Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:13]Br)=[C:6]([CH:12]=1)[C:7]([O:9]CC)=O.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH3:30])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:18][CH:17]=1.C(N(CC)C(C)C)(C)C>C(O)C>[Br:1][C:2]1[CH:12]=[C:6]2[C:5]([CH2:13][N:15]([C:16]3[CH:17]=[CH:18][C:19]([CH:22]([CH3:30])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:20][CH:21]=3)[C:7]2=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(Br)ccc1CBr
Reactant: CC(C(=O)OC(C)(C)C)c1ccc(N)cc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C(=O)OC(C)(C)C)c1ccc(N2Cc3ccc(Br)cc3C2=O)cc1
Temperature: 100 °C
Yield: 38.7 %

Procedure:
A mixture of ethyl 5-bromo-2-(bromomethyl)benzoate (4.00 g, 12.4 mmol), tert-butyl 2-(4-aminophenyl)propanoate (3.4 g, 15.4 mmol) and N,N-diisopropylethylamine (1.98 g, 15.4 mmol) in ethanol (120 mL) was heated in a sealed tube at 100° C. overnight. After this time, the mixture was cooled with an ice bath and the solids collected by filtration to afford tert-butyl 2-(4-(6-bromo-1-oxoisoindolin-2-yl)phenyl)propanoate (2.00 g, 39%) as a white solid: mp 164-165° C.: 1H NMR (300 MHz, CDCl3) δ 8.06 (d, J=1.7 Hz, 1H), 7.81-7.77 (m, 2H), 7.71 (dd, J=8.0, 1.8 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.38-7.34 (m, 2H), 4.81 (s, 2H), 3.63 (q, J=7.1 Hz, 1H), 1.46 (d, J=7.2 Hz, 3H), 1.41 (s, 9H); ESI MS m/z 448 [M+H+CH3OH]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1.Cl.[NH2:17][OH:18]>>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][C:12](=[N:17][OH:18])[CH2:11][CH2:10]1
Reactant: COCCCCCCN1CCC(=O)CC1
Reactant: NO
Agent: Cl
Product: COCCCCCCN1CCC(=NO)CC1

Procedure:
1-(6-Methoxyhexyl)-4-piperidone oxime is prepared from 1-(6-methoxyhexyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([C:28]([NH:30][NH2:31])=[O:29])=[N:20]1>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:31][NH:30][C:28]([C:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[NH:19][N:20]=1)=[O:29])=[O:14]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: NNC(=O)c1n[nH]c2ccccc12
Product: O=C(NNC(=O)c1n[nH]c2ccccc12)c1ccncc1Nc1ccc(I)cc1F

Procedure:
N′-{3-[(2-fluoro-4-iodophenyl)amino]isonicotinoyl}-1H-indazole-3-carbohydrazide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.32 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.47 mmol of 1H-indazole-3-carboxylic acid hydrazide. LC/MS [9.14 min; 517 (M+1)]
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH2:9]1)=O)(C)(C)C.C(Cl)Cl.[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>>[CH3:20][N:17]1[CH2:18][CH2:19][N:14]([CH:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)[CH2:15][CH2:16]1.[C:26]([OH:28])([C:25]([F:30])([F:29])[F:24])=[O:27]
Reactant: CN1CCN(C2CCCN(C(=O)OC(C)(C)C)C2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(C2CCCNC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(4-Methyl-piperazin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (2.25 g, 7.94 mmol) was dissolved in Methylene chloride (50.0 mL, 7.80E2 mmol) and the reaction mixture was treated with Trifluoroacetic Acid (6.0 mL, 78 mmol). The reaction was allowed to stir overnight at room temperature. The solvent was then removed en vacuo to afford 1-Methyl-4-piperidin-3-yl-piperazine as a TFA salt. The crude product contained excess TFA, which was neutralized in the next synthetic step. (M+H)=184.09.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:28][N:29]2[CH2:32][CH:31]([C:33]([O:35][CH3:36])=[O:34])[CH2:30]2)[CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20]1)[N:13]=2)([O-])=O.C(N(CC)C(C)C)(C)C.[H][H]>[Pd].O>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:28][N:29]2[CH2:30][CH:31]([C:33]([O:35][CH3:36])=[O:34])[CH2:32]2)[CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20]1)[N:13]=2
Reactant: [H][H]
Reactant: COC(=O)C1CN(Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c([N+](=O)[O-])c2)C1
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)C1CN(Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(N)c2)C1
Reaction time: 2 h

