Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]=O)(C)(C)C.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([CH2:27][NH2:28])[CH2:25][NH2:26])=[C:20]([CH3:29])[CH:19]=1.C(O)(C)(C)C>CN(C)C=O>[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[CH2:27][N:28]3[C:6](=[O:16])[NH:7][C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=4[C:14]3=[N:26][CH2:25]2)=[C:20]([CH3:29])[CH:19]=1
Reactant: Cc1cc(N)ccc1C(CN)CN
Reactant: CC(C)(C)OC(=O)Nc1ccccc1C=O
Solvent: CC(C)(C)O
Solvent: CN(C)C=O
Product: Cc1cc(N)ccc1C1CN=C2c3ccccc3NC(=O)N2C1
Temperature: 75 °C
Yield: 13.1 %

Procedure:
A flask was charged with (2-Formyl-phenyl)-carbamic acid tert-butyl ester (8.8 g, 0.040 mol), 2-(4-Amino-2-methyl-phenyl)-propane-1,3-diamine (10.0 g, 0.056 mol), t-butanol (177 mL), and N,N-dimethylformamide (53 mL) and purged well with nitrogen. The mixture was stirred at 75° C. for at least 3 h. To the cooled mixture were added anhydrous potassium carbonate (16.6 g) and iodine (12.2 g). The batch was stirred at 80° C. for 10 h. The cooled mixture was filtered through a celite pad (4.4 g) and the filter cake was rinsed with methanol (177 mL). The filtrate and wash were diluted with toluene (88 mL) and concentrated to dryness under reduced pressure. The residue was stirred with aqueous 15 wt % sodium thiosulfate pentahydrate (88 mL) and saturated aqueous sodium chloride (44 mL) for 1 h at ambient temperature. The resulting mixture was extracted with CH2Cl2 (2×177 mL). The separated organic layer was dried over anhydrous magnesium sulfate (4.4 g), filtered, and concentrate to dryness in vacuo. The concentrate (20 g) was dissolved with methanol (20 mL) and loaded onto a KP-Sil samplet (34 g). The sample was allowed to dry before loading it into a Biotage KP-Sil SNAP cartridge (340 g). A Biotage unit was used to elute the cartridge with a ethyl acetate-hexane gradient (0% to 90%). Clean fractions were collected, combined, and concentrated to dryness under reduced pressure to provide the title compound as a yellow solid (1.6 g, 13% yield).
Reaction SMILES: Cl.Cl.[N:3]1([CH:9]([C:16]2[CH:28]=[CH:27][C:19]([C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[C:36]([Cl:39])(=[O:38])[CH3:37]>C(Cl)Cl>[ClH:39].[C:36]([N:6]1[CH2:7][CH2:8][N:3]([CH:9]([C:16]2[CH:17]=[CH:18][C:19]([C:20]([N:22]([CH2:23][CH3:24])[CH2:25][CH3:26])=[O:21])=[CH:27][CH:28]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:4][CH2:5]1)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: CCN(CC)C(=O)c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)c1ccc(C(c2ccccc2)N2CCN(C(C)=O)CC2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 96.3 %

Procedure:
The free amine of compound 64 (100 mg, 0.28 mmol) was dissolved in methylene chloride (5 ml), cooled to 0° C. Triethyl amine (43 μl, 0.31 mmol) was added and then acetyl chloride (22 μl, 0.31 mmol) was added dropwise. After 10 min, the solution was washed with potassium carbonate (10%), dried (K2CO3) and evaporated in vacuo. The residue was purified by chromatography on silica (CH2Cl2 /MeOH/NH3, 95:5:0.5) to give 116 mg of compound 77 (~100 %).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[O:4][Si:5]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6].[Br-].[CH:18]1([Zn+])[CH2:21][CH2:20][CH2:19]1>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C1COCC1>[CH:18]1([C:2]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=2[O:4][Si:5]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6])[CH2:21][CH2:20][CH2:19]1
Reactant: CC(C)(C)[Si](C)(C)Oc1c(F)cccc1Br
Reactant: [Zn+]C1CCC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1c(F)cccc1C1CCC1
Temperature: 45 °C
Yield: 98 %

