Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13]([OH:17])[CH2:14][CH:15]=[CH2:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+](=[CH2:20])=[N-].N#N>ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13]([OH:17])[CH2:14][CH:15]2[CH2:20][CH2:16]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCC(O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: C=[N+]=[N-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: N#N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](C(O)CC2CC2)C1
Temperature: 25 °C

Procedure:
Add palladium (II) acetate (2.31 g; 0.298 mmol) to a stirred solution of (3S)-3-(1-hydroxy-but-3-enyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (S-mix) (14.4 g, 59.7 mmol) in dichloromethane (43.2 mL). Add slowly a freshly prepared solution of diazomethane (100 mL, about 50 mmol in diethyl ether) under nitrogen at −30 to −40° C. (Caution: vigorous N2 gas evolution). Evaporate the solvent and dissolve the crude in dichloromethane (43.2 mL). Add palladium (II) acetate (2.31 g, 0.298 mmol) followed by a freshly prepared solution of diazomethane (100 mL, about 50 mmol in diethyl ether) to the mixture kept under nitrogen at −30 to −40° C. (Caution: vigorous N2 gas evolution). Evaporate the solvent and dissolve the crude in dichloromethane (43.2 mL). Add palladium (II) acetate (2.31 g, 0.298 mmol) followed by a freshly prepared solution of diazomethane (50 mL, about 25 mmol in diethyl ether) to the mixture kept under nitrogen at −30 to −40° C. (Caution: vigorous N2 gas evolution). Evaporate the solvent, add hexanes (140 mL) to the crude residue and stir the suspension over night at room temperature. Filter the suspension over a pad of celite® and concentrate to obtain a quantitative yield (3S)-3-(2-cyclopropyl-1-hydroxyethyl)pyrrolidine-1-carboxylic acid tert butyl ester (S-mix). MS (m/z)=200.1 [M−55].
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C@H:19]1[C@H:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:23]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@@:22]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[C:45]([CH2:50][C:51]3[CH:56]=[CH:55][C:54]([O:57][CH2:58][CH3:59])=[C:53]([F:60])[C:52]=3[F:61])[CH:44]=2)([O:41][CH3:42])[O:21][C@@H:20]1[CH2:62][OH:63])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:11]([O:18][C@H:19]1[C@H:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:23]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C@@:22]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[C:45]([CH2:50][C:51]3[CH:56]=[CH:55][C:54]([O:57][CH2:58][CH3:59])=[C:53]([F:60])[C:52]=3[F:61])[CH:44]=2)([O:41][CH3:42])[O:21][C@@H:20]1[CH:62]=[O:63])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](C=O)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
Oxalyl chloride (0.37 mL, 4.37 mmol) was dissolved in 20 mL dichloromethane and cooled to −78° C., followed by dropwise addition of a solution (10 mL) of dimethyl sulfoxide (0.5 mL, 7.05 mmol) in dichloromethane and a solution (20 mL) of [(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol 3i (2.5 g, 3.36 mmol) in dichloromethane in turn. The reaction mixture was stirred for 30 minutes at −78° C. Triethylamine (2.33 mL, 16.8 mmol) was added before the reaction mixture was warmed and stirred for 16 hours at room temperature. Thereafter, the reaction mixture was partitioned after 15 mL 1 M hydrochloric acid were added. The organic extract was washed with saturated sodium chloride solution (20 mL×2) and combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 3j (2.4 g, yellow grease), yield: 96.0%.
Reaction SMILES: O=O.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[C:14]([CH3:16])[CH3:15])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1>CO>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C@H:10]([CH:14]([CH3:16])[CH3:15])[C:11]([OH:13])=[O:12])=[CH:8][CH:9]=1
Reactant: CC(C)=C(C(=O)O)c1ccc(F)cc1
Agent: O=O
Solvent: CO
Product: CC(C)[C@H](C(=O)O)c1ccc(F)cc1
Yield: 92.5 %

