Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([C:9]([OH:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[CH:6]=[C:5]([CH3:19])[C:3]=1[NH2:4].[C:20]([NH:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](Cl)=[O:33])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1C=CC=CC=1.C(=O)([O-])O.[Na+]>O.C(OCC)(=O)C.O1CCCC1>[CH3:1][C:2]1[CH:8]=[C:7]([C:9]([OH:18])([C:10]([F:12])([F:13])[F:11])[C:14]([F:15])([F:16])[F:17])[CH:6]=[C:5]([CH3:19])[C:3]=1[NH:4][C:32](=[O:33])[C:31]1[CH:35]=[CH:36][CH:37]=[C:29]([NH:28][C:20](=[O:27])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:30]=1
Reactant: O=C(Cl)c1cccc(NC(=O)c2ccccc2)c1
Reactant: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cccc(NC(=O)c2ccccc2)c1
Temperature: 25 °C
Yield: 95.7 %

Procedure:
At room temperature, 2.0 g of 2,6-dimethyl-4-[1-hydroxy-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]aniline, 2.7 g of 3-(benzoylamino)benzoyl chloride and 1.2 g of pyridine were introduced to 50 ml of tetrahydrofuran, and the mixture was stirred at room temperature. After the loss of the starting material was confirmed through TLC, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution and the solution was stirred for a while. Subsequently, ethyl acetate and water were added to the reaction solution, and phase separation was carried out. The separated organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and dried, and thus obtained residue was grinded to give 3.4 g (yield 95%) of the title compound as a powder form.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([N:12]2[CH:16]=[CH:15][CH:14]=[N:13]2)[CH:6]=1)[CH3:2].[Br:18]Br>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([N:12]2[CH:16]=[C:15]([Br:18])[CH:14]=[N:13]2)[CH:6]=1)[CH3:2]
Reactant: BrBr
Reactant: CCOC(=O)c1ccc(C)c(-n2cccn2)c1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc(C)c(-n2cc(Br)cn2)c1
Yield: 102.6 %

Procedure:
A solution of 3-hydrazino-4-methyl benzoic acid (See U.S. provisional application 60/570,284) (1.0 g, 4.93 mmol), malonaldehyde(bismethylacetate) (0.82 mL, 4.93 mmol), and concentrated HCl (1 mL) in EtOH (20 mL) was heated to reflux for 4 h. After cooling to room temperature, the reaction was poured into ice water, neutralized with 2N NaOH, and extracted with CH2Cl2 (3×). The organic layers were dried over Na2SO4, filtered and concentrated to afford 4-methyl-3-pyrazol-1-yl-benzoic acid ethyl ester (536 mg, 47%) as a yellow oil. A solution of the pyrazole (536 mg, 2.33 mmol) and bromine (0.167 mL, 3.26 mmol) in CHCl3 (15 mL) was refluxed for 4.5 h then cooled and concentrated. Chromatography (1:1 EtOAc/hexanes) yielded 3-(4-bromo-pyrazol-1-yl)-4-methyl-benzoic acid ethyl ester (0.739 g, 99%). The bromopyrazole (366 mg, 1.18 mmol) was dissolved in dioxane (2 mL) and flushed with N2. 1-Methyl-5-tributylstannanyl-1H-imidazole (366 mg, 0.986 mmol) was added to the reaction flask in dioxane (0.5 mL) then the flask was purged with N2. After Pd(PPh3)4 (85 mg, 0.074 mmol) was added, the reaction was heated to 100° C. in a sealed tube. The reaction mixture was stirred with a 10% KF solution for 30 min then diluted with EtOAc. The layers were separated and the aqueous layer extracted with EtOAc (3×). The organic layers were combined, dried over Na2SO4, and concentrated. The resulting residue was purified by chromatography on silica gel (5% MeOH/CH2Cl2) to give 4-methyl-3-[4-(3-methyl-3H-imidazol-4-yl)-pyrazol-1-yl]-benzoic acid ethyl ester (81 mg, 22%).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:10]3[O:11][CH2:12][CH2:13][CH2:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:16]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:16][C:15]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][N:9]2[CH2:14][CH2:13][CH2:12][O:11][C:10]=12
Reactant: c1ccc(-c2cc3n(n2)CCCO3)cc1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Brc1c(-c2ccccc2)nn2c1OCCC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-phenyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (6.3 g, 0.031 mol) in 60 mL chloroform is added a solution of bromine (1 eq, 5.03 g, 0.031 mol) in 40 mL chloroform over a period of 25 min at room temperature. The resulting suspension is stirred for 4 h at room temperature. Thereafter the reaction mixture is treated with aqueous sodium thiosulfate, the phases are separated and the organic phase is washed with water and dried over sodium sulfate. The volatiles are evaporated and the crude product is purified by filtration over silica using a 1:1 mixture of ethyl acetate/cyclohexane as eluent. After evaporation of the solvent 7.0 g (90%) of 3-bromo-2-phenyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine are obtained as solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Li]CCCC.[O:11]=[C:12]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:13]1>C1COCC1>[OH:11][C:12]1([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:13]1
Reactant: c1cscn1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(O)(c2nccs2)CC1
Temperature: -60 °C
Reaction time: 0.75 h
Yield: 96.5 %

