Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:15]3[CH:16]=[CH:17][CH:18]=[C:14]3[C:8]3([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]3)[O:7][C:6]=2[CH:19]=1.[F:20][C:21]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:22]=1[C:23](O)=[O:24].CCN=C=NCCCN(C)C.CCN(CC)CC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:15]3[CH:16]=[CH:17][CH:18]=[C:14]3[C:8]3([CH2:13][CH2:12][N:11]([C:23]([C:22]4[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:21]=4[F:20])=[O:24])[CH2:10][CH2:9]3)[O:7][C:6]=2[CH:19]=1
Reactant: Clc1ccc2c(c1)OC1(CCNCC1)c1cccn1-2
Reactant: COc1ccc(F)c(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(F)c(C(=O)N2CCC3(CC2)Oc2cc(Cl)ccc2-n2cccc23)c1
Reaction time: 6 h

Procedure:
7-Chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine] (62 mg, 0.20 mmol), 2-fluoro-5-methoxybenzoic acid (34 mg, 0.20 mmol), EDCI (38 mg, 0.20 mmol), and Et3N (56 μL, 0.40 mmol) were combined in DCM (1 mL) and the mixture was stirred for 6 h. The mixture was diluted with DCM and was washed with 1N HCl, sat. aq. sodium bicarbonate and brine. The organics were dried over sodium sulfate and were evaporated. The crude material was purified by silica gel chromatography eluting with 0-40% ethyl acetate in hexanes to provide (7-chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(2-fluoro-5-methoxyphenyl)methanone. ESI-MS m/z calc. 426.1. found 427.5 (M+1)+. Retention time: 2.12 minutes (3 min run). NMR (400 MHz, CDCl3) δ 7.26 (d, J=8.4 Hz, 1H), 7.13-7.07 (m, 2H), 7.05-6.96 (m, 2H), 6.94-6.85 (m, 2H), 6.33 (t, J=3.2 Hz, 1H), 6.08-5.98 (m, 1H), 4.69 (d, J=13.1 Hz, 1H), 3.80 (s, 3H), 3.63-3.44 (m, 2H), 3.33 (t, J=12.8 Hz, 1H), 2.19 (d, J=13.8 Hz, 1H), 2.09-1.96 (m, 2H), 1.60 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([OH:19])=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:20]([O-])([OH:22])=[O:21]>C(O)(=O)CC>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([OH:19])=[C:14]([N+:20]([O-:22])=[O:21])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccnc2cc(OCc3ccccc3)ccc12
Reactant: O=[N+]([O-])O
Solvent: CCC(=O)O
Product: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1O
Temperature: 125 °C
Reaction time: 1 h

Procedure:
A mixture of 7-benzyloxyquinolin-4-ol (71.47 g, 0.2844 mol) and propionic acid (700 mL) was heated to 125° C. with vigorous stirring. Nitric acid (23.11 mL of 16 M) was slowly added over a period of 30 minutes while maintaining the reaction temperature between 121° C. and 125° C. After the addition, the reaction was stirred at 125° C. for 1 hour then allowed to cool to ambient temperature. The resulting solid was isolated by filtration, washed with water, and dried in an oven for 1.5 days to provide 69.13 g of 7-benzyloxy-3-nitroquinolin-4-ol as a grayish powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH:5]=[O:6].[F:11][C:12]([Si](C)(C)C)([F:14])[F:13].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[C:12]([F:14])([F:13])[F:11])[CH:7]=[C:8]([Cl:10])[CH:9]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: OC(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
To a stirred solution of 3,5-dichlorobenzaldehyde (10 g, 57 mmol) in THF (250 mL) were added trifluoromethyltrimethylsilane (9.79 g, 69.2 mmol) and a catalytic amount of tetrabutylammonium fluoride (TBAF). The reaction mixture was stirred at 25° C. for 8 h. After the reaction was deemed complete by TLC, the reaction mixture was diluted with 3 N hydrochloric acid (HCl) and then was stirred for 16 h. The reaction mixture was diluted with H2O and was extracted with ethyl acetate (EtOAc; 3×). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound as a liquid (8.41 g, 60%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]#[N:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O:16][C:17]([C:19]1[N:23]([CH3:24])[N:22]=[C:21]([CH3:25])[C:20]=1[CH3:26])=O)C.C(C1C=CC(C)=NC=1)C.CO.C[O-].[Na+]>O.CCCCCCC>[O:16]=[C:17]([C:19]1[N:23]([CH3:24])[N:22]=[C:21]([CH3:25])[C:20]=1[CH3:26])[CH:11]([C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=1)[C:12]#[N:13]
Reactant: CC(C)(C)c1ccc(CC#N)cc1
Reactant: CCOC(=O)c1c(C)c(C)nn1C
Agent: CCc1ccc(C)nc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCCCCCC
Product: Cc1nn(C)c(C(=O)C(C#N)c2ccc(C(C)(C)C)cc2)c1C
Temperature: 92.5 °C
Yield: 84.2 %

