Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Br:11])[C:8]=1[O:9][CH3:10])[NH2:5].[Br:12]Br>C(Cl)Cl>[Br:12][C:3]1[C:2]([Br:1])=[C:8]([O:9][CH3:10])[C:7]([Br:11])=[CH:6][C:4]=1[NH2:5]
Reactant: COc1c(Br)cc(N)cc1Br
Reactant: BrBr
Solvent: ClCCl
Product: COc1c(Br)cc(N)c(Br)c1Br
Reaction time: 0.75 h

Procedure:
3,5-Dibromo-4-methoxy-aniline (13.04 g, 46.42 mmol) was dissolved in DCM (500 mL) and a solution of bromine (2.38 mL, 46.42 mmol) in DCM (80 mL) was added dropwise. A thick, beige precipitate formed. After 45 minutes, the mixture was quenched with NaHCO3 solution (saturated, aq) to pH 9, the layers separated and the aqueous layer extracted into DCM (3×50 mL). The combined organic phase was washed with brine, dried over Na2SO4 and concentrated to dryness under reduced pressure to give a brown solid. The mixture was purified by chromatography, Biotage SP4, 2×120 g Si cartridges in series, 10-50% EtOAc in cyclohexane. The relevant fractions were combined to give 2,3,5-tribromo-4-methoxy-aniline which was contaminated with some 2,3,5,6-tetrabromo-4-methoxy-aniline (12.64 g). The column was eluted further to give recovered starting material 3,5-dibromo-4-methoxy-aniline (2.84 g). The recovered starting material, 3,5-dibromo-4-methoxy-aniline (2.84 g, 10.11 mmol) was dissolved in DCM (100 mL) and a solution of bromine (0.52 mL, 10.11 mmol) in DCM (5 mL) was added dropwise. The mixture was stirred at rt for 2.5 h. The mixture was quenched with NaHCO3 solution (saturated, aq) to pH 9, the layers separated and the aqueous layer extracted into DCM (3×50 mL). The combined organic phase was dried over Na2SO4 and concentrated to dryness under reduced pressure. This material was combined with the impure 2,3,5-tribromo-4-methoxy-aniline and purified by chromatography, Biotage SP4, 330 g Si cartridge, 10% EtOAc in cyclohexane. The relevant fractions were combined to give the desired compound as an orange oil, 9.95 g (60%). m/z: 357.93/359.89/361.90/363.84 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)=[O:32])=[CH:26][CH:25]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C=Nc1ccc(Br)cc1
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(Br)cc4)cc3)c2cc1OC
Yield: 64 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (52 mg) was dissolved in toluene (3 ml) with heat, 4-bromophenyl isocyanate (0.2 ml) was added, and the admixture was refluxed with heat for 50 minutes. The separated crystals were filtered and washed with toluene to obtain 56 mg of the title compound (yield: 64%).
Reaction SMILES: [OH:1][C:2](=[C:5]1[C:10](=[O:11])[O:9][C:8]([CH3:13])(C)OC1=O)[CH2:3][CH3:4].[CH2:15](O)C#C>C1C=CC=CC=1>[O:1]=[C:2]([CH2:3][CH3:4])[CH2:5][C:10]([O:9][CH2:8][C:13]#[CH:15])=[O:11]
Reactant: C#CCO
Reactant: CCC(O)=C1C(=O)OC(C)(C)OC1=O
Solvent: c1ccccc1
Product: C#CCOC(=O)CC(=O)CC
Temperature: 25 °C
Yield: 95.4 %

Procedure:
Method A. A solution of 5-(1-hydroxypropylidene)-2,2-dimethyl-[1,3]dioxane-4,6-dione (2) (2.00 g, 10.0 mmol) and 2-propynol (1.10 g, 20.0 mmol) in benzene (20 mL) is stirred at 93° C. for 3.25 h and then cooled to room temperature. After solvent removal at reduced pressure, the residue is purified on silica gel (12.5% to 14.3% ethyl acetate/hexane) to give 1.47 g (95%) of 4 as a colorless liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=1.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([O:10][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=2)[CH:3]=1
Reactant: OCc1cc(O)cc(Br)c1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OCc1cc(Br)cc(Oc2ccc(C(F)(F)F)cn2)c1
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 107 %

