Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Na].[H-].[Na+].[CH:18]([O:20][CH2:21][CH2:22]Cl)=[CH2:19]>CS(C)=O.O>[CH:18]([O:20][CH2:21][CH2:22][C:13]1([CH2:22][CH2:21][O:20][CH:18]=[CH2:19])[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:6][C:5]2[C:14]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[CH2:19]
Reactant: C=COCCCl
Reactant: c1ccc2c(c1)Cc1ccccc1S2
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CS(C)=O
Product: C=COCCC1(CCOC=C)c2ccccc2Sc2ccccc21
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of thioxanthene (29.7 g.) in dimethyl sulphoxide (1,200 ml.) is added gradually to a solution of sodium methylsulphinylmethide [prepared in the usual way from sodium hydride (24 g. of a 60% dispersion in mineral oil) and dimethyl sulphoxide (300 ml.)]. The dark red mixture is cooled in ice and chloroethyl vinyl ether (44 g.) is added dropwise. The mixture is stirred under nitrogen for a further 16 hours, allowed to warm to ambient temperature (18°to 20° C.), poured into water (3 1.) and extracted with ether. The ethereal solution is washed with water, dried, and then evaporated to give crude oily 9,9-bis(2'-vinyloxyethyl)thioxanthene.
Reaction SMILES: [O:1]=[C:2]1[CH:6]([CH2:7][CH2:8][C:9]([O:11]CC)=[O:10])[CH2:5][CH2:4][S:3]1.[OH-:14].[Na+]>C1COCC1>[SH:3][CH2:4][CH2:5][CH:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[C:2]([OH:1])=[O:14]
Reactant: [OH-]
Reactant: CCOC(=O)CCC1CCSC1=O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)CCC(CCS)C(=O)O
Reaction time: 48 h
Yield: 20 %

Procedure:
To a solution of ethyl 3-(2-oxotetrahydro-3-thiophenyl)propanoate (0.77 g, 3.81 mmol) in THF (5 ml) was added sodium hydroxide (1 M in water, 5 ml). The mixture was allowed to stir for two days, then the THF was removed under reduced pressure, the aqueous layer was washed with ether, then acidified to pH 1 with HCl and extracted with ethyl acetate. The combined ethyl acetate extracts were dried over magnesium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by column chromatography yielding a 150 mg of clear oil (20%). 1H NMR (d6-DMSO) δ1.7 (m, 3H), 1.8 (m, 1H), 2.2 (m, 2H), 2.3-2.5 (m, 4H). Analysis calculated for C7H12SO4: C, 43.74;H 6.29; S, 16.68. Found: C, 43.61; H 6.39; S, 16.55.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[O:10][C:11]3([CH:17]4[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]4)[CH2:13]3)[CH2:12][C:5]=12.[C:20]1([SH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CO>O1CCOCC1.O>[C:20]1([S:26][C:4]2[CH:9]=[CH:8][N:7]=[C:6]3[O:10][C:11]4([CH:17]5[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]5)[CH2:13]4)[CH2:12][C:5]=23)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Clc1ccnc2c1CC1(CN3CCC1CC3)O2
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: c1ccc(Sc2ccnc3c2CC2(CN4CCC2CC4)O3)cc1
Temperature: 25 °C
Yield: 51.8 %

Procedure:
Sodium hydride (151 mg, 3.77 mmol) was added to a solution of 97 mg (0.387 mmol) of 4'-chlorospiro[1-azabicyclo[2.2.2]octane-3,2'(3'H)-furo[2,3-b]pyridine], 0.40 mL (3.91 mmol) of thiophenol and 0.10 mL of methanol in 15 mL of dioxane, under a nitrogen atmosphere. The reaction was refluxed for 4 days, cooled to ambient temperature, diluted with 30 mL of water, and extracted with chloroform (3×30 mL). The combined organic extract was dried over anhydrous magnesium sulfate, concentrated in vacuo and the residue flash chromatographed on neutral silica gel using a 98:2 mixture of ammoniated chloroform/methanol to give 65 mg (52%) of the title compound as a colourless oil: electrospray MS (m/z, relative intensity) 325 ([MH]+).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[NH:8][CH:9]([CH3:24])[CH2:10][S:11][CH:12]([C:13]3[CH:18]=[CH:17][C:16]([C:19]#[C:20][CH2:21][OH:22])=[CH:15][C:14]=3[CH3:23])[C:6]=2[C:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)=[N:4]1)[CH3:2].CO>[Pd].C1COCC1>[CH2:1]([N:3]1[C:7]2[NH:8][CH:9]([CH3:24])[CH2:10][S:11][CH:12]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][OH:22])=[CH:15][C:14]=3[CH3:23])[C:6]=2[C:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)=[N:4]1)[CH3:2]
Reactant: CCn1nc(-c2ccccn2)c2c1NC(C)CSC2c1ccc(C#CCO)cc1C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCn1nc(-c2ccccn2)c2c1NC(C)CSC2c1ccc(CCCO)cc1C
Yield: 86.5 %

