Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:15])[CH:4]([NH:6][C:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[O:8])[CH3:5].[CH3:16][NH2:17]>C(O)C>[CH3:16][NH:17][C:3]([CH:4]([NH:6][C:7](=[O:8])[C:9]1[CH:14]=[CH:13][CH:12]=[N:11][CH:10]=1)[CH3:5])=[O:15]
Reactant: CN
Reactant: COC(=O)C(C)NC(=O)c1cccnc1
Solvent: CCO
Product: CNC(=O)C(C)NC(=O)c1cccnc1
Temperature: 55 °C
Yield: 50.2 %

Procedure:
To a solution of 2-[(pyridine-3-carbonyl)-amino]-propionic acid methyl ester (10.4 g, 50 mmol) in ethanol (50 mL) was added methylamine (24 g, 33 wt % solution in ethanol, 250 mmol). The reaction mixture was heated at 55° C. for 45 min. The solvents were removed in vacuo and the residue was recrystallized from hot ethyl acetate and hexanes. The yellow crystals thus obtained were washed with cold ethyl acetate and dried to give the desired product (5.2 g, 50%): 1H NMR (300 MHz, DMSO-d6) δ 9.05 (br s, 1H), 8.77-8.70 (m, 2H), 8.24 (m, 2H), 7.89 (br s, 1H), 7.50 (m, 1H), 2.59 (d, J=4.7 Hz, 3H), 1.33 (d, J=7.4 Hz, 3H); ESIMS m/z 208.1 (M+1), m/z 206.1 (M−1).
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[OH:9][C@@H:10]([CH2:15][O:16][CH2:17][CH3:18])[C:11]([O:13][CH3:14])=[O:12].N1C=CN=C1>CN(C=O)C>[Si:5]([O:9][C@@H:10]([CH2:15][O:16][CH2:17][CH3:18])[C:11]([O:13][CH3:14])=[O:12])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: CCOC[C@H](O)C(=O)OC
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCOC[C@H](O[Si](C)(C)C(C)(C)C)C(=O)OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 57.6 %

Procedure:
A solution of tert-butylchlorodimethylsilane (17.71 g, 117.52 mmol) in dry DMF (50 mL) was added dropwise to a stirred solution of (S)-methyl 2-hydroxy-3-ethoxypropanoate (14.51 g, 97.94 mmol) and 1H-imidazole (13.33 g, 195.87 mmol) in dry DMF (70 mL) at 20° C., over a period of 2 minutes. The resulting solution was stirred at ambient temperature for 20 hours. The reaction mixture was concentrated and diluted with EtOAc (500 mL), washed sequentially with water (4×100 mL) and saturated brine (100 mL). The organic layer was dried (MgSO4) and evaporated. The residue was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane to afford methyl (2S)-2-(tert-butyl-dimethylsilyl)oxy-3-ethoxypropanoate (14.8 g, 57%). 1H NMR (400 MHz, CDCl3) δ 0.10 (6H, d), 0.93 (9H, s), 1.19 (3H, t), 3.50-3.65 (3H, m), 3.57-3.73 (1H, m), 3.75 (3H, s), 4.37-4.40 (1H, m), 7.18 (2H, d).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[OH:16])([CH3:8])([CH3:7])[CH3:6].[CH:17](OCC)(OCC)[O:18]CC.Cl>ClC1C=CC=CC=1>[C:5]([C:9]1[C:10]([OH:16])=[CH:11][C:12]([CH3:15])=[C:13]([CH:14]=1)[CH:17]=[O:18])([CH3:8])([CH3:7])[CH3:6]
Reactant: Cc1ccc(C(C)(C)C)c(O)c1
Reactant: CCOC(OCC)OCC
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: Cc1cc(O)c(C(C)(C)C)cc1C=O
Temperature: -10 °C
Reaction time: 6 h

Procedure:
Aluminum chloride (26.6 g, 200 mmol) was added to chlorobenzene (40 mL), and the mixture was cooled to −10° C. A solution of 2-tert-butyl-5-methylphenol (16.4 g, 100 mmol) in triethyl orthoformate (32.5 g, 220 mmol) was added dropwise. When addition was complete, the reaction mixture was warmed to 0° C. to 5° C. and kept at that temperature for 6 hours. Five percent HCl (100 mL) was added, and the mixture was extracted with 1:1 EtOAC:toluene. The organic phase was extracted with 23% KOH (3×50 mL) and water (25 mL), and the water extract was combined with the KOH extracts. The pH of the combined aqueous extracts was adjusted to 4 with 37% HCl. The resulting precipitate was filtered, washed with water (3×50 mL), and dried to give the title compound. mp 171-171° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)=O.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.[OH-].[Na+]>C(O)C>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]2[N:11]=[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]3[CH:1]=2)=[CH:5][CH:6]=1
Reactant: Nc1ccccn1
Reactant: CC(=O)c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Brc1ccc(-c2cn3ccccc3n2)cc1
Yield: 84.8 %

