Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18](Br)[CH:17]=1)[C:10]([CH3:25])([CH3:24])[CH2:9]2)=[O:5])[CH3:2].[C:26]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[C:18]([C:33]3[CH:34]=[CH:35][C:30]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:31][CH:32]=3)[CH:19]=[C:20]([F:22])[CH:21]=1)[C:10]([CH3:25])([CH3:24])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(F)cc(Br)c1)N2
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(F)cc(-c3ccc(C(C)(C)C)cc3)c1)N2
Temperature: 120 °C
Yield: 37 %

Procedure:
A mixture of 2-(3-bromo-5-fluoro-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.41 g, 1.0 mmol), 4-tert-butylbenzeneboronic acid (0.36 g, 2.0 mmol), bis(triphenylphosphine)palladium (II) chloride (70.2 mg, 0.1 mmol) and 2 M sodium carbonate (1.5 mL, 3.0 mmol) in dioxane (5 mL) was heated for 3 hours at 120° C. After cooling to room temperature, the mixture was treated with ethyl acetate (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company)(10% ethyl acetate/hexanes) to afford 2-(4′-tert-butyl-5-fluoro-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.17 g, 37%) as a white solid: LC/MS m/e calcd for C30H34FNO2 (M+H)+: 460.6, observed: 460.3.
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH:5]=O.[Cl-].[OH:15][NH3+:16].C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:1][CH:2]([CH3:13])[CH:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH:5]=[N:16][OH:15]
Reactant: CC(C)C=C(C=O)c1ccccc1
Reactant: [NH3+]O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)C=C(C=NO)c1ccccc1
Reaction time: 5 h
Yield: 58.3 %

Procedure:
To a solution of 4-methyl-2-phenyl-2-pentenal (5.0 g, 29 mmol) and hydroxylammonium chloride (2.5 g, 36 mmol) in a mixture of absolute ethanol (15 ml) and water (5 ml) was carefully added a solution of sodium carbonate (7.3 g, 69 mmol) in water (20 ml). After stirring for 5 h a precipitate was filtered off and dried in the air. The crude product was purified by column chromatography on silica gel (50 g, cyclohexane/ethyl acetate 3/1) to give 3.2 g of 4-methyl-2-phenyl-2-pentenal oxime as a solid. M.p. 107°-110° C.
Reaction SMILES: [I:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([NH2:9])[CH:3]=1.C(=O)(O)[O-].[Na+].Cl[CH:16]([CH:22]=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(COC)OC.ClCCl>[I:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:22][N:9]=[C:4]2[CH:3]=1
Reactant: Cc1cnc(N)cc1I
Reactant: CCOC(=O)C(Cl)C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: CCOC(=O)c1cnc2cc(I)c(C)cn12
Temperature: 100 °C

Procedure:
To a suspension of 4-iodo-5-methylpyridin-2-amine (I-28A) (1.55 g. 6.6 mmol), sodium bicarbonate (0.67 g, 7.9 mmol) in dry dimethoxyethane (10 mL) at room temperature, ethyl 2-chloro-3-oxopropanoate (1 g, 6.41 mmol) in dimethoxyethane (1 mL) was added dropwise. The reaction mixture was heated to 100° C. for 1 h and then cooled to room temperature and diluted with dichloromethane (50 mL). The organic layer was washed with water, brine, dried over sodium sulfate and concentrated in vacuo. The brown crude oil was purified by silica gel chromatography with a gradient of 0-15% ethyl acetate/hexanes to yield ethyl 7-iodo-6-methylimidazo[1,2-a]pyridine-3-carboxylate (I-28B) as light tan solid. 1H-NMR (400 MHz, DMSO) δ 9.11 (s, 1H), 8.41 (s, 1H), 8.22 (s, 1H), 4.36 (q, J=7.2 Hz, 2H), 2.42 (s, 3H), 1.37 (t, J=7.2 Hz, 3H). MS m/z 331.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]2[C:7]3([O:31][CH2:32][C:33]([F:35])([F:34])[C:4]=2[CH:3]=1)[CH2:12][CH2:11][N:10]([CH2:13][C:14]1[C:15]([C:26](OCC)=[O:27])=[N:16][N:17]([C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:18]=1)[CH2:9][CH2:8]3.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.CCCCCC>O1CCCC1.C(OC)(C)(C)C>[Cl:1][C:2]1[S:6][C:5]2[C:7]3([O:31][CH2:32][C:33]([F:35])([F:34])[C:4]=2[CH:3]=1)[CH2:8][CH2:9][N:10]([CH2:13][C:14]1[C:15]([CH2:26][OH:27])=[N:16][N:17]([C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:18]=1)[CH2:11][CH2:12]3
Reactant: CCOC(=O)c1nn(-c2ncccc2F)cc1CN1CCC2(CC1)OCC(F)(F)c1cc(Cl)sc12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: OCc1nn(-c2ncccc2F)cc1CN1CCC2(CC1)OCC(F)(F)c1cc(Cl)sc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.7 %