Procedure:
To a solution of 3-bromo-5-(hydroxymethyl)phenol (3.0 g, 14.77 mmol) in DMF (15 mL) under a N2 atmosphere was added potassium carbonate (4.08 g, 29.55 mmol) and the mixture was stirred for 20 min. 2-Chloro-5-(trifluoromethyl)pyridine (2.68 g, 14.77 mmol) was added at RT and then the reaction was refluxed at 110° C. overnight. The reaction mixture was cooled and water was added. The mixture was extracted with ethyl acetate three times. The organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness to give the title compound (5.5 g) which was used in the next step without purification. 1H NMR (500 MHz, CDCl3): δ 8.44 (s, 1H), 7.92 (d, J=8.5 Hz, 1H), 7.41 (s, 1H), 7.24 (s, 1H), 7.19 (s, 1H), 7.04 (d, J=9 Hz, 1H), 4.71 (s, 2H); m/z (348, 349.9, M+H+).
Reaction SMILES: [CH2:1]([OH:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[H-].[Na+].C1(C)C(C)=CC=CC=1.Cl[C:27]1[S:31][C:30]([C:32]([OH:34])=[O:33])=[CH:29][CH:28]=1>C(O)(=O)C>[CH2:1]([O:15][C:27]1[S:31][C:30]([C:32]([OH:34])=[O:33])=[CH:29][CH:28]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCO
Reactant: O=C(O)c1ccc(Cl)s1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1C
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)O)s1
Reaction time: 2 h

Procedure:
A mixture of 21.4 g (0.100 mole) of 1-tetradecanol, 5.9 g (0.146 mole) of sodium hydride (59.5% in oil) and 300 ml of dried xylene is heated to reflux with stirring for 2 hours then allowed to cool after which 7.5 g (0.046 mole) of 5-chloro-2-thiophenecarboxylic acid is added. The mixture is refluxed for 64 hours after which the mixture is cooled and poured into a water-ice mixture, acidified with acetic acid, and extracted with the addition of ether. The ether is evaporated and aqueous layer extracted 5 times with water: strong ammonia solution (1:1). The combined aqueous extract is acidified with acetic acid. The solid obtained is crystallized twice from hexane to give 5-(tetradecyloxy)-2-thiophenecarboxylic acid, M.P. 95°-96° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7]O)=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:28][C:29]1[CH:30]=[C:31]2[CH:37]=[C:36]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[NH:35][C:32]2=[N:33][CH:34]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[F:28][C:29]1[CH:30]=[C:31]2[CH:37]=[C:36]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[N:35]([CH2:7][C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[C:32]2=[N:33][CH:34]=1
Reactant: OCc1ccncc1
Reactant: CCOC(=O)c1cc2cc(F)cnc2[nH]1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(F)cnc2n1Cc1ccncc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.4 %

Procedure:
0.19 g (1.8 mmol) of 4-pyridylmethanol and then 0.48 g (1.8 mmol) of triphenylphosphine are successively added with stirring to a solution of 0.25 g (1.2 mmol) of ethyl 5-fluoro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate, obtained according to the protocol described in step 1.3, in 10 mL of dry tetrahydrofuran maintained under an inert atmosphere. 0.32 g (1.8 mmol) of diethyl azodicarboxylate is then added dropwise at 0° C. The reaction mixture is then stirred for 72 hours at room temperature and then concentrated under reduced pressure. The resulting oil is purified by chromatography on a column of silica gel, eluting with a mixture of heptane and ethyl acetate. 0.26 g of the expected product is isolated.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]([OH:11])=[O:10])[CH2:4][CH2:3]1.ClC(Cl)(Cl)C[O:15][C:16](=[O:37])[CH:17]([S:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25]O)=[CH:21][CH:20]=1>>[F:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][CH2:28][S:27][CH:17]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:25][O:10][C:9](=[O:11])[CH2:8][N:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)=[CH:23][CH:24]=2)[C:16]([OH:37])=[O:15])=[CH:31][CH:32]=1
Reactant: CN1CCN(CC(=O)O)CC1
Reactant: O=C(OCC(Cl)(Cl)Cl)C(Cc1ccc(CO)cc1)SCCc1ccc(F)cc1
Product: CN1CCN(CC(=O)OCc2ccc(CC(SCCc3ccc(F)cc3)C(=O)O)cc2)CC1

