Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:8][C:9]1[NH:10][CH:11]=[C:12]([C:14]2[CH:27]=[CH:26][C:17]([O:18][C:19]3[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=3)=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N:32]=[C:33]=[O:34])(C)C>O1CCCC1>[O:1]([CH2:8][C:9]1[NH:10][CH:11]=[C:12]([C:14]2[CH:27]=[CH:26][C:17]([O:18][C:19]3[CH:20]=[CH:21][C:22]([NH:23][C:33]([NH2:32])=[O:34])=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: Nc1ccc(Oc2ccc(-c3c[nH]c(COc4ccccc4)n3)cc2)cc1
Solvent: C1CCOC1
Product: NC(=O)Nc1ccc(Oc2ccc(-c3c[nH]c(COc4ccccc4)n3)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture containing 4-{4-[2-(phenoxymethyl)-1H-imidazol-4-yl]phenoxy}aniline (0.2 g, 0.56 mmol) and trimethylsilyl-isocyanate (0.11 ml, 0.84 mmol) in 3 ml of tetrahydrofuran is stirred for 24 hours at ambient temperature. Aminomethylpolystyrene resin EHL (Novabiochem, 200-400 mesh, 2% DVB) (200 mg, approximately 1 mmol) is added and stirring is maintained for three hours. After filtration on frit, the filtrate is concentrated in a rotavapor. Isopropyl acetate and traces of isopropanol are added to the residue obtained. The mixture is heated to dissolution followed by filtration on frit then left to crystallize for 24 hours. After filtration then drying under a bell jar, a light beige-coloured powder is obtained.
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH3:10])=[O:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].[F:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1>>[NH2:17][C:16](=[C:6]([C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[C:7]([O:9][CH3:10])=[O:8])[C:15]1[CH:18]=[CH:19][C:12]([F:11])=[CH:13][CH:14]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: COC(=O)CC(=O)C(C)C
Product: COC(=O)C(C(=O)C(C)C)=C(N)c1ccc(F)cc1

Procedure:
reacting methyl isobutyrylacetate with 4-fluoro-benzonitrile to produce methyl 2-[1-amino-1-(4-fluorophenyl)methylene]-4-methyl-3-oxopentanate; and
Reaction SMILES: [C:1]1([C:7]2[NH:15][C:14]3[C:9](=[N:10][CH:11]=[CH:12][C:13]=3[N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>CO.[Pd]>[CH:1]1([C:7]2[NH:15][C:14]3[C:9](=[N:10][CH:11]=[CH:12][C:13]=3[N:16]3[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]3)[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C1=C(c2cc3nccc(N4CCCCC4)c3[nH]2)CCCC1
Agent: [Pd]
Solvent: CO
Product: c1cc(N2CCCCC2)c2[nH]c(C3CCCCC3)cc2n1
Reaction time: 16 h
Yield: 98.8 %

