Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH2:11])=[CH:8][C:7]([CH3:12])=[N:6][C:5]=2[S:4][C:3]=1[CH3:13].[Cl:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.C(Cl)Cl.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[Cl:14][C:15]1[CH:20]=[C:19]([C:2]2[C:10]3[C:9]([NH2:11])=[CH:8][C:7]([CH3:12])=[N:6][C:5]=3[S:4][C:3]=2[CH3:13])[CH:18]=[CH:17][CH:16]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Cc1cc(N)c2c(Br)c(C)sc2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O
Product: Cc1cc(N)c2c(-c3cccc(Cl)c3)c(C)sc2n1
Temperature: 150 °C
Yield: 107.1 %

Procedure:
Under nitrogen, 3-bromo-2,6-dimethylthieno[2,3-b]pyridin-4-amine (170 mg, 0.661 mmol) (Description 8) was dissolved in toluene (6 mL) and (3-chlorophenyl)boronic acid (155 mg, 0.992 mmol), PdCl2(dppf).DCM (54.0 mg, 0.066 mmol) and Cs2CO3 (646 mg, 1.983 mmol) were added and the mixture heated in a microwave at 150° C. for 30 min. The reaction mixture was combined with the material (30 mg) from similar reaction. Water (20 mL) was added and the mixture extracted with ethyl acetate (3×15 mL). The organic layer was dried over MgSO4, filtered and solvent removed in vacuo. Purification by chromatography on silica gel, eluting with a gradient of 0-50% ethyl acetate in cyclohexane, afforded the title compound (204.4 mg). LCMS (A) m/z: 291 [M+1]+, Rt 0.84 min (acidic).
Reaction SMILES: Br[CH2:2][CH:3]([CH2:6][CH3:7])[CH2:4][CH3:5].[CH2:8]([CH2:10][NH2:11])[OH:9]>C(O)C>[CH2:4]([CH:3]([CH2:6][CH3:7])[CH2:2][NH:11][CH2:10][CH2:8][OH:9])[CH3:5]
Reactant: NCCO
Reactant: CCC(CC)CBr
Solvent: CCO
Product: CCC(CC)CNCCO
Temperature: 75 °C
Yield: 92.7 %

Procedure:
A mixture of 3-bromomethyl-pentane (6.0 g, 36.4 mmol) and ethanolamine (13 mL, 218 mmol) in ethanol (45 mL) was heated at 75° C. for 16 h. The reaction mixture was concentrated and the resulting residue was diluted with DCM (70 mL). The organic layer was partitioned with water (70 mL) and the aqueous layer extracted with DCM. Combined organic layers, dried over magnesium sulfate, filtered, and concentrated to give the title compound as an oil (4.90 g). 1H NMR (d6-DMSO, 400 MHz) δ (ppm): 3.44 (t, J=5.6 Hz, 2H), 2.54 (t, J=6.0 Hz, 2H), 2.40 (d, J=5.6 Hz, 2H), 1.31-1.25 (m, 5H), 0.83 (t, J=6.8 Hz, 6H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]([CH3:14])[N:11]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][N:25]=[C:24](Cl)[N:23]=3)[CH:17]=2)[CH:10]([CH3:29])[CH2:9]1)=O)(C)(C)C.[F:30][C:31]1[CH:32]=[C:33]([CH2:38][CH2:39][NH2:40])[CH:34]=[C:35]([F:37])[CH:36]=1>>[F:30][C:31]1[CH:32]=[C:33]([CH2:38][CH2:39][NH:40][C:24]2[N:23]=[C:22]([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([CH2:15][N:11]4[C@H:10]([CH3:29])[CH2:9][NH:8][CH2:13][C@@H:12]4[CH3:14])[CH:17]=3)[CH:27]=[CH:26][N:25]=2)[CH:34]=[C:35]([F:37])[CH:36]=1
Reactant: CC1CN(C(=O)OC(C)(C)C)CC(C)N1Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: NCCc1cc(F)cc(F)c1
Product: C[C@@H]1CNC[C@H](C)N1Cc1cccc(-c2ccnc(NCCc3cc(F)cc(F)c3)n2)c1

