Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[CH2:13]([C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18])[CH3:14]>C(O)C>[CH2:13]([C:15]1[CH:16]=[C:17]([N:18]2[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]2=[O:11])[CH:19]=[CH:20][CH:21]=1)[CH3:14]
Reactant: CCc1cccc(N)c1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Solvent: CCO
Product: CCc1cccc(N2CCC(C(=O)O)C2=O)c1
Yield: 35 %

Procedure:
A mixture of 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.500 g; 2.94 mmol) and 3-ethylaniline (1.1 mL; 8.82 mmol) in ethanol (3 mL) was irradiated in a microwave oven for 3 minutes at 100° C. The mixture was concentrated under reduced pressure and the residue was dissolved in a solution of sodium hydroxide 6N, washed with dichloromethane, acidified with a solution of hydrochloric acid 6N to pH=2, extracted with ethyl acetate dried and concentrated under reduced pressure to yield 0.240 g (35%) of a yellow oil, which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH3:17])[CH:12]([CH2:18][NH2:19])[CH2:11]2)=[CH:4][CH:3]=1.C1([O:26][C:27](=O)[NH:28][C:29]2[CH:34]=[C:33]([C:35]3[N:39]([CH3:40])[N:38]=[N:37][N:36]=3)[CH:32]=[C:31]([CH2:41][CH3:42])[CH:30]=2)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[CH2:41]([C:31]1[CH:30]=[C:29]([NH:28][C:27]([NH:19][CH2:18][CH:12]2[CH:13]([CH2:16][CH3:17])[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:11]2)=[O:26])[CH:34]=[C:33]([C:35]2[N:39]([CH3:40])[N:38]=[N:37][N:36]=2)[CH:32]=1)[CH3:42]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)cc(-c2nnnn2C)c1
Reactant: CCC1CCN(CCc2ccc(F)cc2)CC1CN
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1cc(NC(=O)NCC2CN(CCc3ccc(F)cc3)CCC2CC)cc(-c2nnnn2C)c1
Reaction time: 18 h
Yield: 50.9 %

Procedure:
A solution of 1-[2-(4-fluorophenyl)ethyl]-4-ethyl-piperidin-3-ylmethylamine (52 mg, 199 μmol) and [3-ethyl-5-(1-methyl-1H-tetrazol-5-yl)phenyl]-carbamic acid phenyl ester (50 mg, 199 μmol) in N,N-dimethylformamide (1.0 mL) was treated with triethylamine (55 μL, 398 μmol). After 18 hours, the mixture was concentrated under vacuum. The residue was purified by flash chromatography, eluting with 5% methanol in dichloromethane containing 0.5% aqueous ammonium hydroxide, provided an amorphous solid (50 mg, 51%). 1H NMR (300 MHz, CDCl3) δ8.37 (s, 1H), 7.74 (s, 1H), 7.56 (s, 1H), 7.11 (m, 2H), 7.03 (s, 1H), 6.92 (t, J=9 Hz, 2H), 6.11 (m, 1H), 4.12 (s, 3H), 3.53 (m, 1H), 3.18 (m, 2H), 3.00 (m, 1H), 2.80 (m, 2H), 2.63 (m, 4H), 2.2-2.0 (m, 2H), 1.82 (m, 1H), 1.66 (m, 2H), 1.40 (m, 1H), 1.3-1.1 (m, 2H), 1.20 (t, J=7 Hz, 3H), 0.88 (t, J=7 Hz, 3H). Mass spec (ES+) m/z 494.4 (M+H+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])=[C:6]([CH:9]=1)[C:7]#[N:8].[BH4-].[Na+].[OH2:18].[CH3:19][OH:20]>[Ni](Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])=[C:6]([CH:9]=1)[CH2:7][NH:8][C:19](=[O:20])[O:18][C:6]([CH3:9])([CH3:7])[CH3:5]
Reactant: N#Cc1cc(Cl)ccc1N1CCCC1=O
Reactant: O
Reactant: CO
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)NCc1cc(Cl)ccc1N1CCCC1=O
Reaction time: 0.17 h