Procedure:
The title compound was prepared starting from N-methyl piperazino acetic acid and 2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-3-(4-hydroxymethyl-phenyl)-propionic acid 2,2,2-trichloro-ethyl ester in the same manner as described for example 7 (yield: 7.9 mg, 26%). 1H-NMR (300 MHz, CDCl3): δ 2.28-2.54 (m, 4H), 2.42 (s, 3H), 2.63-2.88 (m, 4H), 2.88-3.29 (m, 10H), 3.60-3.67 (m, 1H), 5.00-5.21 (m, 2H), 6.91-7.00 (m, 2H), 7.13-7.20 (m, 2H), 7.22-7.33 (m, 4H); Mass Spectrum: M+H+475.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:28].[NH2:29][C:30]1[CH:31]=[C:32]([OH:36])[CH:33]=[CH:34][CH:35]=1>C1COCC1>[OH:36][C:32]1[CH:31]=[C:30]([NH:29][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]5[S:24][CH:25]=[CH:26][CH:27]=5)=[O:22])=[CH:16][CH:15]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:28])[CH:35]=[CH:34][CH:33]=1
Reactant: Nc1cccc(O)c1
Reactant: O=C1Nc2cc(C(=O)c3ccc(NC(=O)c4cccs4)cc3)ccc2C1=CO
Solvent: C1CCOC1
Product: O=C1Nc2cc(C(=O)c3ccc(NC(=O)c4cccs4)cc3)ccc2C1=CNc1cccc(O)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 60.7 %

Procedure:
A small screw cap test tube was charged with Thiophene-2-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 20, 100 mg, 0.257 mmol) and THF (2 mL). To the resulting solution was added 3-aminophenol (30.7 mg, 0.282 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 61% (75 mg, 0.156 mmol) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8](=[O:13])[CH:7]([CH2:14][C:15]([OH:17])=O)[CH2:6][CH2:5]2.[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8](=[O:13])[CH:7]([CH2:14][C:15]([N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:17])[CH2:6][CH2:5]2
Reactant: C1CCNC1
Reactant: Cc1cc2c(cc1C)C(=O)C(CC(=O)O)CC2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc2c(cc1C)C(=O)C(CC(=O)N1CCCC1)CC2
Reaction time: 3 h
Yield: 96.7 %

Procedure:
To a solution of 1,2,3,4-tetrahydro-6,7-dimethyl-1-oxo-2-naphthalene-acetic acid (8.0 g), pyrrolidine (3.8 g) and benzotriazol-1-yloxy-tris(dimethyl-amino) phosphonium hexafluorophosphate (BOP Reagent,16.7 g) in dichloro-methane (80 ml) was added dropwise triethylamine (3.8 g) at 25° C., and the mixture was stirred for three hours. The mixture was concentrated under reduced pressure to remove the solvent, and to the residue were added water and toluene, and the insoluble materials were removed by filtration. The toluene layer was collected, washed successively with 1N aqueous sodium hydroxide solution, water and a saturated aqueous sodium chloride solution, an dried over anhydrous sodium sulfate. The resultant was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (eluent; toluene-ethyl acetate=10:1), and the fractions containing the desired compound were combined, and concentrated under reduced pressure to give the desired compound (9.5 g) as an oily product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:2]=1.[N:17]1([CH2:22][CH2:23][NH:24][C:25]([C:27]2[C:31]([CH3:32])=[C:30]([CH:33]=O)[NH:29][C:28]=2[CH3:35])=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18]1>>[N:17]1([CH2:22][CH2:23][NH:24][C:25]([C:27]2[C:31]([CH3:32])=[C:30]([CH:33]=[C:11]3[C:10]4[C:14](=[CH:15][C:7]([C:3]5[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=5)=[CH:8][CH:9]=4)[NH:13][C:12]3=[O:16])[NH:29][C:28]=2[CH3:35])=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Reactant: O=C1Cc2ccc(-c3cccnc3)cc2N1
Product: Cc1[nH]c(C=C2C(=O)Nc3cc(-c4cccnc4)ccc32)c(C)c1C(=O)NCCN1CCCC1
Yield: 70.6 %