Procedure:
A catalyst solution was prepared in a glove box (O2 content <1 ppm) at RT by dissolving 0.124 g (0.155 mmol) of Ru(OAc)2[(R)-MeOBIPHEP] in 50 ml of methanol. Then, 30.0 g (154.5 mmol) of 2-(p-fluorophenyl)-3-methylcrotonic acid and 38 ml of methanol were placed in a 185 ml autoclave and the catalyst solution prepared above was added. The autoclave was sealed and the hydrogenation was carried out at 20° while stirring and under a constant pressure of 180 bar. The conversion was 100% after 6 hours. The hydrogenation solution was evaporated at 50°/20 mbar and the residue was distilled in a bulb tube oven at 125°/0.2 mbar. There were obtained 28.04 g (92.5%) of (S)-2-(p-fluorophenyl)-3-methylbutyric acid as a colorless oil which crystallized out at RT; chemical purity 99.9 GC area %; 90% ee.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(CC)CC)C>O1CCCC1.[Cl-].[Na+].O>[N:14]1([S:10]([C:7]2[CH:8]=[CH:9][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=2)(=[O:12])=[O:11])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: C1CCNCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1ccc(S(=O)(=O)N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
A mixture of 4-acetylbenzene-1-sulfonyl chloride (2 g, 9.2 mmol), piperidine (0.85 g, 10.0 mmol) and triethylamine (1.9 g, 18.4 mmol) in tetrahydrofuran (60 mL) was stirred at rt overnight. Brine (100 mL) was added and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate and filtered. Removal of solvent in vacuo gave the title compound as a white solid (2.3 g, 94%). MS (M+H)+ 268.
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.[CH3:7][CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10]>CC(O)(C)C>[CH3:12][O:11][C:9]([C:8]([CH:3]1[CH2:4][CH2:5][C:1](=[O:6])[CH2:2]1)([C:13]([O:15][CH3:16])=[O:14])[CH3:7])=[O:10]
Reactant: O=C1C=CCC1
Reactant: COC(=O)C(C)C(=O)OC
Solvent: CC(C)(C)O
Product: COC(=O)C(C)(C(=O)OC)C1CCC(=O)C1
Temperature: 40 °C
Reaction time: 24 h
Yield: 23.7 %

Procedure:
Under an atmosphere of argon, 12.6 mg (0.02 mmol, S/C=50) of Ru[(S,S)-Tsdpen] (hexamethylbenzene), 84 μL (1.0 mmol) of 2-cyclopentenone, 133 μL (1.0 mmol) of dimethyl methylmalonate, and 1 mL of 2-methyl-2-propanol were placed in a 20 mL Schlenk tube and stirred at 40° C. for 24 hours. This solution was purified by flash column chromatography (hexane/acetone=90/10, SiO2) to give 54 mg (24% yield) of the title compound. The optical purity was measured by HPLC (CHIRALPAK AS manufactured by Daicel Chemical Industries, Ltd., hexane: 2-propanol=80:20, flowrate 1.5 mL/min, detection at 210 nm) and it was found to be 76% ee.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([N:8]2[C:16]([Cl:17])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)[CH:7]=1.[S-:19][C:20]#[N:21].[NH4+].BrBr.O>C(O)(=O)C>[NH2:21][C:20]1[S:19][C:3]2[CH:4]=[C:5]([F:18])[C:6]([N:8]3[C:16]([Cl:17])=[C:15]4[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]4)=[N:9]3)=[CH:7][C:2]=2[N:1]=1
Reactant: Nc1ccc(F)c(-n2nc3c(c2Cl)CCCC3)c1
Reactant: N#C[S-]
Agent: BrBr
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc2cc(-n3nc4c(c3Cl)CCCC4)c(F)cc2s1
Temperature: 100 °C
Reaction time: 8 h
Yield: 31.4 %

