Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[CH2:8][C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]1=2)=[O:4].[C:21]1(C)C=CC(S(O)(=O)=O)=CC=1.C(OC)(OC)OC>CO>[CH3:1][O:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([O:16][CH3:21])=[CH:8][C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]1=2)=[O:4]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC(=O)N1c2ccccc2CC(=O)c2ccccc21
Solvent: COC(OC)OC
Solvent: CO
Product: COC(=O)N1c2ccccc2C=C(OC)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Crude 10-Oxo-10,11-dihydro-dibenzo[b,f]azepine-5-carboxylic acid methyl ester (22.3 g, 0.083 mol, 1 eq.) is dissolved in methanol (112 mL) at 50° C. A catalytic amount of p-toluenesulfonic acid (0.445 mg) is added, followed by trimethyl orthoformate (11.5 mL, 1.25 eq.). The mixture is allowed to react for 5 hours before methanol is allowed to distill off. Fresh methanol is added continuously to replace the distillate. When 100 mL of methanol have been distilled, the mixture is allowed to cool down to 25° C. in 1 hour. The suspension is further cooled down to 3° C. in 20 minutes, stirred at this temperature for 1 hour and filtered. The solid is washed with cold methanol and dried in vacuum for 15 hours (50° C., 50 mbar). Pure title compound is obtained as a light yellow powder (18.02 g, 80.8% yield).
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[NH:12][C:13](=[O:16])[O:14][CH3:15].[C:17](Cl)([Cl:19])=[O:18]>C1(C2C=CC=CC=2)C=CC=CC=1.CO.C1(C)C=CC=CC=1>[Cl:19][C:17]([N:12]([C:6]1[C:5]([CH3:4])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:11])[C:13](=[O:16])[O:14][CH3:15])=[O:18]
Reactant: COC(=O)Nc1c(C)cccc1C
Reactant: O=C(Cl)Cl
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)N(C(=O)Cl)c1c(C)cccc1C
Temperature: 80 °C
Yield: 64.5 %

Procedure:
A mixture of toluene (150 mL), biphenyl (0.2 g) and sodium methoxide in methanol (23.76 g, 0.11 mol, 25% by weight) was heated at reflux, and the methanol-toluene azeotrope was removed. The mixture was allowed to cool to 80° C., and toluene (80 mL) was added. To the resulting mixture was added in five portions methyl (2,6-dimethylphenyl)carbamate (17.9 g, 0.1 mol). The methanol formed in the reaction was removed as the above azeotrope. When most of the methanol had been removed, ethylene glycol dimethyl ether (8 mL) was added, and the mixture was distilled until the head temperature reached 110° C. The mixture was allowed to cool to 25° C., and ethylene glycol dimethyl ether (3 mL) was added. The mixture was then added to phosgene in toluene (22.5 g, 0.56 mol, 25% by weight). When the addition was complete, excess phosgene was removed by distillation. The mixture was allowed to cool to 25° C., and then washed with sodium bicarbonate solution (40 mL, saturated). The organic layer was dried and the volatiles removed by evaporation to give 17.21 g (64.5%) of the title compound as a solid. An analytical sample was prepared by column chromatography on silica gel using 1:3 ethyl acetate-hexanes as the eluent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](Br)[CH:6]=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11].[CH2:13]([OH:16])[C:14]#[CH:15].C1N2CCN(CC2)C1>C(#N)C.C(OCC)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:15]#[C:14][CH2:13][OH:16])[CH:6]=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: COc1cc(Br)ccc1[N+](=O)[O-]
Reactant: C#CCO
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: C1CN2CCN1CC2
Solvent: CC#N
Solvent: CCOCC
Product: COc1cc(C#CCO)ccc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 47.6 %