Procedure:
Dissolving 15 g (54 mmol) of 4-bromoacetophenone and 5.2 g (55 mmol) of 2-aminopyridine into 100 milliliter of ethanol, adding 7.0 g of sodium hydroxide, the resultant suspension was refluxed under heating for 6 hours. After completion of the reaction, resultant crystals were separated with filtration, washed with water and ethanol, thereby obtaining 12.5 g of 2-(4-bromo-phenyl)-imidazo [1,2-a] pyridine (yield: 85%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[OH:17].Br[CH2:19]Br.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:16][C:14]1[CH:13]=[CH:12][C:11]2[O:17][CH2:19][N:1]3[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=[C:2]3[C:10]=2[CH:15]=1
Reactant: Oc1ccc(Cl)cc1-c1nc2ccccc2[nH]1
Reactant: BrCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc2c(c1)-c1nc3ccccc3n1CO2
Temperature: 80 °C
Reaction time: 12 h
Yield: 35.4 %

Procedure:
A mixture of 2-(1H-benzo[d]imidazol-2-yl)-4-chlorophenol (80 mg, 0.33 mmol), dibromo-methane (341 mg, 1.96 mmol), K2CO3 (137 mg, 0.99 mmol) in DMF (6 mL) was allowed to stir at 80° C. for 12 hours. Water (20 mL) was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over Na2SO4. After being concentrated in vacuo, the resulting resulting residue was purified using prep-HPLC to provide 2-chloro-6H-benzo[e]benzo[4,5]imidazo[1,2-c][1,3]oxazine (30 mg, yield: 36%). 1H-NMR (Methanol-d4, 400 MHz) δ 8.07 (d, J=2.1 Hz, 1H), 7.83˜7.81 (m, 1H), 7.78˜7.75 (m, 1H), 7.63 (dd, J=8.8, 2.2 Hz, 1H), 7.54˜7.52 (m, 2H), 7.30 (d, J=8.8 Hz, 1H), 6.33 (s, 2H). MS (M+H)+: 257.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:15]([OH:17])=O)=[CH:13][N:14]=2)[CH:11]=1)#[N:2].C(Cl)(=O)C(Cl)=O.CN(C=O)C.[NH2:29][C:30]1[CH:31]=[C:32]([C:37]2[N:41]=[C:40]([CH:42]3[CH2:45][N:44]([C:46]([O:48][CH3:49])=[O:47])[CH2:43]3)[O:39][N:38]=2)[CH:33]=[CH:34][C:35]=1[CH3:36]>ClCCl.N1C=CC=CC=1>[C:1]([CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:15]([NH:29][C:30]3[CH:31]=[C:32]([C:37]4[N:41]=[C:40]([CH:42]5[CH2:45][N:44]([C:46]([O:48][CH3:49])=[O:47])[CH2:43]5)[O:39][N:38]=4)[CH:33]=[CH:34][C:35]=3[CH3:36])=[O:17])=[CH:13][N:14]=2)[CH:11]=1)#[N:2]
Reactant: N#CCCCc1ccc2ncc(C(=O)O)n2c1
Reactant: COC(=O)N1CC(c2nc(-c3ccc(C)c(N)c3)no2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)N1CC(c2nc(-c3ccc(C)c(NC(=O)c4cnc5ccc(CCCC#N)cn45)c3)no2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirring suspension of 6-(3-cyanopropyl)imidazo[1,2-a]pyridine-3-carboxylic acid (25) (50 mg, 0.218 mmol) in anhydrous dichloromethane (2 mL) at 0° C. under Argon was added dropwise oxalyl chloride (20 μL, 0.240 mmol). Then, a drop of anhydrous DMF was added and the reaction mixture was stirred at 0° C. for 1 hour. The solvent was concentrated and the crude solid was dried under vacuum. To a mixture of the acid chloride and methyl 3-(3-(3-amino-4-methylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (31) (31 mg, 0.109 mmol) cooled to ° C. under Argon was added anhydrous pyridine (2 mL). The reaction was stirred to room temperature under Argon for 20 minutes. The solvent was concentrated. The crude product methyl 3-(3-(3-(6-(3-cyanopropyl)imidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (F59) was purified by silica chromatography. 1H NMR (400 MHz, d6-DMSO) δ 10.13 (s, 1H), 9.38-9.36 (m, 1H), 8.66 (s, 1H), 8.11 (d, J=1.6 Hz, 1H), 7.86-7.82 (m, 2H), 7.63-7.60 (m, 1H), 7.51 (d, J=8.0 Hz, 1H), 4.39-4.34 (m, 2H), 4.31-4.24 (m, 1H), 4.21-4.18 (m, 2H), 3.59 (s, 3H), 2.81-2.77 (m, 2H), 2.60-2.52 (m, 2H), 2.38 (s, 3H), 1.97-1.90 (m 2H). MS m/z 500.52 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[S:9](Cl)(=[O:11])=[O:10].[OH:13][CH2:14][P:15](=[O:22])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18].C(N(CC)CC)C.S(Cl)(Cl)(=O)=O>CCOCC.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[S:9]([O:13][CH2:14][P:15](=[O:22])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])(=[O:10])=[O:11]
Reactant: CCOP(=O)(CO)OCC
Reactant: Cc1cccc(Cl)c1S(=O)(=O)Cl
Solvent: CCOCC
Solvent: O=S(=O)(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOP(=O)(COS(=O)(=O)c1c(C)cccc1Cl)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.2 %

