Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C([NH:5][C:6]1[C:15](=[O:16])[C:14]2[N:13]=[C:12]([CH3:17])[CH:11]=[CH:10][C:9]=2[C:8](=[O:18])[CH:7]=1)(=O)C.C(=O)(O)[O-].[Na+]>CO>[NH2:5][C:6]1[C:15](=[O:16])[C:14]2[N:13]=[C:12]([CH3:17])[CH:11]=[CH:10][C:9]=2[C:8](=[O:18])[C:7]=1[Cl:1]
Reactant: Cl
Reactant: CC(=O)NC1=CC(=O)c2ccc(C)nc2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1ccc2c(n1)C(=O)C(N)=C(Cl)C2=O

Procedure:
A slow stream of hydrogen chloride gas was passed through a solution of 7-acetamido-2-methylquinoline-5,8-dione (6, 230 mg, 1 mmol) in dry methanol (15 ml) at 60° C. for 48 h. (See Equation 11 below) The resulting acidic solution was neutralized with 2% sodium bicarbonate (10 ml), extracted with CH2Cl2 (5×30 ml) and dried over sodium sulfate (2.0 g, 20 min). Evaporation of the solvent in vacuo afforded 98 mg (42%) of pure (59) as red crystals: mp 270° C. (Dec.,MeOH); 1H NMR (CDCl3) δ 8.31 (1 H, d, J=8.0 Hz, H-4), 7.47 (1 H, d, J=8.0 Hz, H-3), 5.70 (2H, br s, NH2), 2.68 (3H, s, CH3); IR (KBr) Vmax 3471, 3329, 3191, 3085, 2960, 2924, 1649, 1605, 1587, 1573, 1382, 1370, 1326, 1273, 1259, 1164, 737 cm-1 ; CIMS, m/e (relative intensity) 223 (M+1, 100), 189 (4.1), 133 (0.4), 81 (0.8), 69 (1.2); EIMS, m/e (relative intensity) 224 (M+2, 27.3), 222 (M+, 97.2), 195 (7.4), 187 (M-Cl, 100), 166 (5.3), 131 (10.4), 104 (12.1), 77 (14.9), 64 (10.5); HRMS, m/e for C10H7ClN2O2 calcd 222.0196, found 222.0194. ##STR48##
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:14](Br)[CH:15]=[CH2:16].O>CN(C=O)C>[CH2:16]([N:2]1[C:3]([CH:6]=[O:7])=[CH:4][CH:5]=[N:1]1)[CH:15]=[CH2:14]
Reactant: O=Cc1cc[nH]n1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCn1nccc1C=O
Yield: 10.1 %

Procedure:
Pyrazole-3-carbaldehyde (3.00 g, 31.2 mmol) was dissolved in DMF (20 ml), and thereto were added potassium carbonate (6.47 g, 46.8 mmol) and allyl bromide (3.50 g, 32.8 mmol) with stirring. The mixture was stirred at room temperature for 6 hours, and thereto was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title compound (429 mg, 10%).
Reaction SMILES: C(O)(C(F)(F)F)=O.O=C1NC[C@H]([C@H](O[C:17]2[C:18]3[N:19]([N:35]=[CH:36][C:37]=3[C:38]#[N:39])[CH:20]=[C:21](C3C=CC(N4CCNCC4)=CC=3)[N:22]=2)C)C1.CCN(C(C)C)C(C)C.O1CC(=O)C1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[N:35]1[N:19]2[CH:20]=[CH:21][N:22]=[CH:17][C:18]2=[C:37]([C:38]#[N:39])[CH:36]=1
Reactant: C[C@@H](Oc1nc(-c2ccc(N3CCNCC3)cc2)cn2ncc(C#N)c12)[C@H]1CNC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C1COC1
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: N#Cc1cnn2ccncc12
Temperature: 50 °C
Reaction time: 3 h