Procedure:
To a solution of ethyl 4-[(2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4′-piperidine]-1′-yl)methyl]-1-(3-fluoro-2-pyridyl)pyrazole-3-carboxylate (2.6 g, 4.93 mmoles) in Tetrahydrofuran (26.00 mL) under N2 atmosphere and cooled to −10 C, Diisobutylaluminum Hydride 1M in toluene (23.68 mL, 23.68 mmoles) is added slowly dropwise. Then, reaction mixture is stirred at that T 15 min and then, the cold bath is removed and the mixture is warmed to room temperature. Then, H2O (100 mL) is added dropwise at −10° C. The resulting suspension is extracted with EtOAc (2×30 mL). Combined organics are washed with H2O (50 mL) and brine (50 mL), dried over Na2SO4 and concentrated to afford a light brown oil that is dissolved in methyl t-butyl ether (10 mL) and white crystals crystallized. Suspension formed is stirred and hexane (10 mL) is added dropwise while stirring. Solid is filtered to give 2 g of the title compound. MS (m/z): 485 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2.[C:17]1([SH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:17]1([S:23][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]3)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1CCc2cc(OCCCBr)ccc2N1
Reactant: Sc1ccccc1
Product: O=C1CCc2cc(OCCCSc3ccccc3)ccc2N1

Procedure:
Prepared analogous to Example 1 from 6-(3-bromopropoxy)-3,4-dihydro-carbostyril (m.p. 111°-118° C.) and thiophenol.
Reaction SMILES: C1COCC1.[CH:6]1([O:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1>Cl>[CH:6]1([O:11][C:12]2[CH:13]=[CH:14][C:15]([CH2:16][NH2:17])=[CH:18][CH:19]=2)[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: N#Cc1ccc(OC2CCCC2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: NCc1ccc(OC2CCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.9 %

Procedure:
Add a solution of 1M BH3-THF complex in THF (4.8 mL, 4.8 mmol) to neat 4-cyclopentyloxy-benzonitrile (300 mg, 1.6 mmol) and stir the mixture for 3 h at room temperature and then for 3 h at reflux. Cool to room temperature, pour the reaction into 2N aqueous HCl (10 mL) and stir the mixture for 1 h at room temperature then concentrate in vacuo. Dissolve the crude mixture in methanol and filter through SCX column eluting with methanol followed by 3M ammonia in methanol to obtain the title compound (223 mg, 73%).
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[F:16])[N:3]=1.[O:17]1[CH2:21][CH2:20][C@@H:19]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C@@H:29]3[O:34][CH2:33][CH2:32][NH:31][CH2:30]3)=[CH:25][CH:24]=2)[CH2:18]1.C(N(CC)CC)C>O1CCCC1>[O:17]1[CH2:21][CH2:20][C@@H:19]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C@@H:29]3[O:34][CH2:33][CH2:32][N:31]([C:2]4[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]5[CH:15]=[CH:14][N:13]=[CH:12][C:11]=5[F:16])[N:3]=4)[CH2:30]3)=[CH:27][CH:28]=2)[CH2:18]1
Reactant: Cn1c(Cl)nc(-c2ccncc2F)cc1=O
Reactant: c1cc([C@H]2CNCCO2)ccc1N[C@@H]1CCOC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(N2CCO[C@@H](c3ccc(N[C@@H]4CCOC4)cc3)C2)nc(-c2ccncc2F)cc1=O
Temperature: 95 °C
Reaction time: 3 h
Yield: 47 %