Procedure:
6-Pyridin-3-yl-1,3-dihydroindol-2-one (60 mg, 0.28 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-ylethyl)amide (75 mg) to give 90 mg (71%) of the title compound as a light orange solid.
Reaction SMILES: [O:1]1[C:5]2[C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1>C(O)(=O)C.[Pd]>[O:1]1[C:5]2[C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: COC(=O)c1cccc2ccoc12
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)c1cccc2c1OCC2
Yield: 99 %

Procedure:
Methyl benzofuran-7-carboxylate (12 g, 68 mmol) was hydrogenated at 60 psi over 10% Pd/C (2 g) in acetic acid (60 ml) for 18 hr. The mixture was filtered, and the filtrate was concentrated in vacuo to give a pale green oil (12 g, 100%),
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([O:9][CH3:10])[N:3]=1.[N:11]([S:14]([C:17]1[CH:27]=[CH:26][CH:25]=[CH:24][C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:16])=[O:15])=[C:12]=[O:13]>C(Cl)Cl>[CH2:22]([O:21][C:19](=[O:20])[C:18]1[CH:24]=[CH:25][CH:26]=[CH:27][C:17]=1[S:14]([NH:11][C:12]([NH:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([O:9][CH3:10])[N:3]=1)=[O:13])(=[O:15])=[O:16])[CH3:23]
Reactant: CCOC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: COc1cc(Cl)nc(N)n1
Solvent: ClCCl
Product: CCOC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(Cl)cc(OC)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To 1.0 g of 2-amino-4-chloro-6-methoxypyrimidine suspended in 25 ml of dry CH2Cl2 was added 1.53 g of ethyl 2-(isocyanatosulfonyl)benzoate (prepared by procedures taught in U.S. Pat. No. 4,305,884). The reaction mixture was stirred at ambient temperature for three days. The solvent was stripped and the product was recrystallized from butyl chloride to give a white solid with m.p. 198°-201°.
Reaction SMILES: [N:1]1([C:8]2[N:13]=[C:12](Cl)[N:11]=[C:10]([NH:15][C@@H:16]3[CH2:21][CH2:20][C@H:19]([C:22]([OH:24])=[O:23])[CH2:18][CH2:17]3)[N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][NH2:26].Cl>CC#N.O>[N:1]1([C:8]2[N:13]=[C:12]([NH:26][CH3:25])[N:11]=[C:10]([NH:15][C@@H:16]3[CH2:21][CH2:20][C@H:19]([C:22]([OH:24])=[O:23])[CH2:18][CH2:17]3)[N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)[C@H]1CC[C@@H](Nc2nc(Cl)nc(N3CCCCCC3)n2)CC1
Reactant: CN
Agent: Cl
Solvent: O
Solvent: CC#N
Product: CNc1nc(N[C@H]2CC[C@@H](C(=O)O)CC2)nc(N2CCCCCC2)n1
Temperature: 80 °C

Procedure:
To the solution of crude cis-4-(4-(azepan-1-yl)-6-chloro-1,3,5-triazin-2-ylamino)cyclohexanecarboxylic acid (0.77 mmol) in CH3CN/H2O (1/1, 20 ml) was added methylamine (0.4 ml, 6 equivalents). The reaction mixture was heated at 80° C. overnight. The reaction solution was acidified with 6N HCl. The solution was condensed to give the crude product, which was further purified by RP-HPLC (Luna 5μ C8(2), 100×21 mm, 15-60% CH3CN/H2O, 0.1% TFA, 17 min) to give the product (29 mg). MS (ES+): m/e 349.33 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl[C:23]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:24]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:23]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:24])[CH:11]=[CH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)COC(=O)Cl
Reactant: Brc1ccc(-c2ncc[nH]2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)COC(=O)n1ccnc1-c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.6 %