Procedure:
A slurry of methyl 1-((3-nitro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)azetidine-3-carboxylate (0.390 g, 0.78 mmol) and 10% palladium on carbon, 50% water, (0.41 g) and N,N-diisopropylethylamine (0.27 mL, 1.6 mmol) was treated with a hydrogen balloon and stirred rapidly for 2 h, then was flushed with nitrogen, filtered through celite, rinsing with MeOH/DCM. The filtrate was concentrated in vacuo and the residue purified by silica gel chromatography 40 g, 20-100% EA/hexanes to give methyl 1-((3-amino-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)azetidine-3-carboxylate as a yellow solid. MS (ESI) m/z: Calculated: 470.2; Observed: 470.8 (M++1).
Reaction SMILES: [CH3:1][O:2][CH:3]1[O:7][CH:6]([CH2:8][OH:9])[CH:5]([OH:10])[CH:4]1[OH:11].C(N(CC)CC)C.[C:19]([Si:23]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)Cl)([CH3:22])([CH3:21])[CH3:20]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:23]([CH:8]([OH:9])[C@H:6]1[O:7][C@@H:3]([O:2][CH3:1])[C@H:4]([OH:11])[C@@H:5]1[OH:10])([C:19]([CH3:22])([CH3:21])[CH3:20])([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC1OC(CO)C(O)C1O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CO[C@@H]1O[C@H](C(O)[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.8 %

Procedure:
To a mixture of methyl-β-D-ribofuranoside (460 mg, 2.8 mmol, Sigma, St. Louis, Mo.) and anhydrous methylene chloride (20 ml) were added triethylamine (0.468 ml, 3.36 mmol), t-butyldiphenylchlorosilane (0.9 ml, 3.46 mmol), and DMAP (13.7 mg, 0.112 mmol) successively at room temperature. The reaction mixture was stirred at room temperature for 18 h under nitrogen. It was washed with water (20 ml), saturated ammonium chloride (20 ml), and brine (20 ml), dried over anhydrous MgSO4, filtered, and concentrated to dryness. The residue was separated by silica gel column chromatography (CHCl3 --MeOH, 50:1) to yield 1-O-methyl 5-(t-butyldiphenylsilyl)-β-D-ribofuranoside (618 mg, 54.8%) as a thick syrup. 1H NMR (DMSO-d6) δ0.96 (s, 9H, t-Bu), 3.22 (s, 3H, --OCH3), 3.61 (dd, J=11.0 and 5.3 Hz, 1H), 3.74 (d, J=4.4 Hz, 1H), 3.81 (dd, J=11.0 and 2.7 Hz, 1H), 3.90 (m, 1H), 4.00 (m, 1H), 4.68 (s, 1H, H-1'), 4.84 (br s, 1H, exchangeable with D2O, OH), 5.05 (br s, 1H, exchangeable with D2O, OH), 7.45 and 7.67 (m, 10H, Ph2).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:19]2[O:23][C:22]([Si](C(C)C)(C(C)C)C(C)C)=[N:21][CH:20]=2)O1>>[O:23]1[C:19]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=2)=[CH:20][N:21]=[CH:22]1
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: CC(C)[Si](c1ncc(B2OC(C)(C)C(C)(C)O2)o1)(C(C)C)C(C)C
Product: O=C(O)c1ccc(-c2cnco2)nc1

