Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][CH:9]2O)=[C:4]([F:13])[CH:3]=1.[NH:14]1[CH:18]=[C:17]([C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])[N:16]=[CH:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC)=O)=NC([O-])=O>C1COCC1>[CH:22]([O:21][C:19]([C:17]1[N:16]([CH:9]2[C:10]3[C:5](=[C:4]([F:13])[CH:3]=[C:2]([Br:1])[CH:11]=3)[CH2:6][CH2:7][CH2:8]2)[CH:15]=[N:14][CH:18]=1)=[O:20])([CH3:24])[CH3:23]
Reactant: CC(C)OC(=O)c1c[nH]cn1
Reactant: OC1CCCc2c(F)cc(Br)cc21
Agent: COC(=O)N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)OC(=O)c1cncn1C1CCCc2c(F)cc(Br)cc21
Reaction time: 1 h

Procedure:
To a solution of 7-bromo-5-fluoro-3,4-dihydro-2H-naphthalen-1-ol (0.280 g, 1.10 mmol) and isopropyl 4-imidazolecarboxylate (0.121 g, 0.77 mmol), which can be prepared as described in Example 1, in THF (6 mL) at 0° C. is added triphenylphosphine (0.291 g, 1.10 mmol) and methyl azodicarboxylate (40% in toluene, 0.41 mL, 1.10 mmol). After 1 hour, the cooling bath is removed and after another hour, the mixture is diluted with ethyl acetate and washed with half-saturated brine, dried over magnesium sulfate, filtered, t and concentrated. The resulting residue is purified by semi-preparative reverse phase HPLC (5 to 100% acetonitrile/water w/0.1% TFA) to furnish affords a pale yellow oil. After free-basing, 3-(7-bromo-5-fluoro-1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid isopropyl ester is obtained; MS: (ESI) m/z 381.1, 383.0 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 1.37 (d, J=6.3 Hz, 3 H), 1.39 (d, J=6.3 Hz, 3 H), 1.71-1.81 (m, 1 H), 1.83-1.92 (m, 1 H), 2.07-2.24 (m, 2 H), 2.72 (dt, J=17.7, 6.8 Hz, 1 H), 2.87 (dd, J=17.7, 5.8 Hz, 1 H), 5.22 (sept, J=6.3 Hz, 1 H), 6.29 (t, J=5.2 Hz, 1 H), 6.94 (br. s, 1 H), 7.18 (dd, J=8.8, 1.8 Hz, 1 H), 7.22 (s, 1 H), 7.79 (s, 1 H).
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7]1[CH2:9][O:8]1)([CH3:4])([CH3:3])[CH3:2].[F:10]CC1COC(=O)C=1.F.[F-].[K+]>>[C:1]([O:5][CH2:6][CH:7]([OH:8])[CH2:9][F:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1C=C(CF)CO1
Reactant: CC(C)(C)OCC1CO1
Agent: F
Agent: [F-]
Agent: [K+]
Product: CC(C)(C)OCC(O)CF

