Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:21](=O)[CH2:22][CH2:23][CH2:24][CH3:25])[C:17](OC)=[O:18])=[CH:11][CH:10]=1)#[N:2].[O:27]1[C:31]2([CH2:36][CH2:35][CH:34]([NH:37][C:38]3[NH:42][C:41]([CH3:43])=[N:40][N:39]=3)[CH2:33][CH2:32]2)[O:30][CH2:29][CH2:28]1.N12CCCN=C1CCCCC2.C(N(CC)C1C=CC=CC=1)C>C(OCC)(=O)C>[CH2:22]([C:21]1[N:39]2[N:40]=[C:41]([CH3:43])[N:42]=[C:38]2[N:37]([CH:34]2[CH2:33][CH2:32][C:31]3([O:27][CH2:28][CH2:29][O:30]3)[CH2:36][CH2:35]2)[C:17](=[O:18])[C:16]=1[CH2:15][C:12]1[CH:11]=[CH:10][C:9]([C:4]2[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:14][CH:13]=1)[CH2:23][CH2:24][CH3:25]
Reactant: Cc1nnc(NC2CCC3(CC2)OCCO3)[nH]1
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)c1ccccc1
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2nc(C)nn12
Temperature: 180 °C
Reaction time: 16 h
Yield: 56.7 %

Procedure:
A mixture of methyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate (15 g), N-(1,4-dioxaspiro[4.5]dec-8-yl)-5-methyl-4H-1,2,4-triazol-3-amine (5 g), 1,8-diazabicyclo[5.4.0]undec-7-ene (1.4 mL) and N,N-diethylaniline (80 mL) was stirred at 180° C. for 16 hr. The obtained reaction mixture was diluted with ethyl acetate, washed 3 times with 1 N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (6.4 g, 57%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([N:12]([CH:16]2[C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][C:19]=3[CH2:18][CH2:17]2)[N:26]=[C:25]([CH3:29])[N:24]([CH2:30][O:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[C:23]4=[O:38])[CH2:13][C:14]#[CH:15])[CH:9]=[CH:8][C:3]=1[CH:4]=C(C)C.[O:39]=[O+][O-]>C(Cl)Cl.C(O)C>[F:1][C:2]1[CH:11]=[C:10]([N:12]([CH:16]2[C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][C:19]=3[CH2:18][CH2:17]2)[N:26]=[C:25]([CH3:29])[N:24]([CH2:30][O:31][C:32](=[O:37])[C:33]([CH3:35])([CH3:36])[CH3:34])[C:23]4=[O:38])[CH2:13][C:14]#[CH:15])[CH:9]=[CH:8][C:3]=1[CH:4]=[O:39]
Reactant: O=[O+][O-]
Reactant: C#CCN(c1ccc(C=C(C)C)c(F)c1)C1CCc2cc3nc(C)n(COC(=O)C(C)(C)C)c(=O)c3cc21
Solvent: CCO
Solvent: ClCCl
Product: C#CCN(c1ccc(C=O)c(F)c1)C1CCc2cc3nc(C)n(COC(=O)C(C)(C)C)c(=O)c3cc21
Temperature: -70 °C

Procedure:
o-Fluoro-p-[N-((6RS)-2-methyl-4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]-β,β-dimethylstyrene (0.626 g) was dissolved in a mixture of methylene chloride (2 ml) and ethanol (250 ml). The mixture was cooled to -70° C. and ozone gas was passed into the solution for 7.5 minutes. Argon gas was bubbled into the solution for 5 minutes. Dimethyl sulphide (4 ml) was added and the mixture was allowed to warm to ambient temperature. The mixture was evaporated and the residue was purified by column chromatography using a 1:1 mixture of hexane and ethyl acetate as eluant. There was thus obtained o-fluoro-p-[N-((6RS)-2-methyl-4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]benzaldehyde (0.47 g);
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:29])[CH:12]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:6][CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH:14]1([CH2:13][CH:12]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([CH2:3][OH:2])=[CH:5][N:6]=2)=[O:29])[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccc(CO)cn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57.3 %