Procedure:
In a 300 mL-reaction flask equipped with a rectification column and a separating tank, 11.3 g (65.2 mmol) of 4-tert-butylphenylacetonitrile, 10.8 g (59.5 mmol) of 1,3,4-trimethylpyrazol-5-carboxylic acid ethyl ester, 100 g of heptane, 10.0 g of 5-ethyl-2-picoline were added, the atmosphere was substituted with nitrogen, then azeotropic dehydration was carried out by heating at 90 to 95° C. for 1 hour. The temperature was maintained, 13.8 g (71.5 mmol) of 28% sodium methoxide methanol solution was added dropwise over 3 hours, and the resulting mixture was further reacted for 11 hours. After cooling to 30° C. or less, 108 g of water was added to separate out heptane phase and obtain an aqueous phase. A quantitative analysis of the obtained aqueous phase with liquid chromatography showed that the aqueous phase contained 15.5 g (yield 84.5%) of 3-oxo-2-(4-tert-butylphenyl)-3-(1,3,4-trimethylpyrazol-5-yl) propionitrile.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([C:11](=[N:26][O:27][CH3:28])[CH2:12][NH:13][C:14](=[O:25])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:23])[F:22])=[N:6][CH:7]=[C:8]([Cl:10])[CH:9]=1.[CH3:29]I>O1CCCC1>[Cl:3][C:4]1[C:5]([C:11](=[N:26][O:27][CH3:28])[CH2:12][N:13]([CH3:29])[C:14](=[O:25])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:22])([F:24])[F:23])=[N:6][CH:7]=[C:8]([Cl:10])[CH:9]=1
Reactant: CON=C(CNC(=O)c1ccccc1C(F)(F)F)c1ncc(Cl)cc1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CON=C(CN(C)C(=O)c1ccccc1C(F)(F)F)c1ncc(Cl)cc1Cl
Temperature: 25 °C
Yield: 65.4 %

Procedure:
To 33 mg of 60% sodium hydride in oil in 5 ml of tetrahydrofuran, 300 mg of the N-[2-(3,5-dichloropyridin-2-yl)-2-(methoxyimino)ethyl]-2-(trifluoromethyl)benzamide prepared in Step 1 in Synthetic Example 16 in 3 ml of tetrahydrofuran was added dropwise with stirring and cooling with ice, and the mixture was stirred at the same temperature for 30 minutes. Then, the reaction mixture was mixed with 157 mg of methyl iodide, warmed to room temperature and stirred for another 1 hour. After completion of the reaction, the reaction mixture was poured into 20 ml of ice-water and extracted with ethyl acetate (50 ml×1), the organic layer was washed with water (20 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 1:9 to 2:8) as the eluent to obtain 203 mg of the desired product as a pale yellow resinous substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.[CH3:12][O:13][NH:14][CH3:15].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([N:14]([O:13][CH3:12])[CH3:15])=[O:11]
Reactant: O=C(O)Cc1ccccc1Cl
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.5 %

Procedure:
A mixture of 2-(2-chlorophenyl)acetic acid (1.0 g, 5.9 mmol), O,N-dimethyl-hydroxylamine (0.631 g, 6.3 mmol), EDCI (1.2 g, 6.3 mmol), HOBT (0.874 g, 6.3 mmol), and NMM (2.6 mL, 23.6 mmol) in anhydrous CH2Cl2 (20 mL) was stirred at room temperature for two hours under nitrogen. The reaction mixture was diluted with a mixture of CH2Cl2 and MeOH (v/v=10:1, 100 mL). The organic layer was washed with aqueous HCl (0.5 mol/L, 30 mL×2), saturated NaHCO3 (30 mL×2) and brine (30 mL), dried over Na2SO4, filtered, and concentrated to give crude 2-(2-chlorophenyl)-N-methoxy-N-methylacetamide (0.7 g, yield: 56.0%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.O=C(Cl)[O:25][C:26](Cl)(Cl)Cl.[CH2:31]([NH:33][CH2:34][CH2:35][CH3:36])[CH3:32]>>[CH2:31]([N:33]([CH2:34][CH2:35][CH3:36])[C:26]([N:17]1[CH2:16][CH2:15][C:12]2([C:11](=[O:20])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:19][CH2:18]1)=[O:25])[CH3:32]
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: CCCNCC
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Product: CCCN(CC)C(=O)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O