Procedure:
2-(4-bromophenyl)imidazole (5.3 g, 23.76 mmol) was taken into THF (100 mL) followed by addition of DIPEA (5 mL, 28.5 mmol) and isobutyl chloroformate (3.4 mL, 26.1 mmol) and the resulting solution was stirred for 30 minutes at room temperature. The solution was then concentrated and the residue partitioned with ethyl acetate and water. The organic phase was washed once with 10% aqueous citric acid, brine then dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (2.5:1 hexanes:ethyl acetate) to give isobutyl 2-(4-bromophenyl)-1H-imidazole-1-carboxylate (3.5 g, 46% yield) as an amorphous residue.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:6][CH2:5][CH:4]([C:7]([O:9]CC)=[O:8])[CH2:3]1.[OH-].[Li+:13]>C1COCC1.O>[CH2:1]=[C:2]1[CH2:6][CH2:5][CH:4]([C:7]([O-:9])=[O:8])[CH2:3]1.[Li+:13]
Reactant: C=C1CCC(C(=O)OCC)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=C1CCC(C(=O)[O-])C1
Temperature: 65 °C

Procedure:
A mixture of ethyl 3-methylenecyclopentanecarboxylate (900 mg, 5.84 mmol) and lithium hydroxide (280 mg, 11.67 mmol) in THF (15 mL) and water (6 mL) was heated at 65° C. for 18 hours. Analysis by TLC indicated that the starting ester had been completely consumed. The organic solvents were removed via rotary evaporator, and the remaining aqueous solution was freeze-dried to yield lithium 3-methylenecyclopentanecarboxylate. 1H NMR (400 MHz, CD3OD) δ ppm 4.84-4.73 (m, 2 H), 2.71-2.59 (m, 1 H), 2.57-2.35 (m, 3 H), 2.29-2.16 (m, 1 H), 2.01-1.91 (1 H, m), 1.84-1.72 (m, 1 H,).
Reaction SMILES: [C:1](OC(OC(C)(C)C)=O)(OC(C)(C)C)=[O:2].[NH2:16][C:17]1[CH:18]=[C:19]([CH2:25][CH:26]([O:32][CH:33]([CH3:35])[CH3:34])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24].S(=O)(=O)(O)O.C(#N)C>C(#N)C.CN(C)C1C=CN=CC=1>[N:16]([C:17]1[CH:18]=[C:19]([CH2:25][CH:26]([O:32][CH:33]([CH3:34])[CH3:35])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24])=[C:1]=[O:2]
Reactant: CCOC(=O)C(Cc1ccc(OC)c(N)c1)OC(C)C
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(O)O
Solvent: CC#N
Product: CCOC(=O)C(Cc1ccc(OC)c(N=C=O)c1)OC(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 21.4 %

Procedure:
0.13 g of di-t-Butyl dicarbonate was dissolved in 2.5 ml of acetonitrile, and a solution containing 60 mg of 4-dimethylaminopyridine and 0.12 g of ethyl 3-(3-amino-4-methoxy-phenyl)-2-isopropoxypropanoate in acetonitrile were added thereto, and the mixture was stirred at room temperature for 10 minutes. The reaction solution was cooled in ice, and 0.73 ml of 40% sulfuric acid-acetonitrile solution was added and stirring was continued at room temperature for 2 minutes, then the mixture was extracted with hexane. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated, to give 28 mg of the title compound.
Reaction SMILES: [NH2:1][C@H:2]([C:9]([OH:11])=[O:10])[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.[C:12](Cl)([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]>>[C:12]([N:6]1[CH:7]=[N:8][C:4]([CH2:3][C@@H:2]([C:9]([OH:11])=[O:10])[NH:1][C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])=[CH:5]1)([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Product: O=C(N[C@@H](Cc1cn(C(=O)OCc2ccccc2)cn1)C(=O)O)OCc1ccccc1

Procedure:
According to the original literature procedure of A. Patchornik et al. (J.A.C.S., 79, 6416/1957), 1,N-dicarbobenzoxy-L-histidine was prepared by the reaction of L-histidine with carbobenzoxy chloride.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[N:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=O)[CH:5]=1>>[CH2:1]([NH:3][CH2:10][C:6]1[CH:5]=[N:4][CH:9]=[CH:8][CH:7]=1)[CH3:2]
Reactant: O=Cc1cccnc1
Reactant: CCN
Product: CCNCc1cccnc1