Procedure:
A 1-L three-neck, round bottomed flask, equipped with a stir bar, temperature probe and nitrogen inlet was charged with (2-bromo-6-fluorophenoxy)(tert-butyl)dimethylsilane (27.2 g, 89.1 mmol), THF (181.2 mL) and bis(tri-tert-butylphosphine)palladium (3.4 g, 6.68 mmol). Cyclobutylzinc bromide (267.2 mL, 134 mmol) was added and the reaction is heated at 45° Celsius for 22 hours. The reaction was cooled to room temperature and quenched with 1M HCl. The aqueous phase is extracted with MTBE and the combined organic extracts were washed with water, saturated aqueous thiourea, 1M HCl brine, dried over sodium sulfate and concentrated to dryness to provide (2-cyclobutyl-6-fluorophenoxy)(tert-butyl)dimethylsilane as a light yellow oil (24.5 g, 98%). MS (EI): calcd. for C16H25FOSi, 280.5; m/z found 280.1 [M]. 1H NMR (400 MHz, CDCl3), δ 7.08-7.04 (m, 1H), 6.90-6.83 (m, 2H), 3.81 (tt, J=9.4, 7.8 Hz, 1H), 2.32 (dtd, J=10.3, 7.8, 2.4 Hz, 2H), 2.14-1.80 (m, 4H), 1.03 (s, 9H), 0.20 (s, 3H), 0.19 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][C:5]=1[C:20]([OH:22])=[O:21])([O-])=O.Cl.[NH2:24]O.[OH-].[Na+].Cl>O.CO>[NH2:1][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[C:7]([NH2:24])=[CH:6][C:5]=1[C:20]([OH:22])=[O:21]
Reactant: O=C1c2ccccc2C(=O)c2c1ccc(C(=O)O)c2[N+](=O)[O-]
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1cc(C(=O)O)c(N)c2c1C(=O)c1ccccc1C2=O
Temperature: 25 °C

Procedure:
10 parts of 1-nitroanthraquinone-2-carboxylic acid and 10 parts of hydroxylamine hydrochloride are suspended at room temperature in 60 parts of methanol and 100 parts of 4 N sodium hydroxide. The mixture is refluxed for 3 hours, then cooled to room temperature, diluted with water and acidified with hydrochloric acid. The mixture is filtered and the filter cake is washed neutral with water and dried, affording 7.6 parts of 1,4-diaminoanthraquinone-2-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH:7]([OH:8])[C:5](=[O:6])[O:4][CH2:3]1>[O-2].[O-2].[O-2].[O-2].[O-2].[V+5].[V+5]>[CH3:1][C:2]1([CH3:9])[C:7](=[O:8])[C:5](=[O:6])[O:4][CH2:3]1
Reactant: CC1(C)COC(=O)C1O
Agent: [V+5]
Agent: [O-2]
Product: CC1(C)COC(=O)C1=O

Procedure:
α-Aluminium oxide coated with 10% vanadium pentoxide (V-0501S from Harshaw) is used as the catalyst in the reactor described in Example 1 and the temperature of the air bath is adjusted to 245° C. 60 l of air and 33 g of pantolactone are subsequently added hourly to the evaporator. 99% of the pantolactone are transformed and ketopantolactone is formed with a selectivity of 85%.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[OH:15][CH:16]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[O:39][CH3:40])[CH2:17][O:18][C:19]1[CH:32]=[CH:31][C:22]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[NH:26][C:25]2=[O:30])=[CH:21][CH:20]=1.CS(C)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:40][O:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C:16](=[O:15])[CH2:17][O:18][C:19]1[CH:32]=[CH:31][C:22]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[NH:26][C:25]2=[O:30])=[CH:21][CH:20]=1
Reactant: COc1ccccc1C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: O=C([O-])O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1ccccc1C(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reaction time: 0.25 h
Yield: 87.3 %