Procedure:
A solution of 4.63 g of 2-chloro-6-methylbenzenesulfonyl chloride dissolved in 20 ml of anhydrous ether was added dropwise over a 15 minute period to a mixture of 3.50 g of diethyl P-(hydroxymethyl)phosphonate (Example 17), 5 ml of triethylamine and 15 ml of anhydrous ether. The addition was mildly exothermic and a white precipitate began to form shortly after the addition of the sulfonyl chloride was begun. The reaction was stirred at room temperature overnight. After 48 hours of additional stirring the reaction solution was diluted with 200 ml of ethyl acetate and 80 ml of water. The organic phase was washed with two 90 ml portions of water, dried with magnesium sulfate, filtered and concentrated to yield 6.4 g of an oil which solidified upon standing, mp 41°-43° C.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]([C:5]1[N:6]=[CH:7][N:8]2[C:12]([C:13]3[C@H:14]([CH3:27])[C@@H:15]4[C@@H:22]([C@H:23]([OH:25])[CH3:24])[C:21](=[O:26])[N:16]4[C:17]=3[C:18]([O-:20])=[O:19])=[CH:11][S:10][C:9]=12)=[O:4].[Na+].C(=O)([O-])O.[Na+].[C:35]([O:41][CH2:42]I)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]>CN(C=O)C>[CH3:28][N:2]([CH3:1])[C:3]([C:5]1[N:6]=[CH:7][N:8]2[C:12]([C:13]3[C@H:14]([CH3:27])[C@@H:15]4[C@@H:22]([C@H:23]([OH:25])[CH3:24])[C:21](=[O:26])[N:16]4[C:17]=3[C:18]([O:20][CH2:42][O:41][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[O:19])=[CH:11][S:10][C:9]=12)=[O:4]
Reactant: CC(C)(C)C(=O)OCI
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3csc4c(C(=O)N(C)C)ncn34)[C@H](C)[C@H]12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(c3csc4c(C(=O)N(C)C)ncn34)[C@H](C)[C@H]12
Temperature: -30 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a solution of 50 mg of sodium (1S,5R,6S)-2-[7-(N,N-dimethylcarbamoyl)imidazo[5,1-b]thiazol-3-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate in 0.7 ml of DMF was added 5.0 mg of sodium hydrogen carbonate, and the mixture was cooled to −30° C. under the atmosphere of argon. After addition of 43 mg of pivaloyloxymethyl iodide, the mixture was stirred for 1 hour, extracted with 20 ml of ethyl acetate, and the organic layer was washed with 12 ml of semi-saturated aqueous saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to a volume of about 1 ml. The residue thus obtained was purified by column chromatography on silica gel (dichloromethane:methanol=95:5) to give 48 mg of the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3](=O)[CH2:4][CH2:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=1.[C:18](#[N:22])[CH2:19][C:20]#[N:21].C(N(CC)CC)C>C(O)C>[NH2:22][C:18]1[O:1][CH:2]=[C:3]([CH2:4][CH2:5][C:6]2[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=2)[C:19]=1[C:20]#[N:21]
Reactant: N#CCC#N
Reactant: CCOC(=O)c1ccc(CCC(=O)CO)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1ccc(CCc2coc(N)c2C#N)cc1

