Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na:1].[CH2:2]1[C:5]2([O:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][S:19]([C:21]4[NH:25][C:24]5[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=5[N:22]=4)=[O:20])[C:13]=3C)[CH2:7][O:6]2)[CH2:4][CH2:3]1.C1C2(OCC(OC3C=CN=C(CO)C=3)CO2)CC1>>[Na:1].[CH2:4]1[C:5]2([O:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][S:19]([C:21]4[NH:22][C:23]5[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=5[N:25]=4)=[O:20])[CH:13]=3)[CH2:7][O:6]2)[CH2:2][CH2:3]1
Reactant: Cc1c(OC2COC3(CCC3)OC2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Agent: OCc1cc(OC2COC3(CCC3)OC2)ccn1
Agent: [Na]
Product: O=S(Cc1cc(OC2COC3(CCC3)OC2)ccn1)c1nc2ccccc2[nH]1

Procedure:
The same procedure as in the steps (9h) to (9j) of Example 9 was repeated using the (4-(5,9-dioxaspiro[3.5]non-7-yloxy)pyridin-2-yl)methanol obtained in the step (83b) above to obtain the title compound (100 mg, the total yield of 3 steps: 50%) as a white solid. Note that, in the same process as in the step (9h), 2-mercaptobenzimidazole was added to the reaction mixture and stirred at room temperature for 25 hours, and thereafter, 3 equivalents of potassium hydroxide relative to the alcohol was added thereto. The mixture was allowed to react at room temperature for 6 hours.
Reaction SMILES: Cl.[NH:2]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]3[N:21]=[CH:20][NH:19][C:17]3=2)[N:12]=[C:11]([CH3:22])[CH:10]=1)C1C=CC=CC=1.N[C:24]1[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[N:28][CH:29]=1.[NH4+].[OH-]>CN(C)C=O>[CH3:31][O:30][C:27]1[N:28]=[CH:29][C:24]([NH:2][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]4[N:21]=[CH:20][NH:19][C:17]4=3)[N:12]=[C:11]([CH3:22])[CH:10]=2)=[CH:25][CH:26]=1
Reactant: COc1ccc(N)cn1
Reactant: Cc1cc(Nc2ccccc2)c2c(ccc3nc[nH]c32)n1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1ccc(Nc2cc(C)nc3ccc4nc[nH]c4c23)cn1
Reaction time: 8 h

Procedure:
A stirred mixture of the compound of Example I, C. (22 g. 0.1 mole) and 5-amino-2-methoxypyridine (12 g., 0.1 mole) in 200 ml. of dimethylformamide, was refluxed for 6 hours. The reaction mixture, after standing at room temperature overnight, was filtered to give a tan solid. The solid was treated with dilute NH4OH and then filtered to yield 30 g. (98%) of tan product.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:31][C:32]([O:34]CC)=[O:33])[C:4]2[C:9]([C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:30])[C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[CH:14][CH:13]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.O.[OH-].[Li+].O1CCCC1.CO>O>[CH3:1][C:2]1[N:3]([CH2:31][C:32]([OH:34])=[O:33])[C:4]2[C:9]([C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:30])[C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[CH:14][CH:13]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CCOC(=O)Cn1c(C)c(Cc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3)cc2)c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(Cc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3)cc2)c2ccccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
Into a dry reaction vessel, ethyl 2-[2-methyl-3-[4-[4-(trifluoromethyl)benzamido]benzyl]-1H-indol-1-yl]acetate (600 mg, 1.21 mmol), lithium hydroxide monohydrate (153 mg, 3.64 mmol), 10 mL tetrahydrofuran, 10 mL methanol, 10 mL water were weighed, and stirred at room temperature for 1 h. The reaction was monitored to be complete by TLC. The solvent was rotate evaporated. It was adjusted to pH=3-4 with 2 N HCl solution. It was filtered, and the filter cake was washed with 20 mL methanol to obtain the product 480 mg as a white solid, at a yield of 85.1%.
Reaction SMILES: [Cl-].[Li+].O.[Cl:4][C:5]1[N:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([N:15]3[C:23](=[O:24])[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]3[CH:25]([C:30](=[O:38])[CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)C(OC)=O)=[N:12]2)=[CH:7][CH:6]=1>CS(C)=O>[Cl:4][C:5]1[N:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([N:15]3[CH:16]([CH2:25][C:30](=[O:38])[CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:17]4[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:23]3=[O:24])=[N:12]2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(C(=O)Cc1ccccc1)C1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(Cc1ccccc1)CC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 45.4 %

