Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([OH:11])[C:9]#[CH:10].[NH2:12][C:13]1[N:22]=[C:21]([C:23]([N:25]2[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:24])[C:20]2[C:15](=[CH:16][CH:17]=[C:18](I)[CH:19]=2)[N:14]=1.C(Cl)Cl>CN(C=O)C.[Cu]I.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>[NH2:12][C:13]1[N:22]=[C:21]([C:23]([N:25]2[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:24])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:10]#[C:9][CH2:8][OH:11])[CH:19]=2)[N:14]=1
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(I)ccc2n1
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(C#CCO)ccc2n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3 ml of triethylamine, 368.7 μl of 2-propyn-1-ol, 36.6 mg of copper(I) iodide and 67.5 mg of bis(triphenylphosphine)palladium(II) chloride (15.2% of palladium) are added to a solution of 2 g of 2-amino-6-iodo-4-(1,3-dihydroisoindol-2-ylcarbonyl)quinazoline in 3 ml of DMF under argon. The mixture is stirred at room temperature for 48 h, 100 ml of DCM are added, and the mixture is subjected to aqueous extraction a number of times. The organic phase was dried and evaporated to dryness under reduced pressure in a rotary evaporator. A little ACN is added to the residue obtained, during which a yellow solid precipitates out. Filtration and drying (drying cabinet at 40° C.) gives 1.3 g of “A964”;
Reaction SMILES: [CH:1]1([O:11][CH2:12][C:13]#[C:14][C:15]2[C:23]3[C:18](=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH3:30])[CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]=2[C:31]([O:33]CC)=[O:32])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>O1CCCC1.CO>[CH3:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:18]=1[NH:17][C:16]([C:31]([OH:33])=[O:32])=[C:15]2[C:14]#[C:13][CH2:12][O:11][CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1[nH]c2c(-c3ccccc3C)cccc2c1C#CCOC1CCCc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccccc1-c1cccc2c(C#CCOC3CCCc4ccccc43)c(C(=O)O)[nH]c12

Procedure:
To a solution of EXAMPLE 564B (180 mg) and 1-(prop-2-ynyloxy)-1,2,3,4-tetrahydronaphthalene (165 mg) in triethylamine (5 ml) was added bis(triphenylphosphine)palladium(II) dichloride (18.71 mg) and copper(I) iodide (4.23 mg). The reaction mixture was stirred at 70° C. for 3 hours, cooled and concentrated. The residue was dissolved in dichloromethane and purified by flash chromatography, eluting with dichloromethane, to provide ethyl 3-(3-(1,2,3,4-tetrahydronaphthalen-1-yloxy)prop-1-ynyl)-7-o-tolyl-1H-indole-2-carboxylate. This ester was hydrolyzed with aqueous NaOH in tetrahydrofuran and methanol to provide the title compound. 1H NMR (400 MHz, methanol-d4) 7.76 (dd, J=7.98, 1.23 Hz, 1H), 7.52 (dd, J=6.75, 2.46 Hz, 1H), 7.34-7.40 (m, 2H), 7.27-7.31 (m, 2H), 7.26 (d, J=7.98 Hz, 1H), 7.13-7.19 (m, 3H), 7.07-7.12 (m, 1H), 4.97 (t, J=3.99 Hz, 1H), 4.52-4.71 (m, 2H), 2.79-2.90 (m, 1H), 2.68-2.78 (m, 1H), 2.14-2.21 (m, 1H), 2.12 (s, 3H), 1.91-2.06 (m, 2H), 1.73-1.84 (m, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][N:8]1[C@@H:11]([CH3:12])[C@@H:10]([CH2:13]/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[C:9]1=[O:23]>CO.[Pd]>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][N:8]1[C@@H:11]([CH3:12])[C@@H:10]([CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[C:9]1=[O:23]
Reactant: Cc1ccc(/C=C/C[C@H]2C(=O)N(OC3CCCCO3)[C@H]2C)cc1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(CCC[C@H]2C(=O)N(OC3CCCCO3)[C@H]2C)cc1
Reaction time: 72 h
Yield: 96.2 %