Procedure:
A mixture of 2.36 g (10 mmol) of ethyl 4-(4-hydroxy-3-oxobutyl)benzoate, 0.66 g. (10 mmol) of malononitrile, and 1.01 g (10 mmol) of triethylamine in 10 mL of ethanol is stirred at 25° C. for 10 hours. Ethyl 4-[2-(2-amino-3-cyanofur-4-yl)ethyl]benzoate is formed as a solid and can be collected by filtration. After washing with a small amount of methylene chloride and drying, a white solid is obtained; m.p. 195°-197° C. Anal. calcd for C16H16N2O3 : C, 67.60; H, 5.67; N, 9.85 Found: C, 67.85; H, 5.71; N, 10.14.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[N:11]([CH2:19][C:20]3[CH:24]=[C:23]([C:25]4[S:26][C:27]([Cl:30])=[CH:28][CH:29]=4)[O:22][N:21]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:3][CH2:2]1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl.CCN(CC)CC>[CH3:31][S:32]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[N:11]([CH2:19][C:20]3[CH:24]=[C:23]([C:25]4[S:26][C:27]([Cl:30])=[CH:28][CH:29]=4)[O:22][N:21]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:3][CH2:2]1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NC1CCNCC1)c1cc2ccccc2n1Cc1cc(-c2ccc(Cl)s2)on1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(NC(=O)c2cc3ccccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Reaction time: 16 h

Procedure:
To a solution of 50 mg 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid piperidin-4-ylamide in 2 ml DCM, 0.3 ml NEt3 and 20 mg Methanesulfonyl chloride were added at RT and stirred for 16 h. After removal of the solvent under reduced pressure the residue was directly purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid). After lyophilization the product was obtained as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([CH3:26])=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])=[CH:14][CH:13]=2)[CH:9]=1)=[O:4]>O1CCCC1>[CH3:25][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:10][C:8]2[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[O:6][C:7]=2[CH3:26])=[CH:17][CH:16]=1
Reactant: COC(=O)c1cc(COc2ccc(-c3ccccc3OC)cc2)c(C)o1
Solvent: C1CCOC1
Product: COc1ccccc1-c1ccc(OCc2cc(C(=O)O)oc2C)cc1
Reaction time: 16 h
Yield: 77.9 %

Procedure:
A solution of 4-(2′-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid methyl ester (125) (40 mg, 0.11 mmoles) in dry tetrahydrofuran (25 ml) was treated with potassium trimethylsilanoate (73 mg, 0.56 mmoles) and the mixture stirred under an argon atmosphere for 16 h. After evaporation of the solvent the residue was acidified to pH=2 with 0.1M aqueous hydrochloric acid and the mixture extracted with ethyl acetate. The dried extracts were evaporated and the residue pumped under high vacuum at 40° C. to afford compound 126(29 mg) as an off-white solid. LC/MS System D; Rt=8.30 mins, m/z (ES+)=339 (M+H for C20H18O5).
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:8]=[C:9]([OH:16])[C:10](=[CH:14][CH:15]=1)[C:11]([OH:13])=[O:12])(=[O:5])[C:2]([CH3:4])=[CH2:3].O.[C:18](OC(=O)C)(=[O:20])[CH3:19]>S(=O)(=O)(O)O>[C:18]([O:12][C:11](=[O:13])[C:10]1[C:9](=[CH:8][C:7]([NH:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])=[CH:15][CH:14]=1)[OH:16])(=[O:20])[CH3:19]
Reactant: C=C(C)C(=O)Nc1ccc(C(=O)O)c(O)c1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: C=C(C)C(=O)Nc1ccc(C(=O)OC(C)=O)c(O)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A few drops of concentrated sulfuric acid is added to a stirring solution of 35.0 g of 4-methacrylamidosalicylic acid (prepared according to Example 1) in 350 mL of acetic anhydride at 0° C. The solution is stirred for 60 minutes at 0° C. and then for an additional 6 hours at room temperature. The reaction mixture is then poured into 800 g of cold deionized water. The solid product precipitates from solution, and is collected by filtration. The product is then air dried at room temperature to afford A-4-MASA in quantitative yield.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=2[OH:11])[CH2:3][CH2:2]1.ClC1C=CC=CC=1Cl.[OH-].[Na+].[OH:22][C:23]1[CH:28]=[C:27]([Cl:29])[N:26]=[N:25][C:24]=1Cl>C(O)(C)(C)C>[Cl:29][C:27]1[N:26]=[N:25][C:24]([O:11][C:5]2[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:4]=2[CH:1]2[CH2:3][CH2:2]2)=[C:23]([OH:22])[CH:28]=1
Reactant: Cc1cccc(C2CC2)c1O
Reactant: Oc1cc(Cl)nnc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: Clc1ccccc1Cl
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.5 %

