Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[Cl:15][C:16]1[O:20][C:19]([CH:21]=[O:22])=[CH:18][CH:17]=1.[Cl-].[NH4+]>C(OCC)(=O)C.O.O1CCCC1>[Cl:15][C:16]1[O:20][C:19]([CH:21]([OH:22])[C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: N#Cc1ccc(I)cc1
Reactant: O=Cc1ccc(Cl)o1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(C(O)c2ccc(Cl)o2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 105.4 %

Procedure:
To a mixture of 4-iodobenzonitrile (3.0 g, 13 mmol) and tetrahydrofuran (40 mL) was added dropwise isopropyl magnesium chloride (1-2 M diethyl ether solution, 11 mL, 11-22 mmol) at −78° C., which was stirred for 1 hour at 0° C. The reaction mixture was cooled to −78° C., 5-chloro-2-furaldehyde (2.2 g, 17 mmol) was added at that temperature, and the temperature was gradually raised to 0° C. Following 30 minutes of stirring at 0° C., saturated aqueous ammonium chloride solution, water and ethyl acetate were added to extract the reaction mixture. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. Ethyl acetate was added to the residue, which was then filtered with NH silica gel. The filtrate was concentrated under a reduced pressure to obtain the title compound (3.2 g) as a crude product. This compound was used in the subsequent reaction without further purification.
Reaction SMILES: Br[C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][CH:9]=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.C[S-:19].[Na+].Cl>CN(C=O)C>[C:2]1([SH:19])[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][CH:9]=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1
Reactant: Brc1ccc2ccc3cccc4ccc1c2c34
Reactant: C[S-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: Sc1ccc2ccc3cccc4ccc1c2c34
Temperature: 150 °C
Yield: 65.3 %

Procedure:
1-Bromopyrene (550 mg, 1.96 mmol) and sodium methanethiolate (480 mg, 6.85 mmol) were dissolved in freshly distilled DMF under dry nitrogen. The reaction was stirred at 150° C. and monitored by GC-MS until complete. After completion 50 mL of HCl 0.1M were added to the reaction mixture and extracted with 3 portions of ether. The organic phase was washed with 2 portions of water. The extracts were dried with magnesium sulfate and evaporated. The crude product was further purified by chromatography on silica gel using 5:1 petroleum ether (60-80):EtOAc as eluent to afford a yellow solid (300 mg, 65%). 1H-NMR (500 MHz, toluene-d8, DMSO-d6): δ 7.35 (s, 1H), 8.10-8.37 (m, 8H), 8.67 (d, J=9.2 Hz, 1H). 13C-NMR (125 MHz, toluene-d8, DMSO-d6): δ 123.7, 123.8, 124.6, 124.9, 125.7, 125.8, 126.3, 127.0, 127.7, 128.6, 130.1, 130.3, 130.6, 130.8, 131.2, 131.7. EI-MS: m/z M+ Calculated 234.0, found 234.0.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[N:17]=[CH:18][C:19]([CH:22]=O)=[N:20][CH:21]=3)[N:12]=2)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[CH2:24]([O:26][C:27]([C@H:29]1[CH2:32][C@@H:31]([NH2:33])[CH2:30]1)=[O:28])[CH3:25].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].ClC(Cl)C>>[CH2:24]([O:26][C:27]([CH:29]1[CH2:32][CH:31]([NH:33][CH2:22][C:19]2[CH:18]=[N:17][C:16]([C:13]3[N:12]=[C:11]([C:8]4[CH:9]=[CH:10][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:6][CH:7]=4)[O:15][N:14]=3)=[CH:21][N:20]=2)[CH2:30]1)=[O:28])[CH3:25]
Reactant: CCOC(=O)[C@H]1C[C@@H](N)C1
Reactant: CC(C)Cc1ccc(-c2nc(-c3cnc(C=O)cn3)no2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCOC(=O)C1CC(NCc2cnc(-c3noc(-c4ccc(CC(C)C)cc4)n3)cn2)C1

