Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=O)=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.Cl.[O:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[C@H:38]([NH2:40])[CH3:39].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O.CN(C=O)C>[O:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[C@H:38]([NH:40][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:30])[CH3:31])[CH:19]=1)=[O:23])[CH3:39]
Reactant: C[C@@H](N)c1ccco1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1ccco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
A round-bottomed flask was charged with 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (300 mg, 0.68 mmol) and (R)-1-furan-2-yl-ethylamine hydrochloride (416 mg, 1.55 mmol). DMF (3.5 ml) was added followed by N,N-diisopropylethylamine (0.85 ml, 4.87 mmol) and HATU (284 mg, 0.75 mmol). The reaction was stirred at room temperature overnight then water and petroleum ether were added. The resulting suspension was filtered. The filter cake was washed with water and petroleum ether then dried under high vacuum to afford 338 mg (88%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-furan-2-yl-ethyl)-amide as a light brown powder.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([I:33])=[CH:29][C:28]=2[F:34])=[C:4]([CH:12]=[C:13](/[CH:16]=[N:17]/[O:18][CH2:19][CH2:20][CH2:21][C:22](=[O:25])[NH:23][CH3:24])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].ClCCl.ClC(Cl)C(O)=O>C(OCC)(=O)C>[F:1][C:2]1[C:3]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([I:33])=[CH:29][C:28]=2[F:34])=[C:4]([CH:12]=[C:13]([CH2:16][NH:17][O:18][CH2:19][CH2:20][CH2:21][C:22](=[O:25])[NH:23][CH3:24])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: CNC(=O)CCCO/N=C/c1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Agent: O=C(O)C(Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CNC(=O)CCCONCc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Temperature: 25 °C
Yield: 63.9 %

Procedure:
To (E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methylcarbamoyl-propoxyimino)-methyl]-benzamide (50 mg, 0.084 mmol) obtained in Step C was added dichloromethane (6 ml). The mixture was stirred at room temperature, and borane-pyridine complex (67 μl, 0.673 mmol) and dichloroacetic acid (55 μl, 0.673 mmol) were added thereto. After stirring for 14 hours, the reaction mixture was diluted with ethyl acetate, and washed with purified water and saturated aqueous sodium chloride. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methylcarbamoyl-propoxyamino)-methyl]-benzamide (Compound C-21, 32 mg, 65% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N:12]1[C:17]([CH3:18])=[CH:16][C:15]([OH:19])=[CH:14][C:13]1=[O:20])[C:5]([O:7][CH3:8])=[O:6].[F:21][C:22]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:23]=1[CH2:24]Br.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.C(#N)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N:12]1[C:17]([CH3:18])=[CH:16][C:15]([O:19][CH2:24][C:23]2[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:22]=2[F:21])=[CH:14][C:13]1=[O:20])[C:5]([O:7][CH3:8])=[O:6]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: COC(=O)c1ccc(-n2c(C)cc(O)cc2=O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: COC(=O)c1ccc(-n2c(C)cc(OCc3ccc(F)cc3F)cc2=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Methyl 3-chloro-4-(4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)benzoate (from Step 1) (2.4 g, 8.17 mmol) was taken up in DMF (10 ml). 2,4-difluorobenzylbromide (1.05 ml, 8.17 mmol) and K2CO3 (1.13 g, 8.17 mmol) were added. The reaction stirred for 6 hours at room temperature. At this time, the reaction was poured into water (200 ml) and extracted with ethyl acetate. The ethyl acetate layer was dried over Na2SO4, filtered, and the solvent removed in vacuo to give amber oil (2.62 g, 77% crude yield). LC/MS, tr=2.79 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 294 (M+H).
Reaction SMILES: Br[C:2]1(Br)[C:10]2[CH:9]=[N:8][C:7]([Cl:11])=[N:6][C:5]=2[N:4]([CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:3]1=[O:17]>C(O)(=O)C.C1COCC1.[Zn]>[Cl:11][C:7]1[N:8]=[CH:9][C:10]2[CH2:2][C:3](=[O:17])[N:4]([CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:5]=2[N:6]=1
Reactant: CCC(CC)N1C(=O)C(Br)(Br)c2cnc(Cl)nc21
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCC(CC)N1C(=O)Cc2cnc(Cl)nc21
Temperature: 0 °C
Reaction time: 0.03 h