Procedure:
The title compound is prepared from 6-bromo-nicotinic acid and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[tris(isopropyl)silyl]-oxazole and following a procedure analogous to that described in Intermediate 45. Mass spectrum (ESI+): m/z=189 [M−H]−.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)#[CH:2].N1C=CC=CC=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C([O-])(O)=O.[Na+]>[C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH:7][S:17]([CH3:16])(=[O:19])=[O:18])=[CH:5][CH:4]=1)#[CH:2]
Reactant: C#Cc1ccc(N)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: C#Cc1ccc(NS(C)(=O)=O)cc1
Yield: 89.2 %

Procedure:
step 1—To a solution of 4-ethynyl aniline (4.00 g, 34.00 mmol) DCM (60 mL) at 0° C. was added sequentially pyridine (3.32 mL, 40.8 mmol) and dropwise addition of methanesulfonyl chloride (3.17 mL, 40.80 mmol). The reaction was stirred and allowed to warm from 0° C. to RT over 3 h then poured into a saturated aqueous NaHCO3 (150 mL). The aqueous layer was separated and extracted with DCM (2×100 mL). The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with 20% EtOAc/hexanes to afford 5.92 g (88%) of N-(4-ethynyl-phenyl)-methanesulfonamide (80) as a solid.
Reaction SMILES: [CH:1](=O)[CH3:2].[NH2:4][C@H:5]([C:8]([OH:10])=[O:9])[CH2:6][SH:7]>>[CH3:1][CH:2]1[NH:4][CH:5]([C:8]([OH:10])=[O:9])[CH2:6][S:7]1
Reactant: CC=O
Reactant: N[C@@H](CS)C(=O)O
Product: CC1NC(C(=O)O)CS1

Procedure:
Acetaldehyde (0.27 g) and L-cysteine (0.75 g) were reacted in aqueous solution 10 ml at room temperature for 1.5 hours, followed by solvent evaporation evaporated in vacuo. The resulting product was recrystallized from methanol to yield the title compound. Melting Point: 161°-163° centigrade Optical Rotation [α]26D: -148°.
Reaction SMILES: [H-].[Na+].[N:3]1[N:4]=[CH:5][N:6]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH:7]=1.[Br:17][CH2:18][CH2:19]Br.C(OCC)(=O)C>CS(C)=O>[Br:17][CH2:18][CH2:19][N:8]([N:6]1[CH:5]=[N:4][N:3]=[CH:7]1)[C:9]1[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=1
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Reactant: BrCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N(CCBr)n2cnnc2)cc1
Reaction time: 8 h

Procedure:
Sodium hydride (60%, 240 mg, 6.0 mmol) was added to a solution of 4-([1,2,4]triazol-4-ylamino)-benzonitrile (926 mg, 5.0 mmol) in DMSO (25 mL) at r.t. The mixture was stirred for 1 hour at this temperature and 1,2-dibromethane (5 mL) was added. The reaction mixture was stirred overnight and ethyl acetate (100 mL) was added. The mixture was transferred into a separation funnel and extracted with water (twice 100 mL) and brine (20 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure (water bath temperature <30° C.). The resulting orange oil was mixed with diethyl ether (100 mL) and filtered through a layer of silica (ca. 5 cm). The silica was washed with more diethyl ether (ca. 100 mL) to remove the excess of 1,2-dibromoethane; the crude product was washed from the silica with acetone (120 mL). The acetone solution was concentrated under reduced pressure and the residue was purified by column-chromatography (eluent: ethyl acetate) to give the title compound as a white solid. Yield: 628 mg (43%). 1H-NMR (400 MHz, d6-DMSO) δ=3.61 (t; J=6.2 Hz, 2H), 4.30 (t, J=6.4 Hz, 2H), 6.64 (d, J=9.0 Hz), 7.74 (d, 9.0 Hz, 2H), 8.97 (s, 2H). LRMS (FAB+):292.0 (100, [M+H]+).
Reaction SMILES: CC([O-])(C)C.[Li+].[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C:15]([O:17][CH3:18])=[O:16])=[N:12][C:13]=1Cl.[F:19][CH2:20][CH2:21][OH:22].Cl>CN(C=O)C.O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C:15]([O:17][CH3:18])=[O:16])=[N:12][C:13]=1[O:22][CH2:21][CH2:20][F:19]
Reactant: OCCF
Reactant: COC(=O)c1ccc(Br)c(Cl)n1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(Br)c(OCCF)n1
Temperature: 70 °C
Reaction time: 6 h
Yield: 11.9 %

