Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][OH:10])[CH:4]=1.Cl[C:12]1[C:13]([NH2:20])=[N:14][C:15]([Cl:19])=[C:16]([Cl:18])[N:17]=1.Cl>COCOC.O>[Cl:18][C:16]1[N:17]=[C:12]([O:10][CH2:9][C:5]2[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=2)[C:13]([NH2:20])=[N:14][C:15]=1[Cl:19]
Reactant: Nc1nc(Cl)c(Cl)nc1Cl
Reactant: OCc1cccnc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCOC
Solvent: O
Product: Nc1nc(Cl)c(Cl)nc1OCc1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.7 %

Procedure:
To a stirred suspension of sodium hydride (1.20 g of a 60% dispersion in oil) in dry dimethoxymethane (40 mL) was added pyridine-3-methanol (2.18 g) in 1,2-dimethoxymethane (10 mL). The resulting suspension was stirred at room temperature for 0.5 h and then 3,5,6-trichloro-2-aminopyrazine (1.2 g) was added and the mixture stirred at 70° C. for 4 h. The reaction mixture was cooled and cautiously added to water (100 mL) and neutralised with 2M hydrochloric acid. The mixture was extracted with ethyl acetate (2×50 mL), dried (MgSO4), filtered and concentrated. The residue was purified by chromatography on silical gel eluting with ethyl acetate to afford the sub-titled compound as a white solid (0.29 g).
Reaction SMILES: [C:1]1(=O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=O.COP([CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=1[C:27]([F:30])([F:29])[F:28])=O)(=O)OC.O.[NH2:32][NH2:33]>>[F:26][C:22]1[C:21]([C:27]([F:30])([F:29])[F:28])=[C:20]([C:18]2[N:33]=[N:32][C:2]3[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:1]=3[CH:17]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: COP(=O)(CC(=O)c1cccc(F)c1C(F)(F)F)OC
Reactant: O=C1CCCCCCC1=O
Reactant: NN
Solvent: O
Product: Fc1cccc(-c2cc3c(nn2)CCCCCC3)c1C(F)(F)F

Procedure:
MS (EI): 324.2 (M+), light-yellow solid. Prepared from cyclooctane-1,2-dione, [2-(3-Fluoro-2-trifluoromethyl-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13]Br)=[CH:6][C:5]=1[NH:15][C:16](=[O:28])[C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1.[C:30]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:35]=[CH:34][C:33]([CH:36]=[N:37][OH:38])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:38]/[N:37]=[CH:36]/[C:33]2[CH:34]=[CH:35][C:30]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)=[CH:31][CH:32]=2)=[CH:6][C:5]=1[NH:15][C:16](=[O:28])[C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc(OCCCBr)cc1NC(=O)c1ccc(OC(F)(F)F)cc1
Reactant: ON=Cc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCCO/N=C/c2ccc(-c3ccccc3)cc2)cc1NC(=O)c1ccc(OC(F)(F)F)cc1
Yield: 80 %

Procedure:
This compound was produced using similar methods as those used in Step 5, example 27, starting with 4-(3-bromo-propoxy)-2-(4-trifluoromethoxy-benzoylamino)-benzoic acid methyl ester (0.46 g, 0.97 mmol), biphenyl-4-carbaldehyde oxime (0.20 g, 1.01 mmol) and cesium carbonate (1.26 g, 3.86 mmol) in acetone (35 mL). The crude material was purified by flash chromatography through silica gel using diethyl ether/hexanes (0/100 gradient to 12/88) to give 4-[3-({[(1E)-1,1′-biphenyl-4-ylmethylidene]amino}oxy)propoxy]-2-{[4-(trifluoromethoxy)benzoyl]amino}benzoic acid methyl ester (0.46 g, 80%) as a white solid. 1H NMR (500 MHz, DMSO-d6); δ 11.93 (s, 1H), 8.34 (d, 1H), 8.31 (s, 1H), 8.06 (d, 2H), 7.99 (d, 1H), 7.70-7.66 (m, 6H), 7.60 (d, 1H), 7.46 (t, 2H), 7.38 (t, 1H), 6.85 (dd, 1H), 4.31 (t, 2H), 4.23 (t, 2H), 3.87 (s, 3H), 2.18 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[S:8][CH:9]=[C:10](C(OCC)=[O:12])[C:3]=12.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][NH2:24])=[CH:19][CH:18]=1.C[CH2:26][O:27]CC.[OH-].[Na+]>C(O)CCC.O>[OH2:12].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:26](=[O:27])[C:7]3[C:2]([C:3]4[CH:10]=[CH:9][S:8][C:4]=4[NH:5][CH:6]=3)=[N:24]2)=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1csc2nccc(Cl)c12
Reactant: NNc1ccc(Cl)cc1
Reactant: CCOCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCCO
Product: O=c1c2c[nH]c3sccc3c-2nn1-c1ccc(Cl)cc1