Procedure:
To a solution of (3R,4S)-1-(2-tetrahydropyranyloxy)-3-((2E)-3-(4-methylphenyl)-2-propene-1-yl)-4-methylazetidin-2-one (165 mg, 0.524 mmol) in 4 mL of methanol is treated with 20 mg of 5% palladium on barium sulfate. The resulting suspension is repeatedly evacuated and purged with a hydrogen balloon, then stirred under 1 atmosphere pressure of hydrogen gas for 72 h. The catalyst is filtered and the filtrate is concentrated in vacuo to provide (3R,4S)-1-(2-tetrahydropyranyloxy)-3-(3-(4-methylphenyl)-1-propyl)-4-methylazetidin-2-one as an oil (160 mg, 96% yield).
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[CH:14]([C@@H:16]1[N:20]([CH3:21])[C:19](=[O:22])[CH2:18][C@@H:17]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:15].[NH4+].[Cl-]>C1COCC1>[OH:15][C@@H:14]([C@@H:16]1[N:20]([CH3:21])[C:19](=[O:22])[CH2:18][C@@H:17]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]#[C:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccccc1
Reactant: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1[C@H](O)C#Cc1ccccc1
Temperature: -20 °C
Reaction time: 2 h
Yield: 39.2 %

Procedure:
To a −20° C. solution of phenylacetylene (0.29 mL, 2.69 mmol) in anhyd. THF (1 mL) was added a solution of n-BuLi (1.6M in hexane, 1.56 mL, 2.50 mmol). The reaction mixture was stirred for 2 h at −20° C., then was cooled to −78° C. A solution of (±)-(4R*,5R*)-5-formyl-1-methyl-4-phenylpyrrolidin-2-one (Intermediate Z, 389 mg, 1.92 mmol) in THF (2 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature, stirred for 18 h, then treated with a saturated NH4Cl solution and extracted with CH2Cl2. The combined organic layers were washed with a saturated NaCl solution, dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by flash chromatography (90% EtOAc/hex) to give (±)-(4R*,5R*)-5-((1R*)-1-hydroxy-3-phenylprop-2-ynyl)-1-methyl-4-phenyl-pyrrolidin-2-one (230 mg, 40%) as a white solid: mp 152-153° C.; 1H NMR (CDCl3) δ 2.78-3.09 (m, 5H), 4.02 (q, J=9.0 Hz, 1H), 4.38 (dd, J=9.0 Hz, 2.0 Hz, 1H), 7.22-7.40 (m, 10H), 9.18 (d,J=2.0 Hz, 1H).
Reaction SMILES: C(O)(=O)C.C(OCC)(=O)C.[Cl:11][C:12]1[C:17]2[C:18]([N+:22]([O-])=[O:23])=[C:19]([CH3:21])[O:20][C:16]=2[C:15]([N:25]2[C:30](=[O:31])[CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[N:27]([CH3:36])[C:26]2=[O:37])=[CH:14][CH:13]=1>[Fe].O>[Cl:11][C:12]1[C:17]2[C:18]([NH:22][OH:23])=[C:19]([CH3:21])[O:20][C:16]=2[C:15]([N:25]2[C:30](=[O:31])[CH:29]=[C:28]([C:32]([F:34])([F:35])[F:33])[N:27]([CH3:36])[C:26]2=[O:37])=[CH:14][CH:13]=1
Reactant: Cc1oc2c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)ccc(Cl)c2c1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1oc2c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)ccc(Cl)c2c1NO
Reaction time: 2 h
Yield: 54 %