Procedure:
A solution of 2-chloro-6-(3-fluoropyridin-4-yl)-3-methyl-3H-pyrimidin-4-one (0.08 g, 0.35 mmol), (2S)-2-(4-(N-((3R)-tetrahydrofuran-3-yl)amino)phenyl)morpholine obtained in Reference Example 7 (0.11 g, 0.44 mmol) and triethylamine (0.22 g, 2.2 mmol) in tetrahydrofuran (10 ml) was stirred at 95° C. for 3 hours. The mixture was partitioned between water and dichloromethane, and the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting 5-10% methanol in chloroform to furnish 2-((2S)-2-(4-(N-((3R)-tetrahydrofuran-3-yl)amino)phenyl)-morpholin-4-yl)-3-methyl-6-(3-fluoropyridin-4-yl)-3H-pyrimidin-4-one (0.07 g, 47%) as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]2[CH:9]([C:10]([OH:12])=[O:11])[C:8]2([CH3:14])[CH3:13])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[O:21]([C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31]O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C=O)C.C1C=CC=CC=1.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH:9]([C:10]([O:12][CH2:31][C:30]3[CH:33]=[CH:34][CH:35]=[C:28]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:29]=3)=[O:11])[C:8]2([CH3:13])[CH3:14])=[CH:15][CH:16]=1
Reactant: OCc1cccc(Oc2ccccc2)c1
Reactant: CC1(C)C(Oc2ccc(Cl)cc2)C1C(=O)O
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccccc1
Product: CC1(C)C(Oc2ccc(Cl)cc2)C1C(=O)OCc1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 3-(4-chlorophenoxy)-2,2-dimethylcyclopropanecarboxylic acid (0.95 g, 3,95 mmol), thionyl chloride (0.342 ml, 4.74 mmol) and DMF (several drops) in 50 ml benzene is stirred at RT for 2 days. The solvent and excess thionyl chloride are evaporated under reduced pressure. The resulting acid chloride is dissolved in 50 ml benzene, and 0.79 g m-phenoxybenzyl alcohol (3.95 mmol) and 0.482 g 4-dimethylaminopyridine (3.95 mmol) are added. The mixture is left at 25° for 18 hr and then heated under reflux for 2 hr. The mixture is then poured into water and extracted with ether. The organic phase is washed with dilute HCl, sat.NaHC3, water and brine, dried and concentrated under vacuum. The crude product is purified by preparative TLC developing with 20% ethyl acetate/hexane to yield m-phenoxybenzyl 3-(4-chlorophenoxy)-2,2-dimethylcyclopropanecarboxylate, MS m/e 422 [M+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10]1.O=CCCCNC(=O)C1C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH:17]=[O:18])[CH2:13][CH2:14]1
Reactant: COc1ccccc1N1CCN(CCCO)CC1
Agent: O=CCCCNC(=O)c1ccccc1
Product: COc1ccccc1N1CCN(CCC=O)CC1

