Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[CH:19][N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:27]N1C(C)(C)C(=O)N(Br)C1=O.[O-]S([O-])=O.[Na+].[Na+]>C1COCC1>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([Br:27])[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: Nc1ncnn2ccc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1ncnn2c(Br)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: -20 °C
Reaction time: 2 h
Yield: 178.9 %

Procedure:
To a cooled (−20° C.) solution 5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (600 mg, 1.76 mmol) in THF (18 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (252 mg, 0.88 mmol) in 3 portions over 10 min. The mixture was stirred at −20° C. for 2 h. Saturated, aqueous Na2SO3 (20 mL) was added and the mixture warmed to rt. The mixture was extracted with ethyl acetate (2×20 mL). The combined organics were washed with 5% aqueous K2CO3 (2×20 mL), brine, dried (Na2SO4) and evaporated to provide 660 mg (89%) of the desired product, which contained trace impurities. ES-MS m/z 419.12 [M+H]+, HPLC RT (min) 3.00.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:14]3[CH2:16][CH2:15]3)[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:23]([O:27][C:28](=[O:38])[C:29]1[CH:34]=[CH:33][C:32]([CH2:35]Br)=[C:31]([Cl:37])[CH:30]=1)([CH3:26])([CH3:25])[CH3:24]>CC(C)=O.O>[C:23]([O:27][C:28](=[O:38])[C:29]1[CH:34]=[CH:33][C:32]([CH2:35][N:11]2[C:10](=[O:13])[N:9]([CH:14]3[CH2:16][CH2:15]3)[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[N:12]2)=[C:31]([Cl:37])[CH:30]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C1CC1
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(Cn2nc(-c3ccc(Cl)cc3)n(C3CC3)c2=O)c(Cl)c1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
An amount of 1.00 g (4.22 mmol) of 5-(4-chlorophenyl)-4-cyclopropyl-2,4-dihydro-3H-1,2,4-triazol-3-one (preparation as per WO 2007/134862 Example 36A) and 2.07 g (6.37 mmol) of caesium carbonate were suspended in 15 ml of acetone and admixed with 1.69 g (5.52 mmol) of tert-butyl-4-(bromomethyl)-3-chlorobenzoate (preparation as per WO 2003/000692, Example 4b). The mixture was stirred at 50° C. for 18 h. The suspension was diluted with water. It was extracted with twice 15 ml of ethyl acetate. The combined organic phases were dried over sodium sulphate and freed from the solvent on a rotary evaporator. Purification by flash chromatography over silica gel with elution with cyclohexane/ethyl acetate (gradient 9:1→3:2) gave 1.41 g (53% of theory) of the target compound in a purity of 74%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:9]([OH:13])(=[O:12])[CH:10]=[CH2:11]>O>[F:1][C:2]1[CH:3]=[C:4]([NH:5][CH2:11][CH2:10][C:9]([OH:13])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(F)c1
Reactant: C=CC(=O)O
Solvent: O
Product: O=C(O)CCNc1cccc(F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 51 %

Procedure:
To 3-fluoroaniline (5.0 g), water (50 ml) and acrylic acid (3.6 g) were added and heated under reflux for 3 hours. After cooling to room temperature, the reaction mixture was stirred for 3 days and further heated under reflux for 7 hours. After cooling at room temperature, the solvent was distilled off under reduced pressure. To the resulting residue, 8M aqueous sodium hydroxide and chloroform were added to separate the aqueous layer. The separated aqueous layer was adjusted to pH 3 with 12M aqueous hydrochloric acid under ice cooling, and then extracted with chloroform. The extracted organic layer was dried over anhydrous magnesium sulfate and then filtered to remove the desiccant, followed by distilling off the solvent under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=4:1) to give 3-[N-(3-fluorophenyl)]aminopropionic acid (4.2 g) as a light-yellow powder. The compound thus obtained (3.8 g) was added to polyphosphoric acid (35g) heated at 130° C., followed by stirring for 1.5 hours. The reaction mixture was neutralized by addition of water and 8M aqueous sodium hydroxide under ice cooling, and then extracted with chloroform. The extracted organic layer was dried over anhydrous magnesium sulfate and then filtered to remove the desiccant, followed by distilling off the solvent under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=9:1 to 4:1 to 2:1) to give the titled compound of low polarity, i.e., 7-fluoro-2,3-dihydro-1H-quinolin-4-one (810 mg) as a yellow powder. On the other hand, a yellow oil obtained as a compound of high polarity was crystallized from a mixture of n-hexane and diethyl ether to give the other titled compound, i.e., 5-fluoro-2,3-dihydro-1H-quinolin-4-one (110 mg) as a yellow powder.
Reaction SMILES: [Mg].[F:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.Br[CH:22]1[CH2:27][CH2:26][O:25][C:23]1=[O:24].S(=O)(=O)(O)O>IC.O1CCCC1>[F:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([CH:22]2[CH2:27][CH2:26][O:25][C:23]2=[O:24])([OH:8])[C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)c2ccc(F)cc2)cc1
Reactant: O=C1OCCC1Br
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CI
Product: CS(=O)(=O)c1ccc(C(O)(c2ccc(F)cc2)C2CCOC2=O)cc1