Procedure:
5 ml of acetic acid, 200 ml of ethyl acetate and 100 ml of water were added to 2.3 g (5.7 mmol) of 3-(4-chloro-2-methyl-3-nitrobenzofuran-7-yl)-1-methyl-6-trifluoromethyluracil and 1.6 g (28 mmol) of iron powder, followed by stirring for 2 hours under heating and refluxing. After completion of the reaction, insoluble matters were filtered off. The organic layer was washed sequentially with water and a sodium chloride aqueous solution and then, dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 1.2 g (yield: 54%) of the desired product as pale yellow crystals. Melting point: 134-136° C.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH2:11])[C:3]([O:5]C(C)(C)C)=[O:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C:2]([CH3:18])([C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[CH2:11])[C:3]([OH:5])=[O:4]
Reactant: C=C(c1ccccc1)C(C)(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C(c1ccccc1)C(C)(C)C(=O)O

Procedure:
tert-Butyl 2,2-dimethyl-3-phenylbut-3-enoate and trifluoroacetic acid were reacted in methylene chloride at room temperature to obtain 2,2-dimethyl-3-phenylbut-3-enoic acid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([O:1][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reaction time: 1 h

Procedure:
To tert-butyl 4-hydroxypiperidine-1-carboxylate (1 eq) in methylene chloride and triethyl amine (1.4 eq) at 0° C. was added methane sulfonyl chloride (1.4 eq) drop-wise. The reaction was brought to ambient temperature and was stirred for 1 h. The reaction mixture was washed with water and saturated sodium chloride solution. The organic layer was then dried with sodium sulfate and concentrated to yield tert-butyl-4-(methylsulfonyloxy)piperidine-1-carboxylate in quantitative yield. The product was confirmed by 1H NMR, and used without further purification.
Reaction SMILES: [H-].[Na+].C([CH:5]([O:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)#N.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1>O1CCCC1.C(OCC)(=O)C.O>[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([C:27](=[O:28])[CH:5]([O:12][C:13](=[O:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)=[CH:25][CH:24]=1
Reactant: COc1ccc(C=O)cc1
Reactant: N#CC(OC(=O)c1ccccc1)c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C(OC(=O)c2ccccc2)c2cccnc2)cc1
Reaction time: 3 h
Yield: 62.1 %

Procedure:
To a solution of sodium hydride (0.27 g, 6.72 mmol) in 10 mL of tetrahydrofuran was slowly added benzoic acid cyano-pyridin-3-yl-methyl ester (1.24 g, 5.61 mmol) prepared in Step 1 at 0° C. After addition was complete, the reaction solution was elevated to room temperature and stirred for 3 hours. Thereafter, 4-methoxybenzaldehyde (0.84 mL, 6.72 mmol) was additionally added to the resulting solution which was then stirred for 3 hours. After the reaction was complete, the reaction materials was diluted with 50 mL of ethyl acetate and 50 mL of water to dissolve salts, followed by separation of layers. The obtained organic layer was successively washed twice with 50 mL of a brine solution. The organic layer was dried over magnesium sulfate, filtered, concentrated under reduced pressure and purified by silica gel column chromatography, to give 1.21 g (yield: 60%) of benzoic acid 2-(4-methoxy-phenyl)-2-oxo-1-pyridin-3-yl-ethyl ester of the following formula.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].F[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17].C(N(CC)CC)C>CS(C)=O>[N+:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(O)[C@@H]1CCCN1c1ccccc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 80.4 %

Procedure:
There were dissolved, in 25 ml of dimethyl sulfoxide, 1 g of L-proline and 1.23 g of 1-fluoro-2-nitrobenzene, then 1.65 ml of triethylamine was added to the resulting solution and the mixture was stirred with heating at 60° C. for 16 hours. The reaction solution was cooled to room temperature then poured into ice water and washed with ether. The aqueous phase was acidified with hydrochloric acid and extracted with ether. After washing the organic phase with water, the phase was dried over anhydrous magnesium sulfate and then concentrated. The resulting residue was treated by silica gel column chromatography, followed by elution with methanol/chloroform (1/49) to give 1.65 g (yield: 80.3%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13]([CH:15]2[CH2:17][CH:16]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:14])[CH:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.O1CCOCC1>CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13]([CH:15]3[CH2:17][CH:16]3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:14])[CH:3]=2)=[CH:28][CH:27]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1cc2nc(NC(=O)C3CC3c3ccccc3)cc(Cl)n2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc(-c2cc(NC(=O)C3CC3c3ccccc3)nc3cc(C)nn23)cc1
Temperature: 100 °C
Yield: 68.9 %

