Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH:3]1[C:15]([O:17]C)=O.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH2:29])=[NH:28])=[CH:22][CH:21]=1.[O-]CC.[Na+]>C(O)C>[Br:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][C:27]2[N:28]=[C:15]([OH:17])[C:3]3[CH2:4][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:6][CH2:7][C:2]=3[N:29]=2)=[CH:24][CH:25]=1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: N=C(N)Nc1ccc(Br)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2nc(Nc3ccc(Br)cc3)nc(O)c2C1
Yield: 88.5 %

Procedure:
1-tert-Butyl 3-methyl 4-oxopiperidine-1,3-dicarboxylate (1 g, 3.89 mmol), 1-(4-bromophenyl)guanidine (0.832 g, 3.89 mmol) and sodium ethoxide (0.264 g, 3.89 mmol) in ethanol (8 mL) were heated to 100° C. in a microwave reactor for 15 minutes. The reaction mixture was allowed to reach room temperature, the solid obtained was filtered and washed with cold ethanol and dried in a vacuum oven yielding tert-butyl 2-(4-bromophenylamino)-4-hydroxy-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (1.45 g, 72%). The compound was used in the next step without purification. MS (ESI) (M+H) m/z 423
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C:9](=O)[CH2:8][CH2:7][CH2:6][C:5]2=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:24][C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([O:17][CH3:16])[CH:19]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: COc1cccc(N)c1
Reactant: O=C1CCCc2c1[nH]c1ccc(Br)cc21
Product: COc1cccc(NC2CCCc3c2[nH]c2ccc(Br)cc32)c1

Procedure:
6-Bromo-N-(3-methoxyphenyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-one (100 mg, 0.38 mmol) and m-anisidine (94 mg, 0.76 mmol) in a similar manner as described above to give 37 mg (26%) of a white solid; 1H-NMR (DMSO-d6): δ 11.04 (s, 1H), 7.55 (s, 1H), 7.23 (d, 1H), 7.12 (dd, 1H), 6.97 (t, 1H), 6.32-6.27 (m, 2H), 6.13 (dd, 1H), 5.96 (d, 1H), 4.76-4.72 (m, 1H), 3.65 (s, 3H), 2.68-2.52 (m, 2H), 2.00-1.87 (m, 2H), 1.82-1.74 (m, 2H); MS m/z (M−1) 369, 371.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[C:7]([CH3:8])=[C:6]([OH:9])[O:5][N:4]=1.CC(C)=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24]([O:26][CH3:27])=[O:25]>O>[F:11][C:2]([F:1])([F:10])[C:3]1[C:7]([CH3:8])=[C:6]([O:9][CH2:23][C:24]([O:26][CH3:27])=[O:25])[O:5][N:4]=1
Reactant: COC(=O)CBr
Reactant: Cc1c(C(F)(F)F)noc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)COc1onc(C(F)(F)F)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
To 1.00 g (6 mmole) of 3-trifluoromethyl-4-methyl-5-hydroxyisoxazole were added 10 ml of dry acetone and 1.00 g (7.2 mmole) of anhydrous potassium carbonate and the resulting mixture was stirred at room temperature for one hour. After addition of methyl bromoacetate (1.10 g, 7.2 mmole), the mixture was refluxed for 30 hours. The reaction mixture was mixed with water (100 ml) and, extracted with diethyl ether. The diethyl ether phase was dried with anhydrous magnesium sulfate, evaporated under reduced pressure, and the residue was purified by chromatography on silica gel to give 0.73 g of the title compound as colorless viscous liquid, yield 53.6%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[N:10][C:9]([C:12]#[C:13][CH:14]([OH:16])[CH3:15])=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2>C(Cl)Cl.O=[Mn]=O>[CH3:1][O:2][C:3]1[CH:11]=[N:10][C:9]([C:12]#[C:13][C:14](=[O:16])[CH3:15])=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2
Reactant: COc1cnc(C#CC(C)O)c2[nH]ccc12
Agent: O=[Mn]=O
Solvent: ClCCl
Product: COc1cnc(C#CC(C)=O)c2[nH]ccc12
Reaction time: 12 h
Yield: 80.6 %