Procedure:
Magnesium turnings (3.5 g) are covered with anhydrous tetrahydrofuran, and a few drops of iodomethane are added. As soon as the reaction has started, a mixture of 24.6 g of 4-fluoro-4'-methanesulfonylbenzophenone and 8.1 ml of α-bromo-γ-butyrolactone in 250 ml of anhydrous tetrahydrofuran is run in dropwise so as to maintain a gentle reflux. When the addition is complete, the reaction medium is cooled and then run into a mixture of ice and 10% dilute sulfuric acid. The organic phase is extracted with tetrahydrofuran, washed with saturated sodium bicarbonate solution and then dried over magnesium sulfate. After evaporation of the solvent, the residue obtained is chromatographed on silica gel with a 9/1 dichloromethane/acetone mixture to give 7 g of 3-[1-(4-fluorophenyl)-1-hydroxy-1-(4-methanesulfonylphenyl)methyl]dihydrofuran-2-one in the form of an amorphous beige powder, which is used as such in the next step.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br.Br.Br[CH2:24][C:25]1[C:26]([NH2:32])=[N:27][C:28]([NH2:31])=[N:29][CH:30]=1>CN(C)C=O>[C:2]1([C:8]2[CH2:13][CH2:12][N:11]([CH2:24][C:25]3[C:26]([NH2:32])=[N:27][C:28]([NH2:31])=[N:29][CH:30]=3)[CH2:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncc(CBr)c(N)n1
Reactant: C1=C(c2ccccc2)CCNC1
Agent: Br
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ncc(CN2CC=C(c3ccccc3)CC2)c(N)n1
Temperature: 25 °C
Reaction time: 65 h
Yield: 56.4 %

Procedure:
A solution of 1.0 g (0.0051 mol) of 4-phenyl-1,2,3,6-tetrahydro-pyridine hydrochloride in 40 ml of dimethylformamide was treated with 2.13 ml (0.0153 mol) of triethylamine and 0.62 g (0.00170 mol) of 5-bromomethyl-pyrimidine-2,4-diamine dihydrobromide and the mixture was stirred at room temperature under argon for 65 hours. The mixture was completely freed from the solvents. The residue was chromatographed over silica with methanol as the eluent, digested in dichloromethane/water 1:1 and subsequently filtered off under suction. The organic phase was then completely freed from the solvents and the residue was digested in diethyl ether and subsequently filtered off under suction. A total of 0.27 g (56%) of 5-(4-phenyl-3,6-dihydro-2H-pyridin-1-ylmethyl)-pyrimidine-2,4-diamine was obtained as white crystals; m.p. 239°-241°.
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[C:35]([N+:36]([O-])=O)=[CH:34][CH:33]=[C:32]([C:39]([CH3:41])=[CH2:40])[N:31]=3)[C@H:14]2[CH3:42])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>CCO.[Pd]>[NH2:36][C:35]1[C:30]([C:21]2[CH:22]=[CH:23][C:24]([C:26]([F:29])([F:28])[F:27])=[CH:25][C:20]=2[CH2:19][N:15]2[C@@H:14]([CH3:42])[C@@H:13]([C:5]3[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:1])([F:43])[F:44])[CH:4]=3)[O:17][C:16]2=[O:18])=[N:31][C:32]([CH:39]([CH3:40])[CH3:41])=[CH:33][CH:34]=1
Reactant: C=C(C)c1ccc([N+](=O)[O-])c(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Agent: [Pd]
Solvent: CCO
Product: CC(C)c1ccc(N)c(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Reaction time: 1.5 h

