) was added at −78° C. under nitrogen chlorosulfonyl isocyanate (0.35 mL, 4.0 mmol). The mixture was kept stirring at −78° C. under nitrogen for 2 hours, treated with anhydrous DMF (5 mL), and allowed to warm to room temperature. Aqueous ammonium sulfate solution (50 mL) and ethyl acetate (100 mL) was added and organic layer was separated, dried (MgSO4), and evaporated. The residue was purified by a silica gel column chromatography(hexane:ethyl acetate/4:1) to afford the title compound as a white solid (0.019 g, 1.78%): 1H-NMR (DMSO-d6) δ 7.48 (d, 1H, J=2.0 Hz), 7.36 (dd, 1H, J=8.3, 2.0 Hz), 7.32 (d, 1H, J=3.6 Hz), 7.14 (d, 1H, J=8.3 Hz), 6.46 (d, 1H, J=4.0 Hz), 5.35 (q, 1H, J=5.2 Hz), 1.58 (d, 3H, J=5.6 Hz), 1.56 (s, 3H), 1.51 (s, 3H), 1.38 (s, 9H); MS (ESI) m/z 366 [M−-H]−.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[N:7]([CH:10]([C:25]([NH:27]O)=[NH:26])[CH2:11][CH2:12][C@H:13]([O:23][CH3:24])[CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].[C:30]([C:36]([O:38][CH3:39])=[O:37])#[C:31][C:32](OC)=[O:33].C[OH:41]>>[CH2:16]([O:15][CH2:14][C@@H:13]([O:23][CH3:24])[CH2:12][CH2:11][CH:10]([C:25]1[NH:27][C:32](=[O:33])[C:31]([OH:41])=[C:30]([C:36]([O:38][CH3:39])=[O:37])[N:26]=1)[N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:29])[CH2:8][CH3:9])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)C#CC(=O)OC
Reactant: CO
Reactant: CCN(C(=O)OC(C)(C)C)C(CC[C@@H](COCc1ccccc1)OC)C(=N)NO
Product: CCN(C(=O)OC(C)(C)C)C(CC[C@@H](COCc1ccccc1)OC)c1nc(C(=O)OC)c(O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl{(4S)-5-(benzyloxy)-1-[(hydroxyamino)(imino)methyl]-4-methoxypentyl}ethylcarbamate (72.6 g, 177 mmol) in MeOH (1773 ml) at 0° C. was added dimethyl acetylene dicarboxylate (26.3 mL, 213 mmol). The reaction mixture was stirred at ambient temperature overnight and then concentrated in vacuo. The residue was dissolved in toluene and concentrated in vacuo (3×) to remove MeOH. The crude product was used in the next reaction without purification. LC-MS: 553.5 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]=[O:12].N1C=CC=CC=1.[CH2:20]([OH:29])[CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([O:29][CH2:20]/[CH:21]=[CH:22]/[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:12]
Reactant: OCC=Cc1ccccc1
Reactant: COC(=O)c1ccccc1N=C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccccc1NC(=O)OC/C=C/c1ccccc1
Reaction time: 12 h
Yield: 85 %

Procedure:
A solution of methyl-2-isocyanatobenzoate (71)(1 g, 5.6 mmol) in CH2Cl2 (100 mL) was cooled to 0° C. and treated with pyridine (7 mL, 84 mmol). Cinnamyl alcohol (2.25 g, 1.68 mmol) in CH2Cl2 (150 mL) was added dropwise to the stirring solution over a period of 1 hour and the reaction mixture was allowed to stir for 12 hours, under nitrogen. The reaction mixture was washed in brine (100 mL). The aqueous phase was washed with CH2Cl2 (3×100 mL). The organic phases were combined and washed with 1N HCl (200 mL) and dried over MgSO4. Purification was achieved through flash column chromatography (80% Pet ether:EtOAc) to furnish the carbamate (72) as a colourless solid (85%). 