Procedure:
Starting from 2-tert-butoxymethyl-oxirane (5), 4-fluoromethyl-5H-furan-2-one can be prepared according to the method described in scheme 2. In the first step, the oxirane ring is opened with potassium hydrogendifluoride to form 1-tert-butoxy-3-fluoro-propan-2-ol (6) which is then oxidized to the corresponding ketone (7). The oxidation can be carried out according to known methods such as e.g. with sodium hypochlorite in the presence of a catalyst such as 2,2,6,6-tetramethyl-1-piperidinyloxy radical (TEMPO). In a next step 1-tert-butoxy-3-fluoro-propan-2-one (7) is reacted with tert-butyl acetate in the presence of a strong base such as lithium diisopropylamine (LDA) to form 3-tert-butoxymethyl-4-fluoro-3-hydroxybutyric acid tert-butyl ester (8) which can be cyclizised to 4-fluoromethyl-4-hydroxy-dihydro-furan-2-one (9) under strong acidic conditions (e.g. by employing trifluoroacetic acid or sulfuric acid 95%). Preferably, the cyclization is carried out with only a small amount of sulfuric acid 95% (e.g. 0.025 mol equivalent in relation to the educt) in a solvent such as 1,2-dimethoxyethane or dioxane. These two last steps can alternatively be carried out in a one-pot procedure, e.g. without isolating 3-tert-butoxymethyl-4-fluoro-3-hydroxybutyric acid tert-butyl ester (8). In a final step 4-fluoromethyl-5H-furan-2-one (III) is obtained by dehydration of 4-fluoromethyl-4-hydroxy-dihydro-furan-2-one (9). The dehydration can be performed according to known methods, e.g with acetic anhydride in the presence of an amine base such as triethylamine. Alternative dehydration methods include the use of thionyl chloride in the presence of pyridine or mesyl chloride in the presence of triethylamine. In a further alternative dehydration method, 4-fluoromethyl-4-hydroxy-dihydro-furan-2-one (9) is reacted with acetic anhydride to form the intermediate 4-acetoxy-fluoromethyl-dihydro-furan-2-one which is then reacted with sodium acetate in de-ionized water to obtain the compound of formula III.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:47][C:48]1[CH:54]=[CH:53][C:51]([NH2:52])=[C:50]([O:55][CH3:56])[CH:49]=1.I[C:58]1[CH:63]=[CH:62][C:61]([Cl:64])=[CH:60][CH:59]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:47][C:48]1[CH:54]=[CH:53][C:51]([NH:52][C:58]2[CH:63]=[CH:62][C:61]([Cl:64])=[CH:60][CH:59]=2)=[C:50]([O:55][CH3:56])[CH:49]=1
Reactant: Clc1ccc(I)cc1
Reactant: COc1cc(Cl)ccc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: COc1cc(Cl)ccc1Nc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A solution of palladium (II) acetate (949 mg, Precious Metals Online) and (+/−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (2.63 g, Alfa-Aesar) in toluene (1000 mL) was heated to 50° C. under argon then cooled to room temperature. 4-Chloro-2-methoxyaniline (66.6 g), 4-iodochlorobenzene (105.81 g, Apollo Scientific) and sodium tert-butoxide (44.68 g, Alfa-Aesar) were added and the mixture was heated to reflux for 90 minutes. The mixture was cooled to room temperature, quenched with water (500 mL) then the organics were separated, dried (MgSO4) and concentrated. The residue was absorbed onto silica and columned eluting ethyl acetate/heptane mixtures to give the product as a dark orange oil that solidified on standing. Yield: 97.86 g. 1H NMR (400 MHz, CDCl3): δ 7.18-7.23 (2H, m, ArH), 7.12 (1H, d, ArH), 7.00-7.05 (2H, m, ArH), 6.82-6.85 (2H, m, ArH), 6.00 (1H, br s, NH), 3.87 (3H, s, OMe).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH3:12])[CH:9]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[Cl-].[NH4+]>O1CCCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH3:12])[C:9]1([CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1CN(C(=O)OC(C)(C)C)C1C(=O)OC(C)(C)C
Reactant: CC(C)=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)=CCC1(C(=O)OC(C)(C)C)C(C)CN1C(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
To a solution of an optically-active compound of 3-methylazetidine-1,2-dicarboxylic acid di-tert-butyl ester (48.0 g) and 1-bromo-3-methyl-2-butene (25.4 ml) in tetrahydrofuran (380 ml) cooled to −69° C. was added lithium hexamethyl disilazide (1.0M tetrahydrofuran solution, 200 ml). The reaction mixture was warmed to −20° C. over 40 minutes, and stirred at the same temperature for additional 20 minutes. To the reaction mixture were sequentially added saturated aqueous ammonium chloride solution (200 ml) and water (300 ml), and the mixture was extracted with n-hexane/ethyl acetate (1/1, 500 ml). The separated organic layer was sequentially washed with water (200 ml) and saturated aqueous sodium chloride solution (200 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=15/1 to 8/1) to give the titled compound (44.5 g).
Reaction SMILES: [C:1]1([C@@H:7]([N@:9]2[CH2:11][CH:10]2[CH2:12][OH:13])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(C)=O.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]1([C@@H:7]([N@:9]2[CH2:11][CH:10]2[CH:12]=[O:13])[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@@H](c1ccccc1)[N@]1CC1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: ClCCl
Product: C[C@@H](c1ccccc1)[N@]1CC1C=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 81 %