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(6-isopropenyl-3-nitropyridin-2-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (example 177) (19.3 mg, 0.0305 mmol) in EtOH (300 μL) was added 10% Pd/C (5 mg). The reaction was placed under a H2 atmosphere (balloon) and stirred vigorously. After 90 minutes, the mixture was loaded on to a PTLC plate and purified (30% EtOAc/hexanes, developed twice), affording (4S,5R)-3-[2-(3-amino-6-isopropylpyridine-2-yl)-5-(trifluoromethyl)benzyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one. Rf=0.63 (30% EtOAc/hexanes, developed twice). LCMS=606.2 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.84 (s, 1H), 7.78 (s, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.69 (s, 2H), 7.55 (d, J=8.0 Hz, 1H), 7.09-7.05 (m, 2H), 5.53-5.52 (m, 1H), 4.92 (d, J=5.5 Hz, 1H), 4.15-4.10 (m, 1H), 3.89-3.78 (m, 1H), 3.48 (s, 2H), 3.00-2.95 (m, 1H), 1.26-1.23 (m, 6H), 0.44 (d, J=5.1 Hz, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15](O)=O)=O)(C)(C)C.[F:18][C:19]1[C:24]([F:25])=[CH:23][CH:22]=[C:21]([NH2:26])[C:20]=1[NH2:27].C(=O)([O-])[O-].[K+].[K+]>>[F:18][C:19]1[C:20]2[N:27]=[C:15]([CH2:14][CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]3)[NH:26][C:21]=2[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Reactant: Nc1ccc(F)c(F)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1ccc2[nH]c(CC3CCCCN3)nc2c1F
Temperature: 140 °C
Yield: 61 %