Procedure:
To a solution of 4-methoxy-7-(3-hydroxy-1-butyn-1-yl)-6-azaindole (0.200 g, 0.88 mmol) in CH2Cl2 (25 mL) was added activated MnO2 (1.72 g) and the reaction mixture was stirred for 12 h. The mixture was then filtered through Celite and the filtrate was concentrated to afford the title compound (0.152 g, 80%) as a light brown solid:
Reaction SMILES: BrC1C=CC=C2C=1CC[NH:6]C2CC(OC)=O.S(=O)(=O)(O)O.[C:22]([N:25]1[CH2:34][CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][C:31]=2[Br:35])[CH:26]1[CH2:36][C:37]([O:39]C)=O)(=[O:24])[CH3:23].C([O-])(O)=O.[Na+]>O.CO>[Br:35][C:31]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:32]=1[CH2:33][CH2:34][N:25]1[C:22](=[O:24])[CH2:23][NH:6][C:37](=[O:39])[CH:36]=[C:26]12
Reactant: COC(=O)CC1c2cccc(Br)c2CCN1C(C)=O
Reactant: COC(=O)CC1NCCc2c(Br)cccc21
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C1C=C2c3cccc(Br)c3CCN2C(=O)CN1
Temperature: 25 °C

Procedure:
methyl 2-(5-bromo-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate. MeOH (1280 mL) was cooled to −15° C. and conc. Sulfuric acid (147 mL, 2759 mmol) was added slowly (exotherm) under cooling. To this solution, methyl 2-(2-acetyl-5-bromo-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate (90 g, 276 mmol) was added and the reaction mixture was stirred under reflux for 96 h. The reaction mixture was cooled to RT and slowly added to a solution of NaHCO3 (540 g) in water (1.35 L). The slightly basic aqueous solution was extracted with AcOEt (3×500 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (300 mL) and brine (300 mL). The organic layer was dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was dried under high vacuo to yield the title compound as yellow foam (76 g) which was used without further purification. UPLC-MS: MS 284.1/286.1 (M+H+); UPLC rt 0.50 min.
Reaction SMILES: [C:1]([O:4][NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25](=[NH:31])[NH:26]OC(=O)C)=[CH:21][CH:20]=3)=[CH:17][CH:18]=2)=[CH:10][N:9]=1)=[NH:7])(=[O:3])[CH3:2].C(O)C>C(O)(=O)C.[Pd]>[C:1]([OH:4])(=[O:3])[CH3:2].[C:25]([C:22]1[CH:21]=[CH:20][C:19]([C:16]2[O:15][C:14]([C:11]3[CH:12]=[CH:13][C:8]([C:6]([NH2:7])=[NH:5])=[N:9][CH:10]=3)=[CH:18][CH:17]=2)=[CH:24][CH:23]=1)(=[NH:26])[NH2:31]
Reactant: CC(=O)ONC(=N)c1ccc(-c2ccc(-c3ccc(C(=N)NOC(C)=O)nc3)o2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: N=C(N)c1ccc(-c2ccc(-c3ccc(C(=N)N)nc3)o2)cc1
Reaction time: 4 h
Yield: 68 %

Procedure:
Continuing with Scheme 3, to a solution of 19 (380 mg, 0.90 mmol) in glacial acetic acid (13 mL), and ethanol (25 mL) was added 10% palladium on carbon (120 mg). The mixture was placed on Parr hydrogenation apparatus at 50 psi for 4 h at room temperature. The mixture was filtered through HYFLO® matrix (available from Word Minerals Corporation of Santa Barbara, Calif., United States of America) and the filter pad washed with water. The filtrate was evaporated under reduced pressure and the precipitate was collected and washed with ether to give 20, in 68% yield, mp 266–268° C.dec.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:16]=[C:15]([CH3:17])[NH:14][N:13]=1.CC(C)([O-])C.[K+].C1COCC1>O>[CH3:17][C:15]1[NH:14][N:13]=[C:12]([NH:11][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH:16]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Nc2ccc([N+](=O)[O-])cc2)n[nH]1
Temperature: 60 °C
Yield: 77.8 %

Procedure:
0.3 g of 4-fluoronitrobenzene, 0.413 g of 3-amino-5-methylpyrazole, and 0.286 g of potassium tert-butoxide were added to a solution of 2.5 ml of THF. The reaction medium was heated at 60° C. for 7 hours and, after cooling to room temperature, was then poured into a water and ice mixture. The yellow precipitate formed was filtered off, reslurried in water and then dried over P2O5. 0.361 g of 5-methyl-N-(4-nitrophenyl)-1H-pyrazol-3-amine (1) was obtained.
Reaction SMILES: [I:1]Cl.[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:12]=2)[N:9]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([I:1])=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=3)[N:12]=2)[N:9]=1
Reactant: ClI
Reactant: Fc1ccc(-c2cn3nc(Cl)ccc3n2)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Fc1ccc(-c2nc3ccc(Cl)nn3c2I)cc1
Reaction time: 4 h
Yield: 72.7 %