Procedure:
A three neck, 250 mL round bottom flask was equipped with a low temperature thermometer and two (2) equalizing dropping funnels. One of these was connected to a nitrogen line and charged with a solution of ((R)-1-((S)-1-phenylethyl)aziridin-2-yl)methanol EBE 06046 (7.0 g, 39.5 mmol) in CH2Cl2 (75 mL), the other was charged with a solution of DMSO (9.25 g, 118.5 mmol) in CH2Cl2 (11 mL). To a solution of oxalyl chloride (7.5 g, 59.3 mmol) in CH2Cl2 (90 mL) under N2 at −78° C., the DMSO solution was added dropwise during 20 min and stirred for 20 min. EBE 06046 (7.0 g, 39.5 mmol) in CH2Cl2 (75 mL) was added dropwise over 50 min. then the dropping funnel was charged with DIEA (42.6 mL, 237 mmol) in CH2Cl2 (10 mL) and the reaction mixture was stirred for 30 min at −45° C. The DIEA solution was added over 5 min with the reaction mixture at −78° C. and the reaction was allowed to warm to room temperature. The reaction mixture was washed with H2O (3×50 mL), dried over MgSO4, filtered, evaporated. The crude product obtained was purified by column chromatography on silica with a gradient of 0-20% [v/v] EtOAc in cyclohexane to give (R)-1-((S)-1-phenylethyl)aziridine-2-carbaldehyde EBE 06048 as a yellow oil (5.59 g, 81% yield).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][C:8]1[O:13][CH2:12][CH2:11][CH2:10][CH:9]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][C:8]1[O:13][CH2:12][CH2:11][CH2:10][CH:9]=1)(=[O:4])=[O:3]
Reactant: OCC1=CCCCO1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1=CCCCO1
Reaction time: 1 h
Yield: 112043.6 %

Procedure:
51.5 g (0.45 mol) of methanesulfonyl chloride are added dropwise to 45 g (0.39 mmol) of 6-hydroxymethyl-2,3-dihydropyran (Example 7a) and 50 g (0.5 mol) of triethylamine in 400 ml of methylene chloride at 0°-5° C. Stirring is carried out for 1 hour at 0° C. and the reaction mixture is poured onto water. The aqueous phase is separated off and the organic phase is extracted once again with water and is then dried over MgSO4 and evaporated down. 84 g of title compound are obtained as a red oil, which is used directly in the next reaction.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH2:7][OH:8].I[CH2:10][CH3:11].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.O>[CH2:10]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH2:7][OH:8])[CH3:11]
Reactant: CCI
Reactant: OCC1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1CCOCC1CO

Procedure:
Morpholin-3-ylmethanol (500 mg) and iodoethane (666 mg) in N,N-dimethylformamide was treated with K2CO3 (1.1 g) overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated to provide the title compound.
Reaction SMILES: CCO[C:4]([CH:6]1[CH2:12][CH2:11][C:9](=[O:10])[CH2:8][CH2:7]1)=[O:5].[CH2:13](O)[CH2:14][OH:15].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH2:13]1[O:10][C:9]2([CH2:8][CH2:7][CH:6]([CH2:4][OH:5])[CH2:12][CH2:11]2)[O:15][CH2:14]1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: OCC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl cyclohexanone-4-carboxylate (335 g.), 550 ml. ethylene glycol and 21 g. of p-toluenesulfonic acid in 5.5 liters of benzene were heated at reflux with stirring for 24 hours while water was separated by means of a water trap. The mixture was cooled and poured into 4 liters of ice water. The benzene layer was separated, washed with 1 liter of 5% sodium bicarbonate, 1 liter of water and 1 liter of saturated sodium chloride solution, dried and evaporated to dryness to give, after distillation, 245.6 g. of ethyl cyclohexanone-4-carboxylate ethylene ketal; b.p. 95°-99.5° C. (0.07 mm.); n25D 1.4620. A solution of 35 g. of the ketal-ester in 50 ml. of dry tetrahydrofuran was added dropwise to 5.7 g. of lithium aluminum hydride in 250 ml. of dry tetrahydrofuran, and the mixture was heated at reflux for five hours and cooled to room temperature. A saturated sodium chloride solution (11.4 ml.) was added dropwise and heating at reflux was continued for one hour. The mixture was cooled and filtered, and the filtrate was dried and evaporated to dryness to give 26.9 g. of 4-hydroxymethylcyclohexanone ethylene ketal as a clear, colorless oil which was used without further purification.
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5]([CH2:7][CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:6])[CH3:3].[H-].[Na+].[O:31]1[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]1>CN(C)C=O>[CH2:2]([O:4][C:5](=[O:6])[CH2:7][CH2:8][CH:9]=[C:34]1[CH2:35][CH2:36][O:31][CH2:32][CH2:33]1)[CH3:3]
Reactant: O=C1CCOCC1
Reactant: CCOC(=O)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCC=C1CCOCC1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 6.6 %