Procedure:
The crude TFA salt of 5.67 (0.089 mmol) was taken up in THF (2 mL) and was treated with iPr2NEt (16 μL, 0.089 mmol), 3-oxetanone (29 μL, 0.45 mmol) and sodium triacetoxyborohydride (132 mg, 0.62 mmol). The resulting mixture was heated to 50° C. and was stirred for 3 h. The reaction mixture was then partitioned between DCM, water, and 5% (w/v) saturated aqueous Na2CO3 and the phases were separated. The aqueous phase was extracted with DCM (3×20 mL) and the combined organics were dried over Na2SO4, filtered, and concentrated. The concentrate was purified by silica gel chromatography (0-20% MeOH in DCM) to provide 6-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-4-4R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyrazine-3-carbonitrile 5.70. LCMS-ESI+ (m/z): [M+H]+ calcd for C26H30N7O3: 488.2; found: 488.0. 1H NMR (400 MHz, Chloroform-d) δ 8.40 (s, 1H), 8.18 (s, 1H), 7.84-7.77 (m, 2H), 7.03-6.96 (m, 2H), 5.99 (s, 1H), 5.64-5.53 (m, 1H), 4.76-4.63 (m, 4H), 3.64-3.51 (m, 2H), 3.50-3.41 (m, 1H), 3.38-3.30 (m, 4H), 3.12-2.97 (m, 1H), 2.60 (dd, J=17.1, 9.2 Hz, 1H), 2.56-2.49 (m, 4H), 2.43 (dd, J=17.1, 8.0 Hz, 1H), 1.54 (d, J=6.2 Hz, 3H).
Reaction SMILES: [I-].[C:2]1([CH2:8][C:9]([NH:11][CH:12]2[C:55](=[O:56])[N:14]3[C:15]([C:39]([O:41][CH:42]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[O:40])=[C:16]([CH2:19][P+](C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH2:17][S:18][C@H:13]23)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:57]1([CH:60]=O)[CH2:59][CH2:58]1.O.[OH-].[Na+]>C(Cl)Cl>[C:2]1([CH2:8][C:9]([NH:11][CH:12]2[C:55](=[O:56])[N:14]3[C:15]([C:39]([O:41][CH:42]([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[C:49]4[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=4)=[O:40])=[C:16](/[CH:19]=[CH:60]\[CH:57]4[CH2:58][CH2:59]4)[CH2:17][S:18][C@H:13]23)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Reactant: O=CC1CC1
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C\C3CC3)CS[C@H]12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
15.9 g (17.9 mmol ) of benzhydryl 7-phenylacetamido-3-(triphenylphosphonio)methyl-3-cephem-4-carboxylate iodide (Example 7) are taken in 100 ml of methylene chloride and 17.56 g (250.6 mmol) of cyclopropanecarboxaldehyde in a 250 ml three-necked flask. The mixture is cooled to 0° C. and 100 ml of water are added. 16.3 ml of 1N NaOH are then added dropwise in the course of 4 hours, the pH being kept constant at 8.6. The reaction solution is diluted with methylene chloride and the organic phase is separated off, washed once with water and then dried over sodium sulphate. After the drying agent has been removed, a further 13 ml (233 mmol) of cyclopropanecarboxaldehyde are added to the methylene chloride solution and the mixture is stirred overnight. The reaction solution is then concentrated to dryness, the residue is again dissolved in a little methylene chloride and the mixture is introduced onto a column filled with 500 ml of silica gel (0.04-0.063 mm). 400 ml fractions are collected and all the fractions are investigated for the cis-isomer compound by means of analytical HPLC.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH2:14])[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35](O)=[O:36])=[CH:27][CH:26]=1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][C:35]([C:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:25]=[CH:26][CH:27]=2)=[O:36])[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1
Reactant: O=C(O)c1ccnc2ccccc12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1)c1ccnc2ccccc12