Procedure:
Intermediate 114 was coupled with 2-(3,5-difluoro-phenyl)-ethylamine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 439. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.57 (s, 1H), 8.36 (t, 2H), 7.94 (d, 1H), 7.74 (m, 2H), 6.99 (d, 2H), 6.75 (t, 1H), 3.77 (m, 5H), 3.64 (m, 5H), 3.07 (t, 2H), 1.69 (d, 6H).
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]([N+:14]([O-:16])=[O:15])[C:8]=1[CH3:17])(=O)=O.CC1C([N+]([O-])=O)=CC=C(C)C=1CCl.[H-].[Na+].O[C:34]1[CH:35]=[CH:36][CH:37]=[C:38]2[C:43]=1[N:42]=[C:41]([CH3:44])[CH:40]=[CH:39]2>CN(C)C=O.O>[CH3:17][C:8]1[C:9]([N+:14]([O-:16])=[O:15])=[CH:10][CH:11]=[C:12]([CH3:13])[C:7]=1[CH2:6][O:5][C:34]1[CH:35]=[CH:36][CH:37]=[C:38]2[C:43]=1[N:42]=[C:41]([CH3:44])[CH:40]=[CH:39]2
Reactant: Cc1ccc([N+](=O)[O-])c(C)c1COS(C)(=O)=O
Reactant: Cc1ccc2cccc(O)c2n1
Agent: Cc1ccc([N+](=O)[O-])c(C)c1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2cccc(OCc3c(C)ccc([N+](=O)[O-])c3C)c2n1
Reaction time: 0.25 h

Procedure:
To a mixture of 2,6-dimethyl-3-nitrobenzyl methanesulfonate and 2,6-dimethyl-3-nitrobenzyl chloride obtained above in N,N-dimethylformamide (13 ml) was added sodium hydride (60% in oil, 335 mg) under ice-bath cooling, and the mixture was stirred for 15 minutes. To the mixture was added 8-hydroxy-2-methylquinoline (1.27 g), and the mixture was stirred for 1 hour at ambient temperature. Water was added there to, and the resulting precipitate was collected by filtration to give 8-(2,6-dimethyl-3-nitrobenzyloxy)-2-methylquinoline (2.53 g).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:36][O:37][CH2:38][CH2:39][CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:10]([NH:12][CH:13]2[C:34](=[O:35])[N:15]3[C:16]([C:21]([O:23]CC4C=CC([N+]([O-])=O)=CC=4)=[O:22])=[C:17]([Cl:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2].CO>[C].[Pd].O1CCCC1>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:36][O:37][CH2:38][CH2:39][CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:10]([NH:12][CH:13]2[C:34](=[O:35])[N:15]3[C:16]([C:21]([OH:23])=[O:22])=[C:17]([Cl:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: CC(C)(C)OC(=O)NCCCON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12)c1csc(NC=O)n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1csc(NC=O)n1
Reaction time: 6 h
Yield: 45.3 %

Procedure:
A suspension of 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-(3-tert-butoxycarbonylaminopropoxyimino)acetamido]-3-chloro-3-cephem-4-carboxylate (syn isomer, 1.9 g.), palladium-carbon (0.9 g.), methanol (20 ml.) and tetrahydrofuran (20 ml.) was subjected to catalytic reduction under ordinary pressure at room temperature for 6 hours. After the insoluble substance was removed by filtration and washed with methanol, the filtrate was concentrated in vacuo. The residue was dissolved in a mixture of ethyl acetate and a sodium bicarbonate aqueous solution, and filtered out. The ethyl acetate layer was separated and extracted with a sodium bicarbonate aqueous solution. The aqueous solution was washed with ethyl acetate and ethyl acetate was added thereto. The mixture was adjusted to pH 2.5 with 10% hydrochloric acid under ice-cooling. The ethyl acetate layer was washed with a sodium chloride saturated aqueous solution, dried over magnesium sulfate and evaporated in vacuo. The residue was pulverized with diisopropyl ether to give 7-[2-(2-formamidothiazol-4-yl)-2-(3-tert-butoxycarbonylaminopropoxyimino)acetamido]-3-chloro-3 -cephem-4-carboxylic acid (syn isomer, 0.7 g.).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C.[CH2:19]([O:21][C:22](=[O:32])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1)[CH3:20].[C:33]1([CH2:39][CH:40]=O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[OH-].[NH4+]>ClCCCl.O>[CH2:19]([O:21][C:22](=[O:32])[CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]([NH:31][CH2:40][CH2:39][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:29][CH:30]=1)[CH3:20]
Reactant: O=CCc1ccccc1
Reactant: CCOC(=O)CCc1ccc(N)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Agent: [NH4+]
Solvent: ClCCCl
Solvent: O
Product: CCOC(=O)CCc1ccc(NCCc2ccccc2)cc1