Procedure:
This material was prepared in analogy to example 251 step B) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, diphosgene and ethyl-propyl-amine. MS (ESI): 428.3 (MH+).
Reaction SMILES: [CH2:1]([O:5][N:6]1[CH:13]=[C:12]([CH3:14])[C:10](=O)[NH:9][C:7]1=[O:8])[CH2:2][CH2:3][CH3:4].C(ONC(N)=O)CCC.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:25]>>[CH2:1]([O:5][N:6]1[CH:13]=[C:12]([CH3:14])[C:10]([SH:25])=[N:9][C:7]1=[O:8])[CH2:2][CH2:3][CH3:4]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCCCOn1cc(C)c(=O)[nH]c1=O
Agent: CCCCONC(N)=O
Product: CCCCOn1cc(C)c(S)nc1=O

Procedure:
In a manner analogous to that described in Example 1 25 g of 1-butoxy-5-methyl-uracil prepared by reacting of butoxyurea with β,β,-diethoxy-α-methylpropionic acid ester was reacted with 50 g of phosphorus pentasulfide to give 1-butoxy-1,2-dihydro-4-mercapto-5-methyl-2-oxo-pyrimidine;
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][N:9]=2)[CH2:4][CH2:3]1.[C:17]1([CH3:26])[CH:22]=[CH:21][C:20]([C:23](Cl)=[O:24])=[CH:19][CH:18]=1.[OH-].[NH4+].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33]>C(O)C.CCOCC>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33].[CH3:26][C:17]1[CH:22]=[CH:21][C:20]([C:23]([N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]([CH:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)=[N:9]2)=[O:24])=[CH:19][CH:18]=1
Reactant: CN1CCC(c2n[nH]c3ccccc23)CC1
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: O=C(O)/C=C/C(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: Cc1ccc(C(=O)n2nc(C3CCN(C)CC3)c3ccccc32)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
A mixture of 3.0 g of 3-(1-methyl-4-piperidinyl)-1H-indazole and 8 ml of 4-toluoyl chloride was heated at 100° C. on a steam bath for 4 hrs. Ether was added to the cooled mixture and the salt was coolected. The salt was converted to its free base by means of ammonium hydroxide solution. The base was dissolved in ethanol (90 ml)-ether (175 ml) and 1.5 g of fumaric acid was added. The mixture was stirred at ambient temperature for 16 hrs, and the resultant fumarate salt was collected. Recrystallization twice from methanol-ether yielded 3.8 g (60%) of product, mp 205°-207° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=2[C:15]([F:18])([F:17])[F:16])[CH2:3][CH2:2]1.[NH2:19][OH:20]>C(O)C>[OH:20][N:19]=[C:11]([NH2:12])[C:10]1[CH:13]=[CH:14][C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[C:8]([C:15]([F:18])([F:17])[F:16])[CH:9]=1
Reactant: NO
Reactant: N#Cc1ccc(N2CCOCC2)c(C(F)(F)F)c1
Solvent: CCO
Product: NC(=NO)c1ccc(N2CCOCC2)c(C(F)(F)F)c1
Temperature: 65 °C
Yield: 95.5 %