Procedure:
A solution of 6-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-nicotinic acid methyl ester (prepared as in Example 53(B)(a), 110 mg, 0.26 mmol) in diethyl ether (500 μL) was cooled to 0° C. and then slowly treated with lithium aluminum hydride (15 mg, 0.38 mmol). The reaction mixture was stirred at 0° C. for 30 min then allowed to warm to 25° C. After 1 h at 25° C., thin layer chromatography still indicated the presence of the starting material. An additional amount of lithium aluminum hydride (10 mg, 0.26 mmol) was added to the reaction mixture, and the reaction mixture was allowed to stir at 25° C. for 1 h. The reaction mixture was then slowly quenched by the dropwise addition of water (10 mL). The resulting mixture was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 1/3 hexanes/ethyl acetate) afforded the 3-cyclopentyl-N-(5-hydroxymethyl-pyridin-2-yl)-2-(4-methanesulfonyl-phenyl)-propionamide (60 mg, 57%) as a yellow foam: mp 74–77° C.; EI-HRMS m/e calcd for C21H26N2O4S (M+) 402.1613, found 402.1617.
Reaction SMILES: [F:1][C:2]1([F:56])[C:6]2[N:7]([CH2:14][C:15]([NH:17][C@H:18]([C:28]3[C:33]([C:34]4[CH:35]=[CH:36][C:37]([F:43])=[C:38]([CH:42]=4)[C:39]([NH2:41])=[O:40])=[CH:32][C:31]([N:44]4C(=O)C5C(=CC=CC=5)C4=O)=[CH:30][N:29]=3)[CH2:19][C:20]3[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=3)=[O:16])[N:8]=[C:9]([C:10]([F:13])([F:12])[F:11])[C:5]=2[C@H:4]2[CH2:55][C@@H:3]12.O.NN>C(O)C>[NH2:44][C:31]1[CH:32]=[C:33]([C:34]2[CH:35]=[CH:36][C:37]([F:43])=[C:38]([CH:42]=2)[C:39]([NH2:41])=[O:40])[C:28]([C@@H:18]([NH:17][C:15](=[O:16])[CH2:14][N:7]2[C:6]3[C:2]([F:56])([F:1])[C@@H:3]4[CH2:55][C@@H:4]4[C:5]=3[C:9]([C:10]([F:11])([F:12])[F:13])=[N:8]2)[CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)=[N:29][CH:30]=1
Reactant: NC(=O)c1cc(-c2cc(N3C(=O)c4ccccc4C3=O)cnc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2C(F)(F)[C@@H]2C[C@H]32)ccc1F
Agent: NN
Solvent: O
Solvent: CCO
Product: NC(=O)c1cc(-c2cc(N)cnc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2C(F)(F)[C@@H]2C[C@H]32)ccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound 30K (13 mg, 0.017 mmol) was dissolved in 1 ml of ethanol; 0.01 ml of hydrazine monohydrate was added and stirred at room temperature for 2 hours. The solvent was removed and the residue was purified by RP-HPLC eluting with acetonitrile/H2O (with 0.1% TFA) to afford the title compound. 1H NMR (400 MHz, CD3OD) δ 8.07 (d, 1H), 7.38 (m, 2H), 7.28-7.07 (m, 2H), 6.71 (t, 1H), 6.35 (m, 2H), 5.14 (m, 1H), 4.90 (s, 2H), 3.13 (m, 1H), 3.01-2.91 (m, 1H), 2.48 (m, 2H), 1.40 (m, 1H), 1.09 (m, 1H). MS (m/z) 650.94 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][NH:14]2)=[O:12])[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C(N(CC)C(C)C)(C)C.[Cl:28][C:29]1[C:30](F)=[N:31][CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1>CS(C)=O>[C:1]([C:5]1[N:6]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:30]2[C:29]([Cl:28])=[CH:34][C:33]([C:35]([F:38])([F:36])[F:37])=[CH:32][N:31]=2)=[O:12])[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ncc(C(F)(F)F)cc1Cl
Reactant: CC(C)(C)c1csc(NC(=O)[C@@H]2CCCN2)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(C)c1csc(NC(=O)[C@@H]2CCCN2c2ncc(C(F)(F)F)cc2Cl)n1
Temperature: 100 °C