Procedure:
Tetramethylammonium triacetoxyborohydride (4.9 g, 18.6 mmol) was added to a solution of 3-(4-aminophenyl)-propionic acid ethyl ester (3.0 g, 15.5 mmol) and phenylacetaldehyde (1.08 mL, 15.5 mmol) in 1,2-dichloroethane (50 mL). The resultant solution was stirred at room temperature for ten minutes, then heated at reflux overnight. The solution was treated with a 1:1 solution of water:ammonium hydroxide. The organic layer was applied to a silica gel column and eluted with ethyl acetate/hexane ( 1/9) to give the product as an oil, 1.3 g (28%). MS: m/z 298 (MH+). 1H NMR (CDCl3): δ 1.24 (t, 3 H), 2.58 (t, 2 H), 2.86 (s, 3 H), 3.53 (t, 2 H), 3.67 (t, 2 H), 4.13 (q, 2 H), 4.32 (t, 2 H), 6.67 (d, 2 H), 7.09 (d, 2 H), 7.19-7.32 (m, 5 H).
Reaction SMILES: Cl.[C:2]([O:6][C:7]([N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].Br[C:16]1[CH:17]=[CH:18][C:19]([F:22])=[N:20][CH:21]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOC(C)=O.CCCCCC.O>[C:2]([O:6][C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:16]2[CH:21]=[N:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)=[O:8])([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Fc1ccc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(F)nc2)CC1
Temperature: 80 °C
Reaction time: 7 h
Yield: 43 %

Procedure:
A suspension of piperazine-1-carboxylic acid tert-butyl ester hydrochloride (0.75 mmol), 5-bromo-2-fluoropyridine (0.90 mmol), (R)-2,2′-bis(diphenylphosphino)-1, 1′-binaphthyl (0.038 mmol), palladium acetate (0.038 mmol) and cesium carbonate (1.8 mmol) in toluene is stirred at 80° C. for 7 h and then 100° C. for 4 h, and poured into water. The mixture is extracted with AcOEt. The organic layer is washed with water, dried over magnesium sulfate, and concentrated. The crude product is purified by silica gel column chromatography to give the product in 43% yield. Rf=0.61 (n-hexane:AcOEt=1:1)
Reaction SMILES: FC(F)(F)C(O)=O.C[O:9][C:10](=[O:34])[C@H:11]([CH2:20][C:21]1[CH:26]=[C:25]([I:27])[C:24]([O:28][CH2:29][CH2:30][CH2:31][Br:32])=[C:23]([I:33])[CH:22]=1)[NH:12]C(OC(C)(C)C)=O.O.[OH-].[Li+].Cl>O1CCCC1.O>[Br:32][CH2:31][CH2:30][CH2:29][O:28][C:24]1[C:23]([I:33])=[CH:22][C:21]([CH2:20][C@@H:11]([C:10]([OH:34])=[O:9])[NH2:12])=[CH:26][C:25]=1[I:27]
Reactant: COC(=O)[C@H](Cc1cc(I)c(OCCCBr)c(I)c1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](Cc1cc(I)c(OCCCBr)c(I)c1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.8 %