Procedure:
To a solution of 4-morpholino-3-(trifluoromethyl)benzonitrile (17.3 g, 67.3 mmol) in ethanol (400 mL) was added a 50% aqueous solution of hydroxylamine (4.9 mL, 74.1 mmol) dropwise. The mixture was heated at about 65° C. for 24 hours. The mixture was cooled to ambient temperature and the solid was removed by filtration. The fitrate was partitioned between ethyl acetate (1.8 L) and water (1.5 L). The organic layer was washed with water (1.0 L) and brine (1.0 L) and dried over anhydrous magnesium sulphate. The solvent was removed in vacuo to give N′-hydroxy-4-morpholino-3-(trifluoromethyl)benzimidamide (18.6 g, 91%) as a mixture of syn/anti isomers. LCMS (Table 1, Method b) Rt=1.85 min, m/z 290.15 (M+H)+; 1H NMR (DMSO-d6, 400 MHz) 9.75 (s, 1H), 8.09-8.16 (m, 1H), 7.89-7.96 (m, 1H), 7.52-7.58 (m, 1H), 3.66-3.72 (m, 4H), 2.83-2.93 (m, 4H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([Cl:25])[C:12]=1[NH:13][C:14]([C:16]1[CH:24]=[C:23]2[C:19]([CH:20]=[CH:21][NH:22]2)=[CH:18][CH:17]=1)=[O:15].CN(C)[CH:28]=[O:29]>>[Cl:25][C:11]1[CH:10]=[N:9][CH:8]=[C:7]([Cl:6])[C:12]=1[NH:13][C:14]([C:16]1[CH:24]=[C:23]2[C:19]([C:20]([CH:28]=[O:29])=[CH:21][NH:22]2)=[CH:18][CH:17]=1)=[O:15]
Reactant: CN(C)C=O
Reactant: O=C(Nc1c(Cl)cncc1Cl)c1ccc2cc[nH]c2c1
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2cc(C(=O)Nc3c(Cl)cncc3Cl)ccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of dimethylformamide (10 ml), under nitrogen and at 0° C., was treated with phosphorus oxychloride (0.6 ml). After stirring for 30 minutes at 0° C. the mixture was treated with a solution of N-(3,5-dichloro-pyridin-4-yl)-1H-indole-6-carboxamide [1.55 g, Example 1(bg)] in dimethylformamide (5 ml). The mixture was then heated at 40° C. for 45 minutes then cooled to room temperature and then partitioned between ethyl acetate (25 ml) and saturated sodium bicarbonate (50 ml). The organic layer was washed with water (75 ml) then dried over sodium sulphate then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and hexane (1:2, v/v) to yield the title compound (0.53 g) as a white solid. [Elemental analysis:—C,53.83; H,2.99; N,12.31%. Calculated for C15H9Cl2N3O2:—C,53.92; H,2.71; N,12.57%].
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]([C:27]3([C:30]([O:32][CH3:33])=[O:31])[CH2:29][CH2:28]3)(O)[O:17][N:16]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:33][O:32][C:30]([C:27]1([C:18]2[O:17][N:16]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])=[CH:10][CH:11]=3)[C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:28][CH2:29]1)=[O:31]
Reactant: COC(=O)C1(C2(O)ON=C(c3ccc(O[Si](C)(C)C(C)(C)C)cc3)C2c2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)C1(c2onc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)c2-c2ccccc2)CC1
Temperature: 80 °C

Procedure:
Methyl 1-[3-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-5-hydroxy-4-phenyl-4,5-dihydroisoxazol-5-yl]cyclopropanecarboxylate (Compound C, 42 g) is dissolved in toluene (100 mL) and p-toluenesulfonic acid hydrate (1.7 g) is added with swirling. The mixture is heated over a steam bath until the internal mixture temperature, measured with a digital thermometer, is raised to 80° C. The mixture is then removed from the steam bath and is treated with water (50 mL.) The layers are shaken and separated and the toluene phase is dried over anhydrous magnesium sulfate and is concentrated under reduced pressure to afford an oil that is purified by flash silica gel column chromatography. Elution through a 400 g Analogix silica cartridge with a gradient (100% hexanes to 35% ethyl acetate over 1800 mL, or three column volumes) afforded an oily product. The product is dissolved in chloroform and is reconcentrated under reduced pressure to afford a residue that solidified overnight under high vacuum to the solid product (32 g.)
Reaction SMILES: [OH-:1].[K+].[CH2:3]1[O:31][C:30]2[CH:29]=[CH:28][C:7]([O:8][C:9]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][O:27][C:21]=5[CH:20]=4)[C:10]=3[CH2:11][C:12]#N)=[CH:6][C:5]=2[O:4]1.[OH2:32]>C(O)C>[CH2:3]1[O:31][C:30]2[CH:29]=[CH:28][C:7]([O:8][C:9]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][O:27][C:21]=5[CH:20]=4)[C:10]=3[CH2:11][C:12]([OH:32])=[O:1])=[CH:6][C:5]=2[O:4]1
Reactant: N#CCc1c(Oc2ccc3c(c2)OCO3)cccc1Oc1ccc2c(c1)OCO2
Reactant: [OH-]
Reactant: O
Agent: [K+]
Solvent: CCO
Product: O=C(O)Cc1c(Oc2ccc3c(c2)OCO3)cccc1Oc1ccc2c(c1)OCO2
Yield: 81 %