Procedure:
(Step 2) To a solution (227 ml) of 5-chloro-2-(2-oxopyrrolidin-1-yl)benzonitrile obtained in Step 1 (5.0 g) and nickel chloride 6 hydrate (0.54 g) in methanol was gradually added sodium tetrahydroborate (4.29 g) at 0° C., and the mixture was stirred for 10 min. Water (50 ml) was slowly added to quench the reaction. The solvent was evaporated under reduced pressure. The residue was extracted with ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate three times. The organic layers were combined, washed with saturated brine, dried over sodium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was dissolved in methylene chloride (150 ml), a solution of di-t-butyl dicarbonate (5.15 ml) in methylene chloride (40 ml) was added to this solution, and triethylamine (7.82 ml) was added at room temperature. The reaction mixture was stirred at room temperature for 2 hr, and quenched with 5% hydrochloric acid (10 ml) and water (50 ml). The organic layer was washed with water and saturated brine, dried over sodium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:10→1:5) to give t-butyl [5-chloro-2-(2-oxopyrrolidin-1-yl)benzyl]carbamate (2.70 g).
Reaction SMILES: C(NC1C=CC=CC=1)=O.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[N+:17]([C:20]1[CH:25]=[CH:24][C:23](Cl)=[CH:22][CH:21]=1)([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+]>C(O)=O>[CH:14]1[CH:15]=[CH:16][C:11]([NH:10][C:23]2[CH:24]=[CH:25][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=2)=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=CNc1ccccc1
Agent: [K+]
Solvent: O=CO
Product: O=[N+]([O-])c1ccc(Nc2ccccc2)cc1

Procedure:
formanilide method, where formic acid and aniline are used as starting materials to prepare formanilide, which in turn reacts with p-nitro-chlorobenzene in the presence of an acid-binding agent such as potassium carbonate, to produce 4-nitrodiphenylamine, and then, 4-nitrodiphenylamine is reduced by sodium sulfide to form 4-aminodiphenylamine;
Reaction SMILES: [C:1]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:16][NH2:17]>C1(C)C=CC=CC=1.CCOCC>[C:2]1([C:1]2[N:17]=[N:16][C:12](=[O:14])[CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(O)CCCC(=O)c1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: O
Product: O=c1cccc(-c2ccccc2)nn1
Yield: 39 %

Procedure:
To a mixture of 10 g (0.052 mole) of 4-benzoylbutyric acid in 300 ml of toluene, hydrazine was added in one portion and the reaction was heated to reflux until all water had ceased to azeotrope. The reaction mixture was cooled and the toluene was stripped off in vacuo. The residue was dissolved in 200 ml Et2O and washed with H2O (100 ml) and brine (100 ml). The ether extract was dried over anhydrous MgSO4, filtered and stripped to yield an orange semisolid which was triturated with ether to yield 3.8 g (39%) of the desired product as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:7]([S:8][CH3:9])=[CH:6][CH:5]=[C:4]([C:10]([C:12]2[C:13](=[O:19])[CH2:14][CH2:15][CH2:16][C:17]=2[OH:18])=[O:11])[C:3]1=[O:20].OO.[S:23]([O-:26])(O)=[O:24].[Na+].[CH3:28]O>[O-][W]([O-])(=O)=O.[Na+].[Na+]>[CH3:1][N:2]1[C:7]([S:8]([CH3:9])=[O:24])=[CH:6][CH:5]=[C:4]([C:10]([C:12]2[C:17](=[O:18])[CH2:16][CH2:15][CH2:14][C:13]=2[OH:19])=[O:11])[C:3]1=[O:20].[CH3:1][N:2]1[C:7]([S:23]([CH3:28])(=[O:26])=[O:24])=[CH:6][CH:5]=[C:4]([C:10]([C:12]2[C:17](=[O:18])[CH2:16][CH2:15][CH2:14][C:13]=2[OH:19])=[O:11])[C:3]1=[O:20]
Reactant: CSc1ccc(C(=O)C2=C(O)CCCC2=O)c(=O)n1C
Reactant: CO
Reactant: O=S([O-])O
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Product: Cn1c(S(C)(=O)=O)ccc(C(=O)C2=C(O)CCCC2=O)c1=O
Product: Cn1c(S(C)=O)ccc(C(=O)C2=C(O)CCCC2=O)c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 12 %
Yield: 29 %