Procedure:
To 5-bromo-2-nitrophenyl methyl ether (4.0 g, 17.24 mmol) in 80 mL of acetonitrile was added, Bis(tri-t-butylphosphine)palladium(0) (0.253 g, 0.5 mmol), 2-propyn-1-ol (3.33 g, 59.4 mmol), and DABCO (4.44 g, 39.6 mmol). The mixture was heated to 60° C. for 1 h. The mixture was rotovaped down and then taken up in diethyl ether. The organic layer was washed with H2O, dried (Na2SO4), filtered, and rotovaped. The crude product was purified by flash chromatography to give the title compound of step A (1.7 g, 8.2 mmol, 41%). 1H NMR (400 MHz, CDCl3) δ ppm 7.80 (d, J=8.24 Hz, 1H), 7.12 (d, J=1.65 Hz, 1H), 7.06 (dd, J=8.33, 1.56 Hz, 1H), 4.52 (s, 2H), 3.94 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([NH2:20])=[C:18](Cl)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si:22]([C:26]#[CH:27])([CH3:25])([CH3:24])[CH3:23]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([NH2:20])=[C:18]([C:27]#[C:26][Si:22]([CH3:25])([CH3:24])[CH3:23])[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc(Cl)c2N)CC1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc(C#C[Si](C)(C)C)c2N)CC1
Temperature: 80 °C
Yield: 25 %

Procedure:
To a solution of 4-(5-amino-6-chloropyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (1 g, 3.19 mmol) and TMS-acetylene (1.5 g, 15 mmol) in TEA (10 mL) and THF (30 mL) were added PdCl2(PPh3)2 (0.33 g, 0.47 mmol) and CuI (0.1 g, 0.53 mmol) under N2. The mixture was heated to 80° C. for 20 hours. The solvent was removed and the residue was subject to chromatography on silica gel to afford the product 4-(5-Amino-6-trimethylsilanylethynyl-pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.3 g, 25%). 1H NMR (CDCl3, 400 Hz) δ 8.00 (s, 1H), 3.74 (s, 2H), 3.28-3.25 (m, 4H), 3.02-2.99 (m, 4H), 1.20 (s, 9H), 0.00 (s, 9H). MS (ESI+) [M+H]+ 376.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH2:19]Cl)[C:10]=1[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-:22].[Li+]>C1COCC1>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH2:19][Br:22])[C:10]=1[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(CCl)nc2ccccc2c1OCc1ccccc1
Reactant: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(CBr)nc2ccccc2c1OCc1ccccc1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
To a solution of 4-(benzyloxy)-2-(chloromethyl)-3-methylquinoline (5.0 g) in THF (50 mL) was added anhydrous lithium bromide (15 g), followed by heating under reflux for 3 hours. The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. Water was added to the residue, followed by stirring, and the resulting solid was collected by filtration. This solid was dried under vacuum at 60° C. to obtain 5.73 g of 4-(benzyloxy)-2-(bromomethyl)-3-methylquinoline as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([O:18][C:19]1[CH:29]=[CH:28][C:22]([CH:23](O)[C:24](O)=[O:25])=[CH:21][CH:20]=1)[CH3:17]>>[C:11]([C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]2[O:15][C:24](=[O:25])[CH:23]([C:22]3[CH:28]=[CH:29][C:19]([O:18][CH2:16][CH3:17])=[CH:20][CH:21]=3)[C:7]=2[CH:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CCOc1ccc(C(O)C(=O)O)cc1
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Product: CCOc1ccc(C2C(=O)Oc3c2cc(C(C)(C)C)cc3C(C)(C)C)cc1
Reaction time: 2 h
Yield: 92.1 %

Procedure:
A mixture of 309 g (1.50 mol) of 2,4-di-tert-butylphenol and 196.2 g (1.0 mol) of 4-ethoxymandelic acid is stirred at 140°-150° C. for 2 hours under a nitrogen atmosphere. Stirring at 150° C. is then continued for 1.5 hours under a slight vacuum (50 mbar). Excess 2,4-di-tert-butylphenol is distilled off in a high vacuum. Crystallisation of the residue from 150 ml of xylene and 250 ml of ethanol gives 337.7 g (92%) of 5,7-di-tert-butyl-3-(4-ethoxyphenyl)benzofuran-2-one, melting point 132°-134° C. (compound (101), Table 1).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[CH:3]1[CH:10]([OH:14])[C:11]#[C:12][CH3:13].[Cr](O)(O)(=O)=O>O>[CH2:1]=[C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[CH:3]1[C:10](=[O:14])[C:11]#[C:12][CH3:13]
Reactant: C=C1CCCC(C)(C)C1C(O)C#CC
Agent: O=[Cr](=O)(O)O
Solvent: O
Product: C=C1CCCC(C)(C)C1C(=O)C#CC
Temperature: 0 °C
Reaction time: 24 h
Yield: 72.1 %