Procedure:
To a stirring solution of phosphorus pentoxide (0.30 g, 1.10 mmol) in DCM (8 mL) at 0° C. was added a solution of 5-{4-[2-hydroxy-2-(2-methoxyphenyl)ethoxy]benzyl}-1,3-thiazolidine-2,4-dione (0.20 g, 0.54 mmol) in DCM (8 mL) followed by dimethyl sulfoxide (0.20 mL, 2.80 mmol). After stirring for 15 minutes, N,N-diiisopropylethylamine (0.28 mL, 1.60 mmol) was added. After 45 minutes, the reaction mixture was cast into cold saturated NaHCO3 and extracted with EtOAc (×2). The combined extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was chromatographed on a small silica gel column eluting with 0-10% EtOAc/DCM. Fractions containing product were combined and evaporated in vacuo to give 175 mg (88%) of the title compound as a light yellow solid. MS (ESI−) for C19H17NO5S m/z 370.1 (M−H)−.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[C:15]1[C:20]([F:21])=[CH:19][C:18]([F:22])=[CH:17][C:16]=1[F:23].Cl>O.COC(C)(C)C.O1CCOCC1>[F:21][C:20]1[CH:15]=[C:16]([F:23])[CH:17]=[C:18]([F:22])[C:19]=1[CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Fc1cc(F)c(Br)c(F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: COC(C)(C)C
Product: CCOC(=O)C(C(=O)OCC)c1c(F)cc(F)cc1F
Temperature: 40 °C
Yield: 43.4 %

Procedure:
Into a mixture of 4.8 g of sodium hydride (60% in oil) and 100 ml of 1,4-dioxane, 19.2 g of diethyl malonate were added dropwise at room temperature, and then 17.2 g of cuprous bromide and 21.1 g of 1-bromo-2,4,6-trifluorobenzene were subsequently added thereto at 40° C. and refluxed for 26 hours under heating. To the reaction mixture, conc. hydrochloric acid was added under ice-cooling, and then tert-butyl methyl ether and water were added. The organic layer was separated, washed with aqueous sodium hydroxide solution, dil. hydrochloric acid and water subsequently, dried over sodium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 12.6 g of diethyl (2,4,6-trifluorophenyl)malonate.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([NH:8]C(=O)OC(C)(C)C)[CH:5]=[CH:4][N:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)Nc1ccnc(Br)c1
Reactant: Cc1ccc(F)c(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccc(F)c(-c2cc(N)ccn2)c1
Yield: 532.9 %

Procedure:
Bis(triphenylphosphine)palladium chloride (0.406 g, 0.578 mmol), tert-butyl 2-bromopyridin-4-ylcarbamate (250 mg, 0.915 mmol), and 2-fluoro-5-methylphenylboronic acid (1.157 g, 7.51 mmol) and sodium carbonate (0.458 ml, 0.915 mmol) were combined in dioxane (10 mL) and heated to reflux for 5 hours. The reaction mixture was cooled, evaporated to remove most of the solvent, and partitioned between brine and EtOAc. The organic layer was separated and dried over Na2SO4, filtered, and concentrate under vacuum to give a residue which was purified by NH silica column chromatography eluting with Hex/EtOAc 1:1 to give a residue which was further purified by repeating the silica column chromatography using the same conditions to give the title compound (986 mg) as clear oil which solidified on standing. ESI-MS: m/z 203.1 (M+H).
Reaction SMILES: [C:1]1([N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:22][C:23]1[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=1.[OH-].[NH4+]>C(Cl)(Cl)Cl.O>[C:1]1([N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[N:22][C:23]2[CH:24]=[CH:25][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:32][CH:33]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CN(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)c1ccc(N=CN(c2ccccc2)c2ccccc2)cc1