Procedure:
Thiazole (21.3 g, 250 mmol) in THF (160 mL) was cooled to −70° C. and then n-BuLi (100 mL, 250 mmol) was added slowly over 5 minutes, keeping the temperature at −60° C. or lower. The resulting slurry was stirred for 45 minutes at this temperature and then the product of Step 1 (48.55 g, 228 mmol) in THF (50 mL) was added dropwise, maintaining the temperature at −60° C. The solution was stirred for one hour and then the cooling bath removed. At −20° C., 2M HCl (114 mL) was added and upon warming to RT the homogeneous solution was diluted with EtOAc (150 mL). The phases were separated and the aqueous layer was extracted with EtOAc (150 mL). The combined organic layers were washed with aqueous saturated NaHCO3 (150 mL), brine (150 mL) and then concentrated to a thick syrup. This was dissolved in EtOAc (140 mL) and then treated with hexane (210 mL) and the slurry filtered to afford tert-butyl 4-hydroxy-4-(1,3-thiazol-2-yl)azepane-1-carboxylate as a white solid (68.0 g, 220 mmol) and the material was then subjected to chiral chromatography to afford tert-butyl (4R)-4-hydroxy-4-(1,3-thiazol-2-yl)azepane-1-carboxylate (14.5 g, 48.6 mmol).
Reaction SMILES: I[C:2]1[C:11]2=[CH:12][N:13]([C@@H:15]3[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@@:16]3([CH3:24])[OH:17])[N:14]=[C:9]3[C:10]2=[C:4]([C:5](=[O:25])[NH:6][N:7]=[CH:8]3)[CH:3]=1.[C:26]([Cu])#[N:27]>CN(C=O)C>[C:26]([C:2]1[C:11]2=[CH:12][N:13]([C@@H:15]3[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@@:16]3([CH3:24])[OH:17])[N:14]=[C:9]3[C:10]2=[C:4]([C:5](=[O:25])[NH:6][N:7]=[CH:8]3)[CH:3]=1)#[N:27]
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc2c(I)cc3c(=O)[nH]ncc(n1)c23
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc2c(C#N)cc3c(=O)[nH]ncc(n1)c23
Temperature: 65 °C
Reaction time: 8 h

Procedure:
To a solution of the title product from Example 19 in DMF is added CuCN/Bu4NCN and the mixture is stirred at 65° C. overnight to form the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:18](C)[C:19](=O)C)[CH:5]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH:7]=1>O1CCOCC1.[OH-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]([NH:18][CH3:19])[CH:5]=[C:6]([S:8][C:9]2[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:7]=1
Reactant: CC(=O)N(C)c1cc(Br)cc(Sc2ccc([N+](=O)[O-])cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CNc1cc(Br)cc(Sc2ccc([N+](=O)[O-])cc2)c1
Yield: 106.6 %

Procedure:
0.79 g (0.002 mol) of N-[3-bromo-5-(4-nitrophenylsulphanyl) -phenyl]-N-methylacetamide was dissolved in a mixture of 10 ml of dioxane and 10 ml of 1N NaOH and heated at reflux for 2 hrs. Subsequently, the organic solvent was distilled off and the residue was made neutral with 1N HCl and extracted with ethyl acetate. The organic phase was washed with water and sat. sodium chloride solution, dried over MgSO4, filtered, concentrated and dried. There was obtained 0.723 g (100%) of [3-bromo-5-(4-nitrophenylsulphanyl)-phenyl]-methylamine as red crystals; m.p.: 96-98° C.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[N:10]=[CH:9][N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[C:7]=2[CH:6]=[CH:5][C:4]=1[C:18]#[N:19])[CH3:2].[BH4-].[Na+]>CO>[CH2:1]([C:3]1[C:11]2[N:10]=[CH:9][N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[C:7]=2[CH:6]=[CH:5][C:4]=1[CH2:18][NH2:19])[CH3:2]
Reactant: CCc1c(C#N)ccc2c1ncn2C1CCCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCc1c(CN)ccc2c1ncn2C1CCCCO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.3 %