Procedure:
A solution of 5-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]pyrazine-2-carbaldehyde (0.100 g, 0.32 mmol), cis-3-amino-cyclobutanecarboxylic acid ethyl ester (0.056 g, 0.388 mmol), sodium triacetoxyborohydride (0.082 g, 0.388 mmol) and dichloroethane (5.0 mL) was stirred at room temperature for 12 hours. The reaction mixture was quenched with 1N NaOH (10 mL) and the organic layer was isolated, washed with H2O (2×10 mL) and brine (10 mL), dried (Na2SO4), filtered and concentrated in vacuo to yield the title compound as a crude solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:11]=3)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CCCCCC.C(C1C=C(C)C(=[C:42]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)C=1)(C)(C)C.O>C(OCC)C>[C:1]([C:5]1[CH:6]=[C:7]([CH:42]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:8]2[CH2:9][C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:11]=3)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc2c(c1)-c1cc(C(C)(C)C)ccc1C2
Reactant: CC1=CC(C(C)(C)C)=CC1=C(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: O
Product: CC(C)(C)c1ccc2c(c1)-c1cc(C(C)(C)C)cc(C(c3ccccc3)c3ccccc3)c1C2
Temperature: 25 °C

Procedure:
In a 200 ml three-necked flask equipped with a magnetic stirrer chip and three-way cock thoroughly purged with nitrogen, 3.01 g of 3,6-di-tert-butyl-fluorene (10.8 mmol) was dissolved in 80 ml of dehydrated diethyl ether in a nitrogen atmosphere. To the solution, 7.6 ml of a n-butyl lithium/hexane solution (1.56M: 11.9 mmol) was gradually added dropwise in an ice bath and stirred at room temperature over night. To the reaction solution, 50 ml of a solution prepared by dissolving 4.86 g of 3-tert-butyl-1-methyl-6,6-diphenyl fulvene (16.2 mmol) in 50 ml of dehydrated diethyl ether was added and stirred with refluxing for 13 days. To the reaction mixture, 30 ml of distilled water was gradually added dropwise in an ice bath, and thereafter diethyl ether was added to separate an organic phase. The organic phase was washed with distilled water and saturated brine. The organic phase was dried with anhydrous magnesium sulfate, thereafter the drying agent was filtered off and the solvent was distilled off from the filtrate under reduced pressure to give red solid. The red solid was re-crystallized using ethanol and dried under reduced pressure, and thereby the aimed compound was obtained in an amount of 4.42 g (7.63 mmol) as a pale yellow solid (yield: 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:9]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:10][C:11]([O-])=[O:12].[K+]>>[CH2:16]([O:15][C:9](=[O:14])[CH2:10][C:11]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[CH:3]=1)=[O:12])[CH3:17]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: Nc1cccc(Cl)c1
Agent: [K+]
Product: CCOC(=O)CC(=O)Nc1cccc(Cl)c1

Procedure:
In a manner similar to that described in Referential Example 370, 3-chloroaniline was condensed with potassium ethyl malonate, whereby the title compound was obtained.
Reaction SMILES: Cl.C[O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][C@H:10]([NH:15][CH2:16][CH2:17][CH3:18])[C@@H:11]2[CH3:14])=[CH:6][CH:5]=1.C(O)C.C(OCC)C.[BrH:27]>>[BrH:27].[OH:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][C@H:10]([NH:15][CH2:16][CH2:17][CH3:18])[C@@H:11]2[CH3:14])=[CH:6][CH:5]=1
Reactant: CCCN[C@H]1CCc2ccc(OC)cc2[C@H]1C
Agent: Br
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CCCN[C@H]1CCc2ccc(O)cc2[C@H]1C
Yield: 70 %