Procedure:
To a flask was added 3-(4-(1-ethyl-7-methyl-3-(pyridin-2-yl)-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepin-4-yl)-3-methylphenyl)prop-2-yn-1-ol (0.126 g, 0.301 mmol, prepared from P with Example #K.1 and prop-2-yn-1-ol), MeOH (7.53 ml) and THF (7.53 ml). The solution was treated with the H-Cube (Pd/C 10 wt %, Manual Control, 20 bar, 1 mL/min, rt) for about 2 h. The mixture was concentrated in vacuo and purified by flash chromatography (25 g silica gel; DCM/MeOH 1:0 to 9:1) to give 3-(4-(1-ethyl-7-methyl-3-(pyridin-2-yl)-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepin-4-yl)-3-methylphenyl)propan-1-ol (0.110 g, 86%); LC-MS (Table 1, Method g) Rt=2.29 and 2.32 min.; MS m/z: 423.14 and 423.14 (M+H)+.
Reaction SMILES: [NH3:1].C([O:4][C:5]([C:7]1[CH:11]=[C:10]([CH3:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=2)[N:8]=1)=O)C>CO>[Cl:20][C:15]1[CH:14]=[C:13]([N:9]2[C:10]([CH3:12])=[CH:11][C:7]([C:5]([NH2:1])=[O:4])=[N:8]2)[CH:18]=[CH:17][C:16]=1[F:19]
Reactant: CCOC(=O)c1cc(C)n(-c2ccc(F)c(Cl)c2)n1
Reactant: N
Solvent: CO
Product: Cc1cc(C(N)=O)nn1-c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 80 %

