Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[C:14]=1[O:15][CH2:16][C@@H:17]1[CH2:19][O:18]1)=[CH:11][CH:10]=[CH:9][CH:8]=3.NCC1CCN([C:28]2[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=2[S:36]([NH2:39])(=[O:38])=[O:37])CC1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[C:14]=1[O:15][CH2:16][C@@H:17]([OH:18])[CH2:19][NH:6][CH2:5][CH:13]1[CH2:14][CH2:2][N:39]([S:36]([C:29]2[CH:28]=[CH:33][C:32]([O:34][CH3:35])=[CH:31][CH:30]=2)(=[O:37])=[O:38])[CH2:11][CH2:12]1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: COc1ccc(S(N)(=O)=O)c(N2CCC(CN)CC2)c1
Reactant: Brc1ccc2[nH]c3ccccc3c2c1OC[C@@H]1CO1
Product: COc1ccc(S(=O)(=O)N2CCC(CNC[C@H](O)COc3c(Br)ccc4[nH]c5ccccc5c34)CC2)cc1
Yield: 100.9 %

Procedure:
Prepared from 3-bromo-4-[(2S)-oxiranylmethoxy]-9H-carbazole (0.083 g, 0.26 mmol) and (4-aminomethyl-1-piperidinyl) 4-methoxybenzenesulfonamide (0.142 g, 0.5 mmol) according to procedure used for Example 2 to give 0.079 g of the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[N+:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31](Cl)(=[O:33])=[O:32])([O-:24])=[O:23]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N+:22]([O-:24])=[O:23])(=[O:32])=[O:33])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-aminopiperidine-1-carboxylic acid tert-butyl ester (400 mg, 200 mmol) in anhydrous dichloromethane (14 mL) under argon was added triethylamine (340 μL, 2.4 mmol) and the solution cooled in an ice bath. 2-Nitrophenylsulfonyl chloride (443 mg, 2.0 mmol) was added and the reaction allowed to stir at rt for 16 h. The crude solution was washed with water (2×30 mL) before removing the solvent in vacuo. The crude material was purified by chromatography using ethyl acetate/petroleum ether (30-60%) as the eluent to give the title compound as an off-white powder. δH (d6 DMSO): 8.43 (2H, m), 8.17 (1H, s), 8.09 (2H, m), 3.80-3.69 (2H, m), 3.31-3.23 (1H, m), 2.86-2.69 (2H, m), 1.63-1.51 (2H, m), 1.39 (9H, s), 1.29-1.17 (2H, m).
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([N:6]=[C:7](SC)[NH:8][CH:9]([CH3:18])[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O)#[N:5].C[O-].[Na+]>CO>[C:4]([NH:6][C:7]1[NH:2][N:3]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]([CH3:18])[N:8]=1)#[N:5]
Reactant: CSC(=NC#N)NC(C)C(=O)c1ccccc1
Reactant: NN
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1N=C(NC#N)NN=C1c1ccccc1
Reaction time: 1 h
Yield: 50.6 %

Procedure:
Hydrazine hydrate (4.55 g) was added to a solution of 2-(3-cyano-2-methyl-1-isothioureido)propiophenone (5.43 g) in methanol (20 ml), and the mixture was allowed to stand at room temperature for 1 hour. After addition of catalytic amount of sodium methoxide to the solution, the mixture was allowed to stand at room temperature for 2 hours with occasional shaking. The resultant preapitates were collected, washed successively with methanol, water and methanol and dried. Thus obtained product was dissolved with dimethylformamide (25 ml), the solution was filtered by suction and then water (25 ml) was added thereto little by little. After cooling, the resultant precipitates were collected by filtration, washed successively with ethanol, water and ethanol, and dried to give 3-cyanoamino-5-methyl-6-phenyl-2,5-dihydro-1,2,4-triazine (2.37 g), m.p. 244.5°~245° C. (decomp.).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8]O)=[C:6]([CH3:10])[CH:5]=[CH:4][N:3]=1.S(Cl)([Cl:13])=O>C(Cl)Cl>[CH3:1][C:2]1[C:7]([CH2:8][Cl:13])=[C:6]([CH3:10])[CH:5]=[CH:4][N:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccnc(C)c1CO
Solvent: ClCCl
Product: Cc1ccnc(C)c1CCl
Temperature: 0 °C
Reaction time: 18 h