Procedure:
prepared by reaction of ethylamine with pyridine-3-carbaldehyde
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.ClC1[CH:33]=[C:32]2C(C(NC3C=CC(C(O)=O)=CC=3)=[CH:29][CH:30]=[N:31]2)=CC=1>>[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([N:10]([CH2:11][CH2:6][N:31]([CH2:30][CH3:29])[CH2:32][CH3:33])[CH2:9][CH3:8])=[O:19])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1
Reactant: O=C(O)c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1
Agent: Cl
Product: CCN(CC)CCN(CC)C(=O)c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1

Procedure:
4-(7-Chloro-4-quinolylamino) benzoyl chloride hydrochloride (prepared by refluxing 9.0 grams of 4-(7-chloro-4-quinolylamino) benzoic acid and evaporating the excess thionyl chloride, was added in portions to a cooled, stirred mixture of 4.32 grams of N,N,N1 -triethylethylene diamine and 32 grams of sodium carbonate in 60 milliliters of chloroform and 70 milliliters of water. After stirring for 2 days at room temperature the reaction mixture was filtered, the chloroform layer separated, dried and evaporated to give an oil. This was triturated with hexane to give a light brown solid, which was triturated with acetone to give 5.3 grams of the title compound as a quarter hydrate.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[C:7](=[NH:14])[S:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[C:23]1([C:29](O)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH2:10]([C:8]1=[CH:9][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[S:6]/[C:7]/1=[N:14]\[C:29]([C:23]1([C:17]2[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=2[Cl:15])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1)=[O:30])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCc1cn(C(C)(C)C)sc1=N
Reactant: O=C(O)C1(c2ccc(F)cc2Cl)CCCCC1
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1(c2ccc(F)cc2Cl)CCCCC1

Procedure:
The product from Example 92B and (2-chloro-4-fluorophenyl)cyclohexanecarboxylic acid (Acros) were processed using the method described in Example 92C to afford the title compound. 1H NMR (DMSO-d6) δ ppm 0.76 (t, J=7.3 Hz, 3H), 1.06-1.18 (m, 2H), 1.33-1.53 (m, 8H), 1.56 (s, 9H), 1.71-1.81 (m, 2H), 1.92-2.00 (m, 2H), 2.34-2.42 (m, 2H), 7.14-7.22 (m, 2H), 7.57 (dd, J=8.6, 6.3 Hz, 1H), 8.46 (s, 1H). MS (ESI+) m/z 451 (M+H)+. Anal. calcd. for C24H32ClFN2OS: C, 63.91; H, 7.15; N, 6.21. Found: C, 64.04; H, 7.08; N, 6.10.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]3[N:11]([S:12]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=4)(=[O:14])=[O:13])[CH:9]([CH:10]=2)[CH2:8][C:7](=[O:25])[CH2:6]3)[CH2:3][CH2:2]1.[CH3:26][N:27]([CH:29](OC)OC)[CH3:28]>>[CH:1]1([C:4]2[CH:5]3[N:11]([S:12]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=4)(=[O:14])=[O:13])[CH:9]([CH2:8][C:7](=[O:25])[C:6]3=[CH:26][N:27]([CH3:29])[CH3:28])[CH:10]=2)[CH2:2][CH2:3]1
Reactant: COC(OC)N(C)C
Reactant: O=C1CC2C=C(C3CC3)C(C1)N2S(=O)(=O)c1ccc(C(F)(F)F)cc1
Product: CN(C)C=C1C(=O)CC2C=C(C3CC3)C1N2S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 100 °C

Procedure:
6-Cyclopropyl-8-(4-(trifluoromethyl)phenylsulfonyl)-8-azabicyclo[3.2.1]oct-6-en-3-one (1.02 g, 2.74 mmol), was dissolved in DMF-DMA (6 mL) and heated to 100° C. for 4 h. The reaction mixture was concentrated under vacuum to give compound 117. MS (ESI) 427.1 (M+H)