Procedure:
Trifluoroacetic acid (2 ml) was added to O-(3-bromo-propyl)-N-t-butoxycarbonyl-3,5-diiodo-L-tyrosine methyl ester (131mg, 0.196 mmol) and the mixture was stirred at room temperature for 8 hrs. The solvent of the reaction mixture was distilled off under reduced pressure. The residue was dissolved in tetrahydrofuran (2 ml)-water (2 ml) and lithium hydroxide monohydrate (25 mg, 0.596 mmol) was added thereto with stirring under ice cooling. The mixture was stirred at the same temperature for 4.5 hrs. To the reaction mixture were added 1N hydrochloric acid (0.2 ml) and water (5 ml), and the mixture was stirred at room temperature for 30 min. The precipitates were collected by filtration, washed with water and dried under reduced pressure to give O-(3-bromopropyl)-3,5-diiodo-L-tyrosine(79 mg, 71%) as colorless crystals.
Reaction SMILES: [OH-].[Na+].[CH:3]1([CH:9]=[C:10]2[NH:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])[CH2:8][CH2:7][CH:6]=[CH:5][CH2:4]1>[Pd]>[CH:3]1([CH2:9][CH:10]2[NH:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: O=C1NC(=O)C(=CC2CC=CCC2)N1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Product: O=C1NC(=O)C(CC2CCCCC2)N1
Temperature: 45 °C
Reaction time: 9 h
Yield: 87.5 %

Procedure:
Twenty-five milliliters of a 5% aqueous sodium hydroxide solution, 3.84 g of 5-(3-cyclohexene-1-yl)methylenehydantoin and 0.43 g of wet 10% palladium on carbon (moisture 50%) were placed in a reactor equipped with a mechanical stirrer and a reflux condenser, and the mixture was reduced while stirring at 45° C. under a hydrogen pressure of 3.5 kg/cm2. After 9 hours, the palladium on carbon was removed by filtration, and the pH of the filtrate was adjusted to about 3 by addition of 1N hydrochloric acid, upon which white crystals were obtained. These were collected by filtration and washed with water, and then dried under reduced pressure at 60° C. overnight to obtain 3.43 g of 5-cyclohexylmethylhydantoin. The yield was 87.4%.
Reaction SMILES: [CH:1]1([NH:6][CH2:7][C:8]2[CH:39]=[CH:38][C:11]3[N:12]=[C:13]([N:15]4[CH2:20][CH2:19][N:18]([C:21](=[O:37])[C@@H:22]([NH:29]C(=O)OC(C)(C)C)[CH2:23][C:24]5[S:25][CH:26]=[CH:27][CH:28]=5)[CH2:17][CH2:16]4)[S:14][C:10]=3[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C(OCC)C>O1CCOCC1.Cl>[NH2:29][C@@H:22]([CH2:23][C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)[C:21]([N:18]1[CH2:19][CH2:20][N:15]([C:13]2[S:14][C:10]3[CH:9]=[C:8]([CH2:7][NH:6][CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:39]=[CH:38][C:11]=3[N:12]=2)[CH2:16][CH2:17]1)=[O:37]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)N1CCN(c2nc3ccc(CNC4CCCC4)cc3s2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: N[C@@H](Cc1cccs1)C(=O)N1CCN(c2nc3ccc(CNC4CCCC4)cc3s2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-tert-Butyl 1-(4-(6-((cyclopentylamino)methyl)benzo[d]thiazol-2-yl)piperazin-1-yl)-1-oxo-3-(thiophen-2-yl)propan-2-ylcarbamate (20 mg) was dissolved in dry 1,4-dioxane (2 ml) and HCl (4N in 1,4-dioxane). 5 mL) was added. The resulting mixture was stirred overnight at room temperature, then concentrated and chromatographed (94.5:5:0.5 dichloromethane:methanol:ammonium hydroxide) to yield a colorless oil, which was added to HCl/diethyl ether. The resulting white precipitate was collected and dried to yield the title compound.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1.C(=O)(O)[O-].[Na+]>[CH2:12]([N:19]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCc1ccccc1
Reactant: O=C1OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1Cc1ccccc1
Temperature: 140 °C