Procedure:
The 2,4-dimethyl-3-hydroxymethylpyridine (19.2 g, 140 mmol) was dissolved in CH2Cl2 (800 mL) and cooled under nitrogen to 0° C. and thionyl chloride (125 mL) was slowly added and the reaction was stirred for 18 hours. The solvent was removed under reduced pressure and the residue was partitioned between CH2Cl2 and saturated aqueous sodium bicarbonate. The organic layer was dried with MgSO4, filtered and the solvent removed under reduced pressure to give the desired 2,4-dimethyl-3-chloromethylpyridine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[C:10]([CH2:14][C:15](OC)=[O:16])(=O)[CH2:11][CH3:12].O>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:11]([C:10]1[NH:1][C:2]2[C:7]([C:15](=[O:16])[CH:14]=1)=[N:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)[CH3:12]
Reactant: COc1ccc(N)cn1
Reactant: CCC(=O)CC(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCc1cc(=O)c2nc(OC)ccc2[nH]1
Yield: 39.3 %

Procedure:
A solution of 5-amino-2-methoxypyridine (50 g), methyl propionylacetate (57.3 g) and p-toluenesulphonic acid (0.5 g) in benzene (200 ml) was heated under reflux with azeotropic removal of water for 20 hours. Volatile material was removed by evaporation and the residue added to a refluxing eutectic mixure of 26.5% v/v diphenyl and 73.5% v/v diphenyl oxide (140 ml). The solution was heated under reflux for 1 hour, cooled and diluted with hexane (500 ml). The precipitated solid was filtered off and triturated with hot methanol (500 ml) to give 2-ethyl-6-methoxy-1,5-naphthyridin-4(1H)-one (E5) (32.3 g), as a pale brown solid, m.p. 279°-281° C.; NMR (d6 -DMSO): 1.2(t,3H), 2.65(q,2H), 3.95(s,3H), 6.3(br s, 1H), 7.15(d,1H), 7.95(d,1H).
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=S)[NH:17][CH2:16]2>>[CH:2]1([NH:1][C:18]2[NH:17][CH2:16][C:15]3[C:20](=[CH:21][CH:22]=[C:13]([O:12][CH3:11])[CH:14]=3)[N:19]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: NC1CCc2ccccc21
Reactant: COc1ccc2c(c1)CNC(=S)N2
Product: COc1ccc2c(c1)CNC(NC1CCc3ccccc31)=N2

Procedure:
The title compound (MS: m/e=294.2 [M+H+]) was prepared in analogy to example 1(b) from (+/−)-1-aminoindan and 6-methoxy-3,4-dihydro-1H-quinazoline-2-thione. 6-Methoxy-3,4-dihydro-1H-quinazoline-2-thione can be prepared by the method of Manetsch, Roman; Zheng, Lei; Reymond, Martine T.; Woggon, Wolf-Dietrich; Reymond, Jean-Louis Chemistry—A European Journal 2004, 10(10), 2487-2506.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH2:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2].C(N(CC)CC)C.[CH:64]1([C:67](Cl)=[O:68])[CH2:66][CH2:65]1>C(Cl)Cl>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH:50][C:67]([CH:64]3[CH2:66][CH2:65]3)=[O:68])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(NC(=O)C4CC4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57.5 %

Procedure:
A solution of 32 mg of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-amino-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (from Example 3) in dry methylene chloride (0.4 ml) was cooled to 0° C. To this solution was added triethylamine (10 μl) followed by a solution of cyclopropane carbonyl chloride (5 mg) in methylene chloride (0.1 ml). The reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was purified by preparative tlc on silica gel (1000 microns, 5% i-PrOH/CH2Cl2) to give 20 mg of the title compound. (Mass, 1H and 13C data were consistent with the proposed structure).
Reaction SMILES: [Cl:1][CH:2]([C:8](=[O:12])[CH2:9][CH2:10][CH3:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4].CO.[H][H]>O>[Cl:1][CH:2]([CH:8]([OH:12])[CH2:9][CH2:10][CH3:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCCC(=O)C(Cl)C(=O)OCC
Reactant: [H][H]
Solvent: O
Solvent: CO
Product: CCCC(O)C(Cl)C(=O)OCC
Temperature: 70 °C
Reaction time: 14 h
Yield: 72.3 %