1H NMR (250 MHz, CDCl3) δ 10.9 (br, s, 1H, NH), 8.45 (dd. 1H, J=1.0, 8.5 Hz, aromatic H), 8.01 (dd, 1H, J=1.66, 8.0 Hz, aromatic H), 7.54 (ddd, 1H, J=1.67, 7.3, 8.5 Hz, aromatic H), 7.5-7.2 (m, 5H, coc aromatic H), 7.03 (ddd, 1H, J=1.2, 8.0 Hz, aromatic H), 6.71 (d, 1H, J=16 Hz, 3′-H), 6.35 (dt, 1H, J=6.3, 16 Hz, 2′-H), 4.48 (dd, 2H, J=1.3, 6.3, 1′-H), 3.91 (s, 1H); 13C NMR (62.9 MHz, CDCl3) δ 169.0 (ester carbonyl), 153.5 (CO-carbamate), 141.9 (aromatic quat), 136.8 (aromatic quat), 135.0 (methine), 131.3 (methine), 129.0 (methine), 128.4 (methine), 127.1 (methine), 123.9 (alkenic methine), 122.0 (methine), 119.3 (methine). 114.8 (aromatic quat), 66.1 (methylene-Coc), 57.7 (OCH3). IR (neat) ν 3295, 3116, 3025, 2957, 2242, 1956, 1927, 1814, 1732, 1697, 1592, 1532, 1450, 1305, 1245, 1165, 1090, 1038, 976, 913, 856, 836, 819, 766, 743, 692 cm−1; MS m/z 311 (M+. +1), 268, 212, 188, 152, 117.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[CH:4][CH:3]=1.O=[C:11]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12](OCC)=[O:13].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([N:7]=1)=[N:8][C:11]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[C:12]([OH:13])[N:9]=2
Reactant: CCOC(=O)C(=O)c1ccccc1
Reactant: Nc1ccc(Cl)nc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Oc1nc2ccc(Cl)nc2nc1-c1ccccc1
Reaction time: 72 h

Procedure:
To a stirred solution of 6-chloropyridine-2,3-diamine (8-1, Oguchi, et. al. J. Med. Chem. (2000), 43, 3052-3066; 15 g, 105 mmol) in DMF (53 mL) was added ethyl oxo(phenyl)acetate (23 mL, 160 mmol) and DIPEA (37 ml, 210 mmol). After 72 hours, the reaction was concentrated to dryness. The resulting material was suspended in ethyl acetate/water and filtered to give 8-2 as a solid. The organic phase was washed with water, NaHCO3 and brine, dried over sodium sulfate, filtered and concentrated. The crude mixture was suspended in DCM (200 mL) and filtered to give another batch of 8-2 as a solid. MS calculated: 257.7; observed: 258.0.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[N:27][NH:28][CH:29]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1.C(O)C.O>[NH:27]1[CH:26]=[C:25]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][C:10]=3[F:16])[CH:5]=[CH:4][N:3]=2)[CH:29]=[N:28]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: Nc1ccc(Oc2ccnc(Cl)c2)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1ccc(Oc2ccnc(-c3cn[nH]c3)c2)c(F)c1
Temperature: 100 °C
Yield: 78.1 %

Procedure:
To a solution of 4-(2-chloropyridin-4-yloxy)-3-fluoroaniline (3.0 g, 12.6 mmol, from Example A2) in a solvent comprised of toluene/ethanol/water (4:4:1, 50 mL) was added 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (3.17 g, 16.4 mmol), sodium carbonate (4.01 g, 37.8 mmol) and tetrakis(triphenylphosphine)palladium (0.73 g, 0.63 mmol). The headspace was evacuated and back-filled with nitrogen (3×) and then the reaction mixture was heated to 100° C. overnight. The reaction was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give 4-(2-(1H-pyrazol-4-yl)pyridin-4-yloxy)-3-fluoroaniline (2.66 g, 78% yield). 1H NMR (400 MHz, DMSO-d6): δ 13.03 (brs, 1H), 8.28-8.31 (m, 2H), 7.99 (s, 1H), 7.24 (s, 1H), 6.95-7.00 (m, 1H), 6.39-6.50 (m, 3H), 5.43 (brs, 2H); MS (ESI): m/z 271.1 [M+H]+.