Procedure:
Lithium 2-methylpropan-2-olate (4.17 mL, 9.18 mmol) was added within 30 minutes at ambient temperature to a solution of methyl 5-bromo-6-chloro-pyridine-2-carboxylate (CAN 1214353-79-3, 1 g, 3.99 mmol) and 2-fluoroethanol (CAN 371-62-0, 332 mg, 300 μL, 5.19 mmol) in DMF (6.67 mL). The reaction mixture was heated to 70° C. and stirred for 6 h. After cooling to ambient temperature, water (5 mL) and 2N HCl (5 mL) were added. The mixture was poured onto ice/brine (50 mL) and extracted with EtOAc (2×50 mL). The combined extracts were washed with ice/brine (50 mL), dried over Na2SO4, filtered and evaporated to dryness. The crude product was purified by flash-chromatography (50 g SiO2, heptane/0-30% EtOAc in 120 min.) to give the title compound (132 mg, 12%) as light brown solid, MS (ESI) m/e=278.0 [MH+].
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])=[O:2].[O:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1[Mg]Br)[CH3:18]>C1COCC1>[OH:2][CH:1]([C:23]1[CH:24]=[C:19]([O:17][CH3:18])[CH:20]=[CH:21][C:22]=1[O:25][CH3:26])[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13]
Reactant: COc1ccc(OC)c([Mg]Br)c1
Reactant: N#Cc1cccc(-c2ccncc2C=O)c1
Solvent: C1CCOC1
Product: COc1ccc(OC)c(C(O)c2cnccc2-c2cccc(C#N)c2)c1

Procedure:
To a solution of 3-(3-formyl-pyridin-4-yl)-benzonitrile (15 mg, 0.075 mmol) in THF (1 mL) at −78° C. was added 0.5 M 2,5-dimethoxylphenylmagnesium bromide in THF (0.3 mL). The reaction mixture was quenched with ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash chromatography eluted with 5% methanol in dichloromethane to yield 3-{3-[hydroxy-(2,5-dimethoxy-phenyl)-methyl]-pyridin-4-yl}-benzonitrile as white crystals.
Reaction SMILES: C(OC[C:5]([CH2:27]OCC)([OH:26])[CH:6]([NH:18]C(OC(C)(C)C)=O)[CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)C.[ClH:31]>>[ClH:31].[NH2:18][C@H:6]1[CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]=2[C@H:27]([Cl:31])[C@@H:5]1[OH:26]
Reactant: CCOCC(O)(COCC)C(Cc1cccc2ccccc12)NC(=O)OC(C)(C)C
Agent: Cl
Product: N[C@H]1Cc2c(ccc3ccccc23)[C@H](Cl)[C@@H]1O
Temperature: 100 °C
Reaction time: 0.05 h

Procedure:
A suspension of α,α-diethoxymethyl-β-tert-butoxycarbonylamino-1-naphthalenepropanol (250 mg), isomer A was stirred in 37% aqueous hydrochloric acid at 0° C. for 1 hour. The resulting emulsion was then stirred at 100° C. for 3 minutes and the flask was immediately cooled in an ice water bath. The precipitate was filtered, washed with water and dried in vacuo to yield the title compound (152 mg) as a white solid.
Reaction SMILES: [CH:1]([NH:3][CH:4]([CH:11](O)[C:12](=[CH2:21])[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:2].S(Br)([Br:25])=O.O>ClCCl>[CH:1]([NH:3][CH:4]([CH:11]=[C:12]([CH2:21][Br:25])[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:2]
Reactant: O=S(Br)Br
Reactant: C=C(CCCC(=O)OCC)C(O)C(CC(=O)OCC)NC=O
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CCCC(=CC(CC(=O)OCC)NC=O)CBr
Reaction time: 1 h