Procedure:
Ammonia gas was bubbled into a chilled solution of ethyl 1-(3-chloro-4-fluorophenyl)-5-methyl-1H-pyrazole-3-carboxylate (from Step 1) (1.0 g, 3 mmol) in MeOH (1.5 ml) for 5 minutes. The resulting mixture was placed in a sealed tube and stirred at room temperature for 2 days. The reaction was then concentrated in vacuo, and the residue obtained was dried under vacuum to give titled product (0.72 g, 80%) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+]>CN(C=O)C.C(OCC)C>[CH2:12]([O:11][C:4]1[C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=[C:2]([Br:1])[CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cc(Br)cn2nccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Brc1cc(OCc2ccccc2)c2ccnn2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
6-bromopyrazolo[1,5-a]pyridin-4-ol (1.10 g, 5.16 mmol) and benzyl bromide (0.676 ml, 5.68 mmol) were dissolved in DMF (20 ml) at 0° C. NaH (413 mg, 10.3 mmol, 60 wt %) was added in one portion and the mixture was allowed to stir at 0° C. After 30 minutes, additional benzyl bromide 0.068 ml, 0.57 mmol) was added and the mixture was allowed to stir 30 minutes at 0° C. The reaction mixture was diluted in diethyl ether, washed with saturated aqueous sodium hydrogen carbonate and brine then dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/isohexane gradient) to afford 4-(benzyloxy)-6-bromopyrazolo[1,5-a]pyridine.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13](Br)=[CH:14][C:15]1[CH:16]=[C:17]([C:20]2([CH3:37])[CH2:24][O:23][C:22]3[CH:25]=[C:26]4[C:31](=[CH:32][C:21]2=3)[C:30]([CH3:34])([CH3:33])[CH2:29][CH2:28][C:27]4([CH3:36])[CH3:35])[S:18][CH:19]=1.Cl[C:40]([O:42][CH3:43])=[O:41].[Cl-].[NH4+]>C1COCC1>[CH3:37][C:20]1([C:17]2[S:18][CH:19]=[C:15]([C:14]#[C:13][C:40]([O:42][CH3:43])=[O:41])[CH:16]=2)[CH2:24][O:23][C:22]2[CH:25]=[C:26]3[C:31](=[CH:32][C:21]1=2)[C:30]([CH3:34])([CH3:33])[CH2:29][CH2:28][C:27]3([CH3:36])[CH3:35]
Reactant: CC1(C)CCC(C)(C)c2cc3c(cc21)OCC3(C)c1cc(C=C(Br)Br)cs1
Reactant: COC(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)C#Cc1csc(C2(C)COc3cc4c(cc32)C(C)(C)CCC4(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 2.5 M solution of butyllithium in hexane (0.82 ml, 2.45 mmol) was added to a solution of 3-[4-(2,2-dibromovinyl)thiophen-2-yl]-3,5,5,8,8-pentamethyl-2,3,5,6,7,8-hexahydronaphtho[2,3-b]furan (478 mg, 0.94 mmol) in THF (5 ml) at -78° C. The stirring was continued for 1 h at -78° C. and then methyl chloroformate (80 μl) was added. The mixture was stirred at room temperature for 1 h, treated with a saturated ammonium chloride solution and extracted with ethyl ether. After washing with water, the organic phase was dried over magnesium sulfate and concentrated in a rotary evaporator under vacuum. The desired compound was purified by column chromatography.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[O:8][C:7]([CH3:10])([CH3:9])[C:6]([CH3:12])([CH3:11])[O:5]1.[CH2:13]([NH2:19])[CH2:14][CH2:15][CH:16]=[CH:17][CH3:18].[OH-].[Na+]>O>[CH2:13]([NH:19][CH2:2][CH2:3][CH:4]1[O:8][C:7]([CH3:10])([CH3:9])[C:6]([CH3:12])([CH3:11])[O:5]1)[CH2:14][CH2:15][CH:16]=[CH:17][CH3:18]
Reactant: CC=CCCCN
Reactant: CC1(C)OC(CCBr)OC1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC=CCCCNCCC1OC(C)(C)C(C)(C)O1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
2-Bromoethyl-4,4,5,5-tetramethyl-1,3-dioxolane (20 grams) and 4-hexenylamine (100 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at a temperature of about 100° C. for a period of about 3 hours. After this time sodium hydroxide (10 grams) dissolved in water (100 ml) is added and the resulting mixture is stirred for a period of about 30 minutes. The reaction mixture is then extracted with ether. The ether extract is dried over anhydrous magnesium sulfate, filtered and stripped of solvent to yield the desired product N-hex-4-enyl-N-(4,4,5,5-tetramethyl-1,3-dioxolan-2-ylethyl)amine.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:10][CH2:9][C@@H:8]([CH2:11][C:12]3[N:13]([C:18]4[CH:23]=[CH:22][C:21](B5OC(C)(C)C(C)(C)O5)=[CH:20][C:19]=4[F:33])[C:14](=[O:17])[NH:15][N:16]=3)[CH2:7]2)=[O:5])[CH2:3][CH2:2]1.Br[C:35]1[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[C:37]([CH3:43])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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].ClCCl>[CH:1]1([C:4]([N:6]2[CH2:10][CH2:9][C@@H:8]([CH2:11][C:12]3[N:13]([C:18]4[CH:23]=[CH:22][C:21]([C:35]5[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[C:37]([CH3:43])[CH:36]=5)=[CH:20][C:19]=4[F:33])[C:14](=[O:17])[NH:15][N:16]=3)[CH2:7]2)=[O:5])[CH2:3][CH2:2]1
Reactant: Cc1cc(Br)ccc1C#N
Reactant: CC1(C)OB(c2ccc(-n3c(C[C@@H]4CCN(C(=O)C5CC5)C4)n[nH]c3=O)c(F)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cc(-c2ccc(-n3c(C[C@@H]4CCN(C(=O)C5CC5)C4)n[nH]c3=O)c(F)c2)ccc1C#N
Temperature: 25 °C
Yield: 57 %