Procedure:
To a mixture of 12.9 g (87.0 mmol) of 2-cyclopropyl-6-methylphenol and 1,2-dichlorobenzene (78.3 mL) was added 3.67 g (87.0 mmol) of 95% sodium hydroxide at room temperature. The resultant mixture was heated to 180° C. and subjected to azeotropic dehydration under reflux while stirring for 30 minutes. To the resultant solution was added dropwise the preliminarily prepared solution of 4.97 g (purity: 95.7%; 29.0 mmol) of 4-hydroxy-3,6-dichloropyridazine in t-butanol (95.0 g) at 160° C. over 9 hours. (The t-butanol was distilled off simultaneously with the dropwise addition of the solution.) After stirring at 180° C. for another 30 minutes, the reaction mixture was cooled to room temperature, and 78.7 g of pure water was added to the cooled mixture and stirred for 30 minutes, and an organic phase containing 2-cyclopropyl-6-methylphenol added in an excess amount was separated. 50.0 g of toluene was added to the resultant aqueous phase and stirred at room temperature for 30 minutes, and an organic phase containing 2-cyclopropyl-6-methylphenol was separated. This operation was repeated twice. Then, the resultant aqueous solution containing a sodium salt of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol was quantitatively determined by an HPLC internal standard analysis method, which showed that 6.86 g of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 86%) and 29 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.4%) were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:10]=[CH:9]2)=[CH:4][CH:3]=1.[C:18]([NH:23][C:24](=[O:29])[O:25][CH:26]([CH3:28])[CH3:27])(=[O:22])/[CH:19]=[CH:20]/[CH3:21]>C(#N)C.O.O.O.O.O.O.[N+]([O-])([O-])=O.[Y+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>[CH3:21][CH:20]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:10]=[CH:9]2)=[CH:6][CH:7]=1)[CH2:19][C:18]([NH:23][C:24]([O:25][CH:26]([CH3:27])[CH3:28])=[O:29])=[O:22]
Reactant: C/C=C/C(=O)NC(=O)OC(C)C
Reactant: CCOC(=O)c1cn(-c2ccc(N)cc2)cn1
Agent: O=[N+]([O-])[O-]
Agent: [Y+3]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1cn(-c2ccc(NC(C)CC(=O)NC(=O)OC(C)C)cc2)cn1
Temperature: 60 °C
Reaction time: 48 h
Yield: 31 %

Procedure:
A mixture of ethyl 1-(4-aminophenyl)-1H-imidazole-4-carboxylate (for a preparation see intermediate 85) (9.4 g, 40.6 mmol), 1-methylethyl (2E)-2-butenoylcarbamate (for a preparation see intermediate 49) (6.96 g, 40.6 mmol), and yttrium nitrate hexahydrate (1.56 g, 4.06 mmol) in dry acetonitrile (200 mL) was stirred at 60° C. for 48 h then cooled to room temperature and concentrated in vacuo. The residue was suspended in AcOEt (250 mL) and the organic phase was washed with water (×2) then brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 60-100% AcOEt in Hexanes followed by 0 to 5% methanol in AcOEt) gave ethyl 1-(4-{[1-methyl-3-({[(1-methylethyl)oxy]carbonyl}amino)-3-oxopropyl]amino}phenyl)-1H-imidazole-4-carboxylate (5 g, 12.42 mmol, 31%) as a colourless gum.
Reaction SMILES: [CH3:1][N:2]([CH3:35])[CH2:3][CH2:4][CH2:5][S:6]([N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[C:23]3[C:18](=[C:19]([C:32]([NH2:34])=[O:33])[CH:20]=[C:21]([C:24]4[CH:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][CH:25]=4)[CH:22]=3)[NH:17][CH:16]=2)[CH2:11][CH2:10]1)(=[O:8])=[O:7].[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:1][N:2]([CH3:35])[CH2:3][CH2:4][CH2:5][S:6]([N:9]1[CH2:10][CH2:11][CH:12]([C:15]2[C:23]3[C:18](=[C:19]([C:32]([NH2:34])=[O:33])[CH:20]=[C:21]([C:24]4[CH:29]=[CH:28][C:27]([CH2:30][N:36]5[CH2:40][CH2:39][CH2:38][CH2:37]5)=[CH:26][CH:25]=4)[CH:22]=3)[NH:17][CH:16]=2)[CH2:13][CH2:14]1)(=[O:8])=[O:7]
Reactant: CN(C)CCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(C=O)cc4)cc23)CC1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CN(C)CCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CN5CCCC5)cc4)cc23)CC1
Yield: 36.2 %