Procedure:
2-[1,2-dihydro-1-methyl-6-methylthio-2-oxopyridine-3-carbonyl]-3-hydroxy-2-cyclohexen-1-one (1.2 g, 4.1 mmol), sodium tungstate (0.13 g, 0.4 mmol) and aqueous 35% hydrogen peroxide (0.48 g, 5.4 mmol) were dissolved in methanol (2 mL), and the mixture was stirred for 5 hours at room temperature. The mixed solution was poured into a sodium hydrogensulfite solution, and extracted with chloroform. The obtained organic layer was dried over anhydrous magnesium sulfate, the inorganic substance was separated by filtration, and then the solvent was distilled off under reduced pressure. Thus obtained residue was purified by column chromatography to obtain 0.36 g of 2-[1,2-dihydro-1-methyl-6-methylsulfinyl-2-oxopyridine-3-carbonyl]-3-hydroxy-2-cyclohexen-1-one (1.2 mmol, yield: 29%) and 0.16 g of 2-[1,2-dihydro-1-methyl-6-methylsulfonyl-2-oxopyridine-3-carbonyl]-3-hydroxy-2-cyclohexen-1-one (0.49 mmol, yield: 12%).
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH2:21][C:22]([O:24][CH2:25]C)=[O:23])[C:17]=3[CH:27]=2)[C:3]1=[O:28].[Se](=O)=[O:30]>C(O)(=O)C>[CH3:1][N:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([C:21](=[O:30])[C:22]([O:24][CH3:25])=[O:23])[C:17]=3[CH:27]=2)[C:3]1=[O:28]
Reactant: CCOC(=O)Cc1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Reactant: O=[Se]=O
Solvent: CC(=O)O
Product: COC(=O)C(=O)c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Reaction time: 2 h

Procedure:
A mixture of ethyl 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-acetate(30.0 g, 0.0750 mol), selenium dioxide (15.0 g, 0.135 mol) and glacial acetic acid is stirred two hours at reflux, cooled and filtered through a pad of Celite. The filtrate is concentrated in vacuo and the residue is stirred in methylene chloride. The mixture is filtered and the filtrate filtered through a pad of Celite. The resultant filtrate is treated with saturated sodium bicarbonate and solid sodium bicarbonate with stirring until bubbling ceases. The organic layer is saved. The aqueous layer is extracted with methylene chloride. The combined organic layers are washed with saturated sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is stirred overnight in diethyl ether-methylene chloride to afford, after filtration, the title compound as a white solid (24.5 g, 79.0%, mp 101-103° C.) which is identified by NMR spectral analysis.
Reaction SMILES: [CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:5]([OH:7])=[O:6])([CH3:3])[CH3:2].[OH-].[K+:16]>C(O)C.O>[CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:5]([O-:7])=[O:6])([CH3:3])[CH3:2].[K+:16]
Reactant: CC(C)C(C(=O)O)c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)C(C(=O)[O-])c1ccc(Cl)cc1