Procedure:
A solution of 6.61 g (40.9 mmol) of iodine monochloride in 40 ml of chloroform is added in a rapid dropwise manner to a solution, cooled to 0° C., of 5.20 g (21.0 mmol) of 6-chloro-2-(4-fluorophenyl)imidazo[1,2-b]pyridazine (CAS number: 244081-70-7) in 130 ml of chloroform. After returning to ambient temperature and after stirring for 4 hours, the mixture is treated with a 5% aqueous solution of sodium thiosulphate. The product is extracted with dichloromethane, the organic phase is dried by filtration over a hydrophobic filtration cartridge and concentrated under reduced pressure. The residue is triturated in acetonitrile, the solid is isolated after filtration and rinsing with diisopropyl ether. 5.7 g of beige powder are isolated after drying under vacuum.
Reaction SMILES: [F:1][C:2]([F:16])([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1)[C:3](OCC)=[O:4].[NH3:17]>CO>[F:1][C:2]([F:16])([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1)[C:3]([NH2:17])=[O:4]
Reactant: CCOC(=O)C(F)(F)Oc1cccc(F)c1
Reactant: N
Solvent: CO
Product: NC(=O)C(F)(F)Oc1cccc(F)c1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A mixture of ethyl 2,2-difluoro-2-(3-fluorophenoxy)acetate (3.5 g, 14.9 mmol), MeOH (10 mL) and ammonia (5.09 g) in a 20 mL of sealing tube was stirred at 100° C. for 24 h. The mixture was cooled to rt and concentrated in vacuo to give the title compound, which was used for next step without further purification.
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[CH:14]=[C:13]([CH2:15]B2OCC(C)(C)CO2)[O:12][C:11]=1[CH3:24])(C)C)(C)(C)C.ClC1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:24][C:11]1[O:12][C:13]([C:15]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=2)=[CH:14][C:10]=1[CH2:9][OH:8]
Reactant: Cc1oc(CB2OCC(C)(C)CO2)cc1CO[Si](C)(C)C(C)(C)C
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1oc(-c2ccc(C(F)(F)F)cn2)cc1CO
Reaction time: 8 h
Yield: 62.8 %

Procedure:
A mixture of tert-butyl({5-[(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)methyl]-2-methylfuran-3-yl}methoxy)dimethylsilane (2.4 g), 2-chloro-5-trifluoromethylpyridine (1.8 g), tetrakis(triphenylphosphine)palladium(0) (0.4 g), 2N aqueous sodium carbonate solution (7 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), 1N tetrabutylammonium fluoride in tetrahydrofuran (10 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, purified by silica gel chromatography (10% ethyl acetate/hexane to 100% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (1.1 g, 62%) as a yellow crystal.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])[N:10]=[C:9]2[C:18]2[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:25])=[CH:4][CH:3]=1.[CH3:26][S:27]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)(=[O:29])=[O:28].C(=O)([O-])[O-].[K+].[K+]>>[Cl:25][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([Cl:24])[C:18]=1[C:9]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([C:34]3[CH:33]=[CH:32][CH:31]=[C:30]([S:27]([CH3:26])(=[O:29])=[O:28])[CH:35]=3)=[CH:3][CH:4]=2)[CH:12]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])[N:10]=1
Reactant: CC(C)(CO)c1cn(-c2ccc(Br)cc2)c(-c2c(Cl)cccc2Cl)n1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(CO)c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)c(-c2c(Cl)cccc2Cl)n1
Temperature: 60 °C
Yield: 14.8 %

Procedure:
A stirred mixture of 2-[1-(4-bromophenyl)-2-(2,6-dichlorophenyl)-1H-imidazol-4-yl]-2-methyl-propan-1-ol (202 mg, 0.46 mmol), 3-methanesulfonyl-phenylboronic acid (92 mg, 0.46 mmol), potassium carbonate (0.19 g, 1.4 mmol), Cl2 Pd(dppf).DCM (19 mg, 5 mol %) and H2O (0.25 mL) in DME (2.5 mL) was sparged with Argon for 5 min and then heated at 60° C. as a sealed flask. After 30 min the reaction mixture was concentrated under reduced pressure and purified by chromatography (silica, EtOAc/Hex, 40:60 to 75:25) to give the title compound (35 mg) as a white solid. 1H-NMR (DCM-d2): δ 8.10 (m, 1H), 7.91 (d, 1H), 7.85 (d, 1H), 7.66 (m, 1-1), 7.60 (d, 2H), 7.29-7.37 (m, 5H), 7.10 (s, 1H), 3.79 (br s, 1H), 3.62 (s, 2H), 3.06 (s, 3H), 1.36 (s, 6H); MS (ES): 515, 517 [M+H]+.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Mg]Cl)=[CH:30][C:29]=1[CH3:36]>>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][N:10]=3)[C:15](=[O:16])[C:6]([C:4](=[O:5])[C:31]3[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[C:29]([CH3:36])[CH:30]=3)=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: COc1ccc([Mg]Cl)cc1C
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ncccc2c1=O
Product: COc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ncccc3c2=O)cc1C