Procedure:
A suspension of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-2-phenylcyclopropanecarboxamide (8C, 200 mg, 0.612 mmol), 4-methoxyphenylboronic acid (186 mg, 1.22 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (35 mg, 49 mmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (660 microliters of 1,4-dioxane and 330 microliters of saturated aqueous NaHCO3) was prepared in a 2 mL microwave reaction vessel and the sealed reaction vessel warmed to 100° C. for 10 minutes. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC (70-75% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (168 mg, 69%). 1H NMR (DMSO-d6) δ: 11.23 (s, 1H), 8.01-8.18 (m, 2H), 7.89 (s, 1H), 7.26-7.37 (m, 2H), 7.08-7.26 (m, 5H), 6.30 (s, 1H), 3.87 (s, 3H), 2.42-2.48 (m, 1H), 2.26-2.43 (m, 4H), 1.49-1.59 (m, 1H), 1.39-1.47 (m, 1H). ESI-MS: m/z 399.0 (M+H)+.
Reaction SMILES: N[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.N([O-])=O.[Na+].C([O-])(O)=O.[Na+].[ClH:21]>>[Cl:21][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Nc1cc2ccccc2cn1
Reactant: Cl
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Product: Clc1cc2ccccc2cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
3-Aminoisoquinoline (1.44 g, 10 mmol) was suspended in 10M HCl (5 mL) and cooled to 0° C. Sodium nitrite (689 mg, 10 mmol) was added in portions over 5 minutes. The reaction mixture was stirred at 0° C. for 2 hours and allowed to warm to room temperature over 1 hour. The reaction mixture was added carefully to saturated NaHCO3 solution (200 mL) and extracted into ethyl acetate. The insoluble byproduct was removed by filtration and the aqueous layer was re-extracted into ethyl acetate. The combined organics were washed with water and brine, dried (Na2SO4) and concentrated to a brown oil which solidified on standing. Flash chromatography on silica, eluting with dichloromethane, gave the title compound as a white solid (827 mg, 5.05 mmol, 51%). 1H NMR (d6-DMSO, 400 MHz) δ 9.12 (s, 1H), 8.41 (s, 1H), 8.12 (dd, 1H, J=7.5, 1.0 Hz), 7.93-7.90 (m, 1H), 7.84-7.80 (m, 1H), 7.74-7.70 (m, 1H). LCMS (1) Rt=1.79 min; m/z (ESI+) 164 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11]([CH2:13][C:14]([NH:16]C2C=CC=CC=2)=O)=[O:12])[N:4]=1.Cl.[OH-].[Na+]>CO>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([C:11]([C:13]2[CH:14]=[CH:13][CH:11]=[CH:5][C:14]=2[NH2:16])=[O:12])[N:6]=1
Reactant: COc1cc(OC)nc(C(=O)CC(=O)Nc2ccccc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(OC)nc(C(=O)c2ccccc2N)n1

Procedure:
In a reactor were placed 0.57 g (1.9 m moles) of 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)acetanilide, 10 ml of methanol and 5 ml of 6 N hydrochloric acid, followed by refluxing for 1 hour with heating. After the completion of the reaction, the reaction mixture was made alkaline with sodium hydroxide, after which extraction with ethyl acetate was made. The ethyl acetate layer was concentrated. The residue was subjected to gas chromatography. As a result, formation of 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)aniline was confirmed. Conversion: 100% (in terms of total area ratio in gas chromatography)
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:13][C:12]3[C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:10][CH:9]=[CH:8][C:7]=3[C:5]=2[N:6]=1.CS(O[CH2:28][CH:29]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=O)=O>>[C:30]1([CH:29]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:28][S:1][C:2]2[S:3][C:4]3[CH2:13][C:12]4[C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:10][CH:9]=[CH:8][C:7]=4[C:5]=3[N:6]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)CCCOc1cccc2c1Cc1sc(S)nc1-2
Reactant: CS(=O)(=O)OCC(c1ccccc1)c1ccccc1
Product: O=C(O)CCCOc1cccc2c1Cc1sc(SCC(c3ccccc3)c3ccccc3)nc1-2
Yield: 35 %

