Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH2:8]([O:10][CH:11]([O:16][CH2:17][CH3:18])[CH2:12][CH2:13][CH2:14][NH2:15])[CH3:9].C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1>[CH2:17]([O:16][CH:11]([O:10][CH2:8][CH3:9])[CH2:12][CH2:13][CH2:14][NH:15][C:1](=[O:3])[CH3:2])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(CCCN)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: CCOC(CCCNC(C)=O)OCC

Procedure:
20 g (196 mmol) of acetic anhydride in 100 ml of benzene are added drop by drop, at reflux, to a stirred suspension of 32 g (198 mmol) of 4,4-diethoxybutylamine and 24 g (174 mmol) of potassium carbonate in 600 ml of benzene. The mixture is heated to reflux for 15 min. and cooled, the precipitate is filtered and the filtrate is evaporated to dryness. The residual oil is treated with vegetable charcoal in 300 ml of diethyl ether and, after filtration and evaporation of the filtrate in vacuo, 37.3 g of oily product are obtained. n20D =1.4472.
Reaction SMILES: Cl([O-])=O.[Na+].[OH2:5].O.P([O-])(O)(O)=O.[Na+].[Cl:13][C:14]1[N:15]=[C:16]2[N:20]([C:21]=1[CH:22]=[O:23])[CH:19]=[CH:18][S:17]2>O.C(O)(C)(C)C>[Cl:13][C:14]1[N:15]=[C:16]2[N:20]([C:21]=1[C:22]([OH:5])=[O:23])[CH:19]=[CH:18][S:17]2
Reactant: O
Reactant: O=Cc1c(Cl)nc2sccn12
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Product: O=C(O)c1c(Cl)nc2sccn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of sodium chlorite (230 mmol) and sodium dihydrogen phosphate dihydrate (176 mmol) in water (195 mL) is added dropwise to a solution of 6-chloro-imidazo[2,1-b]thiazole-5-carbaldehyde (26.8 mmol) in tert.-butanol (195 mL) and the mixture is stirred for 8 h at RT. The solvents are partially removed in vacuo and the obtained precipitate is filtered off. The filtrate is made acidic and the obtained precipitate is filtered off to give the desired product as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:9](=[O:27])[N:10]1[CH2:22][C:21]2[NH:20][C:19]3[CH:18]=[CH:17][CH:16]=[C:15]4[C:23](=[O:26])[NH:24][N:25]=[C:12]([C:13]=2[C:14]=34)[CH2:11]1)(C)(C)C.Cl.NC(C)(C)C(N1CC2NC3C=CC=C4C(=O)NN=C(C=2C=34)C1)=O>>[NH2:7][C@@H:8]([CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:9]([N:10]1[CH2:22][C:21]2[NH:20][C:19]3[CH:18]=[CH:17][CH:16]=[C:15]4[C:23](=[O:26])[NH:24][N:25]=[C:12]([C:13]=2[C:14]=34)[CH2:11]1)=[O:27]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CC2=NNC(=O)c3cccc4[nH]c(c2c34)C1
Agent: CC(C)(N)C(=O)N1CC2=NNC(=O)c3cccc4[nH]c(c2c34)C1
Agent: Cl
Product: N[C@@H](Cc1ccccc1)C(=O)N1CC2=NNC(=O)c3cccc4[nH]c(c2c34)C1