Procedure:
Lithium chloride (4.2 g) and water (1.8 cc) are added at a temperature in the region of 20° C. to a solution, maintained under an argon atmosphere, of methyl 2-[2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl]-3-oxo-4-phenylbutanoate (3 g) in dimethyl sulphoxide (230 cc), and the reaction mixture is heated to reflux for 45 minute$. After the mixture is cooled to a temperature in the region of 40° C., ice-cold water (1500 cc) is added. After 15 minutes.varies. stirring, the solid which precipitates is separated by filtration, washed with distilled water (5×25 cc) and dried in the air. The solid obtained is purified by chromatography on silica gel (140 g) contained in a column 3.4 cm in diameter (eluent: dichloromethane/methanol (98:2 by volume)]. Elution is first performed with 200 cc of solvent: the corresponding eluate is discarded. Elution is then performed with 900 cc of solvent: the corresponding eluate is concentrated to dryness under reduced pressure (2.7 kPa), at 40° C. After recrystallization in acetonitrile, 2-(7-chloro-1,8-naphthyridin-2-yl)-3-(3-phenyl-2-oxopropyl)-1-isoindolinone (1.2 g), m.p. 182° C., is obtained.
Reaction SMILES: [CH2:1]([N:4]([N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1)[C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)[CH2:2][CH3:3].[Cl:16]N1C(=O)CCC1=O.O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[ClH:16].[Cl:16][C:12]1[N:11]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]2[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: CCCN(c1ccncc1)n1cccc1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCN(c1ccncc1)n1cccc1Cl
Product: Cl
Reaction time: 3 h
Yield: 50.3 %

Procedure:
To a solution of N-propyl-N-(1H-pyrrol-1-yl)-4-pyridinamine (11 g) in 250 ml of tetrahydrofuran, cooled with an ice bath, was added N-chlorosuccinimide (8 g) as a powder. The reaction mixture was warmed to ambient temperature and after sixteen hours additional N-chlorosuccinimide (1 g) was added. After stirring for additional three hours, the reaction mixture was stirred with cold water, basified with sodium carbonate and extracted with ethyl acetate. The organic extract was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated to 14 g of oil. This oil was purified by HPLC (silica, ethyl acetate-dichloromethane) to give 4.1 g of pure product as an oil. This oil was converted to the hydrochloride salt and recrystallized twice from isopropanol-ether to give 2.4 g of crystals, mp 210°-211°.
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])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[CH:6]2.[OH-].[K+].Cl.Cl[CH2:21][C:22]1[CH:23]=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2>C1(C)C=CC=CC=1.O.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[C:6]2[CH2:21][C:22]1[CH:23]=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2
Reactant: COc1cc2cc(O)nc(C)c2cc1OC
Reactant: ClCc1cnc2ccccc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc2c(C)nc(O)c(Cc3cnc4ccccc4c3)c2cc1OC
Temperature: 160 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6,7-dimethoxy-1-methylisoquinolin-3-ol CCH 18060 (120 mg, 547 μmol) in toluene (15 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added a 2 N aq. KOH solution (0.58 mL, 1.16 mmol) at RT followed by MDE 32004 (130 mg, 607 μmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with H2O (10 mL) before extraction with CH2Cl2 (50 mL). The organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 92:8) gave 67 mg of 6,7-dimethoxy-1-methyl-4-(quinolin-3-ylmethyl)isoquinolin-3-ol. The free base was dissolved in MeOH (2 mL) in a 25 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.09 M HCl solution in MeOH (6 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 6,7-dimethoxy-1-methyl-4-(quinolin-3-ylmethyl)isoquinolin-3-ol dihydrochloride 26 as a brown solid (80 mg, 31% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.N1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O1CCCC1.C(Cl)(=O)CCCC>O>[CH2:11]([C:10]1[NH:1][C:2]2[C:3]([CH:8]=1)=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][CH2:13][CH3:14]
Reactant: Cc1ccccc1N
Reactant: c1ccncc1
Agent: CCCCC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1cc2ccccc2[nH]1
Temperature: 25 °C
Yield: 84 %