Procedure:
cis-7-Methoxy-1-methyl-2-(n-propylamino) tetralin hydrochloride (100 mg, 0.37 mmol) was heated in 48% aqueous HBr for 3 h at 120° C. under N2. The volatiles were evaporated from the faint pink solution and the residue was treated twice with ethanol followed by evaporation, giving a faint pink residue which was dissolved in abs. ethanol. Dry abs. ethyl ether was added to the solution, yielding white crystals which were then recrystallized from MeOH-ethyl ether, yielding the desired product (75 mg, 70% yield), m.p. 262°-263° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[C:6]1([CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=2[O:18][CH2:19][CH:20]2[CH2:22][O:21]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(#N)C>[N:1]1([CH2:22][CH:20]([OH:21])[CH2:19][O:18][C:17]2[CH:23]=[CH:24][CH:25]=[CH:26][C:16]=2[CH2:15][CH2:14][CH2:13][CH2:12][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1ccc(CCCCc2ccccc2OCC2CO2)cc1
Reactant: c1c[nH]cn1
Solvent: CC#N
Product: OC(COc1ccccc1CCCCc1ccccc1)Cn1ccnc1
Yield: 82.4 %

Procedure:
940 mg of imidazole were added to a solution of 780 mg of 2-[2-(4-phenylbutyl)phenoxymethyl]oxirane [prepared as described in Example 1(a)] in 25 ml of acetonitrile, and the resulting mixture was heated under reflux for 24 hours. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 20:1 by volume mixture of methylene chloride and methanol as the eluent, to give 798 mg (yield 82%) of the title compound as a pale yellow oil.
Reaction SMILES: [N:1]([C:4]1([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:6][CH2:5]1)=[C:2]=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl-].[NH4+]>C1COCC1>[CH3:2][NH:1][C:4]1([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][C:7]2([O:8][CH2:9][CH2:10][O:11]2)[CH2:6][CH2:5]1
Reactant: O=C=NC1(c2cccs2)CCC2(CC1)OCCO2
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CNC1(c2cccs2)CCC2(CC1)OCCO2
Temperature: 60 °C
Reaction time: 0.05 h

Procedure:
8-isocyanato-8-(thiophen-2-yl)-1,4-dioxaspiro[4.5]decane (4 g) was dissolved in dry THF (140 ml) and the solution was cooled to 0°-10° C. LAH (4 g) was added in portions over a period of 30 minutes and the reaction mixture was heated for a further 30 minutes at 60° C. The mixture was cooled to 0°-10° C. and saturated ammonium chloride solution (100 ml) was added. The mixture was now filtered through celite and washed with ethyl acetate (3×150 ml). After removing the solvents the crude product was taken up in ethyl acetate (200 ml) and stirred for 3 minutes at 0°-10° C. The ethyl acetate phase was separated, and aqueous phase was made alkaline (pH 10-14) with saturated NaOH solution and extracted with ethyl acetate (3×200 ml). The combined organic phases were dried over Na2SO4. The solvent was removed under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12](Cl)(=[O:14])=[O:13].[CH:16]([NH2:19])([CH3:18])[CH3:17].C(N(CC)CC)C>>[CH:16]([NH:19][S:12]([C:3]1[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[Cl:1])(=[O:14])=[O:13])([CH3:18])[CH3:17]
Reactant: CC(C)N
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Solvent: CCN(CC)CC
Product: CC(C)NS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Yield: 80.3 %