Procedure:
3-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-propionaldehyde (29B) is prepared from 29A as described for 1E.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]2[O:13][CH2:12][O:11][C:10]=12)[CH:6]=[O:7].[CH2:14]([Mg]Br)[CH3:15].Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6](=[O:7])[CH2:14][CH3:15])[CH:8]=[C:9]2[O:13][CH2:12][O:11][C:10]=12
Reactant: COc1cc(C=O)cc2c1OCO2
Reactant: CC[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CCC(=O)c1cc(OC)c2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-Methoxy-4,5-methylenedioxybenzaldehyde (5.55 g) was dissolved in tetrahydrofuran (150 ml), and ethylmagnesium bromide (IM tetrahydrofuran solution, 46.2 ml) was added thereto, followed by stirring at room temperature for 30 minutes. 1N Hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water, a 5% aqueous solution of sodium bicarbonate and a saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in acetone (300 ml), and Jones' reagent (5.3 ml) was added thereto under ice-cooling, followed by stirring at the same temperature for 30 minutes. 2-Propanol (5.3 ml) was added to the reaction solution and the mixture was concentrated under reduced pressure. The residue was subjected to partitioning between ethyl acetate and water. The organic layer was washed successively with water and a saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3'-methoxy-4',5'-methylenedioxypropiophenone (5.27 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16]([OH:18])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:21](CC)CC)C.C(OC(Cl)=O)C(C)C.N>C1COCC1.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16](=[O:18])[NH2:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCC(OCC(=O)O)CC1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(OCC(N)=O)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-carboxymethoxypiperidine-1-carboxylic acid tert-butyl ester (Preparation 1, 14.13 g, 54.7 mmol) and triethylamine (7.68 ml, 65.6 mmol) in anhydrous THF (250 ml) was cooled to 0° C. and isobutylchloroformate (8.51 ml, 65.6 mmol) introduced dropwise. After stirring at 0° C. for 30 min, the reaction mixture was cooled to −20° C. and added rapidly via cannula to a solution of 0.7M ammonia in anhydrous CH2Cl2 (250 ml, 180 mmol) at −70° C. The reaction was allowed to warm to rt and stirred for 1 h. The mixture was diluted with CH2Cl2 (250 ml) and washed with saturated aqueous NaHCO3 (200 ml), 0.5M HCl (200 ml) and brine (200 ml) then dried (MgSO4). The solvent was evaporated and the residue purified by flash chromatography IH-THF 3:7) to afford the title compound: δH (CDCl3) 1.49 (9H, s), 1.53-1.60 (2H, m), 1.85-1.92 (2H, m), 3.11 (2H, m), 3.58 (1H, m), 3.76-3.83 (2H, m), 3.98 (2H, s), 6.19 (1H, bs), 6.56 (1H, bs).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9].[Cl:22]Cl.O>C(O)(=O)C>[Cl:22][C:11]1[CH:12]=[CH:13][C:5]([O:4][C:3]2[CH:14]=[CH:15][C:16]([C:18]([F:20])([F:19])[F:21])=[CH:17][C:2]=2[Cl:1])=[CH:6][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Reactant: ClCl
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1Cl
Reaction time: 5 h

Procedure:
A solution of 3(2-chloro-4-trifluoromethylphenoxy)benzoic acid (5 g) in glacial acetic acid (30 ml) was heated under reflux while chlorine was passed through the solution for 5 hours. The solution was left to stand for two days at room temperature and then poured into cold water (500 ml). An off-white gummy solid separated. This was extracted with ethyl acetate and the extract dried and evaporated. The brown oil remaining was dissolved in sodium bicarbonate solution and the solution extracted with ethyl acetate. The aqueous solution was acidified with hydrochloric acid. The solution was decanted from the precipitated gum, and the gum taken up in boiling hexane. The hexane solution was filtered and allowed to cool. The required 2-chloro-5(2-chloro-4-trifluoromethylphenoxy)benzoic acid was obtained (1.0 g) as crystals of melting point 103°-104°. This acid was used as starting material for compounds 7 and 8.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[F:11][C:12]1[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[C:16](B(O)O)[CH:17]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(OCC)(=O)C>O1CCCC1.O.C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=[Pd-2](Cl)CC=CC1C=CC=CC=1)(C)C>[F:11][C:12]1[CH:17]=[CH:16][C:15]([O:21][CH3:22])=[C:14]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[NH:8][CH:9]=[CH:10][C:3]=23)[CH:13]=1
Reactant: COc1ccc(F)cc1B(O)O
Reactant: Clc1ccnc2[nH]ccc12
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd-2](Cl)CC=Cc1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(F)cc1-c1ccnc2[nH]ccc12
Temperature: 65 °C
Reaction time: 0.25 h