Procedure:
N-Benzylphthalimide is prepared as described in Example 2, starting with 10 g of phthalic anhydride, 7.3 cm3 of benzylamine and a catalytic amount of paratoluenesulfonic acid in 100 cm3 of toluene. The reaction mixture is heated at a temperature in the region of 140° C. for 3 hours and is then cooled to a temperature in the region of 20° C. The reaction mixture is taken up in 100 cm3 of saturated aqueous sodium bicarbonate solution and the aqueous phase is extracted twice with 100 cm3 of ethyl acetate. The organic extracts are combined, washed with 50 cm3 of brine, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is dried in a desiccator under reduced pressure (2 kPa) at a temperature in the region of 20° C. 10.3 g of N-benzylphthalimide are thus obtained in the form of a white powder. (Rf=0.44, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (75/25 by volume)).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([OH:10])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C1C(=O)N([Br:18])C(=O)C1.O>CN(C=O)C>[Br:18][C:7]1[CH:8]=[C:9]2[C:4]([CH2:3][CH2:2][CH2:1]2)=[CH:5][C:6]=1[OH:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: Oc1ccc2c(c1)CCC2
Solvent: O
Solvent: CN(C)C=O
Product: Oc1cc2c(cc1Br)CCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-indanol (6.32 g, 47 mmol) in DMF (20 mL) is added NBS (8.38 g, 47 mmol) and the mixture is stirred at ambient temperature for 1 h. Water is added and the mixture is then extracted with EtOAc. The organic layer is washed with 1N HCl solution and brine, dried with NaSO4 and concentrated to give the title compound and it is used in the next step without purification.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CC(C)=O.CCCCCCC.CCOC(C)=O>[CH2:15]([O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[I:1])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1ccccc1I
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: Ic1ccccc1OCc1ccccc1
Reaction time: 0.25 h
Yield: 82.3 %

Procedure:
In a 25 mL ovendried flask 2-iodophenol (1.03 g, 4.7 mmol) and potassium carbonate (0.71 g, 5.2 mmol) were dissolved in dry acetone (10 mL). The mixture was stirred for 15 min followed by addition of benzylbromide (0.61 mL, 5.2 mmol) and left over-night at rt. Addition of H2O (50 mL) followed by extraction with ethyl acetate (3×50 mL) and the combined organic phases were dried (MgSO4) and evaporated to dryness, to produce 1.7 g of crude 25. The crude product was subjected to CC [eluent: Heptane:EtOAc (9:1)] to give pure 25 (1.2 g, 81%). LC-MS [M+H]+ 310 (cald. 310.0).
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[C:26]([CH2:27][N:28]2[CH2:47][CH2:46][C:31]3([O:36][CH2:35][CH2:34][N:33]([C:37]([C:39]4[N:40]=[C:41]([CH2:44][CH3:45])[S:42][CH:43]=4)=[O:38])[CH2:32]3)[CH2:30][CH2:29]2)=[CH:25][CH:24]=[CH:23][C:10]=1[CH2:11][CH2:12][O:13][CH2:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17]>C(Cl)Cl>[Cl:8][C:9]1[C:26]([CH2:27][N:28]2[CH2:29][CH2:30][C:31]3([O:36][CH2:35][CH2:34][N:33]([C:37]([C:39]4[N:40]=[C:41]([CH2:44][CH3:45])[S:42][CH:43]=4)=[O:38])[CH2:32]3)[CH2:46][CH2:47]2)=[CH:25][CH:24]=[CH:23][C:10]=1[CH2:11][CH2:12][O:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: CCc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCOCCC(=O)OC(C)(C)C)c4Cl)CC3)C2)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCOCCC(=O)O)c4Cl)CC3)C2)cs1
Reaction time: 2 h

Procedure:
TFA (10 mL) was added to a solution of tert-butyl 3-(2-chloro-3-((4-(2-ethylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)phenethoxy)propanoate [Example 26, step d] (3.1 g) in DCM (30 mL) and the resulting mixture stirred for 2 h, then evaporated. The residue was partitioned between ethyl acetate (100 mL) and saturated sodium bicarbonate solution (50 mL). The phases were separated and the aqueous phase was washed with more ethyl acetate (2×100 mL). The aqueous phase was then acidified with acetic acid and extracted with ethyl acetate (3×100 mL). The combined organic solutions were dried over sodium sulphate, filtered and evaporated to give the subtitled compound as a white foam. Yield 2.7 g.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10](F)=[C:9]([F:14])[CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>CN(C)C(=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[C:9]([F:14])[CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: O=S(=O)(c1ccc(F)c(F)c1)C1CC1
Solvent: CC(=O)N(C)C
Product: O=S(=O)(c1ccc(N2CCNCC2)c(F)c1)C1CC1
Temperature: 80 °C
Yield: 52.8 %