Procedure:
10.3 g (35.9 mmol) of diethyl 2-formylamino-3-hydroxy-4-methylene-heptane-1,7-dicarboxylate are dissolved in 100 ml of dichloromethane and 3.34 ml (43.1 mmol) of thionyl bromide are added dropwise to the solution at room temperature. After 1 hour, 10 ml of water are added and the batch is thoroughly stirred. The organic phase is separated, washed in succession with water, saturated potassium hydrogencarbonate solution and again with water, dried over magnesium sulfate and concentrated by evaporation, giving diethyl 2-formylamino-4-bromomethyl-hept-3-ene-1,7-dicarboxylate as a brownish oil.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[S:10]2)[CH2:6][CH2:5]1)(=O)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([N:4]1[CH2:9][CH2:8][C:7]2([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[S:10]2)[CH2:6][CH2:5]1)[CH3:2]
Reactant: CC(=O)N1CCC2(CC1)SC(c1ccccc1)c1ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN1CCC2(CC1)SC(c1ccccc1)c1ccccc12

Procedure:
A solution of 1'-acetyl-1,3-dihydro-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine], Example 10, in tetrahydrofuran is treated carefully with a stirred suspension of lithium aluminum hydride in tetrahydrofuran to provide 1'-ethyl-1,3-dihydro-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine].
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:15]2([OH:19])[CH2:18][O:17][CH2:16]2)[N:5]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=1.C1C(=O)N([I:27])C(=O)C1>C(#N)C>[I:27][C:6]1[N:5]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:13])([CH3:14])[CH3:12])[C:4]([C:15]2([OH:19])[CH2:18][O:17][CH2:16]2)=[N:3][C:2]=1[CH3:1]
Reactant: Cc1cn(COCC[Si](C)(C)C)c(C2(O)COC2)n1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: Cc1nc(C2(O)COC2)n(COCC[Si](C)(C)C)c1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.8 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 3-(4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)oxetan-3-ol (compound 192.2, 200 mg, 0.70 mmol) in ACN (10 mL). NIS (237.7 mg, 1.06 mmol) was added to the reaction. The reaction mixture was stirred overnight at room temperature, then concentrated under reduced pressure. The reaction mixture was diluted with 40 mL of EtOAc. The organic layer was washed with 3×20 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (2:3) as eluent to furnish 100 mg (35%) of the title compound as an orange oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[N:11][N:12]=2)=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.[C:21]([C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)(=[O:23])[CH3:22]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]([C:21]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)([OH:23])[CH3:22])=[N:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccncc1
Reactant: Fc1ccc(-c2nnco2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)(c1ccncc1)c1nnc(-c2ccc(F)cc2)o1
Reaction time: 0.33 h
Yield: 4 %