Procedure:
α-Isopropyl-4-chlorophenylacetic acid (1.3 g) was dissolved in ethanol (10 ml) and a solution of potassium hydroxide (0.34 g) in water (5 ml) was added to the ethanolic solution. The solvents were then removed by distillation under reduced pressure to give anhydrous potassium α-isopropyl-4-chlorophenylacetate.
Reaction SMILES: COC([C:5]1[NH:6][CH:7]=[C:8]([C:10]2[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:12][O:13][C:14]=2[C:15]([F:18])([F:17])[F:16])[N:9]=1)=O.O.[OH-].[Li+]>C1COCC1.O.Cl.CO>[NH:6]1[CH:7]=[C:8]([C:10]2[C:11]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[N:12][O:13][C:14]=2[C:15]([F:18])([F:16])[F:17])[N:9]=[CH:5]1
Reactant: COC(=O)c1nc(-c2c(-c3ccccc3)noc2C(F)(F)F)c[nH]1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: FC(F)(F)c1onc(-c2ccccc2)c1-c1c[nH]cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
To a solution of 4-(3-phenyl-5-trifluoromethyl-isoxazol-4-yl)-1H-imidazole-2-carboxylic acid methyl ester (100 mg, 0.3 mmol) in THF (1 mL) was added a solution of lithium hydroxide monohydrate (24.8 mg, 0.6 mmol) in water (1 mL) and the resulting mixture stirred at room temperature overnight, and then at 50° C. overnight. After cooling to room temperature the mixture was acidified to pH 1 with HCl (25%, 3 drops) and methanol (2 drops) added. The mixture was then heated at 80° C. for 34 h and left at room temperature for 2 days. The mixture was then extracted with ethyl acetate and the combined organic extracts washed with an aqueous saturated sodium hydrogen carbonate solution, brine, dried over sodium sulfate and evaporated to afford the title compound (70 mg, 85%) which was obtained as an off-white solid. MS: m/e 280.1 [M+H]+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]1[C:16]2[C:15]([NH:17][C@H:18]3[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=O)OC(C)(C)C)[CH2:20][CH2:19]3)=[N:14][CH:13]=[N:12][C:11]=2[S:10][C:9]=1[CH3:32]>C1COCC1>[CH3:7][C:8]1[C:16]2[C:15]([NH:17][C@H:18]3[CH2:23][CH2:22][C@H:21]([NH:24][CH3:25])[CH2:20][CH2:19]3)=[N:14][CH:13]=[N:12][C:11]=2[S:10][C:9]=1[CH3:32]
Reactant: Cc1sc2ncnc(N[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c2c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN[C@H]1CC[C@H](Nc2ncnc3sc(C)c(C)c23)CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a mixture of LiAlH4 (160 mg, 2.1 mmol, 5.0 eq) in THF (5 mL) was added a solution of tert-butyl trans-4-(5,6-dimethylthieno[2,3-d]pyrimidin-4-ylamino)cyclohexylcarbamate (160 mg, 0.42 mmol, 1.0 eq) in THF (5 mL). The mixture was stirred at 80° C. for 2 hours. The reaction was quenched with a mixture of THF/H2O and filtered. The cake was washed with CH2Cl2. The filtrate was concentrated and the residue was purified by column chromatography (CH2Cl2/MeOH/Et3N=20:1:0.5) on silica gel to give desired product compound 1-44 as a white solid (72 mg, 60%). NMR (400 MHz, CDCl3) δ 1.18-1.25 (m, 4H), 1.47 (br s, 2H), 1.95-1.98 (m, 2H), 2.16-2.18 (m, 2H), 2.34 (s, 3H), 2.38 (s, 3H), 2.39 (s, 3H), 4.02-4.08 (m, 1H), 5.23 (m, 1H), 8.23 (s, 1H). MS: m/z 291.2 (M+H)+.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[N:18]=[C:17]([C:19]3[N:23]4[CH:24]=[CH:25][CH:26]=[C:27]([O:28][CH2:29][CH2:30][CH2:31][S:32]([CH3:35])(=[O:34])=[O:33])[C:22]4=[N:21][CH:20]=3)[CH:16]=[CH:15][N:14]=2)[CH2:8][CH2:7]1)=[O:5])C.O[Li].O>C1COCC1.CCO.O>[CH3:35][S:32]([CH2:31][CH2:30][CH2:29][O:28][C:27]1[C:22]2[N:23]([C:19]([C:17]3[CH:16]=[CH:15][N:14]=[C:13]([NH:12][CH:9]4[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]4)[N:18]=3)=[CH:20][N:21]=2)[CH:24]=[CH:25][CH:26]=1)(=[O:34])=[O:33]
Reactant: CCOC(=O)C1CCC(Nc2nccc(-c3cnc4c(OCCCS(C)(=O)=O)cccn34)n2)CC1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)CCCOc1cccn2c(-c3ccnc(NC4CCC(C(=O)O)CC4)n3)cnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
A mixture of 4-{4-[8-(3-methanesulfonyl-propoxy)-imidazo[1,2-a]pyridine-3-yl]-pyrimidin-2-ylamino}-cyclohexanecarboxylic acid ethyl ester (0.1 g) and LiOH—H2O (42 mg) in THF (20 mL), EtOH (5 mL) and water (5 mL) was stirred at RT overnight. The reaction mixture was then concentrated, diluted with water, neutralized with HCl (1 N), and the resulting solid filtered and dried at 50° C. under vacuum overnight to provide 4-{4-[8-(3-methanesulfonyl-propoxy)-imidazo[1,2-a]pyridine-3-yl]-pyrimidin-2-ylamino}-cyclohexanecarboxylic acid (90 mg), which was used without further purification.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[O:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O>>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[O:4][CH:3]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: COC(=O)c1cnc2occ(Br)c2c1
Product: COC(=O)c1cnc2occ(-c3ccccc3Cl)c2c1
Yield: 77 %