Procedure:
A mixture of 3.2 g of ethyl 4-chloro-thieno[2,3-b]pyridine-3-carboxylate (prepared according to J. Heterocyclic Chem., 1977, 14, 807) and 2.08 g of 4-chlorophenylhydrazine in 50 ml of n-butanol is refluxed for 48 hours. The reaction mixture is cooled in an ice bath and the resulting precipitate is collected, washed with a small amount of n-butanol to yield a solid. The solid is treated with ether and 1N sodium hydroxide (20 ml) and water (50 ml). The aqueous phase is washed with ether, then neutralized with ammonium chloride (2 g) to precipitate a yellow solid. The solid is collected, washed with water and dried to yield 2-(4-chlorophenyl)-thieno[2,3-b]pyrazolo[3,4-d]pyridin-3(5H)-one hydrate, m.p. 310°-313°.
Reaction SMILES: [Na].Cl[C:3]1[C:12]2[C:7](=[C:8]([N+:13]([O-:15])=[O:14])[CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1.[CH3:16][OH:17]>>[CH3:16][O:17][C:3]1[C:12]2[C:7](=[C:8]([N+:13]([O-:15])=[O:14])[CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1
Reactant: CO
Reactant: O=[N+]([O-])c1cccc2c(Cl)nccc12
Agent: [Na]
Product: COc1nccc2c([N+](=O)[O-])cccc12