Procedure:
o-Toluidine (55 g) was mixed with 100 ml dry pyridine and 200 ml dry tetrahydrofuran in a 1-L 3-necked round bottom flask fitted with a Trubore stirrer, thermometer and a dropping funnel, under nitrogen. Then, with cooling in a refrigerated bath, valeryl chloride (60.3 g) was added dropwise over 1 hour. The mixture was stirred for another hour at room temperature and then poured onto 500 g ice and water. The precipitate was washed repeatedly with water on a Buchner funnel. The precipitate (88.9 g, 93%) was cyclized according to Verley and Bedure, 1925, Bull. Soc. Chim. Fr. (37): 190 to afford 2-n-butyl indole (67.4 g, 84%) as a very slightly yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:7][C:6](=O)[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[S:17][CH:16]=[C:15]([C:18]#[N:19])[CH:14]=3)=[CH:12][C:3]1=2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>>[CH3:1][C:2]1([CH3:20])[O:7][C:6](=[S:30])[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[S:17][CH:16]=[C:15]([C:18]#[N:19])[CH:14]=3)=[CH:12][C:3]1=2
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cc(C#N)cs3)cc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: CC1(C)OC(=S)Nc2ccc(-c3cc(C#N)cs3)cc21

Procedure:
The title compound was prepared in a manner similar to Example 16 using 5-(4,4-dimethyl -2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)thiophene-3-carbonitrile and Lawesson's reagent. The product was obtained in the form of yellow crystals: m.p. 258-259° C. 1H NMR (DMSO-d6) δ12.3 (s,l H ),8.54 (d, 1H, J=0.9 Hz) ,7.96 (s, 1H), 7.69-7.62 (m, 2H), 7.11-7.08 (d, 1H, J=8.3 Hz), 1.69 (s, 6H); MS (ESI) m/z 299 [M−H]−; Anal. Calcd. For C15H12N2OS2 ½H2O: C, 58.0; H, 4.24; N, 9.05. Found C, 58.33; H, 3.85; N, 8.39.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]([NH2:8])=[N:5][CH:4]=1.[CH3:9][O:10][CH2:11][CH2:12][Br:13]>>[BrH:13].[CH3:1][O:2][C:3]1[S:7][C:6](=[NH:8])[N:5]([CH2:12][CH2:11][O:10][CH3:9])[CH:4]=1
Reactant: COCCBr
Reactant: COc1cnc(N)s1
Product: Br
Product: COCCn1cc(OC)sc1=N

Procedure:
A mixture of Example 185A and commercially available 2-bromoethyl methyl ether (Aldrich) was processed using the method described in Example 46A to afford the title compound. MS (ESI+) m/z 189 (M+H)+.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:41]1[S:42][CH:43]=[CH:44][N:45]=1)[S:7]([C:10]1[C:39]([F:40])=[CH:38][C:13]2[N:14]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:28]=3[CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][C:24]4([F:37])[F:36])[C:15](=[O:17])[O:16][C:12]=2[CH:11]=1)(=[O:9])=[O:8].C(O)(C(F)(F)F)=O.C(Cl)[Cl:60]>>[ClH:60].[F:37][C:24]1([F:36])[C:23]2[C:28](=[C:19]([CH2:18][N:14]3[C:13]4[CH:38]=[C:39]([F:40])[C:10]([S:7]([NH:6][C:41]5[S:42][CH:43]=[CH:44][N:45]=5)(=[O:8])=[O:9])=[CH:11][C:12]=4[O:16][C:15]3=[O:17])[CH:20]=[CH:21][CH:22]=2)[CH2:27][NH:26][CH2:25]1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2cc3oc(=O)n(Cc4cccc5c4CN(C(=O)OC(C)(C)C)CC5(F)F)c3cc2F)c(OC)c1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: O=c1oc2cc(S(=O)(=O)Nc3nccs3)c(F)cc2n1Cc1cccc2c1CNCC2(F)F
Temperature: 25 °C