Procedure:
A solution of 11.2 g (24.5 mmol) of [3-(ethoxycarbonyl)propyl]triphenylphosphonium bromide in dimethylformamide (19 mL) was dropped into a cooled (10° C.) suspension of 1.13 g (28.2 mmol) of a 60% sodium hydride in dimethylformamide (2 mL) under an atmosphere of argon, and stirred for 40 minutes. Into this, 2.5 g (24.5 mmol) of tetrahydropyran-4-one was dropped. After dropping, stirring was continued for 1 hour at 10° C. and for 14 hours at room temperature. After the reaction was completed, the reaction mixture was poured into ice water and extracted with ether. The organic layer was washed with water (three times) and saturated brine successively, then dried over anhydrous magnesium sulfate and concentrated under a reduced pressure. The obtained residue was purified by medium pressure liquid column chromatography on silica gel (developing solvent: hexane:etyl acetate) to obtain 320 mg (yield 6.6%) of 4-(tetrahydropyran-4-ylidene)butanoic acid ethyl ester (IX-127) as colorless liquid. Its physical properties are shown below.
Reaction SMILES: [S:1]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH2:20]O)=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].O=P(Cl)(Cl)[Cl:24]>C1COCC1>[Cl:24][CH2:20][C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]([S:1]([C:4]2[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=2)(=[O:3])=[O:2])[CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(CO)c3ccccc32)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(CCl)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
To a solution of (1-tosyl-1H-indol-3-yl)methanol (1.0 g, 3.318 mmol) in dry THF (10 mL), POCl3 (0.661 g, 4.314 mmol) was added at 0° C. and the mixture was stirred for 10 min. The reaction mixture was allowed to warm to ambient temperature and refluxed for 3 h. The solvent was removed under reduced pressure at 45° C. and the crude reaction mixture was quenched with saturated NaHCO3 solution and extracted with DCM. The organic layer was separated and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield the title compound as a solid (1.04 g, 98%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:31])[C@@H:10]([NH:25][C@H:26]([C:28](O)=[O:29])[CH3:27])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[CH3:44][S:45]([NH2:48])(=[O:47])=[O:46]>C(Cl)Cl.C([O-])(O)=O.[Na+].CCOC(C)=O>[CH2:1]([O:8][C:9](=[O:31])[C@@H:10]([NH:25][C@@H:26]([CH3:27])[C:28]([NH:48][S:45]([CH3:44])(=[O:47])=[O:46])=[O:29])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: C[C@H](N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)OCc1ccccc1)C(=O)O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@H](N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)OCc1ccccc1)C(=O)NS(C)(=O)=O
Reaction time: 0.5 h

