Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[OH:14])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=O.Br[CH2:16][C:17](=[O:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[C:17]([C:18]1[O:14][C:13]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=2[CH:1]=1)(=[O:19])[CH3:16]
Reactant: CCOC(=O)c1ccc(O)c(C=O)c1
Reactant: CC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1ccc2oc(C(C)=O)cc2c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 246.8 %

Procedure:
To a solution of ethyl 3-formyl-4-hydroxybenzoate (4.00 g, 11.5 mmol) in acetonitrile (85 mL) were added bromoacetone (9.68 g, 64.1 mmol) and potassium carbonate (14.7 g, 106 mmol), and the mixture was stirred at 70° C. overnight. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solution was passed through silica gel. The solvent was evaporated under reduced pressure, and the obtained solid was washed with diisopropyl ether to give the title compound (6.59 g, yield 67%).
Reaction SMILES: [CH3:1][Si:2]([CH3:28])([CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[N:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[N:14][CH:15]=1.[CH3:29][Si:30]([CH3:67])([CH2:46][CH2:47][C:48]([F:66])([F:65])[C:49]([F:64])([F:63])[C:50]([F:62])([F:61])[C:51]([F:60])([F:59])[C:52]([F:58])([F:57])[C:53]([F:56])([F:55])[F:54])[CH2:31][CH2:32][CH2:33][CH2:34]OS(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:67][Si:30]([CH3:29])([CH2:46][CH2:47][C:48]([F:65])([F:66])[C:49]([F:63])([F:64])[C:50]([F:62])([F:61])[C:51]([F:59])([F:60])[C:52]([F:57])([F:58])[C:53]([F:54])([F:55])[F:56])[CH2:31][CH2:32][CH2:33][CH2:34][O:22][C:19]1[CH:18]=[CH:17][C:16]([C:13]2[N:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:28])[CH2:23][Si:24]([CH3:25])([CH3:26])[CH3:27])=[CH:15][N:14]=2)=[CH:21][CH:20]=1
Reactant: C[Si](C)(C)C[Si](C)(C)CCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Reactant: Cc1ccc(S(=O)(=O)OCCCC[Si](C)(C)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)C[Si](C)(C)CCCCCCOc1cnc(-c2ccc(OCCCC[Si](C)(C)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of 4-{5-[6-(dimethyltrimethylsilanylmethyl-silanyl)-hexyloxy]-pyrimidin-2-yl}-phenol (0.083 g, 0.200 mmol), toluene-4-sulfonic acid 4-[dimethyl-(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluoro-octyl)-silanyl]-butyl ester (0.126 g, 0.200 mmol) and cesium carbonate (0.078 g, 0.24 mmol) in DMF (10 ml) was stirred at room temperature for 24 h. The reaction mixture was washed with water and the organic layer extracted into ethyl acetatelhexane (3×20 ml, 1:1). The combine extracts were washed with brine, dried (MgSO4) and the solvent removed in vacuo. The residues were purified by column chromatography [silica gel, hexane/ethyl acetate (9:1)] to yield a colorless solid, which was recrystallized from acetonitrile.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH2:15][NH2:16])[CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[C:18]1[C:26](Cl)=[O:27].C(N(CC)CC)C>O1CCOCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH2:15][NH:16][C:26]([C:18]4[O:17][C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=5[CH:19]=4)=[O:27])[CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: NCC1(c2ccc3c(c2)OCO3)CCCC1
Reactant: O=C(Cl)c1cc2ccccc2o1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(NCC1(c2ccc3c(c2)OCO3)CCCC1)c1cc2ccccc2o1
Reaction time: 15 h
Yield: 17.9 %

Procedure:
C-(1-Benzo[1,3]dioxol-5-yl-cyclopentyl)-methylamine (43.8 mg, 0.200 mmol) and benzofuran-2-carbonyl chloride (36.1 mg, 0.200 mmol) were dissolved in 2 mL of 1,4-dioxane containing triethylamine (83.6 μL, 0.600 mmol). The reaction mixture was stirred for 15 hours, evaporated to dryness, and purified by reverse phase preparative liquid chromatography to yield the pure product (13.0 mg, 0.0358 mmol, 17.8%). ESI-MS m/z calc. 363.2, found 364.2 (M+1)+. Retention time of 4.22 minutes.
Reaction SMILES: [C:1]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:6]=[C:5]([C:7]([O-])=[O:8])[CH:4]=[C:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:2]=1.CO>C1COCC1>[OH:8][CH2:7][C:5]1[CH:4]=[C:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:2]=[C:1]([CH:6]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)c1cc(C(=O)[O-])cc(C(=O)OCC)c1
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)c1cc(CO)cc(C(=O)OCC)c1