Procedure:
To 4-cyclopropanesulfonyl-1,2-difluoro-benzene (40 mg, 0.18 mmol) in 5 ml N,N-dimethylacetamide was added piperazine (47 mg, 0.55 mmol) and the mixture was heated at 80° C. for 90 min. The mixture was then concentrated in vacuo to afford the tide compound (27 mg, 52%) as a brown solid. MS (ISP): 285.0 MH+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:13][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]([CH3:12])[CH3:11].C(=O)([O-])[O-:23].[K+].[K+].OO>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH2:19])=[O:23])=[CH:20][CH:21]=2)[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: O=C([O-])[O-]
Reactant: CC(C)COc1ncc(Oc2ccc(C#N)cc2)cc1Cl
Agent: OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)COc1ncc(Oc2ccc(C(N)=O)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-[(5-chloro-6-isobutoxypyridin-3-yl)oxy]benzonitrile (Preparation 32, 162 mg, 0.535 mmol) and potassium carbonate (150 mg, 1.085 mmol) were suspended in DMSO (3 mL). Hydrogen peroxide aqueous solution (0.250 mL, 8.08 mmol) was added dropwise (exothermic reaction) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with EtOAc (15 mL) and washed with water (2×15 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to yield a white solid which was triturated in DCM to yield the title compound. The filtrate was concentrated in vacuo and residue treated again triturated with DCM to yield a second crop of the title compound as a white solid (2 crops combined 85.0 mg, 49%):
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]([NH2:17])=[O:16])=[N:8][C:7]=3[C:6]=2[CH:18]=1.[CH3:20][C:21]1[O:25][N:24]=[C:23]([C@:26]([OH:30])([C:28]#[CH:29])[CH3:27])[CH:22]=1>>[F:19][C:3]1[C:2]([C:29]#[C:28][C@@:26]([OH:30])([C:23]2[CH:22]=[C:21]([CH3:20])[O:25][N:24]=2)[CH3:27])=[CH:18][C:6]2[C:7]3[N:8]=[C:9]([C:15]([NH2:17])=[O:16])[S:10][C:11]=3[CH2:12][CH2:13][O:14][C:5]=2[CH:4]=1
Reactant: NC(=O)c1nc2c(s1)CCOc1cc(F)c(Br)cc1-2
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Product: Cc1cc([C@](C)(O)C#Cc2cc3c(cc2F)OCCc2sc(C(N)=O)nc2-3)no1

Procedure:
Following Procedure F, 9-Bromo-8-fluoro-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide was reacted with (2R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol to give the titled compound as a colorless solid after purification by reverse-phase HPLC. LCMS: 396.1 [M+H]+; 1H NMR (400 MHz, DMSO) δ 8.66 (d, J=8.5 Hz, 1H), 8.45 (s, 1H), 7.84 (s, 1H), 7.02 (d, J=10.4 Hz, 1H), 6.52 (s, 1H), 6.35 (s, 1H), 4.39 (t, J=4.8 Hz, 2H), 3.39 (m, 3H), 2.41 (s, 3H), 1.83 (s, 3H).
Reaction SMILES: [C:1]([CH:5]1[C:10]([C:11]2[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][C:12]=2[CH3:20])=[CH:9][CH2:8][CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH:21]1[CH:22]=[CH:23][N:24]2[CH2:30][C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[NH:27][CH2:26][C:25]=12>>[CH:21]1[CH:22]=[CH:23][N:24]2[CH2:30][C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[N:27]([C:15]([C:14]3[CH:18]=[CH:19][C:11]([C:10]4[CH:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:6][CH2:7][CH2:8][CH:9]=4)=[C:12]([CH3:20])[CH:13]=3)=[O:16])[CH2:26][C:25]=12
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: Cc1cc(C(=O)O)ccc1C1=CCCCC1C(C)(C)C
Product: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1C1=CCCCC1C(C)(C)C
Yield: 95.5 %

Procedure:
4-(6-tert-Butyl-cyclohex-1-en-1-yl)-3-methyl-benzoic acid of Step B (0.104 g, 0.382 mmol) and 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.077 g, 0.420 mmol) were reacted in the manner of Example 15, Step D: Purification by flash column chromatography on silica gel, eluting with 20% ethyl acetate in hexane, followed by recrystallization from pentane afforded the title compound (0.160 g) as white crystals, m.p. 127–129° C.