Procedure:
4.85 g of 2-methylene-6,6-dimethyl-1-[1-hydroxy-but-2-ynyl]-cyclohexane [which can be prepared according to the method described in example 5] (25 millimoles) in 30 ml of a mixture of ether-hexane 1:1 were added dropwise, while stirring, within 30 minutes to an ice-cooled solution of 24 g of chromic acid (0.25N) in 24 ml of water and 15 ml of a mixture of ether-hexane 1:1. The whole was allowed to stand for 24 hours at room temperature, while stirring vigorously, and then diluted with water. The reaction mixture was extracted with pentane, and the organic extracts, after the usual treatments of washing, drying and concentration, gave a residue which, by fractional distillation under reduced pressure, yielded 3.46 g (72 %) of the desired ketone; b.p. 66°-70°/0.03 Torr. An analytical sample was purified by means of vapour phase chromatography (1.25 m, 15 % CARBOWAX, 130°).
Reaction SMILES: [Mg].[F:2][C:3]([F:18])([F:17])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[CH:19](=[O:21])[CH3:20]>O1CCCC1.BrBr>[F:2][C:3]([F:18])([F:17])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:19]([OH:21])[CH3:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1
Reactant: FC(F)(F)c1ccc(-c2ccc(Br)cc2)cc1
Reactant: CC=O
Agent: BrBr
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 0 °C

Procedure:
To a stirred suspension of 1.5 g of magnesium turnings in 10 ml of dry tetrahydrofuran, add a small amount of 4'-trifluoromethyl-4-bromo[1,1']biphenyl and a few drops of bromine. When the reaction is started, add (dropwise) a solution of 16 g of 4'-trifluoromethyl-4-bromo-[1,1']biphenyl in 50 ml of tetrahydrofuran at 50°-60° C. Heat the mixture for one hour, cool to 0° C., and slowly (dropwise) add 7 g of acetaldehyde. Stir the reaction mixture at room temperature for twenty hours. Work-up the reaction mixture following the procedure of example 2, and isolate the desired product by chromatography, m.p. 116°-117°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:27]4[O:26][CH2:25][CH2:24][N:23]([CH2:28][CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])[CH2:22][C:21]=4[CH:20]=[CH:19][CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:27]4[O:26][CH2:25][CH2:24][N:23]([CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH2:22][C:21]=4[CH:20]=[CH:19][CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)CCCN1CCOc2c(cccc2-c2noc(-c3ccc(OC(C)C)c(Cl)c3)n2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3OCCN(CCCC(=O)O)C4)no2)cc1Cl
Reaction time: 1 h
Yield: 49.7 %

Procedure:
A solution of ethyl 4-[9-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]butanoate (Preparation 68) (130 mg, 0.260 mmol) in ethanol was treated with sodium hydroxide (10.4 mg in 1 ml, 0.260 mmol). The reaction mixture was left standing at RT for 1 hour then evaporated. The resulting crude was partitioned between EtOAc/water, acidified with acetic acid, separated and the organivs dried over magnesium sulphate and evaporated. The title compound (61 mg) was obtained by trituration with ether as a white solid. δH (d6DMSO, 400 MHz): 1.36 (6H, d), 1.69 (2H, m), 2.23 (2H, t), 2.43 (2H, t), 3.05 (2H, m), 3.86 (2H, s), 4.07 (2H, m), 4.88 (1H, m), 7.20 (1H, t), 7.43-7.49 (2H, m), 7.78 (1H, dd), 8.09 (1H, dd), 8.17 (1H, d), 12.10 (1H, br. s); MS (ES−): C24H2635ClN3O5 requires 471; found 470 [M−H+].
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[CH3:6][O:7][C:8](OC)(OC)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)(=O)C>[CH3:6][O:7][C:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[N:5][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: COC(OC)(OC)c1ccccc1
Reactant: CS(N)(=O)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Product: COC(=NS(C)(=O)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of methanesulfonamide (4.75 g, 50 mmol)) and trimethyl orthobenzoate (18.2 g, 100 mmol) was heated at 120° C. for 4 h in the presence of a catalytic amount of p-toluenesulfonic acid (50 mg). After being cooled to room temperature, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with a saturated sodium bicarbonate aqueous solution and then water. The organic phase was dried over MgSO4, concentrated, and the resulting residue was treated with hexanes (100 mL) with stirring overnight. A white solid formed was filtered and washed with hexanes to yield a pure N-(methoxyphenylmethylene)methansulfonamide.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[CH3:14][O:15][CH:16]([O:20][CH3:21])N(C)C>CO>[CH3:14][O:15][CH:16]([O:20][CH3:21])[N:11]1[CH2:12][CH2:13][CH:8]([CH2:7][CH2:6][C:2]2[NH:3][CH2:4][CH2:5][N:1]=2)[CH2:9][CH2:10]1
Reactant: COC(OC)N(C)C
Reactant: C1CNC(CCC2CCNCC2)=N1
Solvent: CO
Product: COC(OC)N1CCC(CCC2=NCCN2)CC1
Temperature: 90 °C