Procedure:
To a solution of 4-ethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole-5-carbonitrile 6 (7.0 g, 0.027 mol) in dry MeOH (70 mL) at 0° C. was added CoCl2 (5.69 g, 0.043 mol, 1.6 equiv.) and NaBH4 (12.44 g, 0.33 mol, 12 equiv.). The reaction mixture was warmed to RT and stirred for 16 h, then filtered through a Celite® pad and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with 5% MeOH/CHCl3 to afford (4-ethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl) methanamine (5.2 g, 73%) as off white solid.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[C:5]1[N:10]=[C:9]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1>>[CH3:1][N:2]([CH3:3])[C:5]1[N:10]=[C:9]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1
Reactant: O=C(O)c1ccc(-c2ccnc(Cl)n2)cc1
Reactant: CNC
Product: CN(C)c1nccc(-c2ccc(C(=O)O)cc2)n1

Procedure:
Using dimethylamine and 4-[2-chloro-pyrimidin-4-yl]-benzoic acid as substrates. MS (ion spray) m/z 244 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:53])[CH2:7][C@H:8]([NH:27][C:28]([C@@H:30]1[CH2:35][CH2:34][CH2:33][N:32]([C:36](=[O:52])[CH2:37][CH2:38][CH:39]2[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH2:40]2)[CH2:31]1)=[O:29])[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]#[C:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH2:25][F:26])[CH:18]=2)[CH:14]=1)([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.CO.[Pd]>[C:1]([O:5][C:6](=[O:53])[CH2:7][C@H:8]([NH:27][C:28]([C@@H:30]1[CH2:35][CH2:34][CH2:33][N:32]([C:36](=[O:52])[CH2:37][CH2:38][CH:39]2[CH2:40][CH2:41][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:43][CH2:44]2)[CH2:31]1)=[O:29])[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH2:25][F:26])[CH:18]=2)[CH:14]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(C#Cc2cccc(OCCF)c2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(CCc2cccc(OCCF)c2)c1
Yield: 74.1 %

Procedure:
Tert-butyl 4-{3-[(3R)-3-{[(1S)-3-tert-butoxy-1-(5-{[3-(2-fluoroethoxy)phenyl]ethynyl}pyridin-3-yl)-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (30 mg, 40 μmol) in ethyl acetate (1.2 mL) and methanol (0.2 mL) was stirred for 2.5 hours at room temperature under a hydrogen atmosphere in the presence of palladium on charcoal (10%, 3 mg). The suspension was filtrated through celite, which were washed thoroughly with methanol. The solution was concentrated under reduced pressure and purified by preparative HPLC to yield 21.9 mg of tert-butyl 4-{3-[(3R)-3-{[(1S)-3-tert-butoxy-1-(5-{2-[3-(2-fluoroethoxy)phenyl]ethyl}pyridin-3-yl)-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate
Reaction SMILES: [CH3:1][N:2]([C:4]([NH:6][CH3:7])=[S:5])[NH2:3].N1C=CC=CC=1.[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[C:24](Cl)=[O:25]>O>[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[C:24]([NH:3][N:2]([CH3:1])[C:4]([NH:6][CH3:7])=[S:5])=[O:25]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: CNC(=S)N(C)N
Solvent: c1ccncc1
Solvent: O
Product: CNC(=S)N(C)NC(=O)c1ccc2ccccc2c1