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60, from 55 mg (0.136 mmol) of 1-(6-Bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid methoxy-methyl-amide, and 0.5 ml (0.285 mmol) of 4-methoxy-3-methylphenyl magnesium chloride, to give desired compound as a white solid. LCMS (M+H)+: 464.
Reaction SMILES: [CH2:1]([NH:7][C:8](=[O:11])[CH:9]=[CH2:10])[NH:2][C:3](=[O:6])[CH:4]=[CH2:5].[CH3:12][Si:13]([CH3:16])([CH3:15])Cl.[S]>C(N(CC)CC)C>[CH3:12][Si:13]([CH3:16])([CH3:15])[N:7]([CH2:1][N:2]([Si:13]([CH3:16])([CH3:15])[CH3:12])[C:3](=[O:6])[CH:4]=[CH2:5])[C:8](=[O:11])[CH:9]=[CH2:10]
Reactant: C[Si](C)(C)Cl
Reactant: C=CC(=O)NCNC(=O)C=C
Agent: [S]
Solvent: CCN(CC)CC
Product: C=CC(=O)N(CN(C(=O)C=C)[Si](C)(C)C)[Si](C)(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 60.3 %

Procedure:
850 ml of anhydrous triethylamine and 92.5 g (0.6 mol) of N,N'-methylene-bis-acrylamide are initially introduced into a 2.5 liter sulphonation flask equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel. 220 g (approximately 2 mols) of trimethylchlorosilane are then added dropwise, whilst cooling occasionally with an ice bath, in such a way that the temperature of the reaction mixture does not exceed 15°-25° C. A little sulphur is then added, as a polymerisation inhibitor, to the reaction mixture, which is stirred overnight at 60° C. The following day, the triethylamine hydrochloride which has precipitated is filtered off, the filter cake is washed with approximately 300 ml of triethylamine, and the filtrates are finally combined and distilled in vacuo. 108 g of N,N'-bis-trimethylsilyl-N,N'-methylene-bis-acrylamide are obtained as a fraction distilling at 120° C/0.8 mm Hg.
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([CH2:7][NH:8][C:9](=[O:20])[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[O:11][CH3:12])=[CH:5][CH:4]=1)#[N:2].[CH2:23](I)[CH3:24].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9](=[O:20])[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:23][CH3:24])=[CH:15][CH:14]=2)[O:11][CH3:12])=[CH:21][CH:22]=1)#[N:2]
Reactant: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(O)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOc1ccc(C(OC)C(=O)NCc2ccc(C#N)cc2)cc1

Procedure:
In analogy to example 16.4, (RS)-N-(4-cyano-benzyl)-2-(4-hydroxy-phenyl)-2-methoxy-acetamide was alkylated with ethyl iodide/cesium carbonate in DMF to give (RS)-N-(4-cyano-benzyl)-2-(4-ethoxy-phenyl)-2-methoxy-acetamide as a colorless solid. MS 325.3 ([M+H]+)
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6]Br)(=[O:3])[CH3:2].[CH3:8][CH:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19](=O)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:16]=2)[C:11](=[O:27])[CH2:10]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:5]([O:4][C:1](=[O:3])[CH2:2][N:18]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[CH:9]([CH3:8])[CH2:10][C:11]2=[O:27])[CH3:6]
Reactant: CC(=O)OCCBr
Reactant: CC1CC(=O)c2cc(NC(=O)c3ccccc3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CN(Cc1ccccc1)c1ccc2c(c1)C(=O)CC2C
Yield: 64.1 %