Procedure:
A mixture containing 4-[2-(4,5-dihydro-1H-imidazol-2-yl)ethyl]piperidine (1 g, 0.0055M), methanol (10 ml) and dimethylformamide dimethylacetal (10 ml) was heated at 90° C. for 8 hours. The excess of dimethylformamide was removed in vacuo to give 4-[2-(4,5-dihydro-1H-imidazol-2-yl)ethyl]-1-piperidine carboxaldehyde dimethylacetal. To the mixture of 6-aminopenicillanic acid (1.01 g, 0.0045M) and diisopropylethylamine (0.54 ml) in dried chloroform (30 ml) was added the chloroform solution (20 ml) of the above piperidinecarboxaldehyde dimethylacetal at 0° C. The reaction was stirred at 0° C. for 1 hour and at room temperature for 3 hours. After the reaction, the solvent was removed and the residue dissolved in water (20 ml). The aqueous solution, washed with ethylacetate was acidified to pH3 with dil. HCl and purified on Sephadex LH 20 columns to give [2S-(2alpha,5alpha,6 beta)]-6-[[[4-[2-(4,5-dihydro-1H-imidazol-2-yl)ethyl]-1-piperidinyl]methylene]-amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]-heptane-2-carboxylic acid hydrochloride (1.11 g, 45% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)[CH3:2].[F-].[K+].Br[C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>[CH:20]([C:19]1[CH:22]=[CH:23][C:16]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=2)=[CH:17][CH:18]=1)=[O:21]
Reactant: CCOc1ccc(B(O)O)cc1
Reactant: O=Cc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Product: CCOc1ccc(-c2ccc(C=O)cc2)cc1
Temperature: 25 °C
Yield: 89.7 %

Procedure:
An oven dried resealable Schlenk tube was evacuated and backfilled with argon and charged with palladium acetate (1.1 mg, 0.005 mmol, 0.5 mol %), 2-(di-tert-butylphosphino)biphenyl (3.0 mg, 0.01 mmol, 1.0 mol %), 4-ethoxyphenylboronic acid (249 mg, 1.5 mmol), potassium fluoride (174 mg, 3.0 mmol), and 4-bromobenzaldehyde (185 mg, 1.0 mmol). The tube was evacuated and backfilled with argon, and THF (1 mL) was added through a rubber septum. The tube was sealed with a teflon screwcap, and the reaction mixture was stirred at room temperature until the starting aryl bromide had been completely consumed as judged by GC analysis. The reaction mixture was then diluted with ether (30 mL) and poured into a separatory funnel. The mixture was washed with water (20 mL), and the aqueous layer was extracted with ether (20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography on silica gel to afford 203 mg (90%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH:22]3[CH2:24][CH2:23]3)[NH:19][N:18]=2)[N:3]=1>CC(O)C>[CH:22]1([C:20]2[NH:19][N:18]=[C:17]([NH:16][C:4]3[N:3]=[C:2]([O:12][CH:9]([CH3:10])[CH3:8])[C:11]4[C:6]([CH:5]=3)=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=4)[CH:21]=2)[CH2:24][CH2:23]1
Reactant: COc1cc2cc(Nc3cc(C4CC4)[nH]n3)nc(Cl)c2cc1OC
Solvent: CC(C)O
Product: COc1cc2cc(Nc3cc(C4CC4)[nH]n3)nc(OC(C)C)c2cc1OC