Procedure:
To a vial containing (S)-pyrrolidine-2-carboxylic acid (4-tert-butyl-thiazol-2-yl)-amide; hydrochloride (0.212 g; 0.731 mmol) in dimethylsulfoxide (2 mL) is added N,N-diisopropylethylamine (0.127 mL; 0.731 mmol) and 3-chloro-2-fluoro-5-trifluoromethylpyridine (0.096 mL; 0.731 mmol). The mixture is heated at 100° C. for 1 hour in an oil bath and then cooled to room temperature. The crude mixture is filtered and purified by preparative HPLC chromatography. Product fractions are pooled and concentrated in vacuo to afford title compound. ESI m/z 433 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[C:15]([Cl:21])[C:3]=1[C:4](Cl)=[N:5][C:6]1[C:11]([F:12])=[CH:10][N:9]=[CH:8][C:7]=1F.NC(N)=[S:24].N1C=CC=CC=1.CCN(CC)CC>C(O)(C)C>[Cl:1][C:2]1[CH:18]=[C:17]([CH:16]=[C:15]([Cl:21])[C:3]=1[C:4]1[S:24][C:7]2[CH:8]=[N:9][CH:10]=[C:11]([F:12])[C:6]=2[N:5]=1)[C:19]#[N:20]
Reactant: N#Cc1cc(Cl)c(C(Cl)=Nc2c(F)cncc2F)c(Cl)c1
Reactant: NC(N)=S
Solvent: CC(C)O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: N#Cc1cc(Cl)c(-c2nc3c(F)cncc3s2)c(Cl)c1
Temperature: 90 °C
Reaction time: 18 h
Yield: 29.7 %

Procedure:
A stirred suspension of 2,6-dichloro-4-cyano-N-(3,5-difluoropyridin-4-yl)-benzimidoyl chloride (1.5 g, 4.33 mmol), thiourea (1.32 g, 17.34 mmol) and pyridine (1.19 mL, 14.72 mmol) in isopropanol (13 mL) under a nitrogen atmosphere was heated at 90° C. for 4 hours. After cooling to 60° C., Et3N (3.62 mL, 25.98 mmol) was added and heating at 85° C. was continued for 18 hours, then at 90° C. for a further 18 hours. After cooling to room temperature, the volatiles were removed under reduced pressure and the resultant residue was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×2) and the combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The resultant residue was purified by column chromatography on silica gel eluting with 0-90% EtOAc in cyclohexane to afford the title compound as a yellow solid (417 mg, 30%). LCMS (Method D): RT=3.53 min, m/z: 324 [M+H+].
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]4[O:26][C:27](=S)[N:28]=[C:22]4[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:31]([NH2:35])[CH2:32][CH2:33][CH3:34]>O1CCOCC1>[CH2:31]([NH:35][C:27]([NH:28][C:22]1[CH:21]=[C:20]([CH2:19][N:13]2[C:14]([CH3:18])([CH3:17])[C:15](=[O:16])[N:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:10][CH:9]=3)[C:12]2=[O:30])[CH:25]=[CH:24][N:23]=1)=[O:26])[CH2:32][CH2:33][CH3:34]
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccn4oc(=S)nc4c3)C(C)(C)C2=O)cc1
Reactant: CCCCN
Solvent: C1COCCO1
Product: CCCCNC(=O)Nc1cc(CN2C(=O)N(c3ccc(C(C)(C)C)cc3)C(=O)C2(C)C)ccn1