Procedure:
As presented in the following reaction formula, a solution of bromoethyl acetate (BrCH2COOEt; 7.5 g, 0.045 mol) in acetonitrile (20 mL) was added to a mixture of N-(1-methyl-3-oxo-indan-5-yl)benzamide (10 g, 0.037 mol) and anhydrous potassium carbonate (10.4 g, 0.075 mol) in acetonitrile (150 mL), and the reaction mixture was refluxed for 5 hours. After the completion of reaction, the mixture was filtered and the filtrate was concentrated to give the crude product [benzyl-(1-methyl-3-oxo-indan-5-yl)-amino]-acetic acid ethyl ester (8 g, yield: 63%) as a yellow solid.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15]O)=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1([CH3:25])[CH2:23][NH:22][C:21](=[O:24])[CH2:20][CH2:19]1>>[CH3:17][C:18]1([CH3:25])[CH2:23][N:22]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:8]#[C:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:14][N:13]=2)[C:21](=[O:24])[CH2:20][CH2:19]1
Reactant: CC1(C)CCC(=O)NC1
Reactant: OCc1ccc(C#Cc2ccccc2)cn1
Product: CC1(C)CCC(=O)N(Cc2ccc(C#Cc3ccccc3)cn2)C1

Procedure:
The title compound, yellow oil, MS: m/e=319.2 (M+H+), can be prepared in accordance with the general method of example 31, step 2 from (5-phenylethynyl-pyridin-2-yl)-methanol (example 31, step 1) and 5,5-dimethyl-piperidin-2-one.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2([CH2:19][NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(O)CCC>[N:27]1([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3([CH2:19][NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: ClCCCCOc1ccc(C2(CNc3ccccn3)CCOCC2)cc1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CCCCO
Product: c1ccc(NCC2(c3ccc(OCCCCN4CCCC4)cc3)CCOCC2)nc1
Yield: 28.7 %

Procedure:
A mixture of N-({4-[4-(4-chlorobutoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)pyridin-2-amine (180 mg, 0.481 mmol), pyrrolidine (80 μl, 0.963 mmol), sodium carbonate (102 mg, 0.963 mmol) and sodium iodide (4 mg, 0.024 mmol) were stirred in butanol (5 ml) at 100° C. for 24 hours until complete. Butanol was removed in vacuo and the residue partitioned between ethyl acetate (40 ml) and water (40 ml). Organic layer was dried over sodium sulphate, filtered and concentrated in vacuo to give a brown solid. Solid was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (98:2:02 to 96:4:0.4 by volume), followed by recrystallisation from ether (1.5 ml) to give the title compound (56.6 mg, 29%). 1H NMR (400 MHz, CDCl3) δ 1.78-2.00 (m, 12H), 2.08-2.20 (m, 2H), 2.54-2.90 (m, 4H), 3.50 (d, 2H), 2.54-2.63 (m, 2H), 3.79-3.88 (m, 2H), 3.96-4.08 (m, 2H), 6.23 (d, 1H), 6.50 (t, 1H), 6.90 (d, 2H), 7.25 (d, 2H), 7.32 (t, 1H), 8.01 (d, 1H). LRMS APCI+ m/z 410 [MH]+.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:22])=[CH:8][C:9]=2[NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])[S:4][C:3]=1[CH3:23].CC1(C)C(C)(C)OB([C:32]2[S:33][CH:34]=[C:35]([CH3:37])[CH:36]=2)O1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:21][C:17]1[CH:16]=[C:15]([S:12]([NH:11][C:9]2[CH:8]=[C:7]([CH3:22])[N:6]=[C:5]3[S:4][C:3]([CH3:23])=[C:2]([C:32]4[S:33][CH:34]=[C:35]([CH3:37])[CH:36]=4)[C:10]=23)(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1csc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(Br)c(C)sc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1csc(-c2c(C)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 120 °C
Yield: 36.2 %

Procedure:
Under nitrogen, N-(3-bromo-2,6-dimethylthieno[2,3-b]pyridin-4-yl)-3-chlorobenzenesulfonamide (Example 61) (100 mg, 0.232 mmol) was dissolved in 1,4-dioxane (2 mL) and water (0.7 mL). 4,4,5,5-Tetramethyl-2-(4-methyl-2-thienyl)-1,3,2-dioxaborolane (78 mg, 0.347 mmol), tetrakis(triphenylphosphine)palladium(0) (26.8 mg, 0.023 mmol) and potassium carbonate (96 mg, 0.695 mmol) were added and the mixture heated in a microwave at 120° C. for 15 min. Ethyl acetate (10 mL) was added and the mixture washed with water (2×5 mL). The organic layer was dried over MgSO4, filtered and the solvent removed in vacuo. The residue was purified by normal phase chromatography, eluting with a gradient of 0-30% ethyl acetate in cyclohexane and further triturated with MeOH, to give the title compound (37.7 mg). LCMS (A) m/z: 449 [M+1]+, Rt 1.53 min (acidic).