Procedure:
Following the general procedure of example (99), 3-(1-{[3-(dimethylamino)propyl]sulfonyl}-4-piperidinyl)-5-(4-formylphenyl)-1H-indole-7-carboxamide (50 mg, 0.1 mmol), pyrrolidine (9 mg, 0.1 mmol) and NaBH(OAc)3 (64 mg, 0.3 mmol) were reacted to give the title compound (20 mg, 20%).
Reaction SMILES: [OH2:1].[F:2][C:3]([F:15])=[CH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[CH2:14].[BH4-].[Na+].[Cl-].[Na+]>[OH-].[Na+].[Hg].O1CCCC1>[F:2][C:3]([F:15])=[CH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([OH:1])[CH3:14]
Reactant: C=CCCCCCCCCC=C(F)F
Reactant: O
Agent: [BH4-]
Agent: [Cl-]
Agent: [Hg]
Solvent: C1CCOC1
Product: CC(O)CCCCCCCCC=C(F)F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Under an argon atmosphere 6.3 grams (0.02 mole) of mercuric acetate was placed in a reaction vessel. To this was added 20 ml of water and then 20 ml of tetrahydrofuran. The reaction mixture was cooled, and 4.0 grams (0.02 mole) of 1,1-difluoro-1,11-dodecadiene was added dropwise while maintaining the reaction mixture temperature at 25° C. or lower. Upon completion of addition, the reaction mixture was stirred for 20 minutes. After this time 20 ml of an aqueous 3 Molar solution of sodium hydroxide was added dropwise while maintaining the reaction mixture temperature at 25° C. or below. Sodium borohydride, 0.38 gram (0.01 mole), was dissolved in another 20 ml of the aqueous 3 Molar solution of sodium hydroxide, and this was also added dropwise. The reaction mixture temperature was also maintained at 25° C. or below throughout the latter addition. Upon completion of addition, stirring of the reaction mixture was stopped, and mercury was allowed to settle to the bottom of the reaction vessel. Sufficient sodium chloride was added to the reaction mixture to saturate the water layer. The organic layer was then decanted from the reaction mixture and was dried with magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to a residual oil. The oil was distilled under reduced pressure, yielding 0.53 gram of 12,12-difluoro-11-dodecen-2-ol; b.p. 120° C./3.6 mm. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: O1C=CC=C1C(Cl)=O.[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]([N:16]=[C:17]=[S:18])=[O:15].[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][C:30]=1[O:31][CH3:32])[N:27]=[CH:26][CH:25]=[C:24]2[O:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[C:36]([F:41])[CH:35]=1.C1(C)C=CC=CC=1>C(O)C>[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]([N:16]=[C:17]=[S:18])=[O:15].[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][C:30]=1[O:31][CH3:32])[N:27]=[CH:26][CH:25]=[C:24]2[O:33][C:34]1[CH:40]=[CH:39][C:37]([NH:38][C:17]([NH:16][C:14]([C:10]2[O:9][CH:13]=[CH:12][CH:11]=2)=[O:15])=[S:18])=[C:36]([F:41])[CH:35]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: O=C(Cl)c1ccco1
Agent: O=C(N=C=S)c1ccco1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccco4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
2-Furancarbonyl isothiocyanate was prepared using commercially available 2-furancarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 2-Furancarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (47 mg, yield 68%). Mass spectrometry value (ESI-MS, m/z): 468 (M++1)