Procedure:
To a solution of 5,5-dibromo-2-chloro-7-(1-ethyl-propyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (crude, ˜5.3 mmol) in acetic acid (6 mL) and THF (4 mL) is added Zn dust (1.37 g, 21 mmol) at 0° C. The mixture is stirred at 0° C. for 2 min then warmed up to room temperature, stirred for 30 min. The mixture is filtered through a pad of Celite, rinsed with ethyl acetate. The filtrate is concentrated in vacuo and the residue is purified by flash chromatography (SiO2, EtOAc/hexane 5:95 to 40:60) to give 2-chloro-7-(1-ethyl-propyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[O:11][CH3:12].P(=O)(O)(O)[OH:14].[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1>O>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]2[C:6]3[C:5](=[CH:4][C:3]([O:11][CH3:12])=[C:2]([OH:1])[CH:7]=3)[CH2:8][C:9](=[O:14])[NH:10]2)=[CH:21][CH:20]=1
Reactant: COc1cc(CC#N)ccc1O
Reactant: O=P(O)(O)O
Reactant: O=Cc1ccc(Cl)cc1
Solvent: O
Product: COc1cc2c(cc1O)C(c1ccc(Cl)cc1)NC(=O)C2
Temperature: 120 °C
Reaction time: 2 h
Yield: 58.7 %

Procedure:
To a suspension of 4-hydroxy-3-methoxyphenylacetonitrile (150 g, 0.919 mol) in phosphoric acid 85% (877 mL, 15.000 mol) was added 4-chlorobenzaldehyde (168 g, 1.195 mol), then the reaction mixture was heated at 120° C. for 2 h. After cooling to 90° C., the reaction mixture was slowly poured into the stirred 4 L of iced water. Resulting suspension was stirred at RT for 2 h, then filtered and washed with 500 mL of water 4 times. Crude and wet material was stirred in acetonitrile (1 L) at RT for 1 h, then filtration and dry up gave the title intermediate (163.6 g, 0.539 mol, 58.6%). HPLC: EtRet=4.20 min; LC-MS: m/z 304.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 3.25-3.53 (m, 2H), 3.72 (s, 3H), 5.47 (d, J=3.12 Hz, 1H), 6.53 (s, 1H), 6.72 (s, 1H), 7.24 (d, 2H), 7.37 (d, 2H), 8.42 (d, J=3.51 Hz, 1H), 8.86 (br. s., 1H).
Reaction SMILES: O=C(CCC)OCC(OC(=O)CCC)COC(=O)CCC.[CH2:22]([O:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][C:40]([CH:43]([OH:45])[CH3:44])=[CH:39][CH:38]=2)=[CH:33][CH:32]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C1(N=C=NC2CCCCC2)CCCCC1.[C:61](O)(=[O:67])[CH2:62][CH2:63][CH2:64][CH2:65][CH3:66]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:22]([O:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][C:40]([CH:43]([O:45][C:61](=[O:67])[CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])[CH3:44])=[CH:39][CH:38]=2)=[CH:33][CH:32]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCC(=O)O
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(C)O)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCCC(=O)OCC(COC(=O)CCC)OC(=O)CCC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCOc1ccc(-c2ccc(C(C)OC(=O)CCCCC)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Racemic(±)-4-octyloxy-4'-(1-hydroxyethyl)biphenyl (m.p. 110.9°-111.9° C.) and tributyrin were biochemically transesterified. The obtained 7.0 g (21 mmol) of optically active (-)-4-octyloxy-4'-(1-hydroxyethyl)biphenyl (m.p. 123.6° C., [α]D 24.5 -27.0° (c 1.0, CHCl3)), 7.5 g(36 mmol) of N,N'-dicyclohexylcarbodiimide (abbreviated as DCC) and 1.0 g of 4-dimethylaminopyridine (abbreviated as DMAP) were dissolved in 200 ml of dichloromethane. To the solution, 3.4 g (29 mmol) of caproic acid was added, and the mixture was stirred for six hours at room temperature. The deposited crystals were filtered, 200 ml of water was added to the filtrate, and the organic layer was separated. 6N hydrochloric acid was added to the organic solution, and then the solution was neutralized with the aqueous solution of 2N sodium hydroxide. The neutralized solution was washed with water until the washed water became neutral. The solvent and low-boiling fractions were distilled away from the obtained solution. The residue was recrystallized from ethanol and the desired (-)-4-octyloxy-4'-(1-hexanoyloxyethyl)biphenyl 6.8 g was obtained. The melting point of the obtained biphenyl was 60.8° C. and its specific optical rotation was -78.4° at 25.3° C. for D line (c 0.88, C2H5OH).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[C:12]([O:16][C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13].CC1C=CN=CC=1C1C=CC=C2C=1C=NN2>>[CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([C:23]2[CH:22]=[CH:21][C:20]([NH:19][C:17](=[O:18])[O:16][C:12]([CH3:14])([CH3:13])[CH3:15])=[CH:25][CH:24]=2)=[CH:3][N:4]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(B(O)O)cc1
Reactant: Brc1cncc2ccccc12
Agent: Cc1ccncc1-c1cccc2[nH]ncc12
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cncc3ccccc23)cc1