Procedure:
To a stirred solution of 2,4-dimethylthiosemicarbazide (2.39 g, 2.00×10-2 mole) and pyridine (20 ml) was added dropwise 2-naphthoyl chloride. (3.89 g, 2.04×1031 2 mole) After stirring at room temperature for 48 hours the reaction was evaporated to dryness, affording a beige solid which was treated with H2O (100 ml). Filtration of the aqueous mixture gave the desired compound as a beige product, 5.47 g (100%). If pure 1-(2-naphthoyl)-2,4dimethylthiosemicarbazide is desired, the crude product is purified by crystallization.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][C:15]=2[NH2:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:25](OCC)(OCC)OCC.Cl.N1C=CC=CC=1>>[C:1]1([S:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[C:14]3[C:23]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[N:17]=[CH:16][C:15]=3[N:24]=[CH:25]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cnc2ccccc2c1NCCCCCSc1ccccc1
Reactant: CCOC(OCC)OCC
Agent: Cl
Solvent: c1ccncc1
Product: c1ccc(SCCCCCn2cnc3cnc4ccccc4c32)cc1

Procedure:
Using the general method of Example 1 Part D, N4-[5-(phenylthio)pentyl]quinoline-3,4-diamine (5.1 g, 15.1 mmol) was cyclized using triethyl orthoformate (2.46 g, 16.6 mmol) in the presence of a catalytic amount of pyridine hydrochloride to provide 1-[5-(phenylthio)pentyl]-1H-imidazo[4,5-c]quinoline as a yellow solid.
Reaction SMILES: [OH:1][C:2]1([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][C:14]=2[OH:22])[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)Cl.CC(NP(OC1C=CC(Cl)=CC=1Cl)(OC)=S)C>[C:23]([O:1][C:2]1([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:20])[CH3:21])=[CH:15][C:14]=2[OH:22])[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)c1ccc(C2(O)C(=O)c3ccccc3C2=O)c(O)c1
Reactant: O=C(Cl)c1ccccc1
Agent: COP(=S)(NC(C)C)Oc1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1ccc(C2(OC(=O)c3ccccc3)C(=O)c3ccccc3C2=O)c(O)c1
Yield: 60 %

Procedure:
2-hydroxy-2-(2-hydroxy-4-isopropyl-phenyl)-indan-1,3-dione (1.00 g, 3.37 mmol) was completely dissolved in anhydrous methylene chloride (20 ml). This solution was added with benzoyl chloride (0.94 g, 6.74 mmol), triethylamine (0.41 g, 4.04 mmol), and DMPA (0.01 g), followed by heating 24 hrs under reflux. After the reaction mixture was concentrated, extracted with dichloromethane, and the organic layer was concentrated and purified using column chromatography (ethylacetate:hexane=1:4) to afford the title compound (0.81 g, 14%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=1[C:15]1[CH:19]=[CH:18][NH:17][N:16]=1.Br[CH2:21][C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23]>C(#N)C>[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=1[C:15]1[CH:19]=[CH:18][N:17]([CH2:21][C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])[N:16]=1
Reactant: Fc1cccc(F)c1-c1cc[nH]n1
Reactant: C=CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCOC(=O)Cn1ccc(-c2c(F)cccc2F)n1
Yield: 97.1 %

Procedure:
Potassium carbonate (1.53 g) was added to an acetonitrile (10 mL) solution of 3-(2,6-difluorophenyl)pyrazole (1 g) and allyl 2-bromoacetate (1.49 g), and refluxed for 3 hours. The resulting product was extracted with acetate and diluted hydrochloric acid added thereto at room temperature. The organic layer was dried over anhydrous magnesium sulfate and concentrated, and the resulting concentrate was purified through silica gel column chromatography (chloroform) to obtain allyl 2-{3-(2,6-difluorophenyl)pyrazol-1-yl}acetate (1.5 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[N:7]([CH2:12][CH2:13][CH2:14][NH2:15])[CH2:8][CH:9]1[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[CH2:17]([O:19][C:20](=[O:30])[CH2:21][N:22]1[CH:27]=[CH:26][N:25]=[C:24](Br)[C:23]1=[O:29])[CH3:18].C(N(CC)CC)C>C(O)C>[CH2:17]([O:19][C:20](=[O:30])[CH2:21][N:22]1[CH:27]=[CH:26][N:25]=[C:24]([NH:15][CH2:14][CH2:13][CH2:12][N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:16])[CH2:8][CH:9]2[CH2:10][CH2:11]2)[C:23]1=[O:29])[CH3:18]
Reactant: CCOC(=O)Cn1ccnc(Br)c1=O
Reactant: CC(C)(C)OC(=O)N(CCCN)CC1CC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)Cn1ccnc(NCCCN(CC2CC2)C(=O)OC(C)(C)C)c1=O