Procedure:
To a solution of N,N-diphenylformamide (19.7 g, 0.10 mol) in 100 ml of chloroform was added 22.8 g (0.11 mol) of phosphorus pentachloride in small portions. After the addition was completed the solution was refluxed for 1 hr. Ethyl 4-aminobenzoate (16.5 g, 0.10 mol) was added in small portions and the solution was refluxed 1 hr. The solution was poured into 100 ml of water and neutralized with concentrated ammonium hydroxide. The chloroform phase was separated, dried (MgSO4), filtered and concentrated to yield a yellow oil. Purification by chromatography using silica gel/benzene yielded the desired product. ##STR11##
Reaction SMILES: [CH3:1][S:2][CH2:3][S:4](=[O:6])[CH3:5].O1[CH2:11][CH2:10][CH2:9][CH2:8]1.[H-].[Na+].BrCCCCBr>C(Cl)Cl>[CH3:1][S:2][C:3]1([S:4](=[O:6])[CH3:5])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CSCS(C)=O
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: BrCCCCBr
Solvent: ClCCl
Product: CSC1(S(C)=O)CCCC1
Reaction time: 0.5 h
Yield: 46 %

Procedure:
Formaldehyde dimethyl mercaptal S-oxide (1.49g) was dissolved in 15 ml. of tetrahydrofuran, and with ice cooling, 665 mg of sodium hydride was added. The mixture was stirred for 30 minutes with ice cooling, and then 2.936g of 1,4-dibromobutane was added. The mixture was stirred for 1 hour with ice cooling, for 24 hours at room temperature, and then for 44.5 hours at 50° C. Then, 100 ml. of methylene chloride was added, and the insoluble matter was separated. The filtrate was concentrated at reduced pressure, and the residue was separated by column chromatography (silica gel, eluted with 20% AcOEt-CH2Cl2, AcOEt, and MeOH) to afford 985 mg of cyclopentanone dimethyl mercaptal S-oxide. Also, 463 mg of formaldehyde dimethyl mercaptal S-oxide was recovered. The yield was 46%, and the conversion was 67%.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:11]=[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][N:5]2[N:4]=1.C(OCC)(=O)C.CO.ClCCl>[Pd].C(O)C>[F:12][C:2]([F:1])([F:13])[C:3]1[N:11]=[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][N:5]2[N:4]=1
Reactant: FC(F)(F)c1nc2cnccn2n1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Solvent: ClCCl
Product: FC(F)(F)c1nc2n(n1)CCNC2