Procedure:
A solution of 5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (0.245 mmol) in dioxane (1.5 mL) was treated with 4-bromo-2-methylbenzonitrile (0.245 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (10 mg), and 2M aq potassium carbonate (0.736 mmol). The reaction mixture was purged with nitrogen, sealed, and irradiated in a microwave (Biotage Initiator) at 150° C. for 15 min. The reaction mixture was cooled to room temperature and was diluted with water (50 mL). The aqueous layer was acidified to pH˜4 using 1N aq HCl and was extracted with dichloromethane. The organic layer was dried over magnesium sulfate, treated with Si-Thiol (Silicycle, 20 mg), filtered, and concentrated in vacuo. The crude residue was purified by reverse phase HPLC (20-50% acetonitrile/water+0.1% NH4OH) to afford the title compound as an amorphous off-white solid (57%). MS(ES)+ m/e 446.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[C:10]2[C:14](=O)[O:13][C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])=[N:11]2)=[CH:4][C:3]=1[CH2:23][O:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28].O.[NH3:31].Cl>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])=[N:11][C:10]([C:14]([NH2:31])=[O:13])=[N:9]2)=[CH:4][C:3]=1[CH2:23][O:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28]
Reactant: CC(C)CCOCc1cc(NN=C2N=C(c3ccccc3F)OC2=O)ccc1Cl
Reactant: N
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: CC(C)CCOCc1cc(-n2nc(C(N)=O)nc2-c2ccccc2F)ccc1Cl
Temperature: 25 °C
Yield: 82.3 %

Procedure:
In 10 ml of acetone, 1.294 g (3 mmol) of 4-[4-chloro-3-[(3-methylbutoxy)methyl]phenyl hydrazono]-2-(2-fluorophenyl)-2-oxazolin-5-one synthesized in the similar way to Examples 1~2, Reference Example 1 was suspended, followed by the addition of 0.6 ml of concentrated ammonia water and 30-minute stirring at room temperature. The resulting solution was made acid by adding 0.6 ml of concentrated hydrochloric acid and further stirred at 50° C. for 30 minutes. Acetone was distilled off and the residue was extracted by adding benzene and water. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvents were distilled off to obtain a crude product, and this crude product was purified by subjecting it to silica gel chromatography using hexane/ethyl acetate (1/2, v/v) as developing solvent and recrystallized from ethyl acetate-hexane to obtain 1.062 g (82.3% yield) of 1-[4-chloro-3-[(3-methylbutoxy)methyl]phenyl]-5-(2-fluorophenyl)-1H-1,2,4-triazole-3-carboxamide (m.p. 113°-115° C.).
Reaction SMILES: [CH3:1][C@@H:2]1[C@:7]([CH3:22])([C:8]2[CH:13]=[CH:12][CH:11]=[C:10](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[CH2:6][CH2:5][N:4]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:3]1.C(N(CC)CC)C>CO.CS(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:26][O:25][C:23]([C:10]1[CH:9]=[C:8]([C@:7]2([CH3:22])[CH2:6][CH2:5][N:4]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:3][C@@H:2]2[CH3:1])[CH:13]=[CH:12][CH:11]=1)=[O:24]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CC[C@@]1(C)c1cccc(OS(=O)(=O)C(F)(F)F)c1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1cccc([C@]2(C)CCN(C(=O)OC(C)(C)C)C[C@@H]2C)c1
Temperature: 65 °C
Yield: 154.5 %