Procedure:
Following the general procedure for sulfonamide formation outlined in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.5 g, 5.17 mmol), isopropylamine (0.44 m, 5.17 mmol) and triethylamine (1.08 mL, 7.76 mmol) were reacted to form the desired product (1.3 g, 81 %). EI-MS m/z 312 (M-H)−.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]([C:14]2[C:15]([CH3:21])=[N:16][CH:17]=[C:18]([Cl:20])[CH:19]=2)=[O:13])[CH2:7][CH2:6]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Cl:20][C:18]1[CH:17]=[N:16][C:15]([CH3:21])=[C:14]([CH:19]=1)[C:12]([NH:11][C@H:8]1[CH2:7][CH2:6][C@H:5]([CH2:3][OH:2])[CH2:10][CH2:9]1)=[O:13]
Reactant: COC(=O)[C@H]1CC[C@H](NC(=O)c2cc(Cl)cnc2C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ncc(Cl)cc1C(=O)N[C@H]1CC[C@H](CO)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Trans-4-[(5-Chloro-2-methyl-pyridine-3-carbonyl)-amino]-cyclohexanecarboxylic acid methyl ester (step 2) (2.20 g, 7.08 mmol) is placed in a flask with dry THF (100 mL). This is cooled to 0° C. and lithium aluminum hydride (0.537 g, 14.16 mmol) is added. The reaction mixture is stirred at r.t. for 2 hours and then quenched with water (0.5 mL), 2M NaOH (0.5 mL) and then water again (1.5 mL). The solids are filtered off through Celite® (filter material) and the filtrate is partitioned between EtOAc and water. The organic phase is washed with water and brine, dried over MgSO4, filtered and the solvent is removed in vacuo to afford the title product which is used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 8.53 (1H, d), 8.38*1H, d), 7.79 (1H, d), 4.40 (1H, t), 3.66 (1H, m), 3.21 (2H, t), 2.47 (3H, s), 1.92 (2H, m), 1.78 (2H, m), 1.31 (1H, m), 1.22 (2H, m), 0.98 (2H, m). [MH]+283.30.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Cl:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1.[C:16](=[O:18])=[O:17]>C1COCC1>[Cl:9][C:10]1[C:15]([C:16]([OH:18])=[O:17])=[CH:14][N:13]=[CH:12][CH:11]=1
Reactant: Clc1ccncc1
Reactant: O=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1cnccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
Following the procedures of Guillier et al (1995) J. Org. Chem. 60(2):292-6, to a cold (−78° C.) solution of LDA (21 ml, 1.6 M in hexanes, 33.3 mmol) in anhydrous THF (70 ml) was added 4-chloropyridine (5.0 g, 33.3 mmol) under an argon atmosphere. After 1 hour at −78° C., the solution was rapidly poured onto a bed of solid CO2 contained within a 250 ml conical flask. After allowing the reaction solution to warm to ambient temperature the solution was quenched with water (30 ml). The volatile organic solvents were removed in vacuo and the remaining aqueous suspension was extracted with diethyl ether (3×100 ml). The aqueous phase was cooled to 0° C. and the adjusted to pH 4 by the addition of concentrated hydrochloric acid. The resultant precipitate was aged for 30 minutes then collected by filtration. The solid was washed with cold diethyl ether (10 ml) to afford the title compound as a white solid (3.2 g, 61%).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([NH:13][CH:14]=[O:15])=[C:11]([C:16](=[O:18])[NH2:17])[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>[OH-].[Na+]>[C:14]([NH:13][C:12]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:9]=[N:10][C:11]=1[C:16](=[O:18])[NH2:17])(=[O:15])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC(=O)c1nnn(Cc2ccccc2)c1NC=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)c1nnn(Cc2ccccc2)c1NC(=O)c1ccccc1
Temperature: 0 °C

Procedure:
1-Benzyl-4-carbamoyl-5-formamido-1,2,3-triazole (40 g.; prepared as described by A. Albert, J.Chem.Soc., 1969 (C), 152) was dissolved in 2N sodium hydroxide solution (156 ml.), and treated with alternate successive portions of benzoyl chloride (total 24 ml.) and 2N aqueous sodium hydroxide solution (total 140 ml.) with vigorous agitation, and cooling with ice, over a period of 2 hours. The solution was then acidified to pH 4 with concentrated hydrochloric acid, again cooling with ice, and the precipitated solid was filtered off, dissolved in 2N sodium hydroxide solution (208 ml.) and the solution stirred at 0° C. while portions of benzoyl chloride (total 57 ml.) and 2N sodium hydroxide solution (total 331 ml.) were added alternately over 45 minutes. The resultant mixture was stirred for a further 60 minutes at 0° C. before being acidified to pH 4 with concentrated hydrochloric acid, the temperature being maintained at 0° C. The solid was filtered off and washed successively with water, diethyl ether and water. The solid product was dried, and recrystallised from ethanol to give 5-benzamido-1-benzyl-4-carbamoyl-1,2,3-triazole (23.1 g.), m.p. 191°-192° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([Cl:10])=[C:8]([C:11](OCC)=O)[S:7][C:6]=2[CH:16]=1.[CH2:17]([NH2:20])[CH2:18][NH2:19].[Si](I)(C)(C)C>C(N(CC)CC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([Cl:10])=[C:8]([C:11]3[NH:19][CH2:18][CH2:17][N:20]=3)[S:7][C:6]=2[CH:16]=1
Reactant: CCOC(=O)c1sc2cc(Br)ccc2c1Cl
Reactant: NCCN
Agent: C[Si](C)(C)I
Solvent: CCN(CC)CC
Product: Clc1c(C2=NCCN2)sc2cc(Br)ccc12
Temperature: 80 °C
Reaction time: 120 h