Procedure:
Similar procedure as described in example 10 was used, starting from (1-Chloro-6,7-dimethoxy-isoquinolin-3-yl)-(5-cyclopropyl-1H-pyrazol-3-yl)-amine and propan-2-ol to give (5-Cyclopropyl-1H-pyrazol-3-yl)-(1-isopropoxy-6,7-dimethoxy-isoquinolin-3-yl)-amine. LC-MS m/e 369(MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:9](=[O:12])OC.O[C@H]1C[NH:17][C@H:16]([C:19](O)=O)[CH2:15]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(N)(C)C>[Cu]I.CS(C)=O>[CH:16]([N:17]1[C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[NH:8][C:9]1=[O:12])([CH3:19])[CH3:15]
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: COC(=O)Nc1ccncc1Br
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC(C)N
Product: CC(C)n1c(=O)[nH]c2ccncc21
Temperature: 70 °C
Reaction time: 12 h
Yield: 142 %

Procedure:
A sealed tube was charged with methyl 3-bromopyridin-4-ylcarbamate (1.76 g, 7.6 mmol.), CuI (290 mg, 1.52 mmol.), trans-4-hydroxy-L-proline (400 mg, 3.04 mmol.) and K3PO4 (3.2 g, 15.2 mmol.), evacuated and backfilled with argon. Isopropylamine (674 mg, 11.4 mmol.) and DMSO (15 mL) were added successively. The reaction mixture was stirred at 70° C. for 12 h and then at 130° C. for 12 h. The reaction mixture filtered and the filtrate was concentrated and purified by prep-HPLC to afford 3-isopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one (765 mg, 57%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](C(OC)=O)([CH2:15][CH:16]=[CH2:17])[C:11]([O:13]C)=[O:12])=[CH:5][C:4]=1[O:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[OH-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([CH2:15][CH:16]=[CH2:17])[C:11]([OH:13])=[O:12])=[CH:5][C:4]=1[O:22][CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: C=CCC(Cc1ccc(OC)c(OCCc2ccccc2)c1)(C(=O)OC)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=CCC(Cc1ccc(OC)c(OCCc2ccccc2)c1)C(=O)O
Temperature: 25 °C
Yield: 100.3 %

Procedure:
To a solution of the methyl 3-[4-methoxy-3-(2-phenylethoxy) phenyl]-2-methoxycarbonyl-2-(2-propen-1-yl)propionate (7.50 g) in 75 ml of methanol, 0.73 g of sodium hydroxide in 1.1 ml of water was added and refluxed by heating for 30 hours under stirring. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 61 ml of aqueous solution of 3 N sodium hydroxide. The solution was refluxed by heating for 11 hours under stirring. The reaction solution cooled to room temperature was washed with diethyl ether. Then, concentrated hydrochloric acid was added thereto to make the solution acidic. The resultant solution was extracted with dichloromethane and dried over anhydrous magnesium sulfate. The drying agent was separated by filtration and the filtrate was concentrated under reduced pressure. The residue was stirred at 140-150° C. for 4 hours under heating to obtain 6.21 g of crude 3-[4-methoxy-3-(2-phenylethoxy)phenyl]-2-(2-propen-1-yl) propionic acid. This crude compound was used in the subsequent step without purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[CH:17]([F:19])[F:18])=[CH:4][C:5]([O:8]C)=[N:6][CH:7]=1.[Cl-].[NH+]1C=CC=CC=1>>[Cl:1][C:2]1[C:3]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[CH:17]([F:19])[F:18])=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1
Reactant: COc1cc(-c2cc(Cl)ccc2C(F)F)c(Cl)cn1
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Product: O=c1cc(-c2cc(Cl)ccc2C(F)F)c(Cl)c[nH]1