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CN(C)C=O.C(N(C(C)C)C(C)C)C.[Cl:33][C:34]1[CH:48]=[CH:47][C:37]2[N:38]=[C:39]([N:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)[S:40][C:36]=2[CH:35]=1>>[Cl:33][C:34]1[CH:48]=[CH:47][C:37]2[N:38]=[C:39]([N:41]3[CH2:46][CH2:45][N:44]([C:9]([C:8]4[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:7]=4[N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[O:11])[CH2:43][CH2:42]3)[S:40][C:36]=2[CH:35]=1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Reactant: Clc1ccc2nc(N3CCNCC3)sc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc([N+](=O)[O-])ccc1N1CCOCC1)N1CCN(c2nc3ccc(Cl)cc3s2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 0.25 mmol 2-morpholin-4-yl-5-nitro-benzoic acid (Example 2.1) in 0.7 ml dimethylformamide 0.26 mmol TBTU, 1.6 mmol N-ethyldiisopropylamine and 0.25 mmol 6-chloro-2-piperazin-1-yl-benzothiazole were successively added. The reaction was then stirred at RT for two hours, concentrated in vacuo and treated with 5 ml water. The solid is filtered off and recrystallized form methanol to yield the title compound as a yellow solid.
Reaction SMILES: [OH-].[Na+].[C:3]1([C:9]2[N:14]3[CH:15]=[C:16]([CH2:18][O:19][C:20]4[CH:41]=[CH:40][C:23]([CH2:24][O:25]/[N:26]=[C:27](/[C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)\[CH2:28][CH2:29][C:30]([O:32]C)=[O:31])=[CH:22][CH:21]=4)[N:17]=[C:13]3[CH:12]=[CH:11][CH:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CO.Cl>O1CCCC1>[C:3]1([C:9]2[N:14]3[CH:15]=[C:16]([CH2:18][O:19][C:20]4[CH:21]=[CH:22][C:23]([CH2:24][O:25]/[N:26]=[C:27](/[C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)\[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:40][CH:41]=4)[N:17]=[C:13]3[CH:12]=[CH:11][CH:10]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)CC/C(=N\OCc1ccc(OCc2cn3c(-c4ccccc4)cccc3n2)cc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CC/C(=N\OCc1ccc(OCc2cn3c(-c4ccccc4)cccc3n2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added to a solution of methyl E-4-[4-(5-phenylimidazo[1,2-α]pyridin-2-ylmethoxy)benzyloxyimino]-4-phenylbutyrate (400 mg) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at room temperature for 1 hour. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-4-[4-(5-phenylimidazo[1,2-α]pyridin-2-ylmethoxy)benzyloxyimino]-4-phenylbutyric acid (365 mg, yield 94%) as colorless crystals. m.p. 160-161° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[O:7].C([N-]C(C)C)(C)C.[Li+].[Br:16][C:17]([CH2:19]Br)=[CH2:18]>C1COCC1>[Br:16][C:17](=[CH2:18])[CH2:19][CH:4]1[CH2:5][CH2:6][N:2]([CH3:1])[C:3]1=[O:7]
Reactant: C=C(Br)CBr
Reactant: CN1CCCC1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(Br)CC1CCN(C)C1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 56.9 %

Procedure:
1-Methyl-2-pyrrolidinone (3.87 mL, 40-3 mmol) was combined with 25 mL of THF and cooled to −78° C. Lithium diisopropylamide (26.9 mL, 40.3 mmol) (1.5M in THF) was added slowly and the mixture was agitated for 30 minutes. 2,3-Dibromopropene (4.93 mL, 40.3 mmol) was added and the mixture was agitated overnight and allowed to warm up to ambient temperature. The reaction was quenched with sodium bicarbonate solution and extracted twice with ether. The extracts were washed with brine and evaporated. The crude product was purified by chromatography on silica gel, eluting with 30-50% ethyl acetate/hexane, to provide the title compound (5.01 g, 56.9% yield) as clear oil.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[F:6][C:7]1[CH:8]=[C:9]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]([NH2:13])=[CH:11][CH:12]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:1][CH2:2][C:3]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([F:6])=[CH:8][C:9]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(F)cc1Nc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CCl)Nc1ccc(F)cc1Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 43.9 %