Procedure:
200 mg (0.550 mmol) of (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-4-piperidinamine are reacted in analogy to Example 4a with 105 mg (0.660 mmol) of quinoline-4-carboxylic acid, 168 mg (0.661 mmol) of bis(2-oxo-3-oxazolidinyl)phosphinic chloride and 169 μl (1.21 mmol) of triethylamine. The title compound ##STR85## is obtained (278 mg, 97%) as oil. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.45, FD-MS: M+ =517, 519; IR: 3395, 1755, 1620 cm-1.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[N:10]=2)[N:5]=[N:6][C:7]=1[Cl:8].[NH3:26]>C1COCC1.C(O)C>[Cl:8][C:7]1[N:6]=[N:5][C:4]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[N:10]=2)=[N:3][C:2]=1[NH2:26]
Reactant: Fc1ccccc1Cn1nc(-c2nnc(Cl)c(Cl)n2)c2cccnc21
Reactant: N
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nnc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
7.000 g (purity 38%, 7.090 mmol) of 3-(5,6-dichloro-1,2,4-triazin-3-yl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine in 200 ml of absolute THF were initially introduced. With ice-cooling, 4.254 ml (8.508 mmol) of 2N ammonia solution in ethanol were added and the mixture was stirred for 1 h at 0° C. Again with ice-cooling, 4.254 ml (8.508 mmol) of 2N ammonia solution in ethanol were added and the mixture was stirred for 1.5 h at RT. 30 ml (60.000 mmol) of 2N ammonia solution in ethanol was added and the mixture was stirred for 15 min at RT. The reaction mixture was concentrated on a rotary evaporator, suspended in 100 ml of dichloromethane, admixed with 50 ml (100.00 mmol) of 2N ammonia solution in ethanol and stirred for 2 h at RT. The mixture was concentrated on a rotary evaporator and purified by chromatography on silica gel (mobile phase: dichloromethane/methanol, gradient 20:1→10:1). The product-containing fractions were concentrated and stirred with DMSO. The solid was filtered off with suction, after-washed with acetonitrile and dried under high vacuum. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water, gradient 20:80→100:0). This gave 1.68 g of the target compound (purity 65%; 43% of theory).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=O.[CH3:8][NH:9][C:10](=[S:13])[NH:11][NH2:12].FC(F)(F)C(F)=O>>[F:1][C:2]([F:7])([F:6])[C:3]1[N:9]([CH3:8])[C:10]([SH:13])=[N:11][N:12]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CNC(=S)NN
Agent: O=C(F)C(F)(F)F
Product: Cn1c(S)nnc1C(F)(F)F

Procedure:
This exemplified compound may be readily synthesized by the reaction of methyl isocyanate with hydrazine to give 4-methyl-3-thiosemicarbazide followed by cyclocondensation with trifluoroacetic acid as described in U.S. Pat. No. 4,477,459. This compound may also be prepared by the reaction of 4-methyl-3-thiosemicarbazide with trifluoroacetylfluoride and heat (U.S. Pat. No. 3,780,052).
Reaction SMILES: [NH:1]([C:8]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].C(O)(=O)C>[NH:1]([C:8]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(Nc2ccccc2)CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)C1(Nc2ccccc2)CCNCC1
Temperature: 25 °C