Procedure:
A solution of (3-amino-propyl)-cyclopropylmethyl-carbamic acid tert-butyl ester (5 g, 0.022 mol), (3-bromo-2-oxo-2H-pyrazin-1-yl)-acetic acid ethyl ester (5.2 g, 0.020 mol, preparation described in example 17, step J) and triethylamine (3.3 ml, 0.024 mol) in ethanol (16 ml) was heated to 80° C. in a sealed tube overnight. Concentration and flash chromatography (silica gel, chloroform-diethyl ether, 90: 10) gave {3-[3-(tert-butoxycarbonyl-cyclopropylmethyl-amino)-propylamino]-2-oxo-2H-pyrazin-1-yl}-acetic acid ethyl ester; 1H NMR (CDCl3, 400 MHz) δ 6.85 (d, 1H, J=4.7 Hz), 6.36 (d, 1H, J=4.7 Hz), 4.56 (s, 2H), 4.25 (q, 2H, J=7.1 Hz), 3.42 (m, 2H), 3.36 (m, 2H), 3.10 (m, 2H), 1.87 (m, 2H), 1.46 (s, 9H), 1.30 (t, 3H, J=7.1 Hz), 0.96 (m, 1H), 0.48 (m, 2H), 0.20 (m, 2H).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([S:11][CH2:12][C:13](=O)[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:8]=[CH:9][CH:10]=1)(=O)C>S(=O)(=O)(O)O>[OH:4][C:5]1[CH:10]=[CH:9][C:8]2[C:13]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][S:11][C:7]=2[CH:6]=1
Reactant: CCOC(=O)CCC(=O)CSc1cccc(OC(C)=O)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCc1csc2cc(O)ccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82.2 %

Procedure:
Concentrated sulfuric acid (20 ml) was cooled in an ice-water bath to 0° C. and added to a flask containing ethyl 5-(3-acetyloxyphenylthio)-4-oxopentanoate (920 mg, 3.4 mmol) at 0° C. The reaction was stirred at 0° C. for 15 minutes, and then poured over ice. The mixture was extracted with ethyl acetate, dried, filtered, and evaporated under vacuum to yield 700 mg (82%) of Ethyl 3-(6-hydroxybenzo[b]thiophen-3-yl)propanoate. NMR 1H DMSO-d6 δ: 9.59 (s, 1H), 7.59 (d, 1H, J=8.4 Hz), 7.25 (d, 1H, J=2.4 Hz), 7.08 (s, 1H), 6.89 (dd, 1H, J=2.4, 8.4 Hz), 4.06 (c, 2H, J=7.2 Hz), 2.99 (t, 2H, J=6.8 Hz), 2.70 (t, 2H, J=6.8 Hz), 1.16 (t, 1H, J=7.2 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6]O.S(Cl)([Cl:17])=O.C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6][Cl:17]
Reactant: COc1cc(CO)cc(OC)c1OC
Reactant: O=S(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: COc1cc(CCl)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In 40 ml of benzene was dissolved 10 g of 3,4,5-trimethoxybenzyl alcohol. To the resulting solution was dropwise added under chilling with ice 10 ml of benzene solution containing 7.6 g of thionyl chloride. After the addition was complete, the mixture was stirred at room temperature for 15 min. The reaction solution was poured into a chilled aqueous potassium carbonate, and a separated benzene portion was collected. The benzene portion was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and placed under reduced pressure to distill off the solvent. The desired compound was obtained as a yellow solid (yield: 11.0 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[C:9]([C:10]([NH2:12])=[O:11])[C:8]([OH:14])=[CH:7][CH:6]=1.[O:15]1[CH2:35][CH:16]1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:26]([CH3:34])[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[N:29]=2)=[CH:21][CH:20]=1.CO>CS(C)=O>[C:10]([C:9]1[CH:13]=[C:5]([CH:6]=[CH:7][C:8]=1[OH:14])[O:4][CH2:3][CH2:2][NH:1][CH2:35][CH:16]([OH:15])[CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[N:26]([CH3:34])[CH:27]=[C:28]([C:30]([F:32])([F:33])[F:31])[N:29]=2)=[CH:23][CH:24]=1)(=[O:11])[NH2:12]
Reactant: NCCOc1ccc(O)c(C(N)=O)c1
Reactant: Cn1cc(C(F)(F)F)nc1-c1ccc(OCC2CO2)cc1
Solvent: CS(C)=O
Solvent: CO
Product: Cn1cc(C(F)(F)F)nc1-c1ccc(OCC(O)CNCCOc2ccc(O)c(C(N)=O)c2)cc1
Reaction time: 1 h