Procedure:
A mixture of diethyl 1,3,5-benzenetricarboxylate (5.2 g) and borane methylsulfide complex (6.1 g) is stirred in THF (150 mL) at 20–25 degrees C. overnight. The mixture is then treated with methanol, concentrated to dryness, and chouromatographed (silica gel) to give diethyl 5-(hydroxymethyl)isophthalate. Diethyl 5-(hydroxymethyl)isophthalate (3.4 g) is hydroyzed in ethanol and water with lithium hydroxide monohydrate (0.57 g) at 20–25 degrees C. for 3.5 hours at which time the solvents are removed under reduced pressure. Water (100 mL) is added and the mixture is acidified to pH=4 with concentrated hydrochloric acid. The mixture is extracted with ethyl acetate and dried over magnesium sulfate, filtered, and concentrated to give 3-(ethoxycarbonyl)-5-(hydroxymethyl)benzoic acid, high resolution MS MH+=225.0769. 3-(Ethoxycarbonyl)-5-(hydroxymethyl)benzoic acid (2.3 g), EDC (3.0 g), 1-HOBT (2.1 g), diisopropylethylamine (2.7 mL), dipropyl amine (2.8 mL), and DMF (50 mL) are stirred at 20–25 degrees C. overnight. The mixture is then partitioned between ethyl acetate, water, and saline. The organic phase is separated and dried over magnesium sulfate, filtered, and concentrated. Chromatography (silica gel) gives ethyl 3-[(dipropylamino)carbonyl]-5-(hydroxymethyl)benzoate, NMR (CDCl3) δ 0.77, 1.0, 1.4, 1.6, 1.7, 3.2, 3.5, 4.4, 4.8, 7.6, 8.0 and 8.1.
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:5]2[N:6]=[CH:7][CH:8]=[C:9]([OH:10])[C:4]=2[CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[CH:17][C:18]=1F.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[F:12][C:13]1[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[CH:17][C:18]=1[O:10][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:11][C:2]([CH3:1])=[CH:3][C:4]=12
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: Cc1cc2c(O)ccnc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2[nH]1
Temperature: 50 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
A mixture of 2-methyl-1H-pyrrolo[2,3-b]pyridin-4-ol (90 mg, TFA salt, 0.34 mmol), 3,4-difluoronitrobenzene (0.05 mL) and potassium carbonate (100 mg, 0.72 mmol) in DMF (1 mL) was stirred at 50° C. for 2 h. The mixture was diluted with water and extracted with ethyl acetate (3×5 mL). The combined extracts were washed with water, dried (MgSO4) and concentrated in vacuo to afford the crude product, which was purified by preparative HPLC to give the title compound (45 mg, 46%). 1H NMR (CD3OD) δ 8.25 (dd, 2H, J=10.4, 2.6 Hz), 8.12 (m, 1H), 8.04 (d, 1H, J=5.5 Hz), 7.30 (t, 1H, J=8.3 Hz), 6.67 (d, 1H, J=5.5 Hz), 5.95 (s, 1H), 2.41 (s, 3H); MS(ESI+) m/z 288 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:21][CH2:22]OC)[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:8][CH2:7]1)=O)C.[Cl-].C[Al+]C.[NH2:29][C:30]1[CH:31]=[CH:32][C:33]([Cl:36])=[N:34][CH:35]=1>CCCCCCC>[C:15]1([S:12]([N:9]2[CH2:10][CH2:11][C:6]3([C:4](=[O:3])[N:29]([C:30]4[CH:35]=[N:34][C:33]([Cl:36])=[CH:32][CH:31]=4)[CH2:22][CH2:21]3)[CH2:7][CH2:8]2)(=[O:13])=[O:14])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)c2ccccc2)CC1
Reactant: Nc1ccc(Cl)nc1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: CCCCCCC
Product: O=C1N(c2ccc(Cl)nc2)CCC12CCN(S(=O)(=O)c1ccccc1)CC2
Yield: 5.3 %