Procedure:
305 mg (purity 77%, 0.77 mmol) of 5-chloro-4-[5-chloro-2-(difluoromethyl)phenyl]-2-methoxypyridine and 20 eq. of pyridinium chloride were reacted according to General Method 3A. After work-up, the crude product was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 179 mg (80% of theory)
Reaction SMILES: [O:1]=[S:2]1(=[O:36])[C:8]2[CH:9]=[C:10]([OH:13])[CH:11]=[CH:12][C:7]=2[N:6]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:16][CH:15]=2)[CH2:5][C:4]([CH2:32][CH2:33][CH2:34][CH3:35])([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46]>CC#N.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[O:36]=[S:2]1(=[O:1])[C:8]2[CH:9]=[C:10]([O:13][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH:11]=[CH:12][C:7]=2[N:6]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])=[CH:18][CH:19]=2)[CH2:5][C:4]([CH2:32][CH2:33][CH2:34][CH3:35])([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:3]1
Reactant: CCCCC1(CCCC)CN(c2ccc(NC(=O)OC(C)(C)C)cc2)c2ccc(O)cc2S(=O)(=O)C1
Reactant: CCOC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC#N
Product: CCCCC1(CCCC)CN(c2ccc(NC(=O)OC(C)(C)C)cc2)c2ccc(OCC(=O)OCC)cc2S(=O)(=O)C1
Temperature: 60 °C
Yield: 89 %

Procedure:
1,1-Dioxo-3,3-dibutyl-5-(4-t-butoxycarbonylaminophenyl)-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine Method 107; 597 mg, 1.16 mmol) was dissolved in MeCN (20 ml), K2CO3 (480 mg, 3.5 mmol), tetrabutylammoniumbromide (54 mg, 0.17 mmol) and ethyl bromoacetate (167 μl, 1.5 mmol) was added. The mixture was heated to 60° C. overnight. The solvent was evaporated under reduced pressure. EtOAc and water was added and the water layer was extracted two times with EtOAc. The combined organic layer was washed once with brine, dried, filtered and evaporated under reduced pressure to give the title compound 0.617 g (89%). M/z 603.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[N:7]1>O1CCCC1.NN.[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH:10]=[CH:9][C:8]([NH2:11])=[N:7]1
Reactant: O=[N+]([O-])c1ccn(Cc2ccc(Cl)c(Cl)c2)n1
Agent: [Ni]
Agent: NN
Solvent: C1CCOC1
Product: Nc1ccn(Cc2ccc(Cl)c(Cl)c2)n1
Reaction time: 0.08 h

Procedure:
To a solution containing 1-(3,4-dichloro-benzyl)-3-nitro-1H-pyrazole (115 mg, 0.42 mmol) in tetrahydrofuran (2 mL), anhydrous hydrazine (100 μL) was added to the clear solution. Raney nickel (˜100 mg washed 3 times with 5 mL of anhydrous tetrahydrofuran) was then added in tetrahydrofuran (300 μL). Gas evolved from the mixture and the reaction was allowed to proceed for 5 min, after which time the raney nickel was removed by filtration through a celite plug. The solvent was removed in vacuo to afford 1-(3,4-dichloro-benzyl)-1H-pyrazol-3-ylamine as a yellow oil which was used in the following step with no further purification.
Reaction SMILES: [C:1]([O:6][C:7](=[O:11])[C:8]([CH3:10])=C)(=O)[C:2](C)=C.O[CH2:13][CH2:14][N:15](CC)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>N1C=CC=CC=1>[C:7]([O:6][CH2:1][CH2:2][N:15]([CH2:14][CH3:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:11])[CH:8]=[CH2:10]
Reactant: CCN(CCO)c1ccccc1
Reactant: C=C(C)C(=O)OC(=O)C(=C)C
Solvent: c1ccncc1
Product: C=CC(=O)OCCN(CC)c1ccccc1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
Methacrylic anhydride (7.7 g, 0.05 mol) is added to a solution of N-(2-hydroxyethyl)-N-ethylaniline (6.6 g, 0.04 mol) in pyridine (25 ml) and the mixture is stirred at 55° C. for 2 hours. On cooling the mixture is passed through silica gel to give N-(2-acryloyloxyethyl)-N-ethylaniline as a pale yellow oil. 5.3 g, 65%