Procedure:
A mixture of 2-carboxymethyl-piperidine-1-carboxylic acid tert-butyl ester (Beckett et al, J. Med. Chem., 563, 1969) (6.72 g, 28 mmol) and 3,4-difluoro-benzene-1,2-diamine (4.00 g, 28 mmol) in polyphosphoric acid (130 g) was heated at 140° C. for 7.5 h. The cooled reaction mixture was poured onto excess solid potassium carbonate and crushed ice. The resulting basic, aqueous solution was extracted with ethyl acetate (2×) and the combined organics were washed with brine, dried (Na2SO4) and the solvent removed in vacuo. The residue was triturated with diethyl ether, ethyl acetate and pentane to afford the title compound as a white solid (4.29 g, 62%).
Reaction SMILES: [N:1]#[C:2][NH2:3].C[O-].[Na+].CO[C:9]([CH:13]1[CH2:15][CH2:14]1)=[N:10][C:11]#[N:12]>CO>[C:2]([NH:3][C:9]([CH:13]1[CH2:15][CH2:14]1)=[N:10][C:11]#[N:12])#[N:1]
Reactant: COC(=NC#N)C1CC1
Reactant: N#CN
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#CN=C(NC#N)C1CC1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
At 0° C. 8,4 g of cyanamide in 50 ml methanol are added to 36 g of a 30% solution of sodium methylate in methanol and stirred for 30 min. at 10° C. The resulting solution is then cooled to -20° C. and mixed with a solution of 22 g N-cyano-cyclopropanecarboximidic acid methylester in 60 ml methanol. The reaction mixture is then stirred for 30 min. at 20° C. and then evaporated. 100 ml of dioxane is added to the resulting residue which is then concentrated by evaporation. Then again 100 ml of toluene is added and the solution is concentrated at an ambient temperature of 60° C. up to a residual weight of 33 g.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([C:16]#[N:17])[C:9]=3[CH:8]=[CH:7][C:6]=2[N:5]([C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:4]1.[N+:24]([O-])([OH:26])=[O:25]>C(Cl)Cl>[Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([C:16]#[N:17])[C:9]=3[C:8]([N+:24]([O-:26])=[O:25])=[CH:7][C:6]=2[N:5]([C:18](=[O:23])[C:19]([F:22])([F:20])[F:21])[CH2:4]1
Reactant: O=[N+]([O-])O
Reactant: N#Cc1cccc2c3c(ccc12)N(C(=O)C(F)(F)F)CC3CCl
Solvent: ClCCl
Product: N#Cc1cccc2c3c(cc([N+](=O)[O-])c12)N(C(=O)C(F)(F)F)CC3CCl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
A solution of 126 (60 mg, 0.18 mmol) in CH2Cl2 (10 mL) was treated with fuming HNO3 (1.5 mL) and stirred for 30 min at room temperature. The reaction was quenched with ice and extracted with CH2Cl2 (3×50 ml). The extracts were dried and concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with EtOAc/petroleum ether (from 1:4 to 1:1), to give 1-(chloromethyl)-5-nitro-3-(trifluoroacetyl)-1,2-dihydro-3H-benzo[e]indole-6-carbonitrile (127) (28 mg, 41%) as a brown solid: mp EtOAc/petroleum ether) 201-205° C. (dec.); 1H NMR [(CD3)2SO] δ 8.87 (s, 1H), 8.63 (dd, J=8.5, 1.1 Hz, 1H), 8.40 (dd, J=7.3, 1.0 Hz, 1H), 7.93 (dd, J=8.5, 7.3 Hz, 1H), 4.73-4.61 (m, 2H), 4.55-4.49 (m, 1H), 4.22-4.15 (m, 1H), 4.12-4.07 (m, 1H); 13C NMR δ 153.8 (q, JC-F 37.6 Hz), 146.8, 139.8, 137.7, 132.6, 130.3, 129.4, 128.3, 118.7, 115.4 (q, JC-F 288 Hz), 115.1, 114.8, 105.4, 52.7, 47.4, 41.1. Anal. (C16H9ClF3N3O3) C, H, N.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=O.[NH:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([Cl:23])=[N:15][N:14]=1)[NH2:12].C(N(CC)CC)C>O1CCOCC1>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]1[N:14]2[N:15]=[C:16]([Cl:23])[C:17]3[C:22]([C:13]2=[N:11][N:12]=1)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: O=C(Cl)c1ccccc1Br
Reactant: NNc1nnc(Cl)c2ccccc12
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Clc1nn2c(-c3ccccc3Br)nnc2c2ccccc12
Yield: 60 %

Procedure:
A solution of 2-bromobenzoyl chloride (0.12 mole) in dioxane (50 ml) is added to a mixture of 1-hydrazino-4-chlorophthalazine (0.1 mole), triethylamine (0.12 mole) and dioxane (200 ml). The reaction mixture is refluxed for five hours then the solvent is evaporated off and the obtained residue is washed with a small amount of water and crystallized from methanol giving the compound of the title in 60% yield. M.p. 203°-04° C.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9]C=1C.[C:17]([OH:20])(=[O:19])[CH3:18]>O.[O-2].[O-2].[O-2].[Cr+6]>[F:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:18]=1[C:17]([OH:20])=[O:19]
Reactant: Cc1ccc([N+](=O)[O-])cc1F
Reactant: CC(=O)O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: O
Product: O=C(O)c1ccc([N+](=O)[O-])cc1F
Temperature: 95 °C
Reaction time: 2 h