Procedure:
Ethyl 2-chloro-3-oxohexanoate (2.5 g, 13 mmol), methanol (7.5 ml) and water (0.75 ml) were mixed, and nitrogen substitution was carried out after reducing the pressure. The above catalyst solution was added thereto, and hydrogen substitution (3 atmospheres) was carried out under reduced pressure. The mixture was stirred at 70° C. for 14 hours. After the mixture was cooled to room temperature, the solvent was evaporated away under reduced pressure. The concentrated matter was purified by silica gel column chromatography to obtain the title compound as a colorless oil (1.83 g, yield: 72%) ((2S,3R):(2S,3S):(2R,3S):(2R,3R)=6.2:58.5:33.2:2.2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([CH:17]=1)[C:7]([C:9]1[C:14]([C:15]#[N:16])=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8].Cl.[C:20]([O:24][NH2:25])([CH3:23])([CH3:22])[CH3:21].N1CCCC1>C(O)CC>[C:20]([O:24]/[N:25]=[C:15](/[C:14]1[C:9]([C:7](=[O:8])[C:6]2[CH:17]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[OH:18])=[N:10][CH:11]=[CH:12][CH:13]=1)\[NH2:16])([CH3:23])([CH3:22])[CH3:21]
Reactant: N#Cc1cccnc1C(=O)c1cc(Cl)ccc1O
Reactant: CC(C)(C)ON
Agent: Cl
Solvent: CCCO
Solvent: C1CCNC1
Product: CC(C)(C)O/N=C(\N)c1cccnc1C(=O)c1cc(Cl)ccc1O
Yield: 86 %

Procedure:
A mixture of 2-(5-chloro-2-hydroxybenzoyl)-3-cyanopyridine (217 mg), O-t-butylhydroxylamine hydrochloride (158 mg), pyrrolidine (149 mg) and n-propanol (4.0 ml) was heated for 30 minutes under reflux. The reaction mixture was poured into a saturated aqueous saline solution, which was subjected to extraction with ethyl acetate. The extract solution was washed successively with an aqueous solution of potassium hydrogensulfate and a saturated aqueous saline solution, dried (anhydrous sodium sulfate), and concentrated. The concentrate was purified by means of a silica gel column chromatography (eluent: ethyl acetate/hexane) to give (Z)-2-(5-chloro-2-hydroxybenzoyl)-3-carbamoylpyridine O-t-butyloxime (251 mg) (Compound 152).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12](=[O:42])[CH2:13][N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH:24]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH:16]([C:39]([NH2:41])=[O:40])[CH2:15]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[C:50](Cl)(=[O:53])[CH2:51][CH3:52]>ClC(Cl)Cl>[C:1]([C:4]1[CH:9]=[C:8]([NH:10][C:50](=[O:53])[CH2:51][CH3:52])[CH:7]=[CH:6][C:5]=1[NH:11][C:12](=[O:42])[CH2:13][N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH:24]([C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH:16]([C:39]([NH2:41])=[O:40])[CH2:15]1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(N)ccc1NC(=O)CN1CCN(CCCCC(c2ccc(F)cc2)c2ccc(F)cc2)C(C(N)=O)C1
Reactant: CCC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1ccc(NC(=O)CN2CCN(CCCCC(c3ccc(F)cc3)c3ccc(F)cc3)C(C(N)=O)C2)c(C(C)=O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.7 %

Procedure:
To a stirred solution of 4.5 parts of N-(2-acetyl-4-aminophenyl)-3-(aminocarbonyl)-4-[5,5-bis(4-fluorophenyl)pentyl]-1-piperazineacetamide in 60 parts of trichlormethane were added 1.17 parts of N,N-diethylethanamine. A solution of 0.78 parts of propanoyl chloride in 45 parts of trichloromethane was added dropwise at room temperature (slightly exothermic reaction, the temperature rose from 24° C. to 30° C.). Upon completion, the whole was stirred for 3 hours at room temperature. The separated organic layer was washed with a sodium carbonate solution in water and water, dried, filtered and evaporated. The residue was crystallized from acetonitrile. After cooling to 0° C., the product was filtered off and dried in vacuo, first at 50° C. and then at 100° C., yielding 2.93 parts (57.7%) of N-[2-acetyl-4-[(1-oxopropyl)amino]phenyl]-3-(aminocarbonyl)-4-[5,5-bis(4-fluorophenyl) pentyl]-1-piperazineacetamide; mp. 163.4° C. (compound 32).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].[Li]CCCC.[C:16](=[O:18])=[O:17].O>C1(C)C=CC=CC=1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:16]([OH:18])=[O:17])=[C:3]([CH3:10])[CH:4]=1)#[N:7]
Reactant: Cc1cc(C#N)ccc1Br
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(C#N)ccc1C(=O)O
Temperature: 25 °C
Yield: 20.4 %