Procedure:
To a solution of (S)-2-((S)-1-carboxy-ethylamino)-3-(3′-chloro-biphenyl-4-yl)-propionic acid benzyl ester (600 mg, 1.37 mmol) in DCM (7 mL) and saturated aqueous NaHCO3 solution (2 mL) was added triphosgene (407 mg, 1.37 mmol). After being stirred for 0.5 hours, the reaction mixture was diluted with EtOAc and stirred for additional 0.5 hours until generation of gas was completed. The organic layer was separated, washed with brine and concentrated. This was dissolved in DCM (7 mL) and methanesulfonamide (195 mg, 2.06 mmol) was added. After being stirred at rt for 1 hour, the reaction mixture was diluted with EtOAc and washed with brine. The organic layer was dried over Na2SO4, concentrated and purified by silica gel column chromatography (eluent: 10% MeOH in DCM) to give (S)-3-(3′-chloro-biphenyl-4-yl)-2-((S)-2-methanesulfonylamino-1-methyl-2-oxo-ethylamino)-propionic acid benzyl ester. MS: m/z (MW) 515; HPLC retention time 1.58 min (HPLC condition A).
Reaction SMILES: BrCCBr.Cl[Si](C)(C)C.I[CH:11]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]1.[Cl:22][C:23]1[C:24]([CH3:35])=[C:25](I)[C:26]([O:32][CH3:33])=[C:27]([C:29](=[O:31])[CH3:30])[CH:28]=1>CN(C)C=O.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>[C:29]([C:27]1[C:26]([O:32][CH3:33])=[C:25]([CH:11]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]2)[C:24]([CH3:35])=[C:23]([Cl:22])[CH:28]=1)(=[O:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1I
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: BrCCBr
Product: COc1c(C(C)=O)cc(Cl)c(C)c1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 70 °C
Reaction time: 1 h
Yield: 55.5 %

Procedure:
Zinc (0.227 g, 3.48 mmol) was suspended with 1,2-dibromoethane (0.0434 g, 0.231 mmol) in N,N-dimethylformamide (DMF) (4.1 mL). The mixture was heated at 70° C. for 10 min and then cooled to room temperature. Chlorotrimethylsilane (0.029 mL, 0.23 mmol) was added dropwise and stirring was continued for 1 hour. A solution of tert-butyl 3-iodoazetidine-1-carboxylate (0.82 g, 2.9 mmol, from Oakwood) in DMF (3 mL) was then added and the mixture was heated at 40° C. for 1 h before a mixture of 1-(5-chloro-3-iodo-2-methoxy-4-methylphenyl)ethanone (0.987 g, 3.04 mmol, from Example 60, Step 2), tris(dibenzylideneacetone)dipalladium(0) (0.052 g, 0.057 mmol) and tri-(2-furyl)phosphine (0.027 g, 0.12 mmol) in DMF (8 mL) was added. The reaction mixture was warmed to 70° C. and stirred overnight. The mixture was then cooled to room temperature and partitioned between EtOAc and sat. NH4Cl solution. The organic layer was washed with water, dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 30% EtOAc in hexanes) to give the desired product (0.57 g, 56%). LCMS calculated for C18H24ClNO4Na (M+Na)+: m/z=376.1. found: 376.1.
Reaction SMILES: [Cl:1][C:2]([Cl:20])([Cl:19])[CH:3]1[O:8][CH:7]([C:9]([Cl:12])([Cl:11])[Cl:10])[C:6]2[CH:13]=[C:14]([CH:17]=O)[CH:15]=[CH:16][C:5]=2[O:4]1.[C:21]1([NH:27][NH2:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)(Cl)Cl>[C:21]1([NH:27][N:28]=[CH:17][C:14]2[CH:15]=[CH:16][C:5]3[O:4][CH:3]([C:2]([Cl:1])([Cl:20])[Cl:19])[O:8][CH:7]([C:9]([Cl:11])([Cl:12])[Cl:10])[C:6]=3[CH:13]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1ccc2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2
Reactant: NNc1ccccc1
Solvent: ClC(Cl)Cl
Product: ClC(Cl)(Cl)C1Oc2ccc(C=NNc3ccccc3)cc2C(C(Cl)(Cl)Cl)O1