Procedure:
In the same manner as in Reference Example 19 and using methyl 3-bromofuro[2,3-b]pyridine-5-carboxylate instead of methyl 3-iodoimidazo[1,2-a]pyridine-6-carboxylate and (2-chlorophenyl)boronic acid instead of (4-methoxyphenyl)boronic acid, the title compound (yield 77%) was obtained as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18](I)=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:54][N:55]([CH:57]=[O:58])[CH3:56].N1C[CH2:63][O:62][CH2:61]C1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([C:57]([N:55]2[CH2:56][CH2:63][O:62][CH2:61][CH2:54]2)=[O:58])=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(I)cc2c1O
Reactant: CN(C)C=O
Reactant: C1COCCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(C(=O)N3CCOCC3)cc2c1O
Temperature: 60 °C

Procedure:
To a pressure tube containing N-[(4-chlorophenyl)methyl]-8-fluoro-4-hydroxy-6-iodo-3-quinolinecarboxamide of Example No. 5 (0.23 g), palladium (II) acetate (12 mg), and 1,3-bis(diphenylphosphino)propane (20 mg) is added DMF (5 mL), triethylamine (0.14 mL) and morpholine (0.13 mL). The reaction mixture is placed under an atmosphere of carbon monoxide gas, then tightly sealed and heated at 60° C. overnight. The reaction is cooled to room temperature and concentrated under reduced pressure. The residue is partioned between dichloromethane and aqueous phosphate buffer (0.1M, pH=4). The organic phase is washed with aqueous phosphate buffer (0.1M, pH=10), brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue is chromatographed on silica eluting with 2% MeOH:CH2Cl2 to 8% MeOH:CH2Cl2. The product-containing fractions are evaporated to give 0.13 g of the title compound as a tan solid.
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.[CH3:21][O:22][CH2:23][O:24][C:25]1[CH:30]=[C:29]([O:31][S:32]([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[CH:28]=[CH:27][C:26]=1B(O)O.[Cl-].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[CH:11]1([C:10]2[C:9]3[C:4](=[CH:5][C:6]([C:17]([O:19][CH3:20])=[O:18])=[CH:7][CH:8]=3)[NH:3][C:2]=2[C:26]2[CH:27]=[CH:28][C:29]([O:31][S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])=[CH:30][C:25]=2[O:24][CH2:23][O:22][CH3:21])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COCOc1cc(OS(=O)(=O)c2ccc(C)cc2)ccc1B(O)O
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COCOc1cc(OS(=O)(=O)c2ccc(C)cc2)ccc1-c1[nH]c2cc(C(=O)OC)ccc2c1C1CCCCC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
Methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (prepared as in International patent application WO 2004/087714), (2-(methoxymethoxy)-4-{[(4-methylphenyl)-sulfonyl]oxy}phenyl)boronic acid (1 eq) and bis(triphenylphosphinepalladium(II) chloride (0.1 eq) were dissolved in dioxane (0.08M). The solution was degassed and flushed with argon. A 2M aqueous solution of Na2CO3 (1 eq) was added and the mixture was heated to 100° C. After 3 h the temperature was raised to 110° C. Heating was continued overnight. All volatiles were evaporated and the residual material was dissolved in EtOAc. The solution was washed with 1N aqueous HCl, sat. aq. NaHCO3 and brine. After drying over Na2SO4 all volatiles were evaporated in vacuo. The residual material was subjected to FC (PE:EtOAc, 8:2). After evaporation of the product fractions the product was obtained as a light orange amorphous solid (58%). (ES+) m/z 564 (M+H)+.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[C:26]1([C:32]2[N:33]=[CH:34][NH:35][C:36]=2[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:33]3[C:32]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[C:36]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[N:35]=[CH:34]3)[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[CH:8][CH:9]=1
Reactant: c1ccc(-c2nc[nH]c2-c2ccccc2)cc1
Reactant: COc1ccccc1OCCCc1oc(Cl)nc1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1OCCCc1oc(-n2cnc(-c3ccccc3)c2-c2ccccc2)nc1-c1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 39.2 %