Procedure:
Compound 64 was prepared from Compound 63 with hydrogen chloride according to the procedure similar to that for Compound 62. 1H NMR (DMSO-d6) δ 11.9 (s, 1H), 10.1 (s, 1H), 7.48 (d, 1H, J=8.0 Hz), 7.48-7.52 (m, 2H), 7.10-7.20 (m, 6H), 4.93-4.96 (m, 3H), 4.18-4.25 (m, 2H), 4.00-4.03 (m, 2H), 2.78-2.85 (m, 1H), and 2.61-2.65 (m, 1H). MS (ESI) m/e [M+1]+ 374.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:3]1.Cl[C:20]([O:22][CH3:23])=[O:21].C(N(CC)CC)C>C1COCC1>[CH2:11]([O:10][C:9]([NH:8][C@H:4]1[CH2:5][CH2:6][CH2:7][C@@H:2]([NH:1][C:20](=[O:21])[O:22][CH3:23])[CH2:3]1)=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)Cl
Reactant: N[C@@H]1CCC[C@H](NC(=O)OCc2ccccc2)C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)N[C@@H]1CCC[C@H](NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzyl N-[(1S,3R)-3-aminocyclohexyl]carbamate, 18e, (0.99 g, 3.99 mmol) was dissolved in THF (20 mL) and treated with methyl chloroformate (0.62 mL, 7.97 mmol), followed by triethylamine (1.67 mL, 11.96 mmol). After stirring for 1 hour at room temperature, the solvent was evaporated under reduced pressure and the residue was diluted into 1:3 mixture of CH2Cl2:EtOAc (130 mL) and washed with 1N HCl (50 mL) and 2N Na2CO3 (50 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford the desired product, 19a, as a white solid (1.09 g, 89% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:11])[C:6]([OH:10])=[CH:7][C:8]=1[CH3:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH2:21][C:22]([CH3:28])([CH3:27])[C:23]([O:25][CH3:26])=[O:24]>C(#N)C>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([O:10][CH2:19][CH2:20][CH2:21][C:22]([CH3:28])([CH3:27])[C:23]([O:25][CH3:26])=[O:24])=[C:5]([CH3:11])[CH:4]=1
Reactant: COC(=O)C(C)(C)CCCBr
Reactant: COc1cc(C)c(O)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C(C)(C)CCCOc1cc(C)c(OC)cc1C

Procedure:
A 500 mL, 3 neck round bottom flask is charged with 7.6 g (50 mmol) of 4-methoxy-2,5-xylenol, 8.3 g (60 mmol) of anhydrous potassium carbonate 13.4 g (60 mmol) of 5-bromo-2,2-dimethylvaleric acid, methyl ester (U.S. Pat. No. 4,665,226) and 150 mL of acetonitrile. The mixture is stirred mechanically at reflux for 24 hours. The reaction flask and inorganic solids are washed with fresh acetonitrile and the filtrate evaporated. The residue is taken up in diethyl ether and the solution washed with 50 mL of 2N potassium hydroxide solution, brine, dried (magnesium sulfate) and evaporated. The crude product amounts to 16.6 g. Distillation through a short path apparatus first at aspirator pressure and then at 0.5 mm affords 12.9 g of the title compound; infrared spectrum (IR) (C=0) 1732 cm-1.
Reaction SMILES: O[N:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH3:13])[N:4]=[C:3]1[C:14]1[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1.P(OCC)(OCC)OCC.O>CN(C)C=O>[CH3:23][O:22][C:16]1[CH:15]=[C:14]([C:3]2[NH:2][C:6]([C:7]3[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=3)=[C:5]([CH3:13])[N:4]=2)[CH:19]=[CH:18][C:17]=1[S:20][CH3:21]
Reactant: COc1cc(-c2nc(C)c(-c3cccnc3)n2O)ccc1SC
Agent: CCOP(OCC)OCC
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(-c2nc(C)c(-c3cccnc3)[nH]2)ccc1SC
Temperature: 90 °C
Reaction time: 3 h
Yield: 62.2 %

Procedure:
To a solution of 1-hydroxy-2-(3-methoxy-4-methylthiophenyl)-4-methyl-5-(3-pyridyl)imidazole (0.98 g) in N,N-dimethylformamide (10 ml) was added triethyl phosphite (1.03 ml), and the mixture was stirred at 90° C. for 3 hours. Then the solution was poured into water (60 ml) and stirred at ambient temperature for an hour. The resulting precipitates were filtered, washed with water, and recrystallized from ethanol (6 ml) to give 2-(3-methoxy-4-methylthiophenyl)-4-methyl-5-(3-pyridyl)imidazole (0.58 g).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[NH:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[C:25]([C:26](O)=O)[C:20]=2[N:19]=[CH:18]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[O:14][C:26]([C:25]2[C:20]3[N:19]=[CH:18][NH:17][C:21]=3[CH:22]=[CH:23][CH:24]=2)=[N:16][N:15]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Reactant: O=C(O)c1cccc2[nH]cnc12
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2cccc3[nH]cnc23)o1