Procedure:
To a solution of 1.0 g of sodium (43.4 mmol) in methanol was added 1.42 g (6.8 mmol) of 1-chloro-5-nitroisoquinoline. The mixture was heated under reflux for three hours, cooled, and concentrated. The residue was partitioned between water and methylene chloride, dried, and filtered through SiO2. The filtrate was concentrated to give 1.3 g of the 1-methoxy-5-nitroisoquinoline. This material was suspended in 150 ml of methanol, 0.3 g of 5% Pd-C was added, and the mixture was hydrogenated at room temperature for 18 hours. The mixture was filtered and concentrated. The residue was crystallized from ether/hexane to give 0.32 g (27%) of the desired product; mp 53°-57°.
Reaction SMILES: [C:1]([O:4][CH:5]1[N:8]([C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[O:10])[C:7](=[O:15])[CH:6]1[CH2:16][CH2:17][CH2:18][NH:19][C:20]([NH:32]C(OCC1C=CC=CC=1)=O)=[N:21]C(OCC1C=CC=CC=1)=O)(=[O:3])[CH3:2].[ClH:43]>[Pd].CO.C(OCC)(=O)C>[ClH:43].[C:1]([O:4][CH:5]1[N:8]([C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[O:10])[C:7](=[O:15])[CH:6]1[CH2:16][CH2:17][CH2:18][NH:19][C:20]([NH2:32])=[NH:21])(=[O:3])[CH3:2]
Reactant: CC(=O)OC1C(CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)C(=O)N1C(=O)C(C)(C)C
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)OC1C(CCCNC(=N)N)C(=O)N1C(=O)C(C)(C)C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
A methanol/ethyl acetate solution of compound 41 (300 mg, 0.5 mmol) and 1N HCl (0.52 mL), containing 10% palladium on carbon, was stirred under a hydrogen atmosphere for 30 min. The suspension was filtered through a pad of Celite, and the filtrate was concentrated to afford 0.1 g (64%) of the title product as a mixture of trans and cis (3:2) isomers.
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=CC=C[CH:2]=1.C(O)C=C.[C:24]([O:28][C:29](=[O:57])[CH:30]([NH:45][S:46]([C:49]1[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=1)(=[O:48])=[O:47])[CH:31]([CH2:42][CH:43]=[CH2:44])[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])([CH3:27])([CH3:26])[CH3:25]>O1CCCC1>[C:24]([O:28][C:29](=[O:57])[CH:30]([N:45]([CH2:6][CH:1]=[CH2:2])[S:46]([C:49]1[CH:50]=[CH:51][C:52]([O:55][CH3:56])=[CH:53][CH:54]=1)(=[O:48])=[O:47])[CH:31]([CH2:42][CH:43]=[CH2:44])[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])([CH3:27])([CH3:25])[CH3:26]
Reactant: C=CCC(C(=O)OCc1ccccc1)C(NS(=O)(=O)c1ccc(OC)cc1)C(=O)OC(C)(C)C
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C=CCO
Solvent: C1CCOC1
Product: C=CCC(C(=O)OCc1ccccc1)C(C(=O)OC(C)(C)C)N(CC=C)S(=O)(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Triphenylphosphine (1 g, 3.9 mmol) are solved in 60 ml Tetrahydrofuran (THF) and cooled to 0° C. Diazopropyl dicarboxylate (DIAD) (0.77 ml, 3.9 mmol) are added via syringe and the reaction mixture is stirred for 30 min. Allyl alcohol (16 μl, 0.23 mmol) is added to the yellow suspension and then after 10 min., 2-Allyl-3-(4-methoxy-benzenesulfonylamino)-succinic acid 1-benzyl ester 4-tert-butyl ester (1.4 g, 2.6 mmol) is added. The reaction mixture is stirred for 30 min. at 0° C. and is then allowed to warm to room temp. After evaporation of most of the THF and flash-chromatography with Hexane/Ethylacetate (2:1) the desired product is obtained: 1H NMR (CDCl3 400 MHz), ppm: 7.80 (d, 2H), 7.38 (m, 5H), 6.95 (d, 2H), 5.75 (m, 2H), 5.10 (m, 6H), 3.95 (m, 2H), 3.90 (s, 3H), 3.21 (ddd, 1H), 2.50 (ddd, 1H), 2.35 (ddd, 1H), 1.40 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:11]=1[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19].[CH:22]1([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]OS(C)(=O)=O)[CH:33]=2)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH:22]1([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][S:16][C:13]3[CH:14]=[CH:15][C:10]([C:3]4[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=4[F:1])=[C:11]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=3)[CH:33]=2)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:24][CH2:23]1
Reactant: CCOC(=O)CC(c1cccc(COS(C)(=O)=O)c1)C1CC1
Reactant: COc1ccc(F)c(-c2ccc(S)cc2CC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC(c1cccc(CSc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
To a solution of 2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-thiol (161 mg) in DMF (2.6 mL) were added ethyl 3-cyclopropyl-3-(3-(((methylsulfonyl)oxy)methyl)phenyl)propanoate (207 mg) and potassium carbonate (146 mg) at room temperature, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was poured into water at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (267 mg) as a colorless oil.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:7][C:6]=1[CH2:18][N:19](CC1C=CC(OC)=CC=1OC)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])C.CCC([O-])(C)C.[K+].S(Cl)(Cl)=O>C1COCC1.C(Cl)Cl>[CH2:24]([O:23][C:21]([C:20]1[N:19]=[CH:18][C:6]2[C:5]([C:4]=1[OH:3])=[CH:10][CH:9]=[C:8]([O:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH:7]=2)=[O:22])[CH3:25]
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1cc(Oc2cccnc2)ccc1C(=O)OCC
Agent: CCC(C)(C)[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)c1ncc2cc(Oc3cccnc3)ccc2c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
To an ice-water bath cooled solution of 2-{[(2,4-dimethoxy-benzyl)-ethoxycarbonylmethyl-amino]-methyl}-4-(pyridin-3-yloxy)-benzoic acid ethyl ester (1.71 g) in THF (30 mL) was added a solution of potassium tert-pentoxide (3.36 mL, 1.7 M in toluene); the mixture was stirred for 60 min at rt after addition; then the mixture was quenched with 2 M HCl, diluted with EtOAc and water, EtOAc phase was separated and washed with water, diluted NaCl solution and dried over anhydrous sodium sulphate, filtered off, concentrated to give the desired cyclized intermediate. This intermediate was then dissolved in DCM (30 mL) and treated with thionyl chloride (0.47 mL) overnight. Then concentrated, the residue was dissolved in EtOAc, washed with water, diluted NaCl solution, then dried over sodium sulphate, filtered, concentrated and the residue was column purified to give the desired product (673 mg). LC MS ESI: 311 (M+1)+.
Reaction SMILES: [C:1]([CH:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:4](=[O:10])[C:5]([O:7]CC)=O)#[N:2].[C:17]1([CH2:23][C:24]#[N:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[O-]CC.[Na+].[Na]>C(O)(=O)C.O>[C:17]1([CH:23]([C:5](=[O:7])[C:4](=[O:10])[CH:3]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:1]#[N:2])[C:24]#[N:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N#CCc1ccccc1
Reactant: CCOC(=O)C(=O)C(C#N)c1ccccc1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Product: N#CC(C(=O)C(=O)C(C#N)c1ccccc1)c1ccccc1