Procedure:
Intermediate 10A was prepared from 4-bromoisoquinoline and 4-(tert-butoxy carbonylamino)phenylboronic acid by the procedure described for the preparation of Intermediate 1C, and was obtained as an off-white foam (63% yield). MS (ES): m/z=321.2 [M+H]+. HPLC Ret timea: 2.432 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.51 (s, 9 H) 7.44 (d, J=8.53 Hz, 2 H) 7.65 (d, J=8.53 Hz, 2 H) 7.68-7.75 (m, 1 H) 7.75-7.82 (m, 1 H) 7.88 (d, J=8.53 Hz, 1 H) 8.20 (d, J=7.78 Hz, 1 H) 8.40 (s, 1 H) 9.31 (s, 1 H) 9.57 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:22][C:21](=O)[O:20][C:18](=[O:19])[CH2:17]2)=[CH:12][CH:11]=1>>[S:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:21]1[CH2:22][CH:16]([C:13]1[CH:12]=[CH:11][C:10]([Cl:9])=[CH:15][CH:14]=1)[CH2:17][C:18]([OH:20])=[O:19]
Reactant: O=C1CC(c2ccc(Cl)cc2)CC(=O)O1
Reactant: Nc1ccccc1S
Product: O=C(O)CC(Cc1nc2ccccc2s1)c1ccc(Cl)cc1

Procedure:
By a procedure similar to that of example 1.55, starting from 2-aminothiophenol and 3-(4-chlorophenyl)glutaric anhydride, 4-(2-benzothiazolyl)-3-(4-chlorophenyl)-butanoic acid was obtained as colourless solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1Cl.[CH:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=2[OH:20])[CH2:12][CH2:11]1.COC1C=C(C)C=CC=1.[OH-].[K+].Cl>CO>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:20][C:14]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=2[CH:10]2[CH2:11][CH2:12]2)=[C:2]([OH:1])[CH:7]=1
Reactant: Cc1cccc(C2CC2)c1O
Reactant: Oc1cc(Cl)nnc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: COc1cccc(C)c1
Solvent: CO
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Yield: 74.7 %