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was converted using 1H-benzoimidazole-4-carboxylic acid instead of o-toluic acid to the title compound (SiO2, dichloromethane:methanol:ammonia=95:5:0)=100:0 to 80:20, 32 mg, 10%) which was obtained as a white solid. MS: m/e=344.2 [M+H]+.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.Cl.[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[CH2:27][NH:28][CH2:29]2>>[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[CH2:27][N:28]([CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=3)[N:10]=[CH:9]1)[CH2:29]2
Reactant: Clc1cccc2c1CNC2
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Agent: Cl
Product: O=C(O)c1ccnc(-c2cn(CCN3Cc4cccc(Cl)c4C3)cn2)c1
Yield: 10 %

Procedure:
The title compound was prepared in 10% yield from methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 6) and 4-chloroisoindoline hydrogen chloride according to the procedure for the preparation of Example 58. 1HNMR (400 MHz, DMSO): δ 3.15 (2H, m), 4.05 (4H, br s), 4.25 (2H, m), 7.19-7.27 (2H, m), 7.59 (1H, dd, J=4.9 Hz), 7.66 (1H, dd, J=6.7 and 3.0 Hz), 7.94 (1H, s), 8.11 (1H, s), 8.28 (1H, s), 8.33 (1H, s), 8.65 (1H, d, J=5.2 Hz). [M+H] Calc'd for C19H17ClN4O2, 369. Found, 369.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:12])=[C:8]([CH2:10][OH:11])[CH:9]=1)=[O:4].[CH3:13][C:14]1([CH3:28])[C:18]([CH3:20])([CH3:19])[O:17][B:16]([C:21]2[CH:26]=[CH:25][C:24](O)=[CH:23][CH:22]=2)[O:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:12])=[C:8]([CH2:10][O:11][C:24]2[CH:25]=[CH:26][C:21]([B:16]3[O:17][C:18]([CH3:20])([CH3:19])[C:14]([CH3:28])([CH3:13])[O:15]3)=[CH:22][CH:23]=2)[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(CO)c(C)o1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1cc(COc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c(C)o1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
A mixture of 4-hydroxymethyl-5-methyl-furan-2-carboxylic acid methyl ester (16) (0.5 g), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (1.9 g) and triphenylphosphine (2.3 g) in dry tetrahydrofuan (20 mL) under a nitrogen atmosphere was cooled to 0° C. Di-isopropylazodicarboxylate (1.8 mL) was added drop-wise and the mixture was stirred at room temperature for 72 hours. After concentrating in vacuo, the residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was extracted with pentane and the pentane phase was decanted and concentrated to give compound 51 as an oil. This was used without further purification.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:37]C(OC(C)(C)C)=O)[C:17]([NH:19][C@@H:20]([C@H:24]([NH:26][C@H:27]([C:34]([OH:36])=[O:35])[CH2:28][C:29]1[N:30]=[CH:31][NH:32][CH:33]=1)[CH3:25])[C:21]([OH:23])=[O:22])=[O:18])=O)C1C=CC=CC=1.Br>C(O)(=O)C>[NH2:37][C@@H:16]([CH2:15][CH2:14][CH2:13][CH2:12][NH2:11])[C:17]([NH:19][C@@H:20]([C@H:24]([NH:26][C@H:27]([C:34]([OH:36])=[O:35])[CH2:28][C:29]1[N:30]=[CH:31][NH:32][CH:33]=1)[CH3:25])[C:21]([OH:23])=[O:22])=[O:18]
Reactant: C[C@@H](N[C@@H](Cc1c[nH]cn1)C(=O)O)[C@H](NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)O
Agent: Br
Solvent: CC(=O)O
Product: C[C@@H](N[C@@H](Cc1c[nH]cn1)C(=O)O)[C@H](NC(=O)[C@@H](N)CCCCN)C(=O)O
Temperature: 0 °C
Yield: 89.2 %