Procedure:
This material was prepared in analogy to example 1 step D) from 1-benzenesulfonyl-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (0.2 g), dimethylaluminium chloride in heptane (0.9 molar, 1.88 ml) and 5-amino-2-chloro-pyridine (0.145 g) to give the desired 8-benzenesulfonyl-2-(6-chloro-pyridin-3-yl)-2,8-diaza-spiro[4.5]decan-1-one (0.012 g) as a white solid. MS (ESI): 406.1 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH2:26]([NH2:29])[C:27]#[CH:28]>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:29][CH2:26][C:27]#[CH:28])=[O:20]
Reactant: C#CCN
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Solvent: c1ccccc1
Product: C#CCNC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.8 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), propargylamine (0.180 g, 3.27 mmol), and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the resulting crude product was recrystallized from chloroform/hexane to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-propargyl-3,4,5,6-tetrahydrophthalamide as white crystals (0.366 g, 31.8% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C@H:4](/[CH:5]=[CH:6]\[CH3:7])[C@H:3]1[C:8]([OH:10])=[O:9].[F:12][C:13]1[C:18]([F:19])=[CH:17][C:16]([F:20])=[C:15]([F:21])[C:14]=1[CH2:22]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.O1CCCC1>[CH3:11][C:2]1([CH3:1])[C@H:4](/[CH:5]=[CH:6]\[CH3:7])[C@H:3]1[C:8]([O:10][CH2:22][C:14]1[C:15]([F:21])=[C:16]([F:20])[CH:17]=[C:18]([F:19])[C:13]=1[F:12])=[O:9]
Reactant: C/C=C\[C@@H]1[C@@H](C(=O)O)C1(C)C
Reactant: OCc1c(F)c(F)cc(F)c1F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C/C=C\[C@@H]1[C@@H](C(=O)OCc2c(F)c(F)cc(F)c2F)C1(C)C
Reaction time: 24 h
Yield: 93 %

Procedure:
To a mixture solution of 0.42 g of (1R)-trans-2,2-dimethyl-3-((Z)-1-propenyl)cyclopropanecarboxylic acid, 0.49 g of (2,3,5,6-tetrafluorophenyl)methanol, 0.93 g of triphenylphosphine and 20 ml of tetrahydrofuran, 2.0 ml of 40% toluene solution containing diisopropyl azodicarboxylate was added. After one day, the reaction solution was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography (eluent: hexane/ethyl acetate=20/1) to give 0.80 g of (2,3,5,6-tetrafluorophenyl)methyl (1R)-trans-2,2-dimethyl-3-((Z)-1-propenyl)cyclopropanecarboxylate
Reaction SMILES: [CH2:1]([C:3]1[CH:18]=[C:17]([C:19]2[N:23]=[C:22]([C:24]3[CH:29]=[C:28]([CH3:30])[N:27]=[C:26](NCC)[N:25]=3)[O:21][N:20]=2)[CH:16]=[C:15]([CH3:34])[C:4]=1[O:5][CH2:6][C@@H:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])C.[CH3:35][O:36]C1N=C(C(O)=O)C=C(C)N=1>>[CH3:35][O:36][C:26]1[N:25]=[C:24]([C:22]2[O:21][N:20]=[C:19]([C:17]3[CH:16]=[C:15]([CH3:34])[C:4]([O:5][CH2:6][CH:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])=[C:3]([CH3:1])[CH:18]=3)[N:23]=2)[CH:29]=[C:28]([CH3:30])[N:27]=1
Reactant: CCNc1nc(C)cc(-c2nc(-c3cc(C)c(OC[C@@H](O)CNC(=O)CO)c(CC)c3)no2)n1
Reactant: COc1nc(C)cc(C(=O)O)n1
Product: COc1nc(C)cc(-c2nc(-c3cc(C)c(OCC(O)CNC(=O)CO)c(C)c3)no2)n1