Procedure:
A solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine (15 g, 98 mmol), (5-fluoro-2-methoxyphenyl)boronic acid (18.38 g, 108 mmol), potassium phosphate (62.6 g, 295 mmol), and {1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene}chloro {3-phenylallyl}palladium(II) (0.637 g, 0.983 mmol) in tetrahydrofuran (400 mL) and water (133 mL) was purged with nitrogen and heated at 65° C. overnight. The mixture was cooled and poured into water. Ethyl acetate was added, the mixture was stirred for 15 minutes and the organic layer was washed with brine. The combined aqueous extracts were extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in dichloromethane and placed on a bed of silica gel equilibrated in 30% ethyl acetate/heptanes that was packed in a coarse Buchner funnel. The material was eluted with 30-40% ethyl acetate/heptanes to provide the title compound. MS (ESI+) m/z 243.2 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(=O)([O-])O.[Na+].[CH2:19](Br)[CH:20]=[CH2:21]>O>[CH2:21]([S:11]([C:8]1[CH:7]=[CH:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:10][CH:9]=1)(=[O:13])=[O:12])[CH:20]=[CH2:19]
Reactant: CC(=O)Nc1ccc(S(=O)O)cc1
Reactant: C=CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: C=CCS(=O)(=O)c1ccc(NC(C)=O)cc1
Reaction time: 4 h

Procedure:
50 Parts of p-acetylaminophenylsulfinic acid and 25 parts of sodium hydrogen carbonate are suspended in 300 parts of water. While stirring intensely 36 parts of allyl bromide is dripped in within 3 hours at 50° to 60° C. Stirring is continued for another 4 hours at 60° C. 45 parts of p-allylsulfonylacetanilide is obtained with a melting point of 116° to 118° C.
Reaction SMILES: [C:1]1([C:7]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:11][C:10]3[CH:12]=[CH:13][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:15][C:9]=3[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[C:1]1([C:7]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:11][C:10]3[CH:12]=[CH:13][C:14]([S:16]([N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)(=[O:18])=[O:17])=[CH:15][C:9]=3[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2)N1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.2 %

Procedure:
2,2-diphenyl-benzo[1,3]dioxole-5-sulfonyl chloride (3.36 g, 9 mmol) was dissolved in methylene chloride (135 ml). Piperidine (1.33 ml, 13.5 mmol) and ethyldiisopropyl amine (2.3 ml, 13.5 mmol) were added at room temperature. The reaction was stirred at room temperature overnight and washed twice with 1N aqueous HCl solution, twice with 1N aqueous NaOH solution and once with brine. The organic layer was dried over sodium sulfate and filtered. The solvent was evaporated and the residue was purified by column chromatography (4/1 hexane/ethyl acetate eluant). The product was suspended in diethyl ether and filtered to yield a white crystalline solid (1.98 g, 52%). m.p.: 163-164° C.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][C:13]23[CH2:27][CH:20]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=42)[C:19]2[C:14]3=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:7]1)=O)C>C(O)C.[OH-].[Na+].O>[NH:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][C:13]23[CH2:27][CH:20]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=42)[C:19]2[C:14]3=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:7]1
Reactant: CCOC(=O)N1CCOC(CC23CC(c4ccccc42)c2ccccc23)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: c1ccc2c(c1)C1CC2(CC2CNCCO2)c2ccccc21