Procedure:
Chloroacetyl chloride (0.68 mL, 8.58 mmol) was added dropwise to a stirred solution of 4-fluoro-N2-phenylbenzene-1,2-diamine (1.24 g, 6.13 mmol) and pyridine (2.0 mL, 24.5 mmol) in DCM (8 mL) at 0° C. under a nitrogen atmosphere. Stirring at 0° C. was continued for 20 min then at RT for 2 h. The reaction mixture was partitioned between aq. 1M HCl (50 mL) cooled to 0° C. and DCM. The aqueous phase was further extracted with DCM (×3) and the combined organic fractions were washed with water, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 30-100% DCM in cyclohexane) to afford the title compound as a white crystalline solid (750 mg, 44%). LCMS (Method C): RT 3.39 min [M+H]+ 279.2.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=[O:13].NCCC(O)=O>C(O)(=O)C>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:1]=[C:17]2[NH:11][C:12](=[O:13])[NH:14][C:15]2=[O:16])=[CH:3][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: O=C1CNC(=O)N1
Agent: NCCC(=O)O
Solvent: CC(=O)O
Product: COc1ccc(C=C2NC(=O)NC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 136 g of p-anisaldehyde, 110 g. of hydantoin and 20 g. of β-alanine in 400 ml. of acetic acid is heated under reflux for seven hours. After a short period at reflux a clear solution is obtained; however, a solid appears after a few hours. The mixture is stirred at room temperature overnight, diluted with 400 ml. of water, filtered and the solid washed first with methanol and next with water. The solid is then slurried in 1.5 liters of boiling ethanol and filtered while still hot. The solid is dried in a vacuum oven to give the above named compound as a bright yellow solid, mp. 250°-253° C.
Reaction SMILES: CC(C)([O-])C.[K+].C(O)(C)(C)C.[CH3:12][O:13][C:14](=[O:20])[CH2:15][C:16](=[O:19])[CH2:17][CH3:18].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[F:30]>O1CCCC1.O>[CH3:12][O:13][C:14](=[O:20])[CH:15]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[F:30])[C:16](=[O:19])[CH2:17][CH3:18]
Reactant: CCC(=O)CC(=O)OC
Reactant: Fc1ccc(CBr)c(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CCC(=O)C(Cc1ccc(F)cc1F)C(=O)OC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A suspension of potassium tert-butoxide (3.2 g) in anhydrous tetrahydrofuran (40 mL) at 0° C. was treated with a mixture of tert-butanol (0.15 mL) and 3-oxopentanoic acid methyl ester (3.8 g). The mixture was warmed to room temperature over 30 minutes and then a solution of 1-bromomethyl-2,4-difluorobenzene (6.0 g) in tetrahydrofuran (10 mL) was added and the resulting mixture stirred at room temperature for 72 hours. The mixture was diluted with water (10 mL) and the tetrahydrofuran removed under reduced pressure. The residue was partitioned between ethyl acetate and dilute aqueous ammonium chloride solution and the aqueous phase extracted with diethyl ether. The combined organic phases were dried over magnesium sulfate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of toluene, dichloromethane and ethyl acetate (4:1:0 to 0:1:0 to 0:25:1 by volume) to afford title compound as colourless oil, 4.5 g.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:24][CH2:23][CH2:22][C:21]([C:32]([O:34]C)=[O:33])=[CH:20][C:19]=3[CH:36]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl.O1CCC[CH2:42]1>CO>[CH3:42][CH:24]1[CH2:23][CH2:22][C:21]([C:32]([OH:34])=[O:33])=[CH:20][C:19]2[CH:36]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:10][CH:11]=3)[CH:16]=[CH:17][C:18]=2[N:25]1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCCN3c2ccccc2)cc1