Procedure:
Using ethyl 4-[(2-mercapto-8H-indeno[1,2-d]thiazol-7-yl)oxy]butyrate and 2,2-diphenylethyl methanesulfonate, the procedure of Example 1 was otherwise repeated to synthesize the title compound. Yield 35%.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:8]=[C:9]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[O:10][Si](C(C)C)(C(C)C)C(C)C.CN([CH:28]=[O:29])C.Cl>CCCCCC.C1COCC1>[Cl:24][C:22]1[CH:21]=[C:9]([OH:10])[CH:8]=[C:7]([Cl:6])[C:23]=1[CH:28]=[O:29]
Reactant: CN(C)C=O
Reactant: CC(C)[Si](Oc1cc(Cl)cc(Cl)c1)(C(C)C)C(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1c(Cl)cc(O)cc1Cl
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
A solution of 2.50 M n-butyllithium in hexane (13.3 mL) was added to a stirred solution of (3,5-dichlorophenoxy)(triisopropyl)silane (10.1 g, 31.6 mmol) in THF (40 mL) under an atmosphere of nitrogen at −78° C. After stirring for 45 min at −78° C., DMF (5 mL) was added slowly. The mixture was allowed to warm to −10° C. After hydrolysis with 2 N HCl, the layers were separated and the aqueous layer separated and extracted with ethyl acetate twice. The combined organic solutions were dried over Na2SO4, filtered and concentrated. To the residue was added hexane (30 mL) and the precipitate was filtered and washed with hexane to give the desired product as a white precipitate. (5.50 g, 91%). LCMS for C7H5Cl2O2(M+H)+: m/z=191.
Reaction SMILES: CNCCN(C)C.[Li]CCCC.[CH:13](=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1.[Li]C1C=CC=CC=1.[Cl:30]C(Cl)(Cl)C(Cl)(Cl)Cl>C1(C)C=CC=CC=1.C1COCC1>[Cl:30][C:15]1[C:16]([O:20][CH3:21])=[CH:17][CH:18]=[CH:19][C:14]=1[CH:13]=[O:22]
Reactant: COc1cccc(C=O)c1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: CNCCN(C)C
Agent: [Li]CCCC
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1cccc(C=O)c1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a sol. of N,N′,N′-trimethylethylendiamine (2.77 g, 21.4 mmol) in toluene (50 mL) was added BuLi (13.0 mL, 20.8 mmol) dropwise at 0° C. After stirring for 15 min at 0° C., m-anisaldehyde (2.44 g, 20 mmol) was added, and the mixture was stirred 30 min at 0° C. PhLi (30 mL, 60 mmol) was then added at 0° C., and the mixture was stirred at rt for 4 h. The mixture was cooled to −30° C., and 25 mL THF were added followed by hexachloroethane (14.2 g, 60 mmol) in THF (25 mL). The cooling bath was removed and the mixture was stirred for 3 h. Then it was poured with stirring onto aq. 5M HCl (20 mL). The aq. layer was extracted with EtOAc (2×). The combined org. extracts were washed successively with aq. 1M NaOH, aq. 1M HCl, and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 5:95→1:9) afforded the desired aldehyde, which was further purified by crystallization (EtOAc/heptane, 0° C.) to give 1.50 g of pure title product. LC-MS: tR=0.88 min.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[C:12]([N+:16]([O-:18])=[O:17])=[CH:13][CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[N:5](C(=O)C(F)(F)F)[CH2:4]1.C([O-])([O-])=O.[Cs+].[Cs+].CC(O)=O>O1CCOCC1.O.CO>[Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[C:12]([N+:16]([O-:18])=[O:17])=[CH:13][CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[NH:5][CH2:4]1
Reactant: O=C(N1CC(CCl)c2c1ccc1cccc([N+](=O)[O-])c21)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: O=[N+]([O-])c1cccc2ccc3c(c12)C(CCl)CN3
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.4 %