Procedure:
A mixture of 2,4-bis(trichloromethyl)benzo[1,3]dioxin-6-carboxaldehyde (1.0 g.) and phenylhydrazine (0.27 g.) in chloroform (35 ml.) was heated under gentle reflux for 1 hour. The resulting solution was cooled and evaporated to dryness under reduced pressure, and the residue was crystallised from ethanol to give 6-phenylhydrazonomethyl-2,4-bis(trichloromethyl)benzo[1,3]dioxin, m.p. 203°-204° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:6]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[CH:5][CH:4]=1.[OH:23][C:24]1[CH:25]=[CH:26][C:27]([CH3:37])=[C:28]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C(#N)C>[CH3:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:7]1[N:8]=[C:3]([CH2:2][O:23][C:24]2[CH:25]=[CH:26][C:27]([CH3:37])=[C:28]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:29]=2)[CH:4]=[CH:5][C:6]=1[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[F:22]
Reactant: COc1ccc(F)c(-c2ccc(CCl)nc2CC(C)(C)C)c1
Reactant: CCOC(=O)CCc1cc(O)ccc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)ccc1C
Yield: 87 %

Procedure:
To a solution of 6-(chloromethyl)-2-(2,2-dimethylpropyl)-3-(2-fluoro-5-methoxyphenyl)pyridine (320 mg) in acetonitrile (10 mL) were added ethyl 3-(5-hydroxy-2-methylphenyl)propanoate (230 mg) and cesium carbonate (546 mg), and the mixture was heated under reflux for 15 hr. Ethyl acetate was added to the reaction mixture, and the insoluble material was filtered off. The solvent in the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (427 mg) as a colorless oil.
Reaction SMILES: [I:1]I.[OH-].[K+].[NH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:12]=2)[CH:7]=[N:6]1.O.[Cl-].[NH4+]>CN(C=O)C>[I:1][C:7]1[C:8]2[C:13](=[CH:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=2)[NH:5][N:6]=1
Reactant: CCOC(=O)c1ccc2cn[nH]c2c1
Reactant: II
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc2c(I)n[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a 3.0-liter egg plant type flask, iodine (6.09 g, 24 mmol) and KOH (4.49 g, 68 mmol) were added to a DMF solution (60 mL) of ethyl 1H-indazole-6-carboxylate (4.52 g, 20 mmol), and stirred at room temperature for 2 hours. Saturated ammonium chloride water was added to it, extracted with ethyl acetate, washed with water and saturated saline water in that order, and dried with sodium sulfate. The reaction solution was filtered, concentrated, and the resulting solid was washed with a mixed solution of hexane and ethyl acetate to obtain the title compound as a yellow solid.
Reaction SMILES: [I-].[Li+:2].[CH3:3][C@H:4]1[CH2:9][NH:8][CH2:7][C@H:6]([CH3:10])[N:5]1[C:11]1[O:12][C:13]2[C:14](=[C:16]([C:20]([O:22]C)=[O:21])[CH:17]=[CH:18][CH:19]=2)[N:15]=1>N1C=CC=CC=1>[CH3:3][C@H:4]1[CH2:9][NH:8][CH2:7][C@H:6]([CH3:10])[N:5]1[C:11]1[O:12][C:13]2[C:14](=[C:16]([C:20]([O-:22])=[O:21])[CH:17]=[CH:18][CH:19]=2)[N:15]=1.[Li+:2]
Reactant: COC(=O)c1cccc2oc(N3[C@@H](C)CNC[C@@H]3C)nc12
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: C[C@H]1CNC[C@H](C)N1c1nc2c(C(=O)[O-])cccc2o1
Temperature: 25 °C

Procedure:
To a solution of lithium iodide (185 mg, 1.38 mmol) in refluxing anhydrous pyridine (10 mL) was added methyl 2-((2S,6S)-2,6-dimethylpiperazin-1-yl)benzoxazole-4-carboxylate (100 mg, 0.346 mmol) and the reaction mixture was refluxed for 24 hours. The mixture was cooled to room temperature, concentrated to dryness and dried in vacuo to provide lithium 2-((2S,6S)-2,6-dimethylpiperazin-1-yl)benzoxazole-4-carboxylate as a solid which was used without further purification: MS consistent