Procedure:
A solution of 3.9 g of 5-(2-aminoethoxy)-salicylamide in 30 ml of dimethyl sulphoxide is heated to 70° and 7.2 g of 2-[4-(2,3-epoxypropoxy)-phenyl]-1-methyl-4-(trifluoromethyl)-1H-imidazole are added. The reaction mixture is stirred for 1 hour at 70° and worked up analogously to Example 12. 1-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-phenoxy]-2-propanol having a melting point of 195°-197° is obtained (from methanol).
Reaction SMILES: C([O:4][C@H:5]([CH3:25])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]2[C:17]([CH3:22])=[CH:18][C:19](=[O:21])[NH:20][C:13]=2[N:12]([CH3:23])[C:11]1=[O:24])(=O)C.Cl.C(=O)(O)[O-].[Na+]>CO>[CH3:23][N:12]1[C:13]2[NH:20][C:19](=[O:21])[CH:18]=[C:17]([CH3:22])[C:14]=2[C:15](=[O:16])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]([OH:4])[CH3:25])[C:11]1=[O:24]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(C)cc(=O)[nH]c2n(C)c1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1cc(=O)[nH]c2c1c(=O)n(CCCC[C@@H](C)O)c(=O)n2C
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.5 %

Procedure:
A mixture of (R)-3-(5-acetoxyhexyl)-1,5-dimethylpyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione (175 mg, 0.50 mmol), methanol (5 ml) and 12 M aqueous hydrochloric acid (1 ml) was stirred at room temperature for 18 hours and then treated with saturated aqueous sodium bicarbonate solution (10 ml). After concentrating under reduced pressure to remove the methanol, the aqueous mixture was extracted with ethyl acetate (20 ml). The extract was applied to a short column of silica gel and eluted with ethyl acetate to afford (R)-1,5-dimethyl-3-(5-hydroxyhexyl)pyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione (50 mg, 32% yield) as a white powder. 1H NMR (300 MHz, CDCl3) δ 1.17 (d, 3H), 1.30-1.71 (m, 6H), 2.67 (s, 3H), 3.57 (s, 3H), 3.72-3.88 (m, 1H), 3.98 (t, 2H), 6.23 (s, 1H).
Reaction SMILES: [Mg].[CH3:2][O:3][CH2:4][C:5]#N.[Cl:7][C:8]1[CH:9]=[C:10]([Mg:15][Br:16])[CH:11]=[CH:12][C:13]=1[Cl:14].C([O:19]CC)C>BrC1C=CC(Cl)=C(Cl)C=1>[Cl:7][C:8]1[CH:9]=[C:10]([Mg:15][Br:16])[CH:11]=[CH:12][C:13]=1[Cl:14].[Cl:7][C:8]1[CH:9]=[C:10]([C:5](=[O:19])[CH2:4][O:3][CH3:2])[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: CCOCC
Reactant: COCC#N
Agent: Clc1ccc(Br)cc1Cl
Agent: Clc1ccc([Mg]Br)cc1Cl
Agent: [Mg]
Product: COCC(=O)c1ccc(Cl)c(Cl)c1

Procedure:
A solution (about 100 mL) of 3,4-dichlorophenylmagnesium bromide in diethyl ether was prepared from a mixture of magnesium (flakes) (2.07 g) in diethyl ether (100 mL) and 1-bromo-3,4-dichlorobenzene (17.5 g). A solution of methoxyacetonitrile (5.0 g) in diethyl ether (10 mL) was added dropwise to a solution of 3,4-dichlorophenylmagnesium bromide in diethyl ether under ice-cooling, and the resulting mixture was stirred under ice-cooling for 20 min. The reaction mixture was quenched with water, the mixture was acidified with 1 N hydrochloric acid, and the mixture was stirred under ice-cooling for 15 min. The reaction mixture was extracted with ethyl acetate, the organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated to give a pale-yellow oil. The oil was purified by silica gel column chromatography (eluent; hexane:ethyl acetate (19:1-1:1)) to give the title compound (10.5 g).