Procedure:
A solution of 132 (1.54 g, 4.29 mmol) in dioxane (10 mL) was treated with a solution of Cs2CO3 (3.26 g, 10 mmol) in water (3 mL) and MeOH (7 mL) and the mixture was stirred at room temperature for 10 min. The mixture was treated with AcOH (12 mL), then concentrated under reduced pressure to a small volume and partitioned between water and CHCl2. The organic phase was washed with water (×2), dried, and filtered through a column of silica gel. The resulting oil was crystallised from EtOAc/petroleum ether to give 1-(chloromethyl)-9-nitro-1,2-dihydro-3H-benzo[e]indole (136) (1.03 g, 91%) as a red solid: mp 100° C.; 1H NMR [(CD3)2SO] δ 8.07 (dd, J=8.0, 1.1 Hz, 1H), 7.94 (dd, J=7.6, 1.3 Hz, 1H), 7.87 (d, J=8.7H, 1H), 7.21 (t, J=7.8 Hz, 1H), 7.13 (d, J=8.7 Hz, 1H), 6.63 (s, 1H), 3.81-3.71 (m, 1H), 3.71-3.62 (m, 1H), 3.62-3.54 (m, 1H), 3.33-3.25 (m, 2H). Anal. (C13H11ClN2O2) C, H, N.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@@H:13]([CH3:16])[CH2:14][OH:15])[CH:11]=1)[C:5]([O:7]C)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[F:23][C:24]1[CH:25]=[C:26]([CH:33]=[CH:34][C:35]=1F)[C:27]([N:29]1[CH2:32][CH2:31][CH2:30]1)=[O:28].O.[OH-].[Li+]>CC(N(C)C)=O.O.C(OCC)C.C(OCC)(=O)C>[N:29]1([C:27]([C:26]2[CH:33]=[CH:34][C:35]([O:1][C:2]3[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@@H:13]([CH3:16])[CH2:14][OH:15])[CH:11]=3)[C:5]([OH:7])=[O:6])=[C:24]([F:23])[CH:25]=2)=[O:28])[CH2:32][CH2:31][CH2:30]1
Reactant: O=C(c1ccc(F)c(F)c1)N1CCC1
Reactant: COC(=O)c1cc(O)cc(O[C@@H](C)CO)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Li+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H](CO)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(C(=O)O)c1
Temperature: 120 °C
Reaction time: 24 h

Procedure:
A suspension of methyl 3-hydroxy-5-[(1S)-2-hydroxy-1-methylethoxy]benzoate (10.65 g, 0.047 mmol), cesium carbonate (30.71 g, 0.094 mol) and 1-(3,4-difluorobenzoyl)azetidine (9.28 g, 0.047 mol) in dimethylacetamide (80 mL) was heated at 120° C. for 22 hours. The reaction mixture was cooled and water (60 mL) added followed by lithium hydroxide monohydrate (1.97 g, 0.047 mol) in water (45 mL). The reaction was stirred for a further 24 hours. Water (100 mL) was added and the mixture extracted with ethyl acetate (3×50 mL) to remove any ester. The aqueous layer was acidified and extracted into ethyl acetate (5×50 mL). The extracts were combined and washed with water (100 mL), brine (100 mL), dried (MgSO4), filtered, and evaporated in vacuo to give a yellow liquid. A diethyl ether/ethyl acetate mixture (3:1) was added and the solution washed with water (100 mL), brine (100 mL), dried (MgSO4), filtered and evaporated in vacuo to give the desired compound. (9.8 g)