Procedure:
rac-N-(3-{4-[5-(2-Methoxy-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide is prepared in analogy to N—((S)-3-{2-ethyl-4-[5-(2-ethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide using 2-methoxy-6-methyl-pyrimidine-4-carboxylic acid and 2-hydroxy-N-{2-hydroxy-3-[4-(N-hydroxycarbamimioyl)-2,6-dimethyl-phenoxy]-propyl}-acetamide; LC-MS: tR=0.84 min; [M+H]+=444.19.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([Cl:13])=[N:7][C:8]([Cl:12])=[CH:9][C:10]=1[CH3:11])=[O:4].[Br:14]N1C(=O)CCC1=O.C(O)(=O)C>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([Cl:13])=[N:7][C:8]([Cl:12])=[CH:9][C:10]=1[CH2:11][Br:14])=[O:4]
Reactant: COC(=O)c1c(C)cc(Cl)nc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(CBr)cc(Cl)nc1Cl
Yield: 72.2 %

Procedure:
To a solution of 5.3 g (24.1 mmol) 2,6-dichloro-4-methyl-pyridine-3-carboxylic acid methylester in CCl4 (92 ml) were added 3.1 g (26.5 mmol) N-Bromosuccinimide, 395 mg (2.4 mmol) AlBN and 1.45 ml (25.3 mmol) acetic acid. The mixture was irradiated with a 200 W Wolfram lamp at 60° C. for 24 h. Subsequently the mixture was filtered through celite and the filtrate was concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 97:3) provided 5.2 g of a mixture of 2,6-dichloro-4-methyl-pyridine-3-carboxylic acid methylester and 4-(bromomethyl)-2,6-dichloro-pyridine-3-carboxylic acid methylester which was used in subsequent reactions without further purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[N:5][N:6]=1.[CH2:7]([C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].O>N1C=CC=CC=1>[CH2:7]([C:15]1[CH:16]=[CH:17][C:18]([S:21]([NH:1][C:2]2[S:3][CH:4]=[N:5][N:6]=2)(=[O:23])=[O:22])=[CH:19][CH:20]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nncs1
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCc1ccc(S(=O)(=O)Nc2nncs2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.8 %

Procedure:
To a stirred solution of 2-amino-1,3,4-thiadiazole (2.0 g, 19.7 mmol) in pyridine (30 mL) under argon at −20° C. was added p-octylbenzenesulfonyl chloride (6.06 g, 21 mmol) over 10 min. The reaction mixture was stirred at room temperature for 16 hours. Water (300 mL) was added to quench the reaction. The mixture was extracted with CH2Cl2 and the organic extracts washed with 2N HCl (2×150 mL), brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluted with methanol:DCM 1:33 to give the product (3.83 g, 10.8 mmol, 55% yield) as a solid, mp 123-124° C.; 1H NMR (300 MHz, CDCl3) δ 0.87 (t, 3H, J=7 Hz), 1.36 (m, 10H), 1.59 (m, 2H), 2.63 (t, 2H, J=7 Hz), 7.27 (d, 2H, J=8 Hz), 7.82 (d, 2H, J=8 Hz), 8.23 (s, 1H); 13C NMR (75 MHz, CDCl3) 14.1, 22.6, 29.2, 29.3, 29.4, 31.1, 31.8, 35.9, 126.5, 129.0, 138.1, 142.6, 148.7, 167.3; MS (Q-TOF) Calcd for C16H24N3O2S2 354.1310, found 354.1211 (M+H)+; Calcd for C16H23N3N3O2S2 376.1129, found 376.1154 (M+Na)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[CH:4][C:3]=1[O:9][CH3:10].[CH2:11]([S-:13])[CH3:12].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:13][CH2:11][CH3:12])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1cc(F)ccc1Br
Reactant: CC[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCSc1ccc(Br)c(OC)c1
Reaction time: 72 h
Yield: 17 %