Procedure:
A mixture of 4 g (12.5 mmol) ethyl 6-bromo-3-chlorobenzo[b]thiophen-2-carboxylate and 7.5 g (125 mmol) ethylendiamine were heated at 80° C. overnight. It was concentrated in vacuo, and the crude 2-ethylaminoamide was dissolved in 70 ml dry dichloromethane followed by addition of 10.5 ml triethylamine and 15 g (75 mmol) TMS iodide. After five days stirring at room temperature the reaction was almost complete as detected by TLC. It was extracted with water, dried over sodium sulfate, and concentrated under reduced pressure. The title imidazoline was isolated from the residue by column chromatography on silica gel with dichloromethane/ethanolic ammonia gradient.
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.N1C=CC=CC=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>O>[C:23]([O:1][CH2:2][C:3]1([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)[CH2:4][CH2:5][C:6](=[O:9])[CH2:7][CH2:8]1)(=[O:25])[CH3:24]
Reactant: O=C1CCC(CO)(c2ccc(F)cc2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OCC1(c2ccc(F)cc2)CCC(=O)CC1
Reaction time: 20 h
Yield: 57 %

Procedure:
The 4-hydroxymethyl-4-(4-fluorophenyl)cyclohexanone is dissolved in 50 ml. of pyridine and 30 ml. of acetic anhydride. After about 20 hours of standing at room temperature, the mixture is pured into ice and water. The gum that precipitates is extracted with ether. The organic layer is washed sucessively with water, 2.5 N hydrochloric acid, water, sodium bicarbonate solution and brine, and evaporated to dryness. The solid residue is recrystallized from ether to give 9.77 g. (57% yield) of 4-acetoxymethyl-4-(4-fluorophenyl)cyclohexanone, having a melting point of 80° to 84°C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][Cl:35])=[CH:26][CH:25]=2)(O)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][Cl:35])=[CH:28][CH:29]=2)=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC(Cc1ccccc1)(c1ccc(OCCCCCl)cc1)c1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: CO
Product: ClCCCCOc1ccc(C(=Cc2ccccc2)c2ccc(OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Combine 1-(4-benzyloxyphenyl)-1-(4-(4-chlorobutyloxy) phenyl)-2-phenyl ethanol (1.0 g, 21.0 mmol) and methanol (2 mL). Add aqueous 2M hydrochloric acid solution (4 mL). Heat to reflux. After 2 hours, concentrate at 65° C. to remove most of the methanol. Cool to ambient temperature and extract with dichloromethane. Dry the organic layer over MgSO4, filter, and dry in vacuo to give 1-(4-benzyloxyphenyl)-1-(4-(4-chlorobutyloxy)phenyl)-2-phenyl ethylene: Rf =0.50 (silica gel, 30% ethyl acetate/hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:32][CH2:31][C:14]2([C:18](=[O:19])[N:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][OH:30])=[NH:28])=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:10])=[O:9].[C:33](OC(=O)C)(=O)[CH3:34]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:12][CH2:13][C:14]2([C:18](=[O:19])[N:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]4[N:28]=[C:33]([CH3:34])[O:30][N:29]=4)=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)[CH2:31][CH2:32]1)(=[O:10])=[O:9]
Reactant: CC(=O)OC(C)=O
Reactant: N=C(Cc1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4Cl)CC3)C2=O)cc1)NO
Product: Cc1nc(Cc2ccc(N3CCC4(CCN(S(=O)(=O)c5ccccc5Cl)CC4)C3=O)cc2)no1