Procedure:
To a stirred solution of 2-(4-fluorophenyl)-1,3,4-oxadiazole (0.8 g, 2.4 mmol) in THF (10 mL) was added LDA (2.9 mmol) at −78° C. (0.308 g, 2.9 mmol) and mixture was stirred for 20 min. A solution of 4-acetyl pyridine (0.377 g, 3.1 mmol) in THF (10 mL) was added at −78° C. and stirred for 2 h. The reaction mixture was quenched with saturated NH4Cl solution (50 mL), extracted with ethyl acetate (3×60 mL), washed with brine solution (60 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (100-200 mesh; using 90% ethyl acetate in hexanes) to obtain 1-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)-1-(pyridin-4-yl)ethanol as off-white solid (combined yield for 2 batches: 0.051 g, 4% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.58 (s, 2H), 7.99 (t, 2H), 7.48 (d, 2H), 7.04 (d, 2H), 6.98 (s, 1H), 1.94 (s, 3H); LC-MS m/z calculated for [M+H]+ 286.09, found 286.08.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5](/[C:11](=C\C2C=CC=CC=2)/[C:12]([NH2:14])=[O:13])[CH:6]=[C:7](OC)[CH:8]=1.[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)(Cl)Cl.[CH3:30][OH:31]>ClC1C=CC=CC=1>[OH:31][C:30]1[CH:4]=[C:3]([OH:2])[CH:8]=[C:7]2[C:6]=1[CH:5]=[CH:11][C:12](=[O:13])[NH:14]2
Reactant: CO
Reactant: COc1cc(OC)cc(/C(=C\c2ccccc2)C(N)=O)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=c1ccc2c(O)cc(O)cc2[nH]1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
A solution of compound 2 (19.0 g, 67.1 mmol) in chlorobenzene (120 mL) was taken in a 500 mL round bottom flask equipped with a mechanical stirrer and a reflux condenser. Aluminium chloride (44.6 g, 335.6 mmol) was added in portions over a period of 10 min. The reaction mixture was heated at 130° C. for 3 h and cooled to room temperature (TLC chloroform: methanol 9:1, Rf=0.2). Poured into crushed ice (1 Kg) and stirred at room temperature for further 30 min. The solid separated was filtered and washed with water till neutral to pH. The solid was then washed with hexane (2×50 mL) and dried at 100° C. for 1 h to furnish 5,7-dihydroxy-1,2-dihydro-2-quinolinone (3, 10 g) in 92% yield as a dark brown solid. M.P.>300° C. The quinolinone obtained was further characterised as its diacetate.
Reaction SMILES: Br[CH:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4].[SH:8][C:9]1[C:10]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:11]=2[S:12][C:13]=1[C:14]([NH2:16])=[O:15].C([O-])(O)=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C(OCC)(=O)C>[NH2:16][C:14]([C:13]1[S:12][C:11]2[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:10]=2[C:9]=1[S:8][CH2:7][CH2:2][C:3]([O:5][CH3:6])=[O:4])=[O:15]
Reactant: COc1ccc2sc(C(N)=O)c(S)c2c1
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)CCSc1c(C(N)=O)sc2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
Methyl bromopropionate (75 μL, 0.69 mmol) is added to a room temperature solution of 3-mercapto-5-methoxybenzo[b]thiophene-2-carboxamide (150 mg, 0.63 mmol) in 7 mL of THF followed by NaHCO3 (334 mg, 3.15 mmol). Additional methyl bromopropionate (150 μL) and Na2CO3 (70 mg) are added and the reaction mixture is stirred at room temperature overnight. The reaction mixture is diluted with ethyl acetate and washed with 1N HCl, water, 1N NaOH, water, and brine. The organic layer is dried over MgSO4. Filtration followed by concentration in vacuo and recrystallization from ethyl acetate: hexane followed by recrystallization from methanol: water gives methyl 3-[[2-(aminocarbonyl)-5-methoxybenzo[b]thien-3-yl]thio]propanoate in 46% yield; mp=142°-144° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:9]=1[CH2:10][OH:11].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:20]([O:7][C:8]1[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][C:9]=1[CH2:10][OH:11])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: OCc1cc(C(F)(F)F)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: OCc1cc(C(F)(F)F)ccc1OCc1ccccc1
Temperature: 50 °C
Yield: 100.1 %

Procedure:
Cesium carbonate (2.24 g, 6.9 mmol) was added to a solution of 2-hydroxy-5-trifluoromethyl-benzyl alcohol (885 mg, 4.6 mmol) and benzyl bromide (547 μL, 4.6 mmol) in anhydrous DMF (8 mL) at room temperature. The reaction was heated to 50° C. for 2 hours, cooled, diluted with ethyl acetate (25 mL) and washed with water (3×25 mL), brine (1×25 mL), and dried (Na2SO4), filtered and concentrated to afford 1.3 g of the title compound as a colorless solid. 1H NMR (400 MHz. CDCl3) δ 7.6-7.3 (m, 7H); 7.01 (d, 1H, J=9.1 Hz); 5.18 (s, 2H); 4.79 (s, 2H); 2.8 (bs, 1H).