Procedure:
Potassium hydroxide (304 mg, 5.4 mmol) was added to a solution of 2,6-bis-[3,4-(methylenedioxy)phenoxy]benzyl cyanide (211 mg, 0.54 mmol) in ethanol (~5 ml) that had been dissolved in water (2 ml). The resulting suspension was then refluxed for 15 hours giving a pale yellow clear solution. The solvents were removed in vacuo and the remaining residue was dissolved in water. The aqueous solution was extracted with ethyl acetate (1×5 ml) to remove any unreacted starting material, and then the pH was adjusted to ~2.0 using concentrated HCl. The aqueous solution was then extracted into ethyl acetate and the organic phase was washed with brine (1×5 ml) and dried (MgSO4). Evaporation of solvents left a pale brown residue which was crystallized from MeOH/H2O to give 186 mg (81% yield) of the pure acid as a light tan colored solid (mp. 176-177° C.).
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]2[N:14]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=3[CH3:26])[C:15](=[O:17])[NH:16][C:8]=12)[CH2:4][CH3:5])[CH3:2].[CH3:27][Si]([N-][Si](C)(C)C)(C)C.[Li+]>>[CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]2[N:14]([C:18]3[C:19]([CH3:26])=[CH:20][C:21]([CH3:25])=[CH:22][C:23]=3[CH3:24])[C:15](=[O:17])[N:16]([CH3:27])[C:8]=12)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Oc1cc(C)nc2c1[nH]c(=O)n2-c1c(C)cc(C)cc1C
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CCC(CC)Oc1cc(C)nc2c1n(C)c(=O)n2-c1c(C)cc(C)cc1C

Procedure:
The title compound was prepared by reacting 7-(1-ethyl-propoxy)-5-methyl-3-(2,4,6-trimethyl-phenyl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-one with lithium bis(trimethylsilyl)amide, followed by quenching with methyl iodide. Mp. 151-153° C. Anal. For C22H2N3O2. 1/4H2O calc. C, 71.03; H, 7.99; N, 11.30; found: C, 71.29; H, 8.01; N, 11.03.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[Cl:17]Cl>C(Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[CH3:1][NH:2][C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]=2[CH:8]=[C:7]([Cl:17])[CH:6]=1
Reactant: CNC(=O)Oc1cccc2c1OC(C)(C)C2
Reactant: ClCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CNC(=O)Oc1cc(Cl)cc2c1OC(C)(C)C2
Yield: 88.9 %

Procedure:
To a solution of 2,3-dihydro-2,2-dimethyl-7-benzofuranyl methylcarbamate (33.2 g, 0.15 mol) in 150 ml of chloroform and 300 ml of carbon tetrachloride, chlorine (10.7 g, 0.15 mol) was gradually fed at a temperature of from 10° to 15° C. under stirring. The precipitated crystals were collected by filtration and washed with hexane, whereby 34.1 g of 5-chloro-2,3-dihydro-2,2-dimethyl-7-benzofuranyl methylcarbamate was obtained. The melting of this product was 167°-169° C. The structure was confirmed by 1H-NMR spectrum. Then, the product was added to 100 ml of a 10% aqueous sodium hydroxide-methanol solution and heated at 80° C. for 3 hours. The reaction solution was neutralized with hydrochloric acid and extracted with ether. The ether layer was washed with water, dried over anhydrous sodium sulfate and concentrated, whereby 23.0 g of 5-chloro-2,3-dihydro-2,2-dimethyl-7-benzofuranol was obtained. The melting point of this product was 65.5°-66.5° C. The phenol thus obtained, was reacted with O-ethyl-S-n-propyldithiophosphoryl chloride in the same manner as in Example 1, whereby the compound (No. 18) identified in Table 1 was obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[CH:11]=[C:12]([N:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)[CH:13]=[CH:14][C:15]=1[F:16])#[N:9].O.N>>[F:16][C:15]1[CH:14]=[CH:13][C:12]([N:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]2)=[CH:11][C:10]=1[C:8]#[N:9]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(F)c(C#N)c2)CC1
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: N#Cc1cc(N2CCNCC2)ccc1F
Temperature: 25 °C
Yield: 101.2 %