Procedure:
To a stirred solution of 3 (10.8 g, 0.024 mol, 1 eq) in a mixture of methanol (100 mL) and dimethylsulfoxide (150 mL) was added triethylamine (7.55 mL, 0.054 mol, 2.2 eq). Carbon monoxide gas was bubbled through the mixture for 5 minutes. To the mixture was added palladium (II) acetate (0.554 g, 0.0024 mol, 0.1 eq) followed by 1,1′-bis(diphenylphosphino)ferrocene (2.73 g, 0.0049 mol, 0.2 eq). Carbon monoxide gas was bubbled through the mixture for 15 minutes and it was then stirred under an atmosphere of carbon monoxide and heated at 65° C. overnight. The mixture was cooled to room temperature and poured into water (500 mL). The mixture was extracted with ethyl acetate (3×150 mL). The combined organic extracts were washed with water (200 mL), brine (200 mL) and dried over sodium sulfate. Evaporation of the solvent under vacuum afforded a dark oil. The crude product was purified by column chromatography (eluent:hexane/ethyl acetate=95:5) affording the title compound (6.44 g, 75%).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].CCCCCCC.O1CCCC1.C(C1C=CC=CC=1)C.[O:29]1[C:33]2([CH2:38][CH2:37][CH:36]([C:39]#[N:40])[CH2:35][CH2:34]2)[O:32][CH2:31][CH2:30]1.I[CH:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1>O1CCCC1>[O:45]1[CH2:46][CH2:47][CH:42]([C:36]2([C:39]#[N:40])[CH2:37][CH2:38][C:33]3([O:32][CH2:31][CH2:30][O:29]3)[CH2:34][CH2:35]2)[CH2:43][CH2:44]1
Reactant: IC1CCOCC1
Reactant: N#CC1CCC2(CC1)OCCO2
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Product: N#CC1(C2CCOCC2)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a 2M solution of lithium diisopropylamide in heptane/tetrahydrofuran/ethylbenzene (18 mL, 35.9 mmol, 1.5 eq.) at −78° C. was added dropwise a solution of 1,4-dioxa-spiro[4.5]decane-8-carbonitrile (commercially available or via literature procedure described for example in Becker et al. Synthesis 1992, 11, 1080-1082; 4.0 g, 23.9 mmol) in tetrahydrofuran (40 mL). After stirring for 30 min at −78° C., 4-iodotetrahydro-2H-pyran (5.1 g, 23.9 mmol, 1 eq.) was added carefully. The reaction mixture was allowed to warm to room temperature over night before being quenched by slow addition of ethanol (10 mL) and water (20 mL) subsequently. The resulting suspension was filtered through celite and extracted three times with dichloromethane. The combined organic phases were concentrated in vacuo and purified by flash chromatography (SiO2, 0%→30% methanol in dichloromethane) to give 2.80 g of 8-(tetrahydropyran-4-yl)-1,4-dioxa-spiro[4.5]decane-8-carbonitrile (5). Rt=1.03 min (Method B). Detected mass: 252.3 (M+H+).
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:10]([NH2:13])[CH2:11][NH2:12]>C(O)C>[CH:1](=[N:12][CH:11]=[CH:10][N:13]=[CH:1][C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: O=Cc1ccccc1O
Reactant: NCCN
Solvent: CCO
Product: Oc1ccccc1C=NC=CN=Cc1ccccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.5 %

Procedure:
Salicylaldehyde (3.9 g; 32 mmol) and ethylenediamine (1.0 g; 16 mmol) were added to 40 mL ethanol in a 100-mL one-necked flask. The mixture was stirred for 3 hours at room temperature. The formed precipitate was filtered off with a Büchner funnel. The precipitate was washed three times with 20 mL methanol. The solids were collected and dried overnight at 40° C. under vacuum. The intermediate ligand N,N′-bis(salicylidene)-1,2-diaminoethylene was obtained as a yellow solid with a yield of 80.5% (3.62 g; 13.5 mmol).
Reaction SMILES: C(OCC(C)(NS(C(F)(F)F)(=O)=O)C)(=O)C(C)=C.C(OC1(CC)CCCC1)(=O)C(C)=C.[C:32]([O:37][C:38]12[CH2:47][CH:42]3[CH2:43][CH:44]([CH2:46][C:40]([OH:48])([CH2:41]3)[CH2:39]1)[CH2:45]2)(=[O:36])[C:33](C)=[CH2:34].N(C(C)(C)C#N)=NC(C)(C)C#N>C(C(C)=O)C>[CH2:34]=[CH:33][C:32]([O:37][C:38]12[CH2:39][C:40]3([OH:48])[CH2:46][CH:44]([CH2:43][CH:42]([CH2:41]3)[CH2:47]1)[CH2:45]2)=[O:36]
Reactant: C=C(C)C(=O)OC12CC3CC(CC(O)(C3)C1)C2
Agent: C=C(C)C(=O)OC1(CC)CCCC1
Agent: C=C(C)C(=O)OCC(C)(C)NS(=O)(=O)C(F)(F)F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCC(C)=O
Product: C=CC(=O)OC12CC3CC(CC(O)(C3)C1)C2
Temperature: 25 °C