Procedure:
A solution of 16.9 parts of ethyl 4-anilino-1-benzylisonipecotate in 150 parts of acetic acid is hydrogenated at normal pressure and at a temperature of 45° C with 1.5 parts of palladium-on-charcoal 10%. After the calculated amount of hydrogen is taken up, the reaction mixture is allowed to cool to room temperature, the catalyst is filtered off and the filtrate is evaporated. The oily residue is taken up in water, alkalized with ammonium hydroxide and the product is extracted with chloroform. The extract is washed with water, dried, filtered and evaporated. The oily residue solidifies on triturating in petroleumether. The product is filtered off and crystallized from acetonitrile, yielding ethyl 4-anilinoisonipecotate; mp. 121.8° C.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[S:23]1[CH:27]=[N:26][N:25]=[C:24]1[CH:28]([OH:46])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45].[O-]S([O-])(=S)=O.[Na+].[Na+].CO.C(Cl)Cl>C(Cl)Cl.CCOCC.C([O-])(O)=O.[Na+]>[S:23]1[CH:27]=[N:26][N:25]=[C:24]1[C:28](=[O:46])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]=[CH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: CCCCCCCC/C=C\CCCCCCCC(O)c1nncs1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: CCCCCCCCC=CCCCCCCCC(=O)c1nncs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
A suspension of the Dess-Martin periodinane (1.2 equiv, 0.013 mmol, 14 mg) in anhydrous CH2Cl2 (0.5 mL) was treated with a solution of (Z)-1-(1,3,4-thiadiazol-2-yl)-octadec-9-en-1-ol (4 mg, 0.011 mmol) in anhydrous CH2Cl2 (0.5 mL) at room temperature under N2. After 10 h the suspension was diluted with Et2O (10 mL), and poured into a solution of Na2S2O3 (40 mg) in saturated aqueous NaHCO3 (3.4 mL). The mixture was stirred at room temperature for 1 h and the layers were separated. The ethereal layer was washed with saturated aqueous NaHCO3 and H2O, dried over MgSO4, filtered and condensed. Flash chromatography (SiO2, 1.5 cm×15 cm, 2% MeOH—CH2Cl2) afforded the title compound (3 mg, 70% yield) as a dark yellow oil: 1H NMR (CDCl3, 250 MHz) δ 9.29 (s, 1H), 5.41-5.27 (m, 2H), 3.10 (t, 2H, J=7.4 Hz), 2.12-1.88 (m, 4H), 1.84-1.75 (m, 2H), 1.47-1.19 (m, 20H), 0.87 (br t, 3H, J=6.6 Hz); IR (CDCl3) νmax 2936, 2855, 1710, 1610, 1562, 1516, 1426, 1372 cm−1; MALDI-FTMS (DHB) m/z 351.2464 ([M+H]+, C20H34N2OS requires 351.2470).
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([CH2:12][N:13]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]([CH:16]2[CH2:18][CH2:17]2)=[O:15])[CH:6]=1)C.[Li+].[OH-].O.Cl>CO.C1COCC1>[CH2:19]([N:13]([CH2:12][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[Br:11])[C:4]([OH:26])=[O:3])[C:14]([CH:16]1[CH2:17][CH2:18]1)=[O:15])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1ccc(Br)c(CN(Cc2ccccc2)C(=O)C2CC2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(Br)c(CN(Cc2ccccc2)C(=O)C2CC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-[(N-Benzyl-N-cyclopropanecarbonyl-amino)-methyl]-4-bromo-benzoic acid ethyl ester (2.03 g, 4.9 mmol) was treated with 1N aqueous LiOH (10 mL) in MeOH (60 mL) and THF (10 mL). After stirring for 1 hour at room temperature, additional 1N aqueous LiOH (10 mL) was added, and the reaction was stirred for another 2 hours. The mixture was poured into H2O (200 mL) and neutralized with 1N aqueous HCl (50 mL). The solution was extracted three times with EtOAc to give 3-[(N-benzyl-N-cyclopropanecarbonyl-amino)-methyl]-4-bromo-benzoic acid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[C:10]([Cl:11])=[CH:9][C:8](Cl)=[N:7][C:6]=1[CH3:13])[CH3:2].[CH2:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][CH3:24])[C:18]=1B(O)O)[CH3:16].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:18]2[C:19]([CH2:23][CH3:24])=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:15][CH3:16])=[N:7][C:6]=1[CH3:13])[CH3:2]
Reactant: CCc1cccc(CC)c1B(O)O
Reactant: CCOC(=O)c1c(Cl)cc(Cl)nc1C
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: Cc1ccccc1
Product: CCOC(=O)c1c(Cl)cc(-c2c(CC)cccc2CC)nc1C
Temperature: 25 °C