Procedure:
Concentrated sulfuric acid (32 ml) was added carefully with stirring to a solution of 2-fluoro-4-nitrotoluene (16.5 g, 0.106 mol) in acetic acid (200 ml). The mixture was warmed up to 95° C., and solution of chromium trioxide (37.1 g, 0.371 mol) in water (32 ml) was added dropwise with stirring over 2 h. The mixture was heated with stirring for another 30 minutes, allowed to cool down to r.t, and poured into water (1000 ml). The product was extracted with diethyl ether (3×200 ml). Combined ether layers were washed with water and evaporated to dryness. The residue was dissolved in 10% aqueous potassium carbonate and washed with ether. The aqueous layer was acidified with con. HCl, and the resulting white precipitate filtered and dried (16.3 g, 83%), m.p. 174-177° C. 1H NMR.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:25]([C:26]4[N:30](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:29]=[N:28][N:27]=4)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:50]([O:52][CH:53]([O:55][C:56]([O:58][CH:59]2[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]2)=[O:57])[CH3:54])=[O:51])[N:5]=1.CO>O>[CH3:1][CH2:2][O:3][C:4]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[C:26]3[N:27]=[N:28][NH:29][N:30]=3)=[CH:16][CH:15]=2)[C:11]2[C:10]([C:50]([O:52][CH:53]([O:55][C:56]([O:58][CH:59]3[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64]3)=[O:57])[CH3:54])=[O:51])=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=1
Reactant: CCOc1nc2cccc(C(=O)OC(C)OC(=O)OC3CCCCC3)c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CO
Product: CCOc1nc2cccc(C(=O)OC(C)OC(=O)OC3CCCCC3)c2n1Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1

Procedure:
A mixture of trityl candesartan cilexetil (20 g, 23.45 mmol), methanol (200 ml), and water (1 ml) was gently refluxed for about 16–17 h. The reaction progress was monitored by HPLC. The solution volume was reduced by evaporation under reduced pressure (30 mbar) at a temperature of 55° C. to 60° C. to obtain viscous oil of candesartan cilexetil as a residue.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].C(N(CC)CC)C.[CH2:19]([O:21][CH2:22][C:23](Cl)=[O:24])[CH3:20]>ClCCl>[CH2:19]([O:21][CH2:22][C:23]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9])=[O:24])[CH3:20]
Reactant: COC(=O)c1ccccc1N
Reactant: CCOCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCC(=O)Nc1ccccc1C(=O)OC
Reaction time: 1 h
Yield: 107.6 %

Procedure:
To a solution of 4.53 g (30 mmol) of methyl anthranilate and 6.1 ml of triethylamine in 50 ml of dichloromethane was dropwise added a solution of 4.41 g (36 mmol) of ethoxyacetylchloride in 10 ml of dichloromethane under chilling with ice for a period of 15 min. The resulting mixture was stirred for 1 hr. at room temperature. The stirred mixture was washed sequentially with water, 4 N hydrochloric acid and 5% aqueous sodium carbonate, and then was dried over anhydrous sodium sulfate. The solvent was distilled off to leave 7.66 g of the desired compound (purity: 92.8 %) as a residual pale brown oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[S:5][CH:6]=1.C[CH2:15][O:16]CC.C([Li])CCC.CN(C=O)C>CCCCCC>[CH2:9]([O:8][CH:7]([O:11][CH2:12][CH3:13])[C:4]1[S:5][CH:6]=[C:2]([CH:15]=[O:16])[CH:3]=1)[CH3:10]
Reactant: CCOCC
Reactant: CCOC(OCC)c1cc(Br)cs1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCOC(OCC)c1cc(C=O)cs1
Temperature: -78 °C
Reaction time: 1 h
Yield: 39.7 %

Procedure:
A solution of 4-bromo-2-(diethoxymethyl)thiophene (500 mg, 0.002 mol) in ether (5 mL, 0.05 mol) was cooled at −78° C. To this solution, 2.5 M n-butyllithium in hexane (0.83 mL) was added dropwise. The reaction was stirred at −78° C. for 1 hour. To the reaction was added DMF (0.4 g, 0.006 mol) at −78° C. and the mixture was stirred for 30 minutes. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by flash column chromatography to yield the 5-(diethoxymethyl)thiophene-3-carbaldehyde as an oil (170 mg, 42.0%). By 1H NMR two different regioisomers of aldehydes were formed and were not separated; (note: NMR shifts are for the major isomer only) 1H NMR (400 MHz, CDCl3): δ 9.85 (s, 1H), 8.05, 7.7 (s, 1H), 7.45, 7.15 (s, 1H), 5.7 (s, 1H), 3.65 (m, 2H), 1.25 (m, 2H).
Reaction SMILES: [C:1]([N:9]=[C:10]1[NH:14][CH2:13][CH:12]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:23]1[CH:27]=[C:26]([CH2:28][CH2:29][CH2:30][NH2:31])[N:25]=[CH:24]1>C(#N)C.C(O)C>[C:1]([NH:9][C:10]([NH:14][CH2:13][CH:12]([OH:11])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[N:31][CH2:30][CH2:29][CH2:28][C:26]1[N:25]=[CH:24][NH:23][CH:27]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCCc1c[nH]cn1
Reactant: O=C(N=C1NCC(COc2ccccc2)O1)c1ccccc1
Solvent: CCO
Solvent: CC#N
Product: O=C(NC(=NCCCc1c[nH]cn1)NCC(O)COc1ccccc1)c1ccccc1
Yield: 38 %