Procedure:
To a room temperature solution of 1-bromo-4-fluoro-2-methoxybenzene (5.00 g, 24.39 mmol) in DMF (15 mL) was added sodium ethanethiolate (2.66 g, 31.71 mmol) and the resulting reaction mixture was stirred for 72 hours. The reaction mixture was partitioned between water (20 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer was further extracted with EtOAc (3×50 mL). The organic layers were combined and washed with saturated brine solution (20 mL) then dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography eluting with hexane:EtOAc 98:2 to afford 1-bromo-4-ethylthio-2-methoxybenzene as a colourless liquid in 17% yield, 1.00 g.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C:11]1[N:15]([CH:16]([C:21]2[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=2[C:23]#N)[C:17]([OH:20])([CH3:19])[CH3:18])[CH:14]=[N:13][CH:12]=1)(C(C)(C)C)(C)C.S(=O)(=O)(O)[OH:30].O.[OH-].[Na+]>C1COCC1>[OH:8][CH2:9][CH2:10][C:11]1[N:15]([CH:16]2[C:21]3[C:22](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23](=[O:30])[O:20][C:17]2([CH3:19])[CH3:18])[CH:14]=[N:13][CH:12]=1
Reactant: O=S(=O)(O)O
Reactant: CC(C)(O)C(c1ccccc1C#N)n1cncc1CCO[Si](C)(C)C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OC(=O)c2ccccc2C1n1cncc1CCO

Procedure:
2-(1-{5-[2-(tert-Butyldimethylsilanyloxy)-ethyl]-imidazol-1-yl}-2-hydroxy-2-methyl-propyl)-benzonitrile (1.5 g, 3.75 mmol) is dissolved in THF (15 mL). Concentrated sulfuric acid (0.80 mL, 15.03 mmol) and water (0.80 mL) are added and the mixture is stirred at reflux for 24 h. After cooling down, the mixture is basified to pH 10 using 10% aqueous sodium hydroxide and is then extracted with ethyl acetate twice. The combined organic phase is dried over Na2SO4 and concentration in vacuo. The residue obtained is purified by silica gel chromatography (dichloromethane-methanol, 9:1) to give 4-[5-(2-hydroxy-ethyl)-imidazol-1-yl]-3,3-dimethyl-isochroman-1-one; HRMS (ESI) m/z 287.1403; [(M+H)+ Calcd for C16H19N2O3: 287.1396]; 1H NMR (400 MHz, MeOD) δ ppm 1.26 (s, 3 H), 1.56 (s, 3 H), 3.06 (br. s, 2 H), 3.75-4.18 (m, 2 H), 5.74 (br. s, 1 H), 6.92 (br. s, 1 H), 7.15 (d, J=1.3 Hz, 1 H), 7.57 (d, J=7.3 Hz, 1 H), 7.67 (t, J=7.3 Hz, 1 H), 7.78 (t, J=7.3 Hz, 1 H), 8.24 (d, J=7.3 Hz, 1 H)
Reaction SMILES: [C:1]([C:3]1[C:4](=O)[NH:5][C:6]([CH3:10])=[CH:7][C:8]=1[CH3:9])#[N:2].P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:4]1[C:3]([C:1]#[N:2])=[C:8]([CH3:9])[CH:7]=[C:6]([CH3:10])[N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(C)c(C#N)c(=O)[nH]1
Product: Cc1cc(C)c(C#N)c(Cl)n1

Procedure:
2-Chloro-3-cyano-4,6-dimethylpyridine was prepared from 3-cyano-4,6-dimethylpyrid-2-one and phosphorus oxychloride following the procedure of Kametani and Sato (Yakugaka Kenyu 34, 117, 1962).
Reaction SMILES: [H-].[Na+].[CH3:3][C@@H:4]([CH2:7][CH2:8][OH:9])[CH2:5][OH:6].Cl[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1.O>CN(C=O)C>[CH3:3][C@@H:4]([CH2:7][CH2:8][O:9][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)[CH2:5][O:6][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1
Reactant: C[C@H](CO)CCO
Reactant: N#Cc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](CCOc1ccc(C#N)cc1)COc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
Sodium hydride (2.88 g, 120 mmol) was dispersed in 50 ml DMF and then added with (S)-2-methyl-1,4-butanediol (5.21 g, 50.0 mmol) while being iced with ice. The reaction mixture after being cooled with ice for another one hour was stirred at room temperature for 2 hours and then added with 4-chlorobenzonitrile (15.3 g, 120 mmol), followed by reaction for 20 hours. After completion of the reaction, the reaction mixture was added carefully with 5 ml water to inactivate excess sodium hydride, followed by vacuum-distillation of DMF. After addition of 200 ml water, a precipitate thus obtained was filtrated and recrystallized from 100 ml ethanol thereby providing the intended product (12.5 g, 40.8 mmol, 82%).
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:8]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:9]=3[S:10][CH:11]=2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:29]([O:33][CH3:34])(=[O:32])[CH:30]=[CH2:31]>CN(C=O)C.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>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:8]2[C:7]([O:6][C:5]3[CH:18]=[CH:19][C:2](/[CH:31]=[CH:30]/[C:29]([O:33][CH3:34])=[O:32])=[CH:3][CH:4]=3)=[CH:11][S:10][C:9]=2[CH:12]=1
Reactant: COc1ccc2c(Oc3ccc(Br)cc3)csc2c1
Reactant: C=CC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc(Oc2csc3cc(OC)ccc23)cc1
Temperature: 120 °C
Yield: 63.8 %