Procedure:
A mixture of 4,6-dichloro-2-methyl-nicotinic acid ethyl ester (1.2 g, 5.1 mmol), 2,6-diethyl-phenyl boronic acid (2.18 g, 12.2 mmol), sodium carbonate (2 M aqueous solution, 12.2 mL, 24.4 mmol), and Pd(PPh3)4 (284 mg, 0.26 mmol) is refluxed in toluene for 48 hours and then cooled to room temperature. The organic layer is separated and the aqueous layer is extracted with ethyl acetate (2×50 mL). The organic layers are combined, dried, and solvent removed. The crude product is purified by flash column (hexanes/ethyl acetate 8:1) to give 4-chloro-6-(2,6-diethyl-phenyl)-2-methyl-nicotinic acid ethyl ester. 1H NMR: (CDCl3) 7.26 (t, 1H), 7.18 (s, 1H), 7.13 (d, 2H), 4.47 (q, 2H), 2.62 (s, 3H), 2.28 (q, 4H), 1.44 (t, 3H), 1.04 (t, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][C:5]2[CH:6]=[C:7]([C:9]([OH:11])=[O:10])[O:8][C:4]=2[C:3]=1[CH3:14].[C:15](Cl)(=[O:20])[CH2:16][CH:17]([CH3:19])[CH3:18].[Cl-].[Cl-].[Cl-].[Al+3].Cl>ClCCl>[C:15]([C:13]1[C:2]([CH3:1])=[C:3]([CH3:14])[C:4]2[O:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6][C:5]=2[CH:12]=1)(=[O:20])[CH2:16][CH:17]([CH3:19])[CH3:18]
Reactant: Cc1ccc2cc(C(=O)O)oc2c1C
Reactant: CC(C)CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1c(C(=O)CC(C)C)cc2cc(C(=O)O)oc2c1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 6,7-dimethylbenzofuran-2-carboxylic acid (9 g.) and isovaleryl chloride (7.5 g.) in dichloromethane (100 ml.) at 5°C. is added aluminum trichloride (20 g.) in portions over a 1 hour period. The reaction mixture is stirred at 25°C. for 18 hours, poured into a mixture of ice (300 g.) and hydrochloric acid (50 ml.) to afford 5-isovaleryl-6,7-dimethylbenzofuran-2-carboxylic acid.
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[N:32](COCC[Si](C)(C)C)[C:18]4[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22](=[O:23])[C:17]=4[C:16]=3[CH2:41][O:42][CH2:43][CH:44]([CH3:46])[CH3:45])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1.C1(OC2C=C(C3N(COCC[Si](C)(C)C)C4C=NN(COCC[Si](C)(C)C)C(=O)C=4C=3C)C=CC=2OC(F)F)CC1>>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[NH:32][C:18]4[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:31])[CH3:29])[C:22](=[O:23])[C:17]=4[C:16]=3[CH2:41][O:42][CH2:43][CH:44]([CH3:46])[CH3:45])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1
Reactant: CC(C)COCc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Agent: Cc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Product: CC(C)COCc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)[nH]c2cnn(COCC[Si](C)(C)C)c(=O)c12
Yield: 76.8 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Example 4-(b) except for using 1.35 g (1.99 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-isobutoxymethyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 62-(a) in place of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-methyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one, whereby 0.84 g of the title compound was obtained as a white foam. (Yield: 77%)
Reaction SMILES: [ClH:1].Cl.[Cl:3][C:4]1[S:8][C:7]([C:9]2[NH:10][C:11]([CH2:20]Cl)=[C:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[N:13]=2)=[CH:6][CH:5]=1.[C:22](=O)([O-])[OH:23].[Na+]>CO>[ClH:3].[ClH:1].[Cl:3][C:4]1[S:8][C:7]([C:9]2[NH:10][C:11]([CH2:20][O:23][CH3:22])=[C:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[N:13]=2)=[CH:6][CH:5]=1
Reactant: O=C([O-])O
Reactant: ClCc1[nH]c(-c2ccc(Cl)s2)nc1-c1cccnc1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COCc1[nH]c(-c2ccc(Cl)s2)nc1-c1cccnc1

Procedure:
In methanol (10 ml) was dissolved a crude product of 2-(5-chlorothiophen-2-yl)-5-chloromethyl-4-(3-pyridyl)-imidazole dihydrochloride (260 mg) and the mixture was refluxed for 2 hours. After cooling, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with a mixed solution of ethyl acetate-tetrahydrofuran. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: chloroform:methanol=40:1), and then, treated with hydrogen chloride-dioxane solution to obtain 2-(5-chlorothiophen-2-yl)-5-methoxymethyl-4-(3-pyridyl) imidazole dihydrochloride (63 mg) as pale yellowish powder.
Reaction SMILES: [OH:1][C:2]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)=[CH:3][C:4]1[N:13]2[CH2:14][CH2:15][N:16]=[C:12]2[C:11]2[CH:10]=[CH:9][C:8]([O:17][CH2:18][CH2:19][CH2:20][C:21]([O:23]C)=[O:22])=[C:7]([O:25][CH3:26])[C:6]=2[N:5]=1.Cl>[Li+].[OH-].C(O)C>[OH:1][C:2]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)=[CH:3][C:4]1[N:13]2[CH2:14][CH2:15][N:16]=[C:12]2[C:11]2[CH:10]=[CH:9][C:8]([O:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[C:7]([O:25][CH3:26])[C:6]=2[N:5]=1
Reactant: COC(=O)CCCOc1ccc2c(c1OC)N=C(C=C(O)c1cccnc1)N1CCN=C21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: COc1c(OCCCC(=O)O)ccc2c1N=C(C=C(O)c1cccnc1)N1CCN=C21
Yield: 47.3 %