Procedure:
To a flask containing tert-butyl 8-((6-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)-5-fluoro-2-oxobenzo[d]oxazol-3(2H)-yl)methyl)-4,4-difluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (44-4) (45 mg, 0.060 mmol) (prepared from 43-1 by a sequence analogous to that presented herein) in DCM (3 ml) was added TFA (300 μl, 3.89 mmol). The reaction mixture was then stirred at room temperature. Followed by LC/MS. After 20 minutes the reaction mixture was diluted/quenched with DMSO, then MeOH then filtered (syringe filter) then concentrated (to remove DCM), then diluted with MeOH/DMSO & filtered. The filtrate was purified (without workup) by reverse phase chromatography (5-75% MeCN/H2O; 0.1% TFA in AQ; 20 min gradient; Waters 30×150 mm Sunfire 5 micron C18 column); desired fractions concentrated (GENEVAC), then dissolved in MeOH/DCM & added saturated HCl in EtOAc (˜4N) & concentrated to yield 3-((4,4-difluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)methyl)-5-fluoro-2-oxo-N-(thiazol-2-yl)-2,3-dihydrobenzo[d]oxazole-6-sulfonamide hydrochloride (44-5). HRMS [M+H]: calculated; 497.0560, observed; 497.0556. 1H NMR (499 MHz, DMSO): δ 7.77 (d, J=5.5 Hz, 1H); 7.73 (d, J=7.5 Hz, 1H); 7.58-7.50 (m, 2H); 7.39 (d, J=9.4 Hz, 1H); 7.29 (d, J=4.6 Hz, 1H); 6.88 (d, J=4.6 Hz, 1H); 5.13 (s, 2H); 4.52 (s, 2H); 3.99 (t, J=11.8 Hz, 2H).
Reaction SMILES: [NH2:1][CH:2]1[CH:7]2[CH:3]1[CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6]2.[N-:15]=[N+:16]=[N-:17].[Na+].[C:19](O)(=O)C>>[N:1]1([CH:2]2[CH:7]3[CH:3]2[CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6]3)[CH:19]=[N:17][N:16]=[N:15]1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)N1CC2C(N)C2C1
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CC2C(C1)C2n1cnnn1
Temperature: 100 °C
Yield: 50.3 %

Procedure:
To a solution of tert-butyl 6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate (7.3 g, 25.3 mmol) and triethylorothoformate (24 mL, 152 mmol) in acetic acid (200 mL) was added sodium azide (9.9 g, 152 mmol) and the resulting mixture was set under inert atmosphere. The mixture was heated at 100° C. for 4 h and then cooled to RT at which time the volatiles were removed in vacuo. The residue was taken up in ethyl acetate (200 mL) and washed with aqueous sodium bicarbonate solution, followed by brine. The organics were dried over sodium sulfate, filtered, and concentrate to dryness under vacuum. The residue was placed in the refrigerator overnight and the next day a solid white precipitate was observed. The precipitate was triturated with hexane and the solvent was carefully decanted to give the title compound 3.2 g (50.3%) as a white solid. ESI-MS calculated for C11H17N5O2: Exact Mass: 251.28. Found 252.28.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:7][CH:6]=1)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:24].[Na+]>CO>[NH2:24][CH:11]([C:8]1[CH:9]=[CH:10][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:17])=[CH:6][CH:7]=1)[CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: [BH3-]C#N
Reactant: CCOC(=O)c1ccc(C(=O)CC(C)C)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1ccc(C(N)CC(C)C)cc1
Temperature: 60 °C