Procedure:
This compound may be prepared as obtained in stage c) of Example 9, but starting with 200 mg of 3-(4-tert-butylphenyl)-5,5-dimethyl-1-[(2-thioxo-2H-[1,2,4]oxadiazolo[2,3-a]pyridin-7-yl)methyl]imidazolidine-2,4-dione obtained in stage b) of Example 9, 4 mL of dioxane and 41.3 mg of butan-1-amine. After chromatography on a column of silica, eluting with a mixture of heptane/ethyl acetate (gradient from 100/0 to 0/100 by volume), 150.7 mg of 1-butyl-3-(4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl]methyl}pyridin-2-yl)urea are obtained in the form of a white powder, the characteristics of which are as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[C:15]([C:16]2[C:17]([C:22]#[N:23])=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:14][C:13]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)=[CH:12]1)(=[O:10])=[O:9].C(OCC)(=O)C.Cl>C(OCC)(=O)C.CC(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH:12]=[C:13]([CH2:24][NH:25][CH3:26])[CH:14]=[C:15]1[C:16]1[C:17]([C:22]#[N:23])=[N:18][CH:19]=[CH:20][CH:21]=1)(=[O:10])=[O:9]
Reactant: CN(Cc1cc(-c2cccnc2C#N)n(S(=O)(=O)c2ccccc2Cl)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNCc1cc(-c2cccnc2C#N)n(S(=O)(=O)c2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 157 %

Procedure:
To a solution of tert-butyl {[1-[(2-chlorophenyl)sulfonyl]-5-(2-cyanopyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (211 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethanol-water to give the title compound as a white solid (yield 144 mg, 78%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15](=O)[CH3:16])=[C:13]([OH:18])[C:12]([O:19][C:20]2[C:28]([CH3:29])=[CH:27][C:26]([N+:30]([O-:32])=[O:31])=[C:25]3[C:21]=2[CH2:22][CH2:23][CH2:24]3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.O>ClCCl>[CH2:1]([O:8][C:9]1[C:14]([CH2:15][CH3:16])=[C:13]([OH:18])[C:12]([O:19][C:20]2[C:28]([CH3:29])=[CH:27][C:26]([N+:30]([O-:32])=[O:31])=[C:25]3[C:21]=2[CH2:22][CH2:23][CH2:24]3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)c1c(OCc2ccccc2)ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)c1O
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCc1c(OCc2ccccc2)ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
To a solution of 1-[6-benzyloxy-2-hydroxy-3-(5-methyl-7-nitroindan-4-yloxy)phenyl]ethanone (1.081 g) in dichloromethane (18 mL) were added triethylsilane (0.955 mL) and trifluoroacetic acid (6 mL). The mixture was stirred at room temperature overnight. Adding water, the reaction mixture was stirred for 30 min and extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was crystallized from dichloromethane and hexane to give the title compound (663 mg).
Reaction SMILES: C[O:2][CH2:3][CH2:4][CH:5]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)[CH3:6].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:33][CH2:34][C:35]1[C:36]([OH:43])=[N:37][C:38]([CH3:42])=[CH:39][C:40]=1[CH3:41]>ClCCl>[OH:43][C:36]1[C:35]([CH2:34][NH:33][C:11](=[O:13])[C:10]2[CH:9]=[CH:8][C:7]([CH:5]([CH2:4][CH2:3][OH:2])[CH3:6])=[CH:15][CH:14]=2)=[C:40]([CH3:41])[CH:39]=[C:38]([CH3:42])[N:37]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: COCCC(C)c1ccc(C(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)CCO)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.8 %