Reactant: C1CCOC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCC(C)N3c2ccccc2)cc1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
Methyl 8-(4-(2-butoxyethoxy)phenyl)-1-phenyl-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxylate (230 mg) was dissolved in tetrahydrofuran (15 ml) and methanol (15 ml), after which an aqueous 1N sodium hydroxide solution (5 ml) was added. The mixture was stirred for 3 hours at 90° C. After adding water at 0° C., the reaction mixture was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure to give methyl 8-(4-(2-butoxyethoxy)phenyl)-1-phenyl-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxylic acid (220 mg) as a yellow amorphous material.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2N(O)N=[N:7][C:5]=2C=1.C(N)CCCC.[C:17]([O:21][C:22]([NH:24][C@@H:25]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:40][C:39](=[O:41])[N:38]([CH2:42][C:43]3[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=3)[S:37]2(=[O:52])=[O:51])=[CH:32][CH:31]=1)[C:26]([OH:28])=O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[C:17]([O:21][C:22](=[O:23])[NH:24][C@H:25]([C:26](=[O:28])[NH:7][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[CH2:29][C:30]1[CH:31]=[CH:32][C:33]([N:36]2[CH2:40][C:39](=[O:41])[N:38]([CH2:42][C:43]3[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=3)[S:37]2(=[O:52])=[O:51])=[CH:34][CH:35]=1)([CH3:18])([CH3:19])[CH3:20]
Reactant: COc1ccc(CN2C(=O)CN(c3ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc3)S2(=O)=O)cc1
Reactant: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCCCCN
Product: CCCCCNC(=O)[C@H](Cc1ccc(N2CC(=O)N(Cc3ccc(OC)cc3)S2(=O)=O)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
HOBt (27 mg, 0.175 mmol), pentyl amine (0.020 mL, 0.175 mmol) and 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride (37 mg, 0.192 mmol) are added to a solution of the title A compound in Example 47, (S)-2-t-butoxycarbonylamino-3-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionic acid (91 mg, 0.175 mmol) in CH2Cl2 (4 mL) and the reaction is stirred at RT for 2 h. The mixture is concentrated and the product is taken up in EtOAc, washed with 1N aqueous HCl, saturated aqueous NaHCO3 and brine. The organic solution is dried over anhydrous MgSO4, filtered and concentrated to give a white solid. Chromatography on a 10 g silica gel RediSep (Isco Inc.) column with a 30 mL/min gradient elution of 30:70 (EtOAc:hexane) to 60:40 over 10 min yields ((S)-2-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-1-pentylcarbamoyl-ethyl)-carbamic acid t-butyl ester as a white solid: [M+1]+=589.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][C:10]1[C:11]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)=[N:12][C:13]([Cl:17])=[N:14][C:15]=1[CH3:16]>CN(C)C=O>[ClH:17].[CH3:9][C:10]1[C:11]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)=[N:12][C:13]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)=[N:14][C:15]=1[CH3:16]
Reactant: Cc1nc(Cl)nc(N2CCc3ccccc3C2)c1C
Reactant: Nc1ccc(F)cc1
Solvent: CN(C)C=O
Product: Cc1nc(Nc2ccc(F)cc2)nc(N2CCc3ccccc3C2)c1C
Product: Cl
Yield: 48.4 %

Procedure:
After 4-fluoroaniline(0.7 ml, 7.4 mmol) was added to a mixture solution of 5,6-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-2-chloropyrimidine(1.0 g, 3.6 mmol) and dimethylformamide(5 ml), 0.67 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 1.