Procedure:
To a solution of 3-(4-bromophenoxy)-6-methoxybenzo[b]thiophene (125 g, 373 mmol) and Pd(PPh3)2Cl2 (13.09 g, 18.64 mmol) in DMF (2500 mL) and diisopropyl ethylamine (326 mL, 1864 mmol) at room temperature was added (subsurface) methyl acrylate (845 mL, 9322 mmol) over 3-4 hours. As the addition started, the reaction was heated at 120° C. for 13 hours. Methyl acrylate (150 mL, 1654.8 mmol) was added (subsurface). The reaction was heated at 120° C. for 1 hour. The mixture was cooled to RT. Excess methyl acrylate and diisopropyl ethylamine were remove in vacuo. The resulting mixture was filtered through celite pad and the cake was washed with EtOAc (2000 mL). The resulting mixture was washed with water (2×), dried with anhydrous Na2SO4 and concentrated in vacuo. The crude material was purified by column chromatography (SiO2, 5% to 500/(EtOAc/Heptane) to afford (E)-methyl 3-(4-((6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (81 g, 238 mmol, 64% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm=1.46 (s, 3 H), 3.73 (s, 3 H), 6.28 (d, J=16.17 Hz, 1 H), 6.59 (s, 1 H), 6.90 (dd, J=8.59, 2.02 Hz, 1 H), 7.00 (d, J=8.59 Hz, 2 H), 7.21 (d, J=2.02 Hz, 1 H), 7.37-7.48 (m, 3 H), 7.59 (d, J=16.17 Hz, 1 H), LC/MS (m/z. MH+): 341.1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[Li][CH2:12]CCC.CI>C1COCC1>[CH3:12][CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10]
Reactant: [Li]CCCC
Reactant: O=C1Cc2ccccc2N1
Solvent: CI
Solvent: C1CCOC1
Product: CC1C(=O)Nc2ccccc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
A solution of oxindole (665 mg, 5.0 mmol) in THF (10 ml) was treated dropwise with n-BuLi (4.4 ml, 11.0 mmol) at −78° C., stirred for 30 min. at −78° C. To the reaction methyliodine (2 ml) was added dropwise at −78° C. The resulting solution was warmed up to room temperature. The mixture was quenched with water. The reaction solution was partitioned between ethylacetate and water. The organic layer was washed (brine), dried (Na2SO4), filtered and concentrated under vacumm. Purification on silica gel with 30% ethyl acetate/hexane to provide the title compound (630 mg, 86%). MS (DCI/NH3) m/e 148 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].CC1C=CC(S(O[CH:26]2[CH2:29][O:28][CH2:27]2)(=O)=O)=CC=1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:26]2[CH2:29][O:28][CH2:27]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: Cc1ccc(S(=O)(=O)OC2COC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Brc1ccc(OC2COC2)cc1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
4-Bromophenol (2.5 g, 14.5 mmol) and K2CO3 (5.45 g, 39.4 mmol) were added to a solution of oxetan-3-yl 4-methylbenzenesulfonate (3.00 g, 13.1 mmol) in DMF (10 mL) in a sealed tube. The reaction was heated to 100° C. and stirred at this temperature for 24 h. The reaction was diluted with EtOAc and washed with water. The organic layer was dried (MgSO4), filtered and concentrated to afford the title compound. MS (GCMS) m/z 228. This material was used in subsequent steps without further purification.