Procedure:
To a mixture of 313 mg (purity: 96.0%; 1.82 mmol) of 4-hydroxy-3,6-dichloropyridazine and 839 mg (5.57 mmol) of 2-cyclopropyl-6-methylphenol were added 3-methoxytoluene (2.76 g) and 328 mg (5.56 mmol) of 95% potassium hydroxide at room temperature. The resultant mixture was heated to 180° C. while stirring, and stirred at that temperature for 4 hours. Then, the resultant reaction mixture was cooled to room temperature, and a 1 N aqueous hydrochloric acid solution and methanol were added to the reaction mixture to obtain a uniform solution. The obtained solution was quantitatively determined by an HPLC internal standard analysis method, which showed that 376 mg of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 75%) and 1.9 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.4%) were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[C:19]2[CH:25]=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1.Br[C:27]1[CH:39]=[CH:38][CH:37]=[CH:36][C:28]=1[O:29][C:30]1[N:35]=[CH:34][CH:33]=[CH:32][N:31]=1>>[F:1][C:2]1[CH:7]=[C:6]([C:27]2[CH:39]=[CH:38][CH:37]=[CH:36][C:28]=2[O:29][C:30]2[N:31]=[CH:32][CH:33]=[CH:34][N:35]=2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[C:19]2[CH:25]=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc4[nH]ccc4c3)c(F)c2)OC1(C)C
Reactant: Brc1ccccc1Oc1ncccn1
Product: Fc1cc(-c2ccccc2Oc2ncccn2)ccc1-c1cnc2[nH]ccc2c1

Procedure:
The title compound was prepared using methods analogous to those described in Example 376 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine and 2-(2-bromophenoxy)pyrimidine. MS (ESI): mass calcd. for C23H15FN4O, 382.12; m/z found, 383.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 9.24 (s, 1H), 8.51-8.42 (m, 3H), 8.14-8.05 (m, 1H), 7.57-7.28 (m, 8H), 6.99-6.89 (m, 1H), 6.55 (dd, J=3.6, 1.8, 1H).
Reaction SMILES: [C:1]([C:4]1[C:5]2[C:10]([CH:11]=[C:12]3[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]3)=[CH:9][CH:8]=[CH:7][CH:6]=2)(=[O:3])[CH3:2].[CH2:18]([N:26]=[C:27]=[O:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C([N-]C(C)C)(C)C.[Li+]>>[CH2:18]([NH:26][C:27](=[O:28])[CH2:2][C:1](=[O:3])[C:4]1[C:17]2[C:12]([CH:11]=[C:10]3[C:5]=1[CH:6]=[CH:7][CH:8]=[CH:9]3)=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CC(=O)c1c2ccccc2cc2ccccc12
Reactant: CCCCCCCCN=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CCCCCCCCNC(=O)CC(=O)c1c2ccccc2cc2ccccc12

Procedure:
The title compound, mp 70°-72° C., was prepared from 9-acetylanthracene (5.0 g, 0.022 mol), octyl isocyanate (3.52 g, 0.022 mol), and lithium diisopropylamide (0.032 mol) using the procedure described in Example 1. Purification by flash chromatography (silica gel, 5% EtOAc/hexane) yielded 3.84 g (0.010 mol, 45.2%) of the desired product.
Reaction SMILES: [CH2:1]([CH:4]1[C:10](Cl)([Cl:11])[CH2:9][CH2:8][CH:7]2[C:5]1(Cl)[O:6]2)[CH:2]=[CH2:3].Cl>CN(C=O)C>[CH2:1]([C:4]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:5]=1[OH:6])[CH:2]=[CH2:3]
Reactant: C=CCC1C(Cl)(Cl)CCC2OC21Cl
Agent: Cl
Solvent: CN(C)C=O
Product: C=CCc1c(O)cccc1Cl
Reaction time: 0.12 h
Yield: 88.8 %

Procedure:
2 g (8.28 mmol) of epoxide 2j in solution in 5 cm3 of anhydrous DMF were heated to reflux for 5 h. The solution was acidified (pH<1) with 3N HCl, extracted with ether and concentrated, and a 3N sodium hydroxide solution was added to the ether phase (while the mixture was kept stirred for 5 to 10 min), the ether phase was removed and the material washed once with ether. The aqueous phase was acidified using a solution with 3N HCl (pH=1) and extracted with ether (4×30 cm3), dried over MgSO4, filtered and evaporated down. 1.24 g of phenol 4g were obtained as a liquid whose macrobore GC purity was higher than The yield of phenol 4g was 89%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[CH:17]=1.[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[N:32]=[C:33]=[O:34]>C(Cl)(Cl)Cl>[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[NH:32][C:33]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][N:7]=2)=[CH:17][C:18]=1[CH3:23])=[O:34]
Reactant: COc1cc2ncnc(Oc3ccc(N)c(C)c3)c2cc1OC
Reactant: O=C=Nc1ccc(F)cc1F
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(C)c3)c2cc1OC