Procedure:
A mixture of 4-(4-methoxybutan-2-yl)benzoic acid (177 mg, 0.85 mmol), 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (245 mg, 1.3 mmol), N-hydroxybenzotriazole (176 mg, 1.3 mmol) and triethylamine (258 mg, 2.55 mmol) in dichloromethane (50 mL) was stirred for 30 minutes at room temperature. Then to the mixture, 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (130 mg, 0.85 mmol) was added. The resultant mixture was stirred at room temperature for 12 hours. Then the mixture was washed with water (30 mL×3). The organic layer was concentrated to give a residue and the residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(4-hydroxybutan-2-yl)benzamide (47 mg, 17%). LRMS (M+H+) m/z: calcd 324.19 found 324. 1H. NMR (300 MHz, CD3OD): δ 12.96 (s, 1H), 7.80 (s, 1H), 7.70 (d, J=7.8 Hz, 2H), 7.24 (d, J=7.8 Hz, 2H), 5.95 (s, 1H), 4.56 (d, J=5.7 Hz, 2H), 3.20-3.14 (m, 5H), 2.93 (q, J=7.2 Hz, 1H), 2.37 (s, 3H), 2.27 (s, 3H), 1.82 (q, J=6.9 Hz, 2H), 1.23 (d, J=6.9 Hz, 3H).
Reaction SMILES: C[O:2][C:3](=[O:43])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C@@H:13]2[NH:17][C@@H:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@:15]3([C:30]4[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=4)[NH:24][C:23]3=[O:32])[C@H:14]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[F:40])=[O:12])=[C:6]([O:41][CH3:42])[CH:5]=1.[OH-].[Na+]>CO.C1COCC1.O>[Cl:31][C:27]1[CH:26]=[C:25]2[NH:24][C:23](=[O:32])[C@:15]3([C@@H:14]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=4[F:40])[C@H:13]([C:11]([NH:10][C:7]4[CH:8]=[CH:9][C:4]([C:3]([OH:43])=[O:2])=[CH:5][C:6]=4[O:41][CH3:42])=[O:12])[NH:17][C@H:16]3[CH2:18][C:19]([CH3:21])([CH3:20])[CH3:22])[C:30]2=[CH:29][CH:28]=1
Reactant: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F
Temperature: 40 °C
Reaction time: 8 h
Yield: 69.5 %

Procedure:
To a solution of rac-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-3-methoxy-benzoic acid methyl ester (60 mg, 0.096 mmol) in MeOH (4 mL) and THF (6 mL) was added an aqueous solution (2 N) of NaOH (1.2 mL, 2.4 mmol). The reaction mixture was heated to 40° C. and stirred overnight. The crude mixture was diluted with water (5 mL), concentrated in vacuo to remove some organic solvent. The mixture was filtered, and the filtrate was acidified to “pH” 5-6. The suspension was filtered and the solid was collected, washed with water, and dried to give the desired product as a white powder (Yield, 41 mg, 66%). MS (H+), 614.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].ClCCl.[Br:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1.Cl[C:17]([CH3:25])([CH2:19][CH2:20][C:21](Cl)([CH3:23])[CH3:22])[CH3:18]>O>[Br:8][C:9]1[CH:10]=[C:11]([OH:15])[C:12]2[C:17]([CH3:25])([CH3:18])[CH2:19][CH2:20][C:21]([CH3:23])([CH3:22])[C:13]=2[CH:14]=1
Reactant: Oc1cccc(Br)c1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2c(O)cc(Br)cc21
Temperature: 25 °C

Procedure:
13.40 g (100.0 mmol) of aluminium chloride and 100 ml of dichloromethane are introduced into a three-necked flask under an argon atmosphere. A solution composed of 34.60 g (199.0 mmol) of 3-bromophenol, 89.00 g (486.0 mmol) of 2,5-dichloro-2,5-dimethylhexane and 300 ml of dichloromethane is added dropwise. The reaction mixture is stirred for sixteen hours at room temperature. The reaction mixture is poured into water and extracted with dichloromethane, the extract is washed with water and the organic phase is separated by settling, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column eluted with a mixture composed of 80% heptane and 20% dichloromethane. After evaporating the solvents, 30.00 g (53%) of the expected compound are collected in the form of white crystals with a melting point of 93° C.
Reaction SMILES: [C:1](O)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]C.C(OC(=O)C)(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCCCCCCCCC>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>[CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCC(=O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCCCCCC
Solvent: CC(=O)OC(C)=O
Product: C=CCCCCCCC
Temperature: 255 °C