Procedure:
A mixture of 4-(3-Methyl-butyryl)-benzoic acid ethyl ester (2000 mg, 8.536 mM), ammonium acetate (6580 mg, 85.4 mM) and sodium cyanoborohydride (1070 mg, 17.1 mmol) in methanol (17.1 mL) was heated to 60° C. for 6 h. The reaction was cooled, quenched with NH4Cl solution (10 mL). MeOH was removed under reduced pressure. The aqueous solution was extracted with EtOAc (3×30 mL). The organic solution was separated, dried (Na2SO4) and concentrated. The crude material was separated by a 40 g HC silica gel column with 0-15% MeOH in DCM. The desired product was collected as colorless oily material (1560 mg, 77.7%). 1H NMR (500 MHz, CDCl3) δ ppm 0.91 (dd, J=13.66, 6.59 Hz, 6 H) 1.40 (t, J=7.07 Hz, 3 H) 1.84-1.99 (m, 3 H) 4.27-4.42 (m, 3 H) 6.36 (br. s., 2 H) 7.51 (d, J=8.05 Hz, 2 H) 8.05 (d, J=8.05 Hz, 2 H). GC: m/z 235.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:19][NH:20][O:21][CH3:22].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([N:20]([O:21][CH3:22])[CH3:19])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNOC
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
The product from Example 71A (18 g, 72.96 mmol) in DCM at room temperature was treated with N,O-dimethylhydroxylamine hydrochloride (7.83 g, 80.26 mmol) slowly. The mixture was cooled to 0° C., stirred for 30 minutes, and treated with triethylamine (25.47 mL, 182.41 mmol) dropwise. The mixture was allowed to warm to 25° C., stirred for 16 hours, and treated with DCM (150 mL). The mixture was washed with saturated NaHCO3, brine, and water. The organic phase was dried, filtered, and the filtrate evaporated under reduced pressure to provide the title compound as a pale yellow solid (18.65 g, 95% yield). 1HNMR (300 MHz, CDCl3) δ 3.36 (s, 3H), 3.56 (s, 3H) 6.98 (d, 2H, J=8.9 Hz), 7.33-7.46 (m, 5H), 7.76 (d, 2H, J=8.9 Hz); MS (ESI) m/z 272 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[Cl:7][C:8]1[CH:9]=[C:10]([CH2:15][C:16]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH:19]2[CH2:24][N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:17])[CH:11]=[CH:12][C:13]=1[Cl:14].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.ClCCl>[NH3:2].[Cl:7][C:8]1[CH:9]=[C:10]([CH2:15][C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:3]([N:2]([CH3:6])[CH3:1])=[O:4])[CH2:20][CH:19]2[CH2:24][N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:17])[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCNCC1CN1CCCC1
Reactant: CN(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C)C(=O)N1CCN(C(=O)Cc2ccc(Cl)c(Cl)c2)C(CN2CCCC2)C1
Product: N
Yield: 148.7 %

Procedure:
Dimethylcarbamyl chloride (66 mg) was added to a stirred solution of 1-[(3,4-dichlorophenyl)acetyl]-2-(1-pyrrolidinylmethyl)piperazine (200 mg), pyridine (53 mg) and 4-dimethylaminopyridine (5 mg) in dry dichloromethane at 0° for 4.5 h. The reaction mixture was washed with aqueous 2N sodium carbonate solution (2×10 ml), dried and evaporated to give an oil, which was purified by flash column chromatography eluting with dichloromethane:methanol:0.880 NH3 (200:8:1) to give the title compound as an oil (195 mg).
Reaction SMILES: C([C:3]1[CH:4]=[C:5]([OH:11])[C:6](=[CH:9][CH:10]=1)[CH:7]=[O:8])C.Br[CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+].O1CC[CH2:27][CH2:26]1>>[CH:7]([C:6]1[CH:9]=[C:10]([CH2:26][CH3:27])[CH:3]=[CH:4][C:5]=1[O:11][CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])=[O:8]
Reactant: CCc1ccc(C=O)c(O)c1
Reactant: C1CCOC1
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1ccc(OC(C)C(=O)OC)c(C=O)c1

Procedure:
By the method of Example 1, Step F, 32.33 grams (0.215 mole) of 4-ethylsalicylaldehyde and 35.9 grams (0.215 mole) of methyl 2-bromopropionate was reacted in the presence of 35.7 grams (0.258 mole) of potassium carbonate in 50 mL of tetrahydrofuran, yielding 49.16 grams of methyl 2-(2-formyl-4-ethylphenoxy)propionate. The NMR spectrum was consistent with the proposed spectrum.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl.[CH3:10][N:11]([CH3:15])[CH2:12][CH2:13]Cl.[C:16]1(C)C=CC=CC=1>[OH-].[Na+]>[CH3:10][N:11]([CH2:12][CH2:13][CH2:16][O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH3:15]
Reactant: CN(C)CCCl
Reactant: Cc1ccccc1
Reactant: Oc1ccc(Br)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CN(C)CCCOc1ccc(Br)cc1