Procedure:
Above 2-{4-[8-(2-chloro-benzenesulfonyl)-1-oxo-2,8-diaza-spiro[4.5]dec-2-yl]-phenyl}-N-hydroxy-acetamidine (150 mg) were treated at RT with acetic anhydride (40 ml) and then refluxed for 30 minutes. The reaction mixture was concentrated in vacuo, the residue purified by chromatography on silica gel to give the desired 8-(2-chloro-benzenesulfonyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-ylmethyl)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one as a light yellow crystalline solid. MS (ESI): 502.1 (MH+).
Reaction SMILES: CN(C)C=O.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.N1C=CN=C1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>O>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])=[CH:9][CH:8]=1
Reactant: OCc1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a dimethylformamide (30 mL) solution of (4-bromophenyl)methanol (3.00 g), imidazole (2.18 g) and tert-butyldimethylsilyl chloride (2.89 g) were added in this order. The reaction solution was stirred at room temperature for one hour. To the reaction solution, water (10 mL) was added and the aqueous layer was extracted twice with ethyl acetate (50 mL). The combined organic layer was washed in turn with 1N hydrochloric acid (10 mL) and saturated sodium chloride solution (10 mL) and then dried over anhydrous magnesium sulfate. After removing the anhydrous magnesium sulfate by filtration, the filtrate was concentrated. The residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0→9:1) to obtain the title compound (3.77 g) having the following physical properties.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Cl:18])[C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.P(Cl)(Cl)(Cl)=O.CN(C)[CH:26]=[O:27]>>[Cl:1][C:2]1[CH:3]=[C:4]([Cl:18])[C:5]2[N:6]([C:8]([CH:26]=[O:27])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[N:10]=2)[CH:7]=1
Reactant: Fc1ccc(-c2cn3cc(Cl)cc(Cl)c3n2)cc1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c(-c2ccc(F)cc2)nc2c(Cl)cc(Cl)cn12
Yield: 75 %

Procedure:
6,8-Dichloro-2-(4-fluorophenyl)imidazo[1,2-α]pyridine (6 g, 0.021 moles) was treated with phosphorous oxychloride (3.0 mL, 33 mmol) in N,N-dimethylformamide in a similar manner as described in Example 2 to give 6,8-dichloro-2-(4-fluorophenyl)imidazo[1,2-α]pyridine-3-carbaldehyde (4.9 g, 75%) as a white solid. 1H NMR (CDCl3): δ 10.05 (s, 1H), 9.69 (d, 1H), 7.86 (q, 2H), 7.65 (d, 1H), 7.25 (t, 2H); 19F NMR (CDCl3) δ −110.3; MS m/z 309 (M+1).
Reaction SMILES: N[C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:5]=[C:4]([O:14][CH3:15])[N:3]=1.N([O-])=O.[Na+].OC1C(N2CCOCC2)=NC=C(OC)N=1.P(Cl)(Cl)([Cl:37])=O>>[Cl:37][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:5]=[C:4]([O:14][CH3:15])[N:3]=1
Reactant: COc1cnc(N2CCOCC2)c(N)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: COc1cnc(N2CCOCC2)c(O)n1
Agent: O=N[O-]
Agent: [Na+]
Product: COc1cnc(N2CCOCC2)c(Cl)n1

Procedure:
The 2-amino substituent of Step A product when treated with sodium nitrite as described in Step E of Preparation 81 is converted to the 2-hydroxy group. Treatment of the 2-hydroxy-3-morpholino-6-methoxypyrazine with phosphorus oxychloride by Preparation 13, Step B method, gives 2-chloro-3-morpholino-6-methoxypyrazine.