Procedure:
Ethyl 3-cyano-3-phenylpyruvate (50.0 g., 0.23 mol.) and 41.0 g. (0.35 mol.) of phenylacetonitrile were added to an alcoholic solution of sodium ethoxide [prepared from 13.4 g. (0.58 g. -atom) of sodium and 360 ml. of absolute ethanol] and the resulting yellow solution was refluxed for 1.75 hours. The cooled solution was diluted with 700 ml. of water and acidified by slow addition of acetic acid. After further cooling in ice, the suspension was filtered and the solid was washed with water and dried to give 2,5-diphenyl-3,4-dioxoadiponitrile, m.p. 284°-286° (dec.).
Reaction SMILES: [C:1]([O:5][C:6](/[C:8](=[CH:13]\[C:14]1[CH:24]=[CH:23][C:17]2[O:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=2[CH:15]=1)/[C:9]([O:11][CH3:12])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO>[C:1]([O:5][C:6]([C@@H:8]([CH2:13][C:14]1[CH:24]=[CH:23][C:17]2[O:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=2[CH:15]=1)[C:9]([O:11][CH3:12])=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)/C(=C/c1ccc2c(c1)OC(C)(C)O2)C(=O)OC(C)(C)C
Solvent: CO
Product: COC(=O)[C@H](Cc1ccc2c(c1)OC(C)(C)O2)C(=O)OC(C)(C)C
Yield: 103.9 %

Procedure:
To a slurry of (Z)-methyl 2-(tert-butoxycarbonyl)-3-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)acrylate (5000 mg, 14311 μmol) in 30 mL of MeOH was added [Rh(duanphos)cod]BF4 (101.1 mg, 143.1 μmol) followed by an additional 15 mL of methanol. The mixture was purged with hydrogen 3 times and then sealed at 50 psi of H2. After 3 hours reaction the reaction was concentrated and purified by silica gel chromatography to provide (S)-methyl 2-(tert-butoxycarbonyl)-3-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)propanoate (5000 mg, 99.43% yield) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]#N)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[OH-:13].[Na+].Cl.C[OH:17].O>>[F:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:17])=[O:13])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: CO
Reactant: COc1cc(F)cc(CC#N)c1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1cc(F)cc(CC(=O)O)c1
Temperature: 65 °C
Reaction time: 4 h

Procedure:
To a solution of 2-(3-fluoro-5-methoxyphenyl)acetonitrile (2.62 g, 16 mmol) in MeOH:H2O (1:1; 15 mL), NaOH (1.28 g, 32 mmol) was added. Then the mixture was stirred at 65° C. for 4 h. The mixture was cooled to room temperature, and 4M aqueous HCl solution was added until the pH was adjusted to 4-5. The mixture was filtered and the solid obtained was washed with H2O (2×5 mL) to give 2.33 g of 2-(3-fluoro-5-methoxyphenyl)acetic acid. 1H NMR (CDCl3): δ 6.52-6.62 (m, 3H), 3.78 (s, 3H), 3.59 (s, 2H).
Reaction SMILES: [CH3:1][N:2]([CH:4]([CH:7]1[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9][CH2:8]1)[C:5]#N)[CH3:3].[S:17]1C=[CH:20][CH:19]=[C:18]1[Mg]Br.[Cl-].[NH4+].O>C1COCC1>[O:14]1[C:10]2([CH2:15][CH2:16][CH:7]([CH:4]([N:2]([CH3:3])[CH3:1])[C:5]3[S:17][CH:18]=[CH:19][CH:20]=3)[CH2:8][CH2:9]2)[O:11][CH2:12][CH2:13]1
Reactant: Br[Mg]c1cccs1
Reactant: CN(C)C(C#N)C1CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(c1cccs1)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of the aminonitrile 4 (2.24 g, 10 mmol) in absolute THF (10 ml) was added dropwise to a 1 M solution of thiophen-2-yl-magnesium bromide in THF (20 ml, 20 mmol) under argon and while cooling with ice, and the mixture was stirred at RT for 20 hours. The reaction mixture was worked up by adding saturated ammonium chloride solution (10 ml) and water (10 ml) while cooling with ice, and extracting the mixture with diethyl ether (3×10 ml). The organic phase was washed with water and saturated sodium chloride solution, dried and concentrated.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.[Cl-].[CH3:18][O:19]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH:6]([CH:18]=[O:19])[CH2:5][CH2:4]1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: CN(C)C1(c2ccccc2)CCC(C=O)CC1