Procedure:
2-(5-Amino-2-fluorophenyl)-3-chloro-4,5,6,7-tetra-hydro-2H-indazole (22.97 g) was dissolved in 95 % aqueous acetic acid (79.53 g), and ammonium thiocyanate (15.92 g) was added thereto at room temperature (ca. 20° C). To the resultant mixture, a solution of bromine (15.89 g) in acetic acid (23.77 g) was dropwise added in 105 minutes. After being allowed to stand overnight, the mixture was heated to 100° C., and hot water (173 ml) was added thereto, followed by filtration. The filtrate was cooled and neutralized with sodium carbonate. The precipitated crystals were collected by filtration and dried to give 2-(2-amino-6-fluorobenzothiazol-5-yl)-3-chloro-4,5,6,7-tetrahydro-2H-indazole (8.77 g). m.p., 212.4° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-])=O)=[CH:4][CH:3]=1>[Ni].CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([NH2:14])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Agent: [Ni]
Solvent: CO
Product: Cc1ccc(-c2ccccc2N)cc1
Yield: 92.6 %

Procedure:
3 g of Raney nickel are added to 23.9 g (0.112 mol) of 4'-methyl-2-nitrobiphenyl (R. B. Muller and S. Dugar, Organometallics 1984, 3, 1261) in 50 ml of methanol and the mixture is hydrogenated under normal pressure at room temperature until the theoretical amount of H2 has been absorbed. The catalyst is then removed by filtration and the filtrate is concentrated. Chromatography on SiO2 (500 g) using EA/HEP(1:6) as the eluent yields 19 g of the title compound as an oil (92.5%)
Reaction SMILES: C(OC(OCC)C(=O)CC1C=CC(CC)=CC=1)C.[CH:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]2[NH:35][C:34]([C:36]3[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=3)=[CH:33][N:32]3[C:27]=2[N:28]=[C:29]([CH2:43][C:44]2[CH:49]=[CH:48][C:47]([OH:50])=[CH:46][CH:45]=2)[C:30]3=[O:31])=[CH:21][CH:20]=1.Cl>O1CCOCC1.O>[CH:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]2[C:27]3[N:32]([CH:33]=[C:34]([C:36]4[CH:37]=[CH:38][C:39]([OH:42])=[CH:40][CH:41]=4)[N:35]=2)[C:30]([OH:31])=[C:29]([CH2:43][C:44]2[CH:49]=[CH:48][C:47]([OH:50])=[CH:46][CH:45]=2)[N:28]=3)=[CH:21][CH:20]=1
Reactant: O=c1c(Cc2ccc(O)cc2)nc2c(Cc3ccccc3)[nH]c(-c3ccc(O)cc3)cn1-2
Agent: CCOC(OCC)C(=O)Cc1ccc(CC)cc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Oc1ccc(Cc2nc3c(Cc4ccccc4)nc(-c4ccc(O)cc4)cn3c2O)cc1
Temperature: 0 °C
Reaction time: 17 h
Yield: 64.2 %

Procedure:
Under an argon atmosphere, 1,1-diethoxy-3-(4-ethylphenyl)propan-2-one (43) (301 mg, 1.20 mmol) was dissolved in 1,4-dioxane (2 mL) and water (0.4 mL). To this was added coelenteramine (238 mg, 858 μmol) and, after cooling to 0° C., conc. hydrochloric acid (0.20 mL) was further added thereto, and then stirred overnight (17 hours) at 100° C. After cooling to room temperature, the mixture was concentrated under reduced pressure and the residue was purified by silica gel flash chromatography in an argon flow (n-hexane/ethyl acetate=1/2→ethyl acetate→ethyl acetate/methanol=50/1→10/1). The solid obtained was further reprecipitated (n-hexane/acetone) to give et-coelenterazine (44, et-CTZ) as a yellow powder (240 mg, 551 μmol, 64.2%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][OH:6].[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:17][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COCCCO
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COCCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 76.5 %