Procedure:
2-Cyclohex-1-enyl-7-piperidylpyrrolo[3,2-b]pyridine (Example 43(b)) (280 mg, 1 mmol) was dissolved in MeOH (5 mL), and 10% palladium on charcoal (28 mg) was added. The flask was purged with H2 and a doubled-walled balloon filled with H2 was attached to the flask (˜30 psi H2). After 16 h, the mixture was filtered through celite, and the filtrate was concentrated in vacuo. The crude material was purified by flash chromatography 1:9 MeOH:EtOAc to afford 0.28 g (99%) of the title compound as an off-white solid. 1H NMR (DMSO-d6; 500 MHz): δ 2.0-1.2 (m, 16), 2.72 (m, 1), 3.18 (t, 4, J=5.2), 6.22 (s, 1), 6.55 (d, 1, J=5.3), 8.04 (d, 1, J=5.3), 10.61 (s, 1). MS m/z: 284 (M+1). Anal. Calcd for C18H25N3.0.2H2O: C, 75.33; H, 8.92; N, 14.64. Found: C, 75.39; H, 8.64; N, 14.64.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:18][CH3:19])=[C:6]([CH:8]2[C:14](=[O:15])[CH:13]3[CH2:16][CH:10]([CH2:11][CH2:12]3)[C:9]2=[O:17])[CH:7]=1.[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1B(O)O.[F-].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(COC)OC>[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[C:2]1[CH:3]=[CH:4][C:5]([CH2:18][CH3:19])=[C:6]([CH:8]2[C:14](=[O:15])[CH:13]3[CH2:16][CH:10]([CH2:11][CH2:12]3)[C:9]2=[O:17])[CH:7]=1
Reactant: CCc1ccc(Br)cc1C1C(=O)C2CCC(C2)C1=O
Reactant: OB(O)c1ccc(Cl)cc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cs+]
Solvent: COCCOC
Product: CCc1ccc(-c2ccc(Cl)cc2Cl)cc1C1C(=O)C2CCC(C2)C1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a microwave vial is added 3-(5-bromo-2-ethylphenyl)bicyclo[3.2.1]octane-2,4-dione (0.200 g, 0.623 mmol), 2,4-dichlorophenyl boronic acid (0.167 g, 0.87 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.040 g, 0.05 mmol) and cesium fluoride (0.284 g, 1.87 mmol). Degassed dimethoxyethane is next added (washing down any solids from the slides of the vial), followed by purging with nitrogen then stirring at room temperature for 5 minutes. The mixture is heated at 160° C. under microwave irradiation for 15 minutes, cooled to room temperature, then partitioned between 2M hydrochloric acid and dichloromethane. After separation of the organic layer the aqueous phase is again washed with dichloromethane, then all organic fractions are combined and concentrated in vacuo to afford a crude gum. This crude product is purified by flash column chromatography on silica gel (30% to 100% ethyl acetate/iso-hexane eluant ratio) to afford 3-(2′,4′-dichloro-4-ethylbiphen-3-yl)bicyclo[3.2.1]octane-2,4-dione.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][N:8]1[CH2:23][CH2:22][N:11]2[C:12]3[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=3[NH:14][C:15](=O)[CH2:16][CH:10]2[CH2:9]1>O1CCCC1>[CH3:7][N:8]1[CH2:23][CH2:22][N:11]2[C:12]3[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=3[NH:14][CH2:15][CH2:16][CH:10]2[CH2:9]1
Reactant: CN1CCN2c3ccccc3NC(=O)CC2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCN2c3ccccc3NCCC2C1

Procedure:
Solid LiAlH4 (100 mg, 2.63 mmol) was added to a stirred solution of the product of Example 22E (72 mg, 0.311 mmol) in tetrahydrofuran (10 mL) at room temperature. The resulting mixture was heated at reflux under nitrogen for 2 hours, then cooled in ice and quenched by successive addition of ethyl acetate (4 mL), water (0.1 mL), 15% NaOH (0.1 mL) and water (0.3 mL). The mixture was filtered through a pad of diatomaceous earth with an ethyl acetate (25 mL total) rinse. The filtrate was concentrated under vacuum to provide the title compound, sufficiently pure for use in the next step: 1H NMR (300 MHz, CDCl3) δ ppm 2.06-2.20 (m, 2H), 2.25-2.42 (m, 2H), 2.37 (s, 3H), 2.62 (d, J=9.5 Hz, 1H), 2.77-2.87 (m, 1H), 3.08 (dt, J=11.6, 3.1 Hz, 1H), 3.18 (ddd, J=12.2, 5.3, 2.8 Hz, 1H), 3.22-3.33 (m, 1H), 3.64-3.75 (m, 2H), 6.53 (dd, J=7.5, 2.0 Hz, 1H), 6.76 (td, J=7.4, 1.8 Hz, 1H), 6.83 (td, J=7.4, 1.8 Hz, 1H), 6.92 (dd, J=7.5, 1.6 Hz, 1H); MS (DCI) m/z 218 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:23])[NH:7][N:8]=[C:9]2[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([F:22])=[C:17]([CH:21]=2)[C:18]([OH:20])=O)=[CH:4][CH:3]=1.[CH3:24][O:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.CCN(C(C)C)C(C)C.C(OCC)(=O)C>CN(C=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5](=[CH:4][CH:3]=1)[C:6](=[O:23])[NH:7][N:8]=[C:9]2[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([F:22])=[C:17]([C:18]([N:29]2[CH2:30][CH2:31][CH:26]([O:25][CH3:24])[CH2:27][CH2:28]2)=[O:20])[CH:21]=1
Reactant: COC1CCNCC1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccc(Br)cc23)ccc1F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccc(Br)cc34)ccc2F)CC1
Reaction time: 1 h
Yield: 5.3 %