Procedure:
46 mmol (10.0 g) of 4-dimethylamino-4-phenylcyclohexanone were dissolved in toluene. This solution was added dropwise at 70° C. to a suspension of 138.1 mmol, (47.33 g) methoxymethyl triphenylphosphonium chloride and 138.1 mmol (25.82 g) potassium tert.-butylate. The mixture was stirred for a few more hours at 70° C., hydrolysed with water and extracted using EE. The combined organic phases were washed with saturated NaCl solution, dried over sodium sulphate and concentrated. The resultant brown resin was chromatographed using silica gel. The desired aldehyde is obtained as a cis/trans-mixture.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][N:7]=[C:6](NCC3C=CC(F)=CC=3)[C:5]=2[C:4]([CH3:20])=[C:3]1[CH3:21].[ClH:22].CN1[C:32]2[CH:31]=[CH:30]N=[C:28]([NH:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[C:27]=2[C:26]([CH3:42])=C1C.C(=O)(O)[O-].[Na+].[F:49]C1C=CC(CBr)=CC=1>>[ClH:22].[F:49][C:30]1[CH:42]=[CH:26][C:27]([CH2:28][N:33]([C:9]2[C:10]3[N:2]([CH3:1])[C:3]([CH3:21])=[C:4]([CH3:20])[C:5]=3[CH:6]=[N:7][CH:8]=2)[CH2:34][C:35]2[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=2)=[CH:32][CH:31]=1
Reactant: Cc1c(C)n(C)c2ccnc(NCc3ccc(F)cc3)c12
Reactant: Fc1ccc(CBr)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1c(C)n(C)c2c(N(Cc3ccc(F)cc3)Cc3ccc(F)cc3)cncc12
Yield: 49.9 %

Procedure:
In accordance with the same procedures as in Example 47, except for using 1,2,3-trimethyl-4-(4-fluorobenzylamino)-1H-pyrrolo[3,2-c]pyridine obtained by treating the compound of Example 34 with a saturated sodium bicarbonate solution and 4-fluorobenzyl bromide, the titled compound was obtained as a white solid. (Yield: 49.9%)
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:19])[NH:4][C:5](C)=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](F)=[CH:12][C:11]=1F.Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH2:9]([O:8][C:7]1[CH:6]=[CH:5][N:4]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)[C:3](=[O:19])[C:2]=1[Br:1])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cn2ccc(OCc3ccccc3)c(Br)c2=O)cc1
Temperature: 80 °C
Yield: 45.7 %

Procedure:
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one(1.0 g, 3.6 mmol) was dissolved in N,N-dimethylformamide (5 mL). α-Bromo-p-tolunitrile (0.85 g, 4.3 mmol) was added followed by K2CO3 (0.59 g, 4.3 mmol). The resulting mixture was heated to 80° C. for 16 h. The reaction was concentrated to an oil that was partitioned between water and ethyl acetate and extracted with ethyl acetate (3×100 ml). The organic extracts were combined, washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated to an oil, and purified by chromatography (silica gel, hexane/ethyl acetate) to yield a white solid (0.65 g, 46%). 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J=8.4 Hz, 2H), 7.41-7.31 (m, 7H), 7.23 (d, J=7.6 Hz, 1H), 6.11 (d, J=8.0 Hz, 1H), 5.24 (s, 2H), 5.18 (s, 2H). ES HRMS m/z 395.0404 (M+H C20H15BrN2O2 requires 395.0390).
Reaction SMILES: [C:1]([O:13]C)(=O)[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH3:15][C:16]([CH3:18])=[O:17].[H-].[Na+].Cl>C1(C)C=CC=CC=1.C(COC)OC.C1(C)C=CC=CC=1.O>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([C:1](=[O:13])[CH2:15][C:16](=[O:17])[CH3:18])=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Reactant: CC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(=O)CC(C)=O)cc1
Temperature: 100 °C
Yield: 24.5 %