Procedure:
To a solution of 3-methoxypropan-1-ol (15.9 mL, 166 mmol) in CH2C12 (75 mL) and pyridine (50 mL) was added 4-(dimethylamino)pyridine (1.0 g, 8.3 mmol) followed by p-toluenesulfonyl chloride (31.7 g, 166 mmol). The mixture was allowed to stir at ambient temperature for 72 hours then was quenched with 5% aqueous HCl (20 mL), extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by column chromatography (SiO2, 75% hexanes in EtOAc) afforded the title compound (31 g, 127 mmol, 76% yield). MS (DCI/NH3) m/z 262 (M+NH4)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C@H:7]3[NH:18][CH2:17][CH2:16][C@@:13]4([C:14]=2[CH:15]=1)[C@H:8]3[CH2:9][CH2:10][CH2:11][CH2:12]4.[OH-].[Na+].[CH:21]1[CH:26]=[CH:25][C:24]([CH2:27][O:28][C:29](Cl)=[O:30])=[CH:23][CH:22]=1>O1CCOCC1.O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C@H:7]3[N:18]([C:29]([O:28][CH2:27][C:24]4[CH:25]=[CH:26][CH:21]=[CH:22][CH:23]=4)=[O:30])[CH2:17][CH2:16][C@@:13]4([C:14]=2[CH:15]=1)[C@H:8]3[CH2:9][CH2:10][CH2:11][CH2:12]4
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Oc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)NCC3
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(O)cc13
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
To (+)-3-hydroxymorphinan (HM) hydrobromide (50.0 g, 154.2 mmol), sodium hydroxide (12.3 g, 308.4 mmol) in a mixture of 1,4-dioxane (200 mL) and water (200 mL) was added Cbz-Cl (24.2 mL, 169.6 mmol) dropwise at room temperature. The reaction mixture was stirred vigorously at room temperature overnight. After the reaction was completed, water (200 mL) was added. The mixture was extracted with diethyl ether (500 mL×2). The combined organics were dried over MgSO4, filtered, and evaporated under vacuum. Standing under high vacuum provided the title compound (57.7 g, 99%) as a light yellow solid. The compound was used for the next step without further purification.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13](Br)[N:12]=1>CN(C)C=O>[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:12]=1
Reactant: Oc1ccccc1
Reactant: Brc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cccc(Oc2ccccc2)n1
Yield: 79 %

Procedure:
To a solution of 6.5 g (0.135 mol) of 50% sodium hydride in 75 ml of dimethylformamide at 0° C. and under N2 was added a solution of 11.9 g (0.127 mol) of phenol in 75 ml of dimethylformamide. Once dropwise addition was complete, 30.0 g (0.127 mol) of 2,6-dibromopyridine was added in one portion and the mixture was heated at 60° to 65° C. for 18 hours. The mixture was then cooled and partitioned between ether and 1N aqueous NaOH. The ether extracts were washed two times with aqueous NaHCO3, dried over MgSO4, filtered and concentrated under vacuum. The solid residue was slurried in hexane, filtered and dried to afford 25.1 g (79%) of the title compound as a white powder: m.p. 83° to 86° C.; 1H NMR (CDCl3) δ 6.70 (d, 1H), 7.0-7.5 (m, 7 H).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(O)(O)(=O)=O.[NH2:20][OH:21].[OH-].[Na+]>CO>[C:1](=[N:20][OH:21])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: NO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: ON=C(c1ccccc1)c1ccccc1
Temperature: 5 °C