Procedure:
A solution of (2S,3R)-2-[[(2S)-6-benzyloxycarbonylamino-2-t-butoxycarbonylaminohexanoyl]amino]-3-[[(1S)-1-carboxy-2 (4-imidazolyl)ethyl]amino]butyric acid (720 mg) and 30% hydrogen bromide in acetic acid (20 ml) was sitrred for 3 hours at room temperature and the mixture was poured into ice-water (40 ml). The aqueous solution was washed with ether and subjected to a column of Dowex 50W x 8 (H+, 15 ml). The column was washed with water and the elution was carried out with 2.8% aqueous ammonia. The object fractions were collected and evaporated in vacuo. The residue was dissolved in water and lyophilized to give (2S,3R)-2-[[(2S)-2,6-diaminohexanoyl]amino]-3-[[(1S)-1-carboxy-2-(4-imidazolyl)ethyl]amino]butyric acid (399 mg) as a pale yellow powder.
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6](=[O:13])[CH:7]=[C:8]([C:10]([OH:12])=[O:11])[N:9]=2)[CH2:3][CH2:2]1.[ClH:14].Cl[O-].[Na+].S(=O)(O)[O-].[Na+]>O>[Cl:14][C:7]1[C:6](=[O:13])[NH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[N:9][C:8]=1[C:10]([OH:12])=[O:11]
Reactant: Cl
Reactant: O=C(O)c1cc(=O)[nH]c(C2CC2)n1
Agent: O=S([O-])O
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Product: O=C(O)c1nc(C2CC2)[nH]c(=O)c1Cl
Temperature: 9 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-cyclopropyl-1,6-dihydro-6-oxo-4-pyrimidinecarboxylic acid (i.e. the product of Step A1 or A2) (184 g, 1.02 mol) in water (45 mL) and concentrated hydrochloric acid (292 g, 3 mol) at 8-12° C. was added dropwise aqueous sodium hypochlorite solution (8.4%, 1.02 kg, 1.15 mol) over 2 h so that with cooling the reaction mixture was maintained at 8-10° C. The mixture was then held at 10-12° C. for 1 h and the conversion was monitored by HPLC. When less than 5% of the starting material remained solid sodium bisulfite was added until a negative KI starch paper test was obtained. The mixture was cooled to 5° C., and the suspended product was isolated by filtration and washed with a minimum amount of cold water. The product was then dried to constant weight in vacuum-oven at 50° C. to afford the title compound (194 g); m.p. 189-190° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]4[NH:24][C:25](=O)OC)[C:14]([F:29])=[CH:13][N:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]4[NH:24][CH3:25])[C:14]([F:29])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COC(=O)N[C@H]1CCCC[C@@H]1Nc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(Cl)cc23)ncc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN[C@H]1CCCC[C@@H]1Nc1nc(-c2c[nH]c3ncc(Cl)cc23)ncc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl (1S,2S)-2-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexylcarbamate, 23c, (0.09 g, 0.16 mmol) in THF (3 mL) at room temperature was added LiAlH4 (0.06 g, 1.66 mmol) and the mixture was stirred at room temperature for additional 2 hours. The reaction was quenched with 0.06 mL KOH (5% aq) followed by water (3×0.06 mL). Then, additional Et2O (6 mL) was added and stirring was continued for 20 minutes. The milky white suspension was filtered and rinsed with EtOAc and the cake was rinsed with additional EtOAc. The combined organic phases were concentrated in vacuo and purified by preparative HPLC followed by preparative TLC to provide the desired product as the free base that was then converted to the HCl salt by treatment with HCl (4N in dioxane).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O.[CH:34]([O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[CH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)([CH3:36])[CH3:35]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([N:47]2[CH2:48][CH2:49][CH:44]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=3[O:37][CH:34]([CH3:36])[CH3:35])[CH2:45][CH2:46]2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccccc1C1CCNCC1
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)Oc1ccccc1C1CCN(C2CCC(NC(=O)OC(C)(C)C)CC2)CC1
Reaction time: 48 h
Yield: 48 %

Procedure:
A (4-oxo-cyclohexyl)-carbamic acid tert-butyl ester Compound 1b (1.54 g, 7.21 mmol), NaBH(OAc)3 (64.45 g, 21.0 mmol) and HOAc (0.3 mL) were added to a solution of 4-(2-isopropoxy-phenyl)-piperidine Compound 1a (1.32 g, 6.01 mmol) in CH2Cl2 (100 mL). The mixture was stirred under N2 for two days, then the reaction was quenched with MeOH. The mixture was evaporated and the resulting residue was redissolved with CH2Cl2, washed using 10% aqueous Na2CO3 and brine, then dried (Na2SO4). The crude product was purified by column chromatography to provide {4-[4-(2-isopropoxy-phenyl)-piperidin-1-yl]-cyclohexyl}-carbamic acid tert-butyl ester Compound 1c as a mixture of cis/trans isomers (MS 416; yellowish oil; 1.19 g, 48% yield).
Reaction SMILES: Br[C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:17][C:3]=1[O:4][C:5]1[C:6]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:7][CH:8]=[CH:9][CH:10]=1.[Cu](C#N)[C:36]#[N:37].CN1CCCC1=O>O>[C:36]([C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:17][C:3]=1[O:4][C:5]1[C:6]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:7][CH:8]=[CH:9][CH:10]=1)#[N:37]
Reactant: N#C[Cu]C#N
Reactant: COC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Br
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1C#N
Temperature: 160 °C
Reaction time: 2 h
Yield: 77.1 %