Procedure:
5-((7-bromo-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)-2-fluorobenzoic acid (97) (1.0 g, 2.65 mmol), 4-methoxypiperidine (0.336 g, 2.92 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (0.936 g, 2.92 mmol) were dissolved in DMF (40 mL), to this was added DIPEA (0.509 mL, 2.92 mmol) and the reaction was stirred for 1 hour. The DMF was evaporated and the crude gum was quenched with 2M NaOH (75 mL), extracted with EtOAc (3×75 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford a brown gum. The gum was passed through a plug of silica eluting with ethyl acetate to afford a white solid, most of which was used without further purification. A sample (100 mg) was purified via preparative HPLC (Waters XTerra C18 column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material as a white solid (66 mg); 1H NMR (400.132 MHz, CDCl3) δ 1.62-1.48 (1H, m), 1.85-1.68 (2H, m), 1.94-1.89 (1H, m), 3.18-3.07 (1H, m), 3.35 (3H, s), 3.47-3.40 (2H, m), 3.67-3.53 (1H, m), 4.06-3.89 (1H, m), 4.23 (2H, s), 7.04 (1H, t), 7.31-7.26 (2H, m), 7.86-7.84 (2H, m), 8.33-8.31 (1H, m), 10.55 (1H, s); m/z (LC-MS, ESI+), RT=1.94 (M+H 476).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[N:4]=1)[NH2:2].Cl.[O-:11][C:12]#[N:13].[K+]>O>[F:9][C:5]1[N:4]=[C:3]([NH:1][NH:2][C:12]([NH2:13])=[O:11])[CH:8]=[CH:7][CH:6]=1
Reactant: N#C[O-]
Reactant: NNc1cccc(F)n1
Agent: Cl
Agent: [K+]
Solvent: O
Product: NC(=O)NNc1cccc(F)n1
Temperature: 35 °C

Procedure:
A solution was prepared by admixing 55 g (0.43 m) of 2-hydrazino-6-fluoropyridine in 240 ml of water with 40 g of concentrated hydrochloric acid in 60 ml of water. The mixture was stirred at 35° C. until a clear solution formed. To this reaction mixture was added 37 g (0.46 ml) of potassium cyanate in 100 ml of water. After the addition was completed, the reaction mixture was stirred for 21/2 hours at room temperature and then cooled to 10° C. on an ice bath. The 2-(6-fluoro-2-pyridinyl)hydrazinecarboxamide product was isolated by filtration and washed with methylene chloride in quantitative yield. The product melted at 210°-212° C. and upon analysis, was found to have carbon, hydrogen and nitrogen contents of 42.42, 4.23 and 32.83 percent, respectively, as compared with the theoretical contents of 42.35, 4.14 and 32.93 percent, respectively, as calculated for the above named compound.
Reaction SMILES: C(C1C=C(C=O)C(O)=C(C2C=CC(OC(F)(F)F)=CC=2)C=1)(C)(C)C.Br[C:26]1[C:27]([OH:38])=[C:28]([CH:31]=[C:32]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:33]=1)[CH:29]=[O:30].[Cl:39][C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][C:45]=1[Cl:46]>>[C:34]([C:32]1[CH:31]=[C:28]([CH:29]=[O:30])[C:27]([OH:38])=[C:26]([C:43]2[CH:42]=[CH:41][C:40]([Cl:39])=[C:45]([Cl:46])[CH:44]=2)[CH:33]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)c1cc(Br)c(O)c(C=O)c1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(OC(F)(F)F)cc2)c1
Product: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(Cl)c(Cl)c2)c1