Procedure:
Trifluoroacetic acid was added to 500 mg of t-butyl 4-(3-cyano-4-fluorophenyl)-1-piperazinecarboxylate (compound in Production Example 354) and stirred at room temperature for several hours. After the reaction solution was cooled on ice, ammonia water was added thereto and stirred, the aqueous layer was extracted with dichloromethane, and all the organic layer was combined, dried and concentrated to give 340 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[C:28](I)[CH:27]=1>CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:25][C:26]1[CH:27]=[CH:28][C:29]([F:32])=[C:30]([C:3]2[C:4]([OH:8])=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH:31]=1
Reactant: Fc1ccc(Br)cc1I
Reactant: OB(O)c1c(O)cccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: Oc1cccc(F)c1-c1cc(Br)ccc1F
Temperature: 105 °C
Yield: 88.5 %

Procedure:
(2-Fluoro-6-hydroxyphenyl)boronic acid (50 mg, 0.321 mmol, 1.0 equiv), Pd(PPh3)4 (37.1 mg, 0.032 mmol, 0.1 equiv) and aqueous Na2CO3 (2 M, 401 μl, 0.802 mmol, 2.5 equiv) were mixed with toluene (2 mL) in a sealed microwave tube. 4-Bromo-1-fluoro-2-iodobenzene (96 mg, 0.321 mmol, 1.0 equiv) in MeOH (1.00 mL) was added to the above mixture. The resulted mixture was heated at 105° C. overnight. TLC showed the starting material disappeared and a new spot was produced. The reaction was allowed to cool to ambient temperature and then loaded on 12 g ISCO column and purified by 30% EtOAc/hexane to afford 5′-bromo-2′,6-difluoro-[1,1′-biphenyl]-2-ol (81 mg, 89%). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.54 (dd, J=6.3, 2.5 Hz, 1H), 7.48 (ddd, J=8.7, 4.5, 2.6 Hz, 1H), 7.21 (td, J=8.2, 6.7 Hz, 1H), 7.07 (t, J=8.9 Hz, 1H), 6.81 (d, J=8.3 Hz, 1H), 6.71 (t, J=8.8 Hz, 1H). LCMS (M+1)=286.1.
Reaction SMILES: [O:1]=[C:2]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)[CH2:3][C:4]([OH:6])=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.ClC(Cl)(Cl)C#N.[NH2:44][C:45]([C:57]1[CH:62]=[CH:61][C:60]([O:63][CH2:64][CH2:65][CH2:66][C:67]([F:70])([F:69])[F:68])=[CH:59][CH:58]=1)([CH3:56])[CH2:46][C:47]([C:49]1[CH:54]=[CH:53][C:52]([CH3:55])=[CH:51][CH:50]=1)=[O:48].N1C=CC=CC=1>C(Cl)Cl>[O:48]=[C:47]([C:49]1[CH:54]=[CH:53][C:52]([CH3:55])=[CH:51][CH:50]=1)[CH2:46][C:45]([NH:44][C:4](=[O:6])[CH2:3][C:2]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:1])([C:57]1[CH:58]=[CH:59][C:60]([O:63][CH2:64][CH2:65][CH2:66][C:67]([F:68])([F:69])[F:70])=[CH:61][CH:62]=1)[CH3:56]
Reactant: O=C(O)CC(=O)Nc1ccc(OC(F)(F)F)cc1
Reactant: Cc1ccc(C(=O)CC(C)(N)c2ccc(OCCCC(F)(F)F)cc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: N#CC(Cl)(Cl)Cl
Product: Cc1ccc(C(=O)CC(C)(NC(=O)CC(=O)Nc2ccc(OC(F)(F)F)cc2)c2ccc(OCCCC(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.2 %

Procedure:
To a solution of Intermediate 11F (41.6 mg, 0.158 mmol) in anhydrous CH2Cl2 (0.6 mL) was added PPh3 (124 mg, 0.474 mmol) followed by dropwise addition of trichloroacetonitrile (27.4 mg, 0.19 mmol). The reaction was stirred at rt for 3 h. To the freshly prepared acid chloride was added a solution of Intermediate 11E (20 mg, 0.053 mmol) in anhydrous CH2Cl2 (0.3 mL) followed by pyridine (19 mL, 0.237 mmol). The mixture was stirred at rt overnight. The solvent was removed in vacuo. The product was purified by preparative HPLC (MeOH/H2O/TFA) to yield Intermediate 11G (11 mg, 33%) as a brown solid. LCMS Anal. Calc'd for C31H30F6N2O5 624.57, found [M+H] 625.4.