Procedure:
A mixture of 0.23 g of 3-{2-bromo-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxypyridine [present compound 9-7], 75 mg of copper cyanide and 2 ml of N-methyl-2-pyrrolidone was stirred at 160° C. for 2 hours. There action mixture was cooled to room temperature, water was added to the mixture and the resultant was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.16 g of 3-{2-cyano-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxypyridine [present compound 9-27].
Reaction SMILES: Br[C:2]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8](Br)=[C:9]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[CH3:24][C:25]1[CH:30]=[CH:29][C:28](OB(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>C(O)C.CCCCCC.ClCCl.COCCOC>[C:4]1([CH3:5])[CH:12]=[CH:13][C:14]([C:13]2[C:14]([C:15]([CH3:17])([CH3:18])[CH3:16])=[CH:2][C:3]3[C:7]4[C:6](=[CH:11][C:10]([C:28]5[CH:29]=[CH:30][C:25]([CH3:24])=[CH:26][CH:27]=5)=[C:9]([C:19]([CH3:21])([CH3:20])[CH3:22])[CH:8]=4)[CH2:5][C:4]=3[CH:12]=2)=[CH:2][CH:3]=1
Reactant: CC(C)(C)c1cc2c(cc1Br)Cc1cc(Br)c(C(C)(C)C)cc1-2
Reactant: Cc1ccc(OB(O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCCCCC
Solvent: COCCOC
Product: Cc1ccc(-c2cc3c(cc2C(C)(C)C)-c2cc(C(C)(C)C)c(-c4ccc(C)cc4)cc2C3)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 165.6 %

Procedure:
Under a nitrogen atmosphere, 120 mL of dehydrated 1,2-dimethoxyethane was added to 8.00 g (18.3 mmol) of 2,7-dibromo-3,6-ditert-butyl-fluorene synthesized in Synthesis Example 1-1(i) and 1.05 g (0.909 mmol) of Pd(PPh3), and the mixture was stirred at room temperature for 20 minutes. To this solution, a solution prepared by dissolving 5.50 g (40.5 mmol) of 4-methylphenylboric acid in 20 mL of ethanol was added. The mixture was stirred at room temperature for 20 minutes, and then 36.8 mL (73.6 mmol) of a 2.0 mol/L aqueous solution of sodium carbonate was added. Subsequently, the mixture was heated to reflux for 21 hours, left to be naturally cooled, and then 1N hydrochloric acid was added in an ice bath to terminate the reaction. Dichloromethane was then added to perform a liquid-liquid phase separation, and the aqueous layer was subjected to extraction with diethyl ether twice. The resultant was combined with the organic layer obtained previously. The resultant liquid was then washed two times with a saturated aqueous solution of sodium hydrogen carbonate, two times with water, and once with saturated brine, and then dried over magnesium sulfate. Subsequently, the solvent was distilled off, and the resultant was subjected to separation by silica gel chromatography. To the whitish yellow powder obtained, small amount of a mixed solution of n-hexane and ethanol was added. The mixture was heated to 65° C., and then was left to stand for 1 hour at room temperature. Crystals Precipitated were washed 10 times with 2 mL of cold methanol and 20 times with 1 mL of cold n-hexane to obtain a target product as a white powder (yield 6.95 g (83%)). The target product was identified by 1H-NMR and FD-MS spectroscopy.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:18][CH3:19])=[CH:4][C:5]2[CH2:11][N:10]([CH2:12][CH3:13])[CH2:9][C:8](=[O:14])[N:7]([CH2:15]C)[C:6]=2[CH:17]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=2[N:36]2[CH:40]=[CH:39][CH:38]=[N:37]2)[C:24]([Cl:41])=[CH:23][N:22]=1>>[Cl:41][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=2[N:36]2[CH:40]=[CH:39][CH:38]=[N:37]2)=[N:26][C:21]([NH:1][C:2]2[C:3]([O:18][CH3:19])=[CH:4][C:5]3[CH2:11][N:10]([CH2:12][CH3:13])[CH2:9][C:8](=[O:14])[N:7]([CH3:15])[C:6]=3[CH:17]=2)=[N:22][CH:23]=1
Reactant: COc1ccc(Nc2nc(Cl)ncc2Cl)c(-n2cccn2)c1
Reactant: CCN1CC(=O)N(CC)c2cc(N)c(OC)cc2C1
Product: CCN1CC(=O)N(C)c2cc(Nc3ncc(Cl)c(Nc4ccc(OC)cc4-n4cccn4)n3)c(OC)cc2C1