Procedure:
2-(Trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyrazine (340 mg, 1.81 mmol, from Step C) was hydrogenated under atmospheric hydrogen with 10% palladium on carbon (60 mg) as a catalyst in ethanol (10 mL) at ambient temperature for 18 h. Filtration through Celite followed by concentration gave a dark colored oil. Flash chromatography (100% ethyl acetate, then 10% methanol/dichloromethane) gave the title compound as a white solid. 1H-NMR (500 MHz, CDCl3): δ 1.80 (br, 1H), 3.40 (t, 2H, J=5.5 Hz), 4.22-4.26 (m, 4H); LC/MS 193 (M+1).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:16][CH3:17])[C:3]([C:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]=1)=[O:4].[N:18]1([C:24](=[O:41])[CH2:25][CH:26]([CH2:30][S:31]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)(=[O:33])=[O:32])[C:27](O)=[O:28])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(OCC)(=O)C.C([O-])(O)=O.[Na+].C(Cl)Cl>[N:18]1([C:24](=[O:41])[CH2:25][CH:26]([CH2:30][S:31]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)(=[O:32])=[O:33])[C:27]([NH:1][C@H:2]([C:3]([C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:6]=2)=[O:4])[CH2:16][CH3:17])=[O:28])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: O=C(O)C(CC(=O)N1CCOCC1)CS(=O)(=O)Cc1ccccc1
Reactant: CC[C@H](N)C(=O)c1nc(-c2ccccc2)no1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC[C@H](NC(=O)C(CC(=O)N1CCOCC1)CS(=O)(=O)Cc1ccccc1)C(=O)c1nc(-c2ccccc2)no1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (S)-2-amino-1-(3-phenyl-[1,2,4]oxadiazol-5-yl)-butan-1-one, prepared as in Reference 11, 4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyric acid (200 mg, 0.56 mmol), EDC (200 mg, 1.05 mmol), HOBt (200 mg, 1.30 mmol), CH2Cl2 (4 mL) and 4-methylmorpholine (0.5 mL) was stirred at ambient temperature for 2 hours. After dilution with ethyl acetate (150 mL), the solution was washed with water (30 mL), saturated aqueous NaHCO3 solution and brine, dried with MgSO4 and evaporated under vacuum. The crude product was dissolved in dry dichloromethyl (10 mL) and 1,1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martin periodinane) (500 mg, 1.2 mmol) was added. After stirring at ambient temperatures for 1 hour, the mixture was diluted with ethyl acetate (150 mL) and treated with Na2S2O3 solution (0.26M) in saturated aqueous NaHCO3. The organic phase was washed with saturated aqueous NaHCO3 and brine, dried with MgSO4 and evaporated. The product was purified by flash chromatography on silica gel (hexane/ethyl acetate in a 1:2 to 1:4 ratio) to yield 4-Morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-N-{-(S)-1[1-(3-phenyl-[1,2,4]oxadiazol-5-yl)-methanoyl]-propyl}-butyramide (150 mg) as mixture of diastereomers; 1H NMR: (DMSO), 9.03 (d, J=5.9 Hz), 8.89 (d, J=6.4 Hz), 1H], 8.09–8.03 (m, 2H), 7.66–7.55 (m, 3H), 7.42–7.33 (m, 5H), 4.97–4.78 (m, 1H), 4.53–4.35 (m, 2H), 3.58–3.02 (m, 1H), 2.65–2.50 (m, 2H), 2.06–1.90 (m, 1H), 1.83–1.66 (m, 1H), 0.97 (t, J=7.2 Hz, 3H); MS: (M++1) 569.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[CH:19]1[C:32]2[CH:31]=[C:30](B(O)O)[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]=2[CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.COC>C(Cl)(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:31]4[C:32]5[C:23]([C:24]6[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=6[CH:30]=4)=[CH:22][CH:21]=[CH:20][CH:19]=5)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: OB(O)c1cc2ccccc2c2ccccc12
Agent: [Pd]
Agent: COC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cc5ccccc5c5ccccc45)cc3CC[C@@H]12
Yield: 30.3 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 9-phenanthreneboronic acid (173 mg, 0.78 mmol), triethylamine (0.2 mL, 1.3 mmol), and 2 mL of dimethyl ether, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 80 mg (30%) of the title compound as a white solid. mp 218°-220°. FDMS: m/e=405. α[D]589 =+63.01 (c=0.98, chloroform).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[Cl:36][C:37]1[CH:50]=[CH:49][C:40]([O:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[NH2:48])=[CH:39][CH:38]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[NH:48][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[O:41][C:40]2[CH:49]=[CH:50][C:37]([Cl:36])=[CH:38][CH:39]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccccc1Oc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccccc2Oc2ccc(Cl)cc2)CC1
Reaction time: 0.5 h
Yield: 54.8 %