Procedure:
5-(tert-Butyl)-3′,4′-dichloro-2-hydroxy-[1,1′-biphenyl]-3-carbaldehyde was prepared as a yellow solid using the procedure described in Intermediate 5 from 3-bromo-5-(tert-butyl)-2-hydroxybenzaldehyde (Intermediate 4) and 3,4-dichlorophenylboronic acid.
Reaction SMILES: [C:1]([CH2:13][C:14]([O:16]CC)=O)(=O)[C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>>[CH3:6][O:5][C:4]1[CH:3]=[C:2]([C:1]2[N:19]=[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]3[C:14](=[O:16])[CH:13]=2)[CH:11]=[CH:10][C:7]=1[O:8][CH3:9]
Reactant: Nc1ccccn1
Reactant: CCOC(=O)CC(=O)c1ccc(OC)c(OC)c1
Product: COc1ccc(-c2cc(=O)n3ccccc3n2)cc1OC
Temperature: 100 °C
Reaction time: 3 h
Yield: 150.8 %

Procedure:
Ethyl veratroylacetate (4.5 g) was added dropwise under stirring at 60°-70° C. to a suspension of 2-aminopyridine (0.84 g) in polyphosphoric acid (13.7 g). The reaction mixture was stirred at 100° C. for 3 hrs and poured into ice-water (50 ml). The aqueous solution was extracted with chloroform, washed with water, dried and evaporated to give dark oily residue which was chromatographed on silica gel using n-hexaneethyl acetate. The fractions were evaporated and the resulting residue was triturated with ethanol-isopropyl ether to give 2-(3,4-dimethoxyphenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine (3.8 g).
Reaction SMILES: [N:1]1[N:2]([C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[CH:3]=[C:4]2[CH2:10][CH2:9][NH:8][CH2:7][CH2:6][C:5]=12.[C:19]1(=O)[CH2:22][CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>ClCCl.C(O)(=O)C>[CH:19]1([N:8]2[CH2:9][CH2:10][C:4]3=[CH:3][N:2]([C:11]4[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=4)[N:1]=[C:5]3[CH2:6][CH2:7]2)[CH2:22][CH2:21][CH2:20]1
Reactant: O=C1CCC1
Reactant: N#Cc1ccc(-n2cc3c(n2)CCNCC3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: N#Cc1ccc(-n2cc3c(n2)CCN(C2CCC2)CC3)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(5,6,7,8-Tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl)benzonitrile (may be prepared as described in Description 11) (assumed 0.148 mmol) was dissolved in dichloromethane (2 ml) and acetic acid (2 drops). Cyclobutanone (17 μl, 0.22 mmol) and sodium triacetoxyborohydride (47 mg, 0.22 mmol) were added and the mixture stirred at room temperature for 1 hour. Methanol was added and the solution poured onto a 2 g SCX column which was eluted with methanol then 2M ammonia in methanol. The basic fractions were evaporated and the residue purified by flash chromatography eluting with 0-5% 2M ammonia in methanol/dichloromethane to give the title compound (E32).
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([O:7][C:8]1[CH:13]=[CH:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:10](=[O:21])[C:9]=1[C:22](Cl)=[O:23])[CH3:6].[NH2:25][C:26]1[C:59]([F:60])=[CH:58][C:29]([O:30][C:31]2[CH:36]=[CH:35][N:34]=[C:33]([N:37]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:32]=2[C:52]2[CH:53]=[N:54][N:55]([CH3:57])[CH:56]=2)=[C:28]([F:61])[CH:27]=1.CCN(CC)CC>C1COCC1>[CH3:50][C:48]([CH3:51])([O:47][C:45]([N:37]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:33]1[C:32]([C:52]2[CH:53]=[N:54][N:55]([CH3:57])[CH:56]=2)=[C:31]([O:30][C:29]2[C:28]([F:61])=[CH:27][C:26]([NH:25][C:22]([C:9]3[C:10](=[O:21])[N:11]([C:14]4[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=4)[CH:12]=[CH:13][C:8]=3[O:7][CH2:5][CH3:6])=[O:23])=[C:59]([F:60])[CH:58]=2)[CH:36]=[CH:35][N:34]=1)=[O:46])[CH3:49]
Reactant: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Cl
Reactant: Cn1cc(-c2c(Oc3cc(F)c(N)cc3F)ccnc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cn1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(F)c(Oc2ccnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2-c2cnn(C)c2)cc1F
Yield: 65 %