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-methylaniline (50 mg) was dissolved in chloroform (3 ml), and 2,4-difluorophenyl isocyanate (23 μl) was then added to the solution. The mixture was heated under reflux overnight. The precipitated crystal was collected by filtration and was washed to quantitatively give the title compound.
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[C:5]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)=O.Cl.[NH2:20][C:21]([NH2:23])=[NH:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[O:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:5]1[C:4]([C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)=[CH:3][N:20]=[C:21]([NH2:23])[N:22]=1
Reactant: CN(C)C=C(C(=O)c1ccco1)c1ccncc1
Reactant: N=C(N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncc(-c2ccncc2)c(-c2ccco2)n1
Temperature: 70 °C
Reaction time: 12 h
Yield: 80 %

Procedure:
A suspension of 3-(dimethylamino)-1-(2-furyl)-2-(4-pyridyl)-2-propene-1-one (2.2 g, 9.08 mmol), guanidine hydrochloride (2.6 g, 27.2 mmol) and potassium carbonate (7.5 g, 54.3 mmol) in N,N-dimethylformamide (20 mL) was stirred at 70° C. for 12 hours. After cooling as it was, the reaction mixture was diluted with water. The resulting crystals were collected by filtration and washed with water, to give the title compound (1.73 g, 80%) as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][C:10]([CH:19]=O)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21]1([C:27]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:28]2[CH2:33][CH2:32][C:31](=[O:34])[CH2:30][CH2:29]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1CCCC1>C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C:12]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][C:10](/[CH:19]=[C:32]2\[CH2:33][N:28]([C:27]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:29][CH2:30][C:31]\2=[O:34])=[N:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)Cc1cc(C=O)nn1C(=O)OC(C)(C)C
Reactant: O=C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Solvent: c1ccccc1
Solvent: C1CCNC1
Product: CCOC(=O)Cc1cc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2=O)nn1C(=O)OC(C)(C)C
Yield: 57 %

Procedure:
Following a procedure similar to that described in Example 132-(c), ethyl [1-(t-butoxycarbonyl)-3-formyl-1H-pyrazol-5-yl]acetate (7.84 g) was subjected to the reaction with 1-(triphenylmethyl)piperidin-4-one in benzene using pyrrolidine. The crude product thus obtained was purified by silica gel chromatography using hexane, ethyl acetate, and dichloromethane (3:1:1) as an eluent to afford the title compound (9.64 g, yield: 57%) as a yellow amorphous solid.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[NH:13]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CC(O)=O>CCO>[CH2:21]([N:13]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(CN(Cc1ccccc1)Cc1ccccc1)[C@@H](O)[C@H](O)[C@H](O)CO
Yield: 79.3 %