Procedure:
A mixture of decanoic acid (100 g, 0.581 mol), acetic anhydride, dichlorobis(triphenylphosphine)palladium (0.0407 g, 5.81×10-5 mol), and triphenylphosphine (0.761 g, 0.00290 mol) was heated under a slow stream of nitrogen using an oil bath maintained at 255° C. As product distilled from the reactor, it was continuously replaced with a mixture of decanoic acid and acetic anhydride, identical in ratio to that of the initial charge, in a rate that maintained the initial level of the reactor contents throughout the course of the entire reaction. The distillate products from several runs which contained varied decanoic acid: acetic anhydride ratios were examined by GC analysis (using n-decane as internal standard) and the catalyst efficiency and product α-olefin selectivity calculated. For example, using of a 1:1.5 ratio of decanoic acid:acetic anhydride throughout the course of an entire reaction produced 1-nonene with a catalyst TON of 14,800 and an α-olefin selectivity of 97.4%. The data for this series of reactions appears in Table 4.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:10])[O-:9])=[CH:4][CH:3]=1.[CH2:11](N(CC)CC)[CH3:12].[C:18]1([C:28](Cl)=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:10][C:28]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)=[O:29])[O:9][CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: N=C([O-])c1ccc(Br)cc1
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=NC(=O)c1cccc2ccccc12)c1ccc(Br)cc1
Temperature: 10 °C
Reaction time: 10 h
Yield: 74.6 %

Procedure:
4-Bromobenzene carboximidate (6.0 g, 0.0263 mol) and triethyl amine (3.0 g, 0.0297 mol) is dissolved in toluene (15 ml). It is then cooled to 10° C. 1-naphthoyl chloride (5.0 g, 0.0263 mol) in toluene (10 ml) is added slowly to the reaction mixture over a period of 15 minutes under a nitrogen atmosphere. The reaction mixture is then stirred for 10 hours at 25° C. It is then filtered to remove the triethyl amine hydrochloride salt and the filtrate is concentrated to obtain a yellowish solid, which is washed with hexane (20 ml) and methanol (10 ml) respectively to obtain the pure desired product (Yield=7.5 g (75%)).
Reaction SMILES: [F:1][C@@:2]1([CH2:15][OH:16])[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[H-].[Na+].Cl[C:20]1[N:29]=[C:28]([Cl:30])[CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][CH:24]=[N:25]2>CN(C=O)C.C(Cl)Cl>[Cl:30][C:28]1[CH:27]=[C:26]2[C:21]([CH:22]=[CH:23][CH:24]=[N:25]2)=[C:20]([O:16][CH2:15][C@:2]2([F:1])[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:3]2)[N:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@](F)(CO)C1
Reactant: Clc1cc2ncccc2c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@](F)(COc2nc(Cl)cc3ncccc23)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
To an ice cooled solution of 1,1-dimethylethyl (3S)-3-fluoro-3-(hydroxymethyl)-1-piperidinecarboxylate (1.406 g, 6.03 mmol) in DMF (20 ml) was added sodium hydride (0.313 g, 7.84 mmol) (60% dispersion in mineral oil). This was stirred for 15 min before adding 5,7-dichloro-1,6-naphthyridine (1.2 g, 6.03 mmol). This was warmed to room temp and stirred for 4 h. The reaction had gone to completion and so was cautiously quenched with aqueous ammonium chloride before partitioning between aqueous ammonium chloride and ethyl acetate. The layers were separated and the aqueous was re-extracted with ethyl acetate. The combined organics were washed with brine and concentrated in vacuo to give the crude product. This was dissolved in DCM and purified through silica (50 g), eluting with a gradient of 0-50% ethyl acetate in DCM. Appropriate fractions were concentrated in vacuo to yield the title compound as a cream foamy gum (1.91 g).