Procedure:
Using the method of Example 4, thionyl chloride (5 mL) and Example B2 (0.19 g, 0.7 mmol) were combined to prepare 4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carbonyl chloride as a solid. This solid was dissolved in THF (3 mL) and added to a solution of Example A6 (0.18 g, 0.35 mmol) and Et3N (0.2 ml, 1.4 mmol) in THF (3 mL). The resultant mixture was stirred at RT for 2 h. The mixture was partitioned between EtOAc (20 mL) and sat aq NaHCO3 (30 mL). The aqueous layer was further extracted with EtOAc (15 ml) and the combined organics were washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc-hexanes) to afford N-(4-(2-[bis[(1,1-dimethylethoxy)carbonyl]amino]-3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide as colorless foam (175 mg, 65% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.22 (s, 1H), 8.33 (dd, J=12.7 Hz, 7.2 Hz, 1H), 8.20 (d, J=5.7 Hz, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.87 (s, 1H), 7.48 (m, 4H), 7.36 (t, J=8.8 Hz, 2H), 6.83 (d, J=5.6 Hz, 1H), 6.55 (d, J=7.9 Hz, 1H), 4.28 (q, J=7.0 Hz, 2H), 3.86 (s, 3H), 1.33 (t, J=7.1 Hz, 3H), 1.26 (s, 18H); MS (ESI) m/z: 777.2 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:4]([CH2:13][CH3:14])[CH:3]=1.CC1(C)C(C)(C)OB([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)O1>>[CH2:13]([C:4]1[CH:3]=[C:2]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)[CH:7]=[CH:6][C:5]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH3:14]
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: CCc1cc(Br)ccc1CC(=O)OC
Product: CCc1cc(-c2ccc(O)cc2)ccc1CC(=O)OC
Yield: 84 %

Procedure:
According to a method similar to Example (26-3), from methyl (4-bromo-2-ethylphenyl)acetate (138 mg, 0.537 mmol) synthesized in Example (85-3) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (142 mg, 0.644 mmol), methyl (3-ethyl-4′-hydroxy-1,1′-biphenyl-4-yl)acetate was obtained (122 mg, yield: 84%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>CN(C=O)C>[N:22]1([CH2:21][CH2:20][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: ClCCN1CCOCC1
Reactant: COC(=O)c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCN2CCOCC2)cc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Methyl 4-hydroxybenzoate (40 g, 260 mmol) was dissolved in DMF (300 ml), K2CO3 (90 g, 650 mmol) was added and heated to 100° C. 4-(2-Chloroethyl)morpholine hydrochloride (53 g, 280 mmol) was added slowly (35 min) to the slurry. After 2 h at 100° C., the solid was removed by filtration and the solution was evaporated in vacuo. The residue was dissolved in EtOAc and washed with aqueous NaHCO3, brine and dried (Na2SO4) to give the pure product as a white powder in quantitative yield.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=1[C:4](=NN)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[K+]>C(O)COCCO>[CH2:4]([C:3]1[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:2]=1[NH2:1])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: NN=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1N
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Product: Nc1ccc([N+](=O)[O-])cc1Cc1ccccc1

Procedure:
In the manner given in Preparation 11, 2-amino-5-nitrobenzophenone hydrazone is refluxed with potassium hydroxide in diethylene glycol to give 2-benzyl-4-nitroaniline.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:12]=[C:13]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:14]([CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.C(O)(C)C.C(O)C.[CH3:43][S:44]([OH:47])(=[O:46])=[O:45]>ClCCCl>[CH3:43][S:44]([OH:47])(=[O:46])=[O:45].[Cl:1][C:2]1[C:11]2[N:12]=[C:13]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:14]([CH2:15][CH2:16][N:17]3[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCn2c(-c3ccccc3)nc3c(Cl)nc4ccccc4c32)CC1
Agent: CS(=O)(=O)O
Solvent: CCO
Solvent: CC(C)O
Solvent: ClCCCl
Product: Clc1nc2ccccc2c2c1nc(-c1ccccc1)n2CCN1CCNCC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 1.20 g of tert-butyl 4-[2-(4-chloro-2-phenyl-1H-imidazo-[4,5-c]quinolin-1-yl)ethyl]-1-piperazinecarboxylate in 12 ml of 1,2-dichloroethane, 1.2 ml of methanesulfonic acid was added, and the mixture was stirred at room temperature for 5 minutes. The reaction mixture was added with isopropanol and ethanol, and the precipitated crystals were collected by filtration to give 1.24 g of colorless crystals. Recrystallization from methanol gave colorless crystals having the melting point of from 256 to 270° C. (decomposition).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH2:12]([S:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[C:21]1[N:33]([CH3:34])[C:24]2=[N:25][CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=[C:23]2[N:22]=1)[CH3:13].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH2:12]([S:14]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[C:21]1[N:33]([CH3:34])[C:24]2=[N:25][CH:26]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:28]=[C:23]2[N:22]=1)=[O:6])[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSc1ccncc1-c1nc2cc(C(F)(F)F)cnc2n1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)c1ccncc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 48.9 %