Procedure:
To a suspension of D-glucose (36.0 g, 200.0 mmol) and Bn2NH (39.5 g, 200.0 mmol) in absolute EtOH (200 mL) was added AcOH (12.0 g, 200.0 mmol). Upon refluxing for 3 h, the reaction mixture was cooled and filtered with suction. The resulting filter cake was washed with EtOH to colorless and dried in a desiccator over calcium chloride to give 1-dibenzylamino-1-deoxy-D-fructose as a white solid (57.0 g, 79%).
Reaction SMILES: C(OC(=O)[NH:10][C:11]1([CH3:24])[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=2)[CH2:13][CH2:12]1)C1C=CC=CC=1.I[Si](C)(C)C>C(#N)C>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([N:14]2[CH2:15][CH2:16][C:11]([NH2:10])([CH3:24])[CH2:12][CH2:13]2)=[N:18][CH:19]=1
Reactant: CC1(NC(=O)OCc2ccccc2)CCN(c2ccc(Cl)cn2)CC1
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: CC1(N)CCN(c2ccc(Cl)cn2)CC1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (5′-chloro-4-methyl-3,4,5,6-tetrahydro-2H-(1,2′)bipyridinyl-4-yl)-carbamic acid benzyl ester (0.060 g, 0.17 mmol ) in acetonitrile (1.0 mL) at room temperature was added iodotrimethysilane (0.04 mL, 0.25 mmol). The reaction mixture was stirred at 50° C. for 30 minutes, concentrated under reduced pressure, and purified by flash chromatography with 3% methanol in dichloromethane to provide titled compound. MS (CI) m/z 226 (M+1)+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([F:28])[C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:15][CH:14]=2)=[N:11][CH:12]=1.B(OC(C)C)(OC(C)C)[O:30]C(C)C.[Cl-].[NH4+]>CCCCCC.O1CCCC1.CCOCC>[F:28][C:9]1[C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:15][CH:14]=2)=[N:11][CH:12]=[C:7]([OH:30])[CH:8]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCCCCCCCOc1ccc(-c2ncc(Br)cc2F)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCCCOc1ccc(-c2ncc(O)cc2F)cc1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
15 ml (24.00 mmol) of 1.6 molar n-butyllithium solution in hexane are added dropwise to a solution, cooled to -70° C., of 7.61 g (20.00 mmol) of 5-bromo-3-fluoro-2-(4-octyloxyphenyl)pyridine in 400 ml of tetrahydrofuran, and the mixture is stirred at -70° C. for 15 minutes. 7.5 g (40.00 mmol) of triisopropyl borate are subsequently added dropwise, the mixture is stirred at -70° C. for 1.5 hours and warmed to room temperature, 500 ml of ammonium chloride solution and 500 ml of ether are added, and the organic phase is separated off and washed twice with aqueous sodium chloride solution, dried over sodium sulfate and evaporated. The resultant 3-fluoro-2-(4-octyloxyphenyl)pyridine-5-boronic acid is refluxed for 2 hours in 100 ml of tetrahydrofuran with 30 ml of 17.5% strength by weight aqueous hydrogen peroxide solution and subsequently cooled to 0° C., and 200 ml of aqueous sodium sulfite solution are added dropwise. The organic phase is separated off, washed twice with aqueous sodium chloride solution, dried over sodium sulfate and evaporated to dryness. Recrystallization from 1,2-dichloroethane gives 5.08 g of 3-fluoro-5-hydroxy-2-(4-octyloxyphenyl)pyridine. ##STR17##
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:7]2[C:8](=O)[CH2:9][CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[CH2:11][C:6]=2[O:5][CH:4]=1.[C:22]([NH:25][NH2:26])([NH2:24])=[NH:23].[ClH:27].Cl.O>C(O)C>[ClH:27].[F:1][C:2]([F:21])([F:20])[C:3]1[C:7]2[C:8](=[N:26][NH:25][C:22]([NH2:24])=[NH:23])[CH2:9][CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[CH2:11][C:6]=2[O:5][CH:4]=1
Reactant: Cc1ccccc1C1CC(=O)c2c(C(F)(F)F)coc2C1
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccccc1C1CC(=NNC(=N)N)c2c(C(F)(F)F)coc2C1
Yield: 40.6 %

Procedure:
A mixture of 3-trifluoromethyl-6-(2-methylphenyl)-4,5,6,7-tetrahydrobenzofuran-4-one (0.15 g), aminoguanidine hydrochloride (0.06 g), concentrated hydrochloric acid (0.025 ml), water (0.025 ml) and ethanol (30 ml) was refluxed for 6 hours. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethanol-ethyl acetate to give 3-trifluoromethyl-4-guanidinoimino-6-(2-methylphenyl)-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 52) (0.08 g) as colorless crystals.