Procedure:
To a 100 mL roundbottom flask, 2-methyl-2-(trifluoromethylsulfonamido)propyl methacrylate (2,2-diMe-EATf-MA) (1.0 g, 3.5 mmol, 0.15 eq.), 1-ethylcyclopentyl methacrylate (ECPMA) (1.9 g, 10.4 mmol, 0.45 eq.), 3-hydroxyadamantyl methacrylate (HADMA) (2.18 g, 9.2 mmol, 0.40 eq.), 2,2′-azobis(2-methylpropionitrile) (AIBN) (151 mg, 0.04 eq.), and methyl ethyl ketone (10 mL) were added. A reflux condenser with a rubber septum was added and the oxygen was removed from the solution by three sequential pump-backfill cycles using nitrogen while stirring vigorously. The reaction flask was placed under nitrogen and transferred to an oil bath to reflux overnight. Upon completion, the reaction flask was cooled to room temperature and the polymer precipitated into a 30-fold excess of methanol. The polymer was isolated using a medium porosity ceramic fitted Buchner funnel. The white polymer was redissolved into a minimal amount of methyl ethyl ketone and the precipitation process repeated one time. Upon final isolation on the Buchner funnel, the polymer was washed 1 time with methanol. The polymer was dried in vacuo at 80° C. overnight. The polymer was allowed to cool to room temperature under vacuum prior to determining the yield. The final composition was 17:42:41 as determined by inverse-gated 13C NMR using Cr(acac)3 as a relaxation agent in acetone-d6. Yield: 4.3 g (84%). Mn: 6750 g/mol. PDI: 2.43. Tg: >Tdecomp.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:15]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][N:16]=1.Cl>O1CCOCC1.[Cu](Cl)Cl.C(OCC)(=O)C.O>[F:22][C:21]([F:24])([F:23])[C:20]1[C:15]([CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: FC(F)(F)c1cccnc1Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl[Cu]Cl
Agent: Cl
Agent: [H-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)C(C(=O)OCC)c1ncccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.4 %

Procedure:
8.73 g of sodium hydride (55% oil dispersion) was suspended in 100 ml of 1,4-dioxane. Into this, 32.03 g of diethyl malonate was added dropwise over a period of about 1 hour at 60° C. under a nitrogen atmosphere. The mixture was stirred further for 0.5 hours at the same temperature, then, 8.26 g of copper chloride (I) was added to the mixture. Thereafter, into the mixture, a solution prepared by dissolving 15.00 g of 2-chloro-3-(trifluoromethyl)pyridine in 50 ml of 1,4-dioxane at 80° C. was dropped. The mixture was stirred for 16 hours under reflux with heating. The reaction mixture was allowed to cool to room temperature, and to the reaction mixture was added 15 ml of concentrated hydrochloric acid. To the mixture were added water and ethyl acetate, and the mixture was filtrated through celite. The filtrate was liquid-separated. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 51.14 g of the resultant residue was subjected to silica gel column chromatography, to obtain 6.90 g of diethyl (3-trifluoromethyl-2-pyridyl)malonate.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[S:9](=[O:12])(=[O:11])[N:8]=[CH:7][NH:6][C:5]=2[S:4][CH:3]=1.[C:13](=O)([O-])[O-].[K+].[K+].IC>C(#N)C>[CH3:13][N:6]1[C:5]2[S:4][CH:3]=[C:2]([CH3:1])[C:10]=2[S:9](=[O:12])(=[O:11])[N:8]=[CH:7]1
Reactant: Cc1csc2c1S(=O)(=O)N=CN2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: Cc1csc2c1S(=O)(=O)N=CN2C
Temperature: 65 °C

Procedure:
150 mg of the compound obtained in Step A above are suspended in 5 ml of acetonitrile. 300 mg of potassium carbonate and 0.15 ml of iodomethane are added thereto. The reaction mixture is heated at 65° C. for 30 minutes, with stirring. After evaporation of the solvents under reduced pressure, the residue is taken up in 5 ml of water and then collected by filtration, washed with water and dried.