Procedure:
448 mg of 3-chloroperoxybenzoic acid (purity of 65% or more) was added to a mixture of 420 mg of 2-(4-ethylsulfanylpyridin-3-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine and 9 ml of chloroform under ice cooling. The mixture was stirred at 0° C. for 1 hour, then stirred at room temperature for 30 minutes. A saturated aqueous sodium bicarbonate solution was poured to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with water and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 215 mg of 2-(4-ethylsulfinylpyridin-3-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter, referred to as Compound of Present Invention 10) and 211 mg of 2-(4-ethylsulfonylpyridin-3-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter, referred to as Compound of Present Invention 11).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[Cl:14][C:15]1[C:23]2[CH2:22][CH2:21][NH:20][CH:19]([CH3:24])[C:18]=2[S:17][CH:16]=1>>[Cl:14][C:15]1[C:23]2[CH2:22][CH2:21][N:20]([C:11]([C:9]3[CH:10]=[C:5]4[N:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]4[N:8]=3)=[O:13])[CH:19]([CH3:24])[C:18]=2[S:17][CH:16]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CC1NCCc2c(Cl)csc21
Product: CC1c2scc(Cl)c2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 3-chloro-7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine to provide the title compound.
Reaction SMILES: ClC1C=CC=C(C(OO)=O)C=1.[F:12][C:13]1[CH:23]=[CH:22][C:16]2S[CH2:18][CH2:19][CH2:20][O:21][C:15]=2[CH:14]=1.[S:24]([O-:28])([O-])(=O)=[O:25].[Mg+2].O>C(Cl)Cl>[F:12][C:13]1[CH:23]=[CH:22][C:16]2[S:24](=[O:28])(=[O:25])[CH2:18][CH2:19][CH2:20][O:21][C:15]=2[CH:14]=1
Reactant: O=S(=O)([O-])[O-]
Reactant: Fc1ccc2c(c1)OCCCS2
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Mg+2]
Solvent: O
Solvent: ClCCl
Product: O=S1(=O)CCCOc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
meta-Chloroperbenzoic acid (50-55%) (514 mg, 1.49 mmol) was added to a mixture of 8-fluoro-3,4-dihydro-2H-1,5-benzoxathiepine (110 mg, 0.6 mmol) and magnesium sulphate (1 spatula) in DCM (10 mL) and stirred at RT for 24 hours. Water was added and the mixture extracted into ethyl acetate. The combined organics were washed with a saturated solution of sodium bicarbonate (50 mL), brine (40 mL), dried (MgSO4), filtered and reduced in vacuo to give a white solid which was chromatographed on silica, eluting with 0-10% ethyl acetate in isohexane to give a colourless oil. The oil was redissolved in organics, washed with 2M sodium hydroxide solution (40 mL), and concentrated in vacuo to give the desired compound as a white solid (100 mg).
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:5][CH2:4]2)[CH2:2]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>CO>[O:30]1[CH2:31][CH2:32][N:27]([CH2:2][C:3]2([OH:1])[CH2:4][CH2:5][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:7][CH2:8]2)[CH2:28][CH2:29]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CO4)c(F)c2)C(=O)O1
Reactant: C1COCCN1
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(CN4CCOCC4)CC3)c(F)c2)C(=O)O1
Yield: 82 %

Procedure:
The title compound was prepared by reacting (S)-N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.37 mmol) with morpholine (2.05 mmol) in methanol (15 ml) at a temperature 25° C. for 14 hours and by purifying the compound by silica gel column chromatography in 82% yield.