Procedure:
A solution of methyl 4-{[5-(2-hydroxy-2-pyridin-3-ylvinyl)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-yl]oxy}butanoate (example 1-5) 20.0 mg (0.05 mmol) in 1N LiOH solution 0.1 mL and ethanol 1.0 mL was stirred at room temperature for overnight. The reaction mixture was neutralized with 1N HCl solution and concentrated in vacuo. The residue was triturated in water. The precipitate was collected to give the title compound 10.0 mg as white solid. Yield 51.7%.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C@@H:5]1[CH2:9][O:8][C:7](=[O:10])[N:6]1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[O:18])=[C:13]([F:25])[CH:12]=1)[CH3:2].Cl[C:27]1[C:32]([Cl:33])=[CH:31][C:30]([Cl:34])=[CH:29][N:28]=1>>[Cl:33][C:32]1[C:27]([N:22]2[CH2:23][CH2:24][N:19]([C:17]([C:14]3[CH:15]=[CH:16][C:11]([N:6]4[C@H:5]([CH2:4][O:3][CH2:1][CH3:2])[CH2:9][O:8][C:7]4=[O:10])=[CH:12][C:13]=3[F:25])=[O:18])[CH2:20][CH2:21]2)=[N:28][CH:29]=[C:30]([Cl:34])[CH:31]=1
Reactant: Clc1cnc(Cl)c(Cl)c1
Reactant: CCOC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCNCC2)c(F)c1
Product: CCOC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(Cl)cc3Cl)CC2)c(F)c1
Yield: 66.6 %

Procedure:
By reaction and treatment in the same manner as in Example 147 and using (R)-4-ethoxymethyl-3-[3-fluoro-4-(piperazine-1-carbonyl)phenyl]oxazolidin-2-one (1.23 g) described in Preparation Example 160 and 2,3,5-trichloropyridine (1.28 g), the title compound (1.16 g) was obtained. MS(ESI)m/z:497(M+H)+.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[N:22]=[C:23]([CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([S:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=2)[O:24][CH:25]=1.O>CN(C=O)C>[F:38][C:35]([S:34][C:31]1[CH:32]=[CH:33][C:28](/[CH:27]=[CH:26]/[C:23]2[O:24][CH:25]=[C:21]([CH2:20][O:18][C:15]3[CH:14]=[CH:13][C:12]([CH2:11][O:10][CH2:9][CH2:8][N:3]4[CH:7]=[CH:6][N:5]=[N:4]4)=[CH:17][CH:16]=3)[N:22]=2)=[CH:29][CH:30]=1)([F:36])[F:37]
Reactant: FC(F)(F)Sc1ccc(C=Cc2nc(CCl)co2)cc1
Reactant: Oc1ccc(COCCn2ccnn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)Sc1ccc(/C=C/c2nc(COc3ccc(COCCn4ccnn4)cc3)co2)cc1
Reaction time: 0.25 h

Procedure:
25 mg (1.00 mmol) 95% Sodium hydride were given to a solution of 219 mg (1.00 mmol) 4-(2-[1,2,3]triazol-1-yl-ethoxymethyl)-phenol in 5.0 ml DMF and stirred for 15 min. 304 mg (1.00 mmol) 4-Chloromethyl-2-[2-(4-trifluoromethylsulfanyl-phenyl)-vinyl]-oxazole were added and stirring continued at r.t. overnight. After addition of 20 ml water the resulting precipitate was washed twice with 10 ml water, 2×10 ml methanol, diethyl ether and dried at 45° C. in vacuum. Yield 301 mg (60%) pale beige powder.
Reaction SMILES: C([C:3]1[C:4]([CH:9]=[N:10]O)=[N:5][CH:6]=[CH:7][CH:8]=1)C.[Cl:12]NC(=O)CCC(N)=O>CN(C=O)C>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:3][C:4]=1[C:9]([Cl:12])=[NH:10]
Reactant: NC(=O)CCC(=O)NCl
Reactant: CCc1cccnc1C=NO
Solvent: CN(C)C=O
Product: N=C(Cl)c1ccccn1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
To a mixture of ethyl 2-pyridin-aldoxime (15 gm) and N-chlorosuccinamide (25 gm) in DMF (30 ml) was stirred at 30° C. over a period of 2 h. The reaction mixture was quenched with ice-cold water (150 ml). The suspension was filtered and the wet cake washed with small quantity of water to provide pure title compound in 7 gm quantity (55%) as a white solid.