Procedure:
4-bromophenol (5.0 g, 28.9 mmol) and 2-dimethylaminoethyl chloride hydrochloride (4.6 g, 31.8 mmol) were combined in a mixture of toluene (100 mL) and 1 M NaOH (50 mL) and heated at reflux for 16 h. The layers were separated and the organic phase was washed with 1 M NaOH, dried (MgSO4) and concentrated to yield 4.2 g of the title compound as a yellow oil which was used without further purification. 1H NMR (400 MHz, CDCl3): δ 2.34 (6H, s), 2.72 (2H, t), 4. 01 (2H, t), 6.73 (2H, m), 7.33 (2H, m).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[O:5][C:6]=1[CH3:7].C(=O)([O-])[O-].[K+].[K+].[CH3:18][N:19]1[C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][CH:21]=[N:20]1>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:7][C:6]1[O:5][C:4]([C:8]([O:10][CH3:11])=[O:9])=[CH:3][C:2]=1[C:23]1[N:19]([CH3:18])[N:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1cc(Br)c(C)o1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccnn2C)c(C)o1
Reaction time: 1 h
Yield: 80.5 %

Procedure:
A solution of methyl 4-bromo-5-methyl-2-furancarboxylate (2.1 g, 9.59 mmol), potassium carbonate (6.63 g, 47.9 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.19 g, 10.55 mmol)[prepared according to Preparation 7] and bis(tri-t-butylphosphine)palladium(0) (0.24 g, 0.48 mmol) in 1,4-dioxane (40 ml) and water (8 ml) was stirred at 80° C. in a sealed tube for 1 h. 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.19 g, 10.55 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.245 g, 0.48 mmol) were added and the reaction stirred an additional 1 h and was partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (10-40% EtOAc in hexanes) affording methyl 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (1.7 g, 7.72 mmol, 81% yield) as a yellow oil: LCMS (ES) m/e 221 (M+H)+.
Reaction SMILES: C1C=C(Cl)C(S[CH:9]([CH2:19][N:20]2[CH:24]=[N:23][CH:22]=[CH:21]2)[CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=C(Cl)C=1.[N+]([O-])(O)=O.[Cl:30]C1C=CC=CC=1CCC(O)CN1C=CN=C1.S(Cl)(Cl)=O>>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][CH:9]([Cl:30])[CH2:19][N:20]2[CH:21]=[CH:22][N:23]=[CH:24]2)=[CH:17][CH:16]=1
Reactant: Clc1ccc(CCC(Cn2ccnc2)Sc2c(Cl)cccc2Cl)cc1
Reactant: OC(CCc1ccccc1Cl)Cn1ccnc1
Solvent: O=[N+]([O-])O
Solvent: O=S(Cl)Cl
Product: Clc1ccc(CCC(Cl)Cn2ccnc2)cc1

Procedure:
in the presence of sodium hydride reagent in dimethylformamide solvent. This substitution reaction takes a long time and gives the (1-[4-(4-chlorophenyl)-2-hydroxy-n-butyl]-imidazole) (IV) with a poor yield (51.7%). In the next step of the butoconazole nitrate synthesis (1-[4-(chlorophenyl)-2-hydroxy-n-butyl]-imidazole) (IV) is treated with thionyl chloride (which is at once a reagent and a solvent) at 65-70° C. to yield 1-[4-(4-chlorophenyl)-2-chloro-n-butyl]-imidazole of the formula (V).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=O)[CH:6]=1.[CH2:10](OCC)C.C[Li].O>C(O)C>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([CH3:10])=[O:9])[CH:6]=1
Reactant: Cc1cc(C(=O)O)cs1
Reactant: CCOCC
Agent: [Li]C
Solvent: CCO
Solvent: O
Product: CC(=O)c1csc(C)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-Methylthiophene-4-carboxylic acid (14.2 g., 0.1 mole) prepared by the method of Shvedov et al., Khim. Geterotsikl. Soedin. 1010 (1967); Chem. Abstrs., 69, 51922j (1968) in 250 ml. of ethyl ether is cooled to -10° to 0° C. and an ethereal solution of methyl lithium (4.4 g., 0.2 mole) is added dropwise while maintaining the reaction mixture below 0° C. After stirring for 1 hour at 0° C., a solution of 4 g. of water in 100 ml. of ethanol is added cautiously and the mixture allowed to warm to room temperature. The desired product is then isolated by partitioning the reaction mixture between ether and water and evaporation of the organic extracts.