Procedure:
A solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (AMR01030, 417 mg, 1.82 mmol) in dry DCM (8 mL) was stirred under nitrogen, and 4-dimethylaminopyridine (DMPA, 40 mg, 0.327 mmol), (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 1.05 g, 5.46 mmol) and triethylamine (0.25 mL) were added. The resulting mixture was stirred for 30 min under nitrogen and 2-(4-chloro-phenoxy)-phenylamine (AMR01029, 400 mg, 1.82 mmol) in dry DCM (4 mL) was added. After stirring at room temperature for 24 h, the mixture was diluted with DCM, washed with HCl 1M (3×25 mL), water, saturated NaHCO3 (2×25 mL) and brine. The organic layer was dried (MgSO4), filtered and evaporated. Flash chromatography on silica gel of the crude product using hexane/EtOAc 8:2 as eluent gave starting material (104 mg). Further elution using hexane/EtOAc 7:3 gave 4-[2-(4-chlorophenoxy)-phenylcarbamoyl]piperidine-1-carboxylic acid tert-butyl ester (430 mg, 55%) as a white solid, mp 97-99° C. Rf: 0.22 (hexane/EtOAc 7:3) LC/MS (APCI) tr=3.83 min, m/z 431.23 (33), 429.21 (M−−H, 100). 1H NMR (270 MHz, CDCl3) δ 1.44 (9H, s, 3CH3), 1.68 (2H, m, CH2), 1.83 (2H, m, CH2), 2.36 (1H, tt, J=11.4, 3.7 Hz), 2.75 (4H, br t, 2CH2), 4.11 (4H, m, 2CH2), 6.81 (1H, dd, J=8.2, 1.5 Hz, ArH), 6.93 (2H, AA′BB′, ArH), 7.01 (1H, td, ArH), 7.12 (1H, td, ArH), 7.31 (2H, AA′BB′, ArH), 7.68 (1H, br s, NH) and 8.40 (1H, dd, J=6.9, 1.5 Hz, ArH).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([CH2:11][CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:18][C:19]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:20]=1[C:21](Cl)=[O:22].CCOC(C)=O>C1COCC1.CCN(CC)CC.CO>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:21](=[O:22])[C:20]2[CH:24]=[C:25]([C:28]([F:29])([F:30])[F:31])[CH:26]=[CH:27][C:19]=2[F:18])[N:7]([CH2:11][CH2:12][CH2:13][C:14]([F:16])([F:17])[F:15])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(N)n(CCCC(F)(F)F)n1
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(=O)c2cc(C(F)(F)F)ccc2F)n(CCCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.2 %

Procedure:
To a solution of Example 135B (2.0 g, 8.1 mmol) and Et3N (3.4 mL, 24.3 mmol) in THF (40 mL) was added 2-fluoro-5-(trifluoromethyl)benzoyl chloride (1.2 mL, 8.1 mmol). The mixture was allowed to stir at ambient temperature for 3 h then partitioned between saturated aqueous NaHCO3 (10 mL) and EtOAc (10 mL). The layers were separated and the aqueous phase was extracted EtOAc (3×10 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification by column chromatography (SiO2, 50% hexanes/EtOAc then 100% EtOAc then 9:1:0.1 EtOAc:MeOH:Et3N) afforded the title compound (2.9 g, 6.5 mmol, 80% yield). MS (ESI+) m/z 440 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:17][CH2:16][CH2:15][C:14]3[CH:13]=[C:12]([C:18](=[O:29])[N:19]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])[CH3:20])[S:11][C:10]=3[C:9]=2[CH:30]=1)=[O:4].[OH-].[Na+].Cl>C1COCC1.C(O)C>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[N:19]([CH3:20])[C:18]([C:12]1[S:11][C:10]2[C:9]3[CH:30]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[CH:7][C:8]=3[O:17][CH2:16][CH2:15][C:14]=2[CH:13]=1)=[O:29]
Reactant: COC(=O)c1ccc2c(c1)-c1sc(C(=O)N(C)c3ccc(Cl)cc3Cl)cc1CCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CN(C(=O)c1cc2c(s1)-c1cc(C(=O)O)ccc1OCC2)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[(2,4-dichloro-phenyl)-methyl-carbamoyl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-9-carboxylic acid methyl ester (700 mg) in THF (8 mL) and ethanol (4 mL) was added sodium hydroxide solution (121 mg in 4 mL of water) and the reaction stirred at room temperature for 16 h. The reaction was then acidified with 2 M hydrochloric acid and the resulting solid was filtered and air-dried to give 2-[(2,4-dichloro-phenyl)-methyl-carbamoyl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-9-carboxylic acid.