Procedure:
The title compound was prepared from 8-Amino-1,4-diethyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one and (2,5-Dichloro-pyrimidin-4-yl)-(4-methoxy-2-pyrazol-1-yl-phenyl)-amine in an analogous manner to example 730 (0.071 g, 48%). Mp 105-107° C.; LCMS (m/e) 549 (M); 1H-NMR (DMSO, 400 MHz) δ 9.85 (s, 1H), 8.25 (s, 1H), 8.11 (s, 1H), 7.97-7.94 (d, 1H, J=9.10 Hz), 7.92 (s, 1H), 7.85 (s, 1H), 7.82 (s, 1H), 7.16 (m, 1H), 7.03 (s, 1H), 6.83-6.80 (d, 1H, J=9.34 Hz), 6.53 (s, 1H), 3.84 (s, 3H), 3.81 (s, 3H), 3.48 (s, 2H), 3.00 (s, 4H), 2.57-2.50 (q, 2H, J=6.82 Hz), 1.08-1.04 (t, 3H, J=8.03 Hz).
Reaction SMILES: OCCC[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[C:35](=[O:36])[C:14]2=[CH:15][N:16]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH:34]=[CH:33][CH:32]=[N:31]4)=[CH:26][CH:25]=3)[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[C:13]2=[N:12]1.CC(OI1(OC(C)=O)(OC(C)=O)O[C:48](=[O:49])[C:47]2C1=CC=C[CH:46]=2)=O.C(=O)(O)[O-].[Na+].O.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[C:48]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[C:35](=[O:36])[C:14]2=[CH:15][N:16]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH:34]=[CH:33][CH:32]=[N:31]4)=[CH:26][CH:25]=3)[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[C:13]2=[N:12]1)(=[O:49])[CH2:47][CH3:46]
Reactant: O=c1c2cn(Cc3ccc(-n4cccn4)cc3)c3ccccc3c-2nn1-c1ccccc1CCCO
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCC(=O)c1ccccc1-n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Reaction time: 0.5 h

Procedure:
(±)-2-[2-(Hydroxypropyl)phenyl]-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (Example 657, 81 mg, 0.17 mmol), 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (Dess-Martin periodinane, 0.11 g, 0.25 mmol, 1.5 equiv), sodium bicarbonate (71 mg, 0.85 mmol, 5 equiv) and water (8.0 μL, 0.44 mmol, 2.6 equiv) were combined in dichloromethane (8 mL) and stirred vigorously for 30 minutes. Additional Dess-Martin periodinane (0.11 g, 0.25 mmol, 1.5 equiv) was added and the mixture was stirred for an additional 45 minutes. The mixture was treated with sodium bicarbonate (3 mL, aqueous saturated) and sodium thiosulfate (3 mL, aqueous saturated) and stirred vigorously for 30 minutes. The mixture was poured into sodium bicarbonate (15 mL, aqueous saturated) and extracted with dichloromethane (2×50 mL) and the combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 0:100; hexanes:ethyl acetate containing 5% methanol), providing the titled compound: 1H-NMR (400 MHz, CDCl3) δ 8.45 (1H, s), 8.37 (1H, dd, J=7.2, 2.2 Hz), 7.94-7.91 (2H, m), 7.74-7.72 (3H, m), 7.57-7.43 (5H, m), 7.35 (1H, d, J=7.6 Hz), 7.31 (2H, d, J=8.4 Hz), 6.47 (1H, m), 5.49 (2H, s), 2.73 (2H, q, J=7.6 Hz), 1.13 (3H, t, J=7.2 Hz) ppm; high resolution mass spectrometry (ES+) m/z 474.1919 [(M+H)+; calculated for C29H24N5O2: 474.1925].