Procedure:
Benzophenone (182 g; 1.0 mol) mixed with absolute methanol (400 mL) was placed in a 2-liter 3-neck flask (baffled) fitted with over-head stirrer. To the solution was added hydroxylamine sulfate (120 g; 0.73 m) and maintained vigorously stirred with cooling in ice bath (5° C.). A solution of sodium hydroxide pellets (60 g; 1.50 mol) in absolute methanol (400 mL) was then added slowly with continued agitation. After stirring for 6 hours with cooling, it was heated under reflux (67° C.). pH of the mixture was 11.2. Heating at reflux continued for a total of 12 hours and the solution filtered while still hot.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.F[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 140 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
To a solution of 4-fluorophenol (10 g, 89 mmol) and 4-fluorobenzaldehyde (11.07 g, 89 mmol) in DMF (200 mL) was added K2CO3 (13.33 g, 96 mmol). The mixture was heated at 140° C. for 4 h. After cooling to room temperature, the mixture was poured into of ice water (300 mL), and left stand overnight. The solid was collected by filtration, washed with water, re-dissolved in EA (200 mL) and washed with brine (100 mL). The organic phase was dried with sodium sulfate, filtered and concentrated to afford the title compound (17 g, 75 mmol, 84% yield) as yellow solid. LCMS: rt=1.52 min, [M+H+]=217
Reaction SMILES: [CH2:1]([CH:3]([CH2:14][CH3:15])[CH2:4][C:5]1([C:11](O)=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH3:2].C1(C(O)=O)CCCCC1.S(Cl)([Cl:27])=O.C(C(CC)CC1(C(OC(C2(CC(CC)CC)CCCCC2)=O)=O)CCCCC1)C>>[CH2:1]([CH:3]([CH2:14][CH3:15])[CH2:4][C:5]1([C:11]([Cl:27])=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH3:2]
Reactant: CCC(CC)CC1(C(=O)O)CCCCC1
Reactant: O=S(Cl)Cl
Agent: CCC(CC)CC1(C(=O)OC(=O)C2(CC(CC)CC)CCCCC2)CCCCC1
Solvent: O=C(O)C1CCCCC1
Product: CCC(CC)CC1(C(=O)Cl)CCCCC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
A mixture of 103.0 mmol 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid and 38.9 mmol cyclohexanecarboxylic acid was warmed to 50° C. 12.4 mL (170.3 mmol=1.2 Eq. relative to the sum of both acids) of thionyl chloride was added during 16 minutes at a temperature of 44-50° C. (reaction is endothermic) and the reaction mixture was kept at 52-53° C. After 1 hr the reaction was incomplete (5.2% 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid and 13.8% 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid anhydride), after 6 hrs still incomplete (1.9% 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid and 2.8% 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid anhydride). After addition of another 4.0 mL (55 mmol) thionylchloride and 3 hr at 52-53° C. the reaction was almost complete (0.18% 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid and 0.47% 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid anhydride). After removing volatile components in vacuo (60° C. bath, 3.3-3.7 mbar followed by 120° C. bath, 9.3-9.6 mbar) 20.21 g of residue was obtained (assay 96.6% 1-(2-ethyl-butyl)-cyclohexanecarbonyl chloride, yield 82.1%).
Reaction SMILES: [CH2:1]([CH:3]([CH2:14][CH3:15])[CH2:4][C:5]1([C:11](O)=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH3:2].C1(C(O)=O)CCCCC1.C(N(CCCC)CCCC)CCC.S(Cl)([Cl:40])=O.C(C(CC)CC1(C(OC(C2(CC(CC)CC)CCCCC2)=O)=O)CCCCC1)C>>[CH2:1]([CH:3]([CH2:14][CH3:15])[CH2:4][C:5]1([C:11]([Cl:40])=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH3:2]
Reactant: CCC(CC)CC1(C(=O)O)CCCCC1
Reactant: O=S(Cl)Cl
Agent: CCC(CC)CC1(C(=O)OC(=O)C2(CC(CC)CC)CCCCC2)CCCCC1
Solvent: CCCCN(CCCC)CCCC
Solvent: O=C(O)C1CCCCC1
Product: CCC(CC)CC1(C(=O)Cl)CCCCC1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 95.8 %