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-[3-(2-methoxyphenoxy)propyl]oxazole (378 mg), 4,5-diphenylimidazole (270 mg), anhydrous potassium carbonate (220 mg) and N,N-dimethylformamide (10 ml) was stirred at 100° C. for 12 hours. The reaction mixture was poured into water, the resulting solid precipitate was filtered and air-dried. Recrystallization of this solid from acetone-isopropyl ether gave 4-(4-chlorophenyl)-2-(4,5-diphenyl-1-imidazolyl)-5-[3-(2-methoxyphenoxy)propyl]oxazole as pale yellow prisms (220 mg, 46%). Melting point 118-119° C.
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]([F:19])([F:18])[F:17])[CH:10]=1.[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22]>C(OCC)(=O)C.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:20][Si:21]([CH3:23])([CH3:22])[C:24]#[C:25][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]([F:19])([F:18])[F:17])[CH:10]=1
Reactant: C#C[Si](C)(C)C
Reactant: FC(F)(F)Oc1cccc(Br)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[Si](C)(C)C#Cc1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
Add copper (I) iodide (45.0 mg, 0.24 mmol), bis(triphenylphosphine)palladium (II) dichloride (147.4 m g, 0.21 mmol) and triethylamine (2.37 mL, 16.8 mmol), to a solution of 1-bromo-3-trifluoromethoxybenzene (0.62 mL, 4.15 mmol) and trimethylsilylacetylene (0.78 mL, 5.4 mmol), in ethyl acetate (4 mL) and stir at 50° C. for 18h. Cool the reaction mixture to room temperature, concentrate and purify by silica gel chromatography, eluting with hexanes to give the title compound (1.07 g, 100%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N+:16]([O-])=O)[C:8]([O:14][CH3:15])=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].O.CC1CCC=CC1>C(O)C.[Pd].C(OCC)(=O)C>[C:1]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:14][CH3:15])=[C:7]([NH2:16])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c([N+](=O)[O-])cc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: CC1CC=CCC1
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: COc1c(N)cc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
2 g 5-tert-butyl-2-methoxy-1,3-dinitro-benzene are dissolved in 20 ml ethanol and combined with 2 ml of water and 100 mg of 10% palladium on charcoal. The mixture is refluxed, 1.9 ml of 4-methyl-1-cyclohexene are added and the mixture is refluxed for a further 2 hours. Then a further 1.0 ml of 4-methyl-1-cyclohexene are added dropwise and the mixture is refluxed for a further 16 hours. Then it is cooled to ambient temperature, the solvents are eliminated in vacuo and the residue is taken up in ethyl acetate. The mixture is washed with saturated aqueous sodium hydrogen carbonate solution, water, saturated aqueous sodium chloride solution and dried with sodium sulphate. The solvent is eliminated in vacuo and the product thus obtained is further reacted directly.
Reaction SMILES: [CH:1]12[O:6][CH:2]1[CH2:3][CH2:4][CH2:5]2.[NH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>>[N:7]1([C@@H:2]2[CH2:3][CH2:4][CH2:5][C@H:1]2[OH:6])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: C1CCNCC1
Reactant: C1CC2OC2C1
Product: O[C@@H]1CCC[C@H]1N1CCCCC1
Yield: 81 %

Procedure:
The title compound was prepared in 81% yield from cyclopentene oxide and piperidine by essentially following the procedures outlined in Example 20, Part A.