Procedure:
A solution of dimethyl terephthalate (10 g, 51.5 mmole) and acetone (4.15 mL, 56.6 mmole) in a mixture of toluene/dimethoxyethane (75 mL/25 mL) was added to a suspension of NaH 60% (2.68 g, 66.9 mmole) in dry toluene (25 mL) under argon. The mixture was heated at 100° C. for 4 hours. The reaction mixture was cooled to rt and 25 mL of water were added. The pH was adjusted to 3-4 with HCl 2N and the mixture was poured into water (300 mL). The aqueous mixture was extracted with ethyl acetate (3×150 mL), dried over sodium sulphate and evaporated to afford a yellow solid which was purified by column cromatography (n-Hex/EtOAc 9:1 to 7:3) to afford the title compound (2.78 g, 25% yield) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[S:9]([NH:12][C:13]1[C:14]([F:23])=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16](OC)=[O:17])(=[O:11])=[O:10].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:34][C:35]1[N:40]=[C:39]([CH3:41])[CH:38]=[CH:37][N:36]=1>O1CCCC1>[Cl:34][C:35]1[N:40]=[C:39]([CH2:41][C:16]([C:15]2[C:14]([F:23])=[C:13]([NH:12][S:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])(=[O:10])=[O:11])[CH:22]=[CH:21][CH:20]=2)=[O:17])[CH:38]=[CH:37][N:36]=1
Reactant: Cc1ccnc(Cl)n1
Reactant: COC(=O)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Cc1ccnc(Cl)n1)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1F
Temperature: -5 °C
Reaction time: 2 h
Yield: 33.3 %

Procedure:
To a solution of methyl 3-(2,6-difluorophenylsulfonamido)-2-fluorobenzoate (6.6 g, 19.11 mmol) in tetrahydrofuran (THF) (80 mL) stirred under nitrogen at −30° C. was added the solution of LiHMDS (65 mL, 65 mmol) in tetrahydrofuran dropwise over 40 mins. The reaction mixture was stirred at −5° C. for 2 hours. The reaction mixture was cooled again to −30° C. 2-Chloro-4-methylpyrimidine (2.95 g, 22.94 mmol) in tetrahydrofuran (THF) (10 mL) was added dropwise to the reaction mixture. The reaction mixture was stirred at −10° C. for 1 h, and warmed to room temperature for another 1.5 hours. The reaction mixture was cooled to 0° C. and quenched by addition of the satureated aqueous NH4Cl (80 mL) and extracted with ethyl acetate (100 ml×3). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product, which was purified by silica gel chromatography with petroleum ether/EtOAc (2:1) to produce the N-(3-(2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (5.05 g, 6.37 mmol, 33.3% yield). LCMS [M+H]+=442.
Reaction SMILES: [Br:1]CCCN=C=S.Br[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[S:18])=[CH:12][CH:11]=1.N12CCC(CC1)CC2.[CH3:27][N:28]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:29]>>[Br-:1].[CH2:30]([N+:28]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[S:18])=[CH:12][CH:11]=1)([CH3:29])[CH3:27])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CN(C)Cc1ccccc1
Reactant: S=C=Nc1ccc(CBr)cc1
Reactant: S=C=NCCCBr
Agent: C1CN2CCC1CC2
Product: C[N+](C)(Cc1ccccc1)Cc1ccc(N=C=S)cc1
Product: [Br-]

Procedure:
The procedure in the step a in Example 9 was followed except that instead of 3-bromopropyl isothiocyanate, 4-(bromomethyl)phenyl isothiocyanate (is-14 mentioned earlier) was used and instead of quinuclidine, N,N-dimethylbenzylamine (ta-32 mentioned earlier) was used to obtain the title compound.