Procedure:
A mixture of 103.0 mmol 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid, 38.9 mmol cyclo-hexanecarboxylic acid and 173 μL tributylamine (0.71 mmol=0.005 eq. relative to the sum of both acids) was warmed to 50° C. 12.4 mL (170.3 mmol=1.2 Eq. relative to the sum of both acids) of thionyl chloride was added during 16 minutes at a temperature of 44-51° C. (reaction is endothermic, vigorous gas evolution) and the reaction mixture was kept at 53-55° C. After 15 minutes the reaction was complete (0.08% 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid and no 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid anhydride). After removing volatile components in vacuo (60° C. bath, 2.7-1.9 mbar followed by 120° C. bath, 8.8-13 mbar) 24.86 g of the residue was obtained (assay 95.8% 1-(2-ethyl-butyl)-cyclohexanecarbonyl chloride, yield 100%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(O)ccc1Br
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(OS(C)(=O)=O)ccc1Br
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-bromo-3-methylphenol (9.87 g, 52.8 mmol) and triethylamine (10.70 g, 106 mmol) in CH2Cl2 (50 mL) at 0° C. was added methanesulfonyl chloride (7.25 g, 63.3 mmol), dropwise. After 30 min at 0° C., the reaction mixture was concentrated in vacuo. The residue was partitioned between saturated aqueous NaHCO3 and EtOAc. The layers were separated and the organic extract was washed with aqueous NaHCO3, then 3 N aqueous HCl, then brine, then dried over Na2SO4, filtered, and concentrated in vacuo to provide the titled product.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:11]([NH2:13])[CH3:12]>C1(C)C(C)=CC=CC=1>[CH2:11]([NH:13][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)[CH3:12]
Reactant: CCN
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: Cc1ccccc1C
Product: CCNc1ncccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 110.8 %

Procedure:
A stirred mixture of 2-chloro-3-nitropyridine (8.60 g, 0.054 mol), ethylamine (5.37 g, 0.12 mol), and xylene (10 ml) was heated at 100° C. in a sealed tube for three hours. After cooling, the solvent was removed in vacuo, and water was added to the residue. The product was extracted with methylene chloride, dried (sodium sulfate), and concentrated in vacuo to give 10.0 g of the title compound as a yellow oil, suitable for use in the next reaction.
Reaction SMILES: C[O-].[Na+].[CH3:4][S:5][C:6]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:7]=1[C:8]([O:10]C)=O.[CH3:20][C:21]([CH:23]1[CH2:25][CH2:24]1)=[O:22]>C1(C)C=CC=CC=1>[CH:23]1([C:21](=[O:22])[CH2:20][C:8]([C:7]2[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][C:6]=2[S:5][CH3:4])=[O:10])[CH2:25][CH2:24]1
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1SC
Reactant: CC(=O)C1CC1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CSc1cc(C(F)(F)F)ccc1C(=O)CC(=O)C1CC1
Temperature: 56 °C
Yield: 92.9 %

Procedure:
Sodium methoxide (3.51 g. 0.065M) was added to a mixture of methyl 2-methylthio-4-trifluoromethylbenzoate (12.5 g 0.050M) and cyclopropyl methyl ketone (7 ml, 0.070M) in toluene. The mixture was heated at 55-57° C. for 1 hour. Methanol was distilled under reduced pressure. After cooling to 20° C. the mixture was acidified and the organic phase washed (sodium bicarbonate solution and with water) and evaporated to give 1-cyclopropyl-3-(2-methylthio-4-trifluoromethylphenyl)propane-1,3-dione as yellow crystals (14.03 g), m.p. 64° C. A yield of 92.9% was obtained. The purity of the product was 95%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[N:6][CH:7]=1.[C:9]1([CH3:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(=O)([O-])[O-].[Na+].[Na+]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH3:15])=[N:6][CH:7]=1
Reactant: Cc1ccccc1
Reactant: Brc1ccc(I)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccccc1-c1ccc(Br)cn1
Yield: 84 %

Procedure:
To an argon-purged and evacuated slurry of 910 mg (3.21 mmol) of 5-bromo-2-iodopyridine and 436 mg (3.21 mmol, 1.0 eq.) of 2-o-tolylboronic acid in 8 mL of toluene and 3.2 mL of 2 M aqueous sodium carbonate, was added 36 mg (0.032 mmol, 0.01 eq) of tetrakis(tri-phenylphosphine)palladium. The reaction mixture was purged and evacuated with argon twice more and then set to reflux under argon for 15 h. The reaction was cooled and partitioned between water and EtOAc. The layers were separated, and the aqueous layer extracted once more with EtOAc. The organic extracts were combined, dried over magnesium sulfate, filtered, concentrated and dried in vacuo to give the crude product as an orange oil. Purification by silica gel chromatography (7:3 CH2Cl2/hexanes) provided the title compound as a yellow oil, 666 mg, 84% yield.