Procedure:
A mixture of 9-(4-ethoxycarbonyl-2-morpholinylmethyl)-9,10-dihydro-9,10-methanoanthracene (400 mg) in ethanol (6 ml) and 25% aqueous sodium hydroxide solution (6 ml) was refluxed for 6 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to give 9-(2-morpholinylmethyl)-9,10-dihydro-9,10-methanoanthracene, M.P. 189° - 190° C.
Reaction SMILES: [OH:1][C:2]1([C:5]([OH:7])=O)[CH2:4][CH2:3]1.S(Cl)(Cl)=O.[C:12]1([S:18]([C:21]2[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C>CC(N(C)C)=O>[C:12]1([S:18]([C:21]2[CH:22]=[CH:23][C:24]([NH:25][C:5]([C:2]3([OH:1])[CH2:4][CH2:3]3)=[O:7])=[CH:26][CH:27]=2)(=[O:19])=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccc(S(=O)(=O)c2ccccc2)cc1
Reactant: O=C(O)C1(O)CC1
Agent: C
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: O=C(Nc1ccc(S(=O)(=O)c2ccccc2)cc1)C1(O)CC1
Temperature: -15 °C
Reaction time: 1 h

Procedure:
A solution of 1-hydroxycyclopropanecaboxylic acid (0.66 g, 6.44 mmol) in dry dimethylacetamide (10 ml) was stirred under a nitrogen atmosphere at -15° C. Thionyl chloride (0.77 g, 6.44 mmol) was added and the resulting mixture was allowed to stir at -15° C. for 1 hour. 4-Phenylsulfonylaniline (1.0 g, 4.29 mmol) was then added and the reaction mixture was stirred at -15° C. for a further 15 mins. The solution was then allowed to warm to room temperature where it was stirred overnight. The reaction mixture was poured onto ice, extracted with ethyl acetate, and the combined ethyl acetate portions were washed with 1M HCl. After drying (MgSO4) the ethyl acetate was removed by evaporation to give a buff-colored solid. Crystallization of this material from ethyl acetate/hexane yielded the title tertiary carbinol, (0.82 g, 60%) as a white solid; mp=214.5°-216° C. 1H-NMR (250 MHz, d6 -DMSO): 0.98 (m, 2H, 2 CH2), 1.15 (m, 2H, CH2), 6.63 (s, 1H, OH), 7.65 (m, 3H, ArH), 7.95 (m, 6H, ArH), 10.29 (s, 1H, NH). MS (CI, CH4): 318(M+1, 100).
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([F:10])[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].C(N)(=[O:14])C.C1COCC1>[Pd](Cl)Cl.O.CCCCCC.CCOC(C)=O>[Cl:1][C:2]1[N:9]=[C:8]([F:10])[C:7]([F:11])=[CH:6][C:3]=1[C:4]([NH2:5])=[O:14]
Reactant: N#Cc1cc(F)c(F)nc1Cl
Reactant: CC(N)=O
Agent: Cl[Pd]Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)c1cc(F)c(F)nc1Cl
Temperature: 25 °C
Yield: 83.1 %

Procedure:
To a mixture of 2-chloro-5,6-difluoronicotinonitrile (89.66 g, 514 mmol), acetamide (66.8 g, 1130 mmol), THF (337.5 mL), and water (113 mL) was added palladium(II) chloride (1.822 g, 10.27 mmol) with stirring. The reaction mixture was stirred at 60° C. for 18 hours under a nitrogen atmosphere. The reaction mixture was subsequently cooled to room temperature and was added to a stirred mixture of EtOAc (900 mL), hexane (90 mL) and water (180 mL). The layers were allowed to separate and the aqueous layer was removed. The organic layer was washed with water (180 mL) and concentrated on a rotary evaporator at 29° C. to afford an oil that solidified. The solid was suspended in hexanes (270 mL) and filtered after 1 hour. The flask was rinsed forward with hexanes (50 mL). The filter cake was washed with additional hexanes (20 mL) and dried in a vacuum oven at 40° C. to give the title compound as a light tan solid (82.21 g, 83%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.93 (s br, 1H), 8.10 (s br, 1H), 8.32-8.37 (m 1H).