Procedure:
1.48 g (5 mmol) of 2-benzoylimino-5-phenoxymethyloxazolidine and 0.69 g (5.5 mmol) of 3-(imidazole-4-yl)-propylamine are heated together under reflux in a mixture of 40 ml of acetonitrile and 10 ml of ethanol for 8 hours. The reaction mixture is concentrated by evaporation under vacuum and the product is isolated and purified by preparative layer chromatography (silica gel 60 PF254 containing gypsum: solvent; chloroform/methanol 98:2, ammoniacal atmosphere). Crystallisation from acetonitrile results in 0.8 g (38%) of colourless crystals, melting point 129° C.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:31]=[CH:30][CH:29]=[CH:28][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16](B2OC(C)(C)C(C)(C)O2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=O.[C:36]([O:40][C:41](=[O:65])[CH2:42][N:43]([S:55]([C:58]1[CH:63]=[CH:62][C:61](Br)=[CH:60][CH:59]=1)(=[O:57])=[O:56])[CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=1)([CH3:39])([CH3:38])[CH3:37].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(OCC)(=O)C>[C:36]([O:40][C:41](=[O:65])[CH2:42][N:43]([S:55]([C:58]1[CH:63]=[CH:62][C:61]([C:16]2[CH:15]=[CH:14][C:13]([C:12]3[C:11]4[CH:28]=[CH:29][CH:30]=[CH:31][C:10]=4[O:9][C:8]=3[CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:18][CH:17]=2)=[CH:60][CH:59]=1)(=[O:57])=[O:56])[CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: CC1(C)OB(c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)CN(Cc1cccc(C(F)(F)F)c1)S(=O)(=O)c1ccc(Br)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CN(Cc1cccc(C(F)(F)F)c1)S(=O)(=O)c1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1
Temperature: 80 °C
Yield: 23 %

Procedure:
A solution of 2-benzyl-3-[4′-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)phenyl]-benzofuran (268 mg 0.653 mmol) in anhyd DMSO (5 mL) was added to a stirred suspension of tert-Butyl-[(4-bromobenzenesulfonyl)-(3-trifluoromethylbenzyl)amino]-acetate (296 mg, 0.58 mmol) and tripotassium phosphate (0.37 g, 1.76 mmol) in anhyd DMSO (5 mL). [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)-DCM complex (60 mg, 0.07 mmol) was added as a solid, and the resulting suspension was heated to 80° C. for 25 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, filtered though celite, and washed with sat'd aq LiCl (3×10 mL), sat'd aq NaCl (1×10 mL), dried over anhyd MgSO4, filtered and concentrated in vacuo. Purification by flash column chromatography (heptane) afforded the title compound as a white solid (95 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[C:9]([CH3:20])=[N:10][O:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:22]([O:24][C:25]([C:27]1([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)[CH2:30][CH2:29][CH2:28]1)=[O:26])[CH3:23]>>[CH2:22]([O:24][C:25]([C:27]1([C:31]2[CH:36]=[CH:35][C:34]([C:16]3[CH:17]=[CH:18][C:13]([C:12]4[O:11][N:10]=[C:9]([CH3:20])[C:8]=4[NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:21])=[CH:14][CH:15]=3)=[CH:33][CH:32]=2)[CH2:28][CH2:29][CH2:30]1)=[O:26])[CH3:23]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CCC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OC(C)(C)C
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)OC(C)(C)C)cc3)cc2)CCC1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid tert-butyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclobutanecarboxylic acid ethyl ester.