Procedure:
To a solution of 4-bromo-3-methylbenzonitrile (0.48 g, 2.43 mmol) in 1 ml of toluene at −78° C. was added 1 ml of 2.6M n-BuLi in toluene followed by quenching with dry ice (0.5 g, 12.5 mmol). The reaction mixture was warmed to room temperature, then taken into water and extracted with ethyl acetate (2×15 ml). The water layer was acidified to pH 1-2 by addition of concentrated aqueous hydrochloric acid and extracted with ethyl acetate (3×15 ml). The organic layer was dried over anhydrous sodium sulfate, then filtered and concentrated to give 4-cyano-2-methylbenzoic acid (0.08 g, 20% yield). 1H-NMR (400 MHz, DMSO-d6): 13.10 (br s, 1H), 7.92 (d, 1H), 7.84 (m, 1H), 7.76 (d, 1H), 2.53 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]4[CH2:29][O:28]4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN1C(=O)CCC1>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:28])[CH2:29][NH:37][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C4CO4)cc3)cc2)CC1
Solvent: CN1CCCC1=O
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)CNCc4ccccc4)cc3)cc2)CC1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
1-[4′-(3-Methyl-4-oxiranyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.100 g, 0.26 mmol) and benzylamine (0.034 mL, 0.31 mmol) were combined in NMP (5 mL) and the reaction was stirred overnight at 85° C. Additional benzylamine (0.05 mL, 0.46 mmol) was added and the reaction was stirred for two days at 85° C. Aqueous workup provided the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]1([C:15]2([CH3:22])[O:21][CH:16]2[C:17]([O:19][CH3:20])=[O:18])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:15]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)([CH3:22])[CH:16]([OH:21])[C:17]([O:19][CH3:20])=[O:18])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: COC(=O)C1OC1(C)c1ccccc1
Product: COC(=O)C(O)C(C)(Oc1ccc(Br)cc1)c1ccccc1
Yield: 19.7 %

Procedure:
51.9 g (0.3 mol) of 4-bromophenol and 19.2 g (0.1 mol) of methyl 3-phenyl-2,3-epoxybutyrate are stirred at 100° C. for 8 h and at room temperature for 12 h. After removal of the excess phenol by distillation, the residue is purified by flash chromatography (silica gel, n-hexane/ethyl acetate 9:1) to result in 7.2 g of a white solid.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.Br[CH2:14][CH2:15][CH2:16]Br>CS(C)=O.O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:11]#[N:12])[CH2:16][CH2:15][CH2:14]2)=[CH:6][CH:5]=1
Reactant: N#CCc1ccc(Br)cc1
Reactant: BrCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CC1(c2ccc(Br)cc2)CCC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 41.1 %

Procedure:
To a stirred suspension of sodium hydride (60% susp. in oil, 12.24 g, 255 mmol) in anhydrous DMSO (240 mL) is added dropwise 2-(4-bromophenyl)acetonitrile (20.0 g, 102 mmol) dissolved in anhydrous DMSO (40 mL). After 45 min, the reaction mixture is cooled to 0° C. and 1,3-dibromopropane (30.9 g, 15.5 mL, 153 mmol) dissolved in anhydrous DMSO (40 mL) is added slowly to maintain the temperature below 45° C. The reaction mixture is stirred overnight at room temperature and poured in cold water (1.2 L). The product is extracted with CH2Cl2 (6×100 mL), dried on MgSO4, filtered and concentrated under reduced pressure. The product is purified by flash chromatography eluting with hexane:EtOAc (100% to 95:5) to provide the expected product 1-(4-bromophenyl)cyclobutanecarbonitrile (9.9 g, 41%) as a yellowish oil. 1H NMR (300 MHz, CHLOROFORM-D): δ 7.57-7.49 (2H, m), 7.33-7.24 (2H, m), 2.89-2.77 (2H, m), 2.66-2.34 (3H, m), 2.15-1.99 (1H, m).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:53])[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH:38]([O:43][Si](C(C)(C)C)(C)C)[C:39]([CH3:42])([CH3:41])[CH3:40])=[C:32]([CH3:51])[CH:31]=3)([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:21][C:20]=2[CH3:52])=[CH:15][CH:14]=1)[OH:12]>ClCCl>[CH3:8][O:9][C:10](=[O:53])[CH:11]([C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([CH2:26][CH3:27])([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH:38]([OH:43])[C:39]([CH3:41])([CH3:42])[CH3:40])=[C:32]([CH3:51])[CH:31]=3)[CH2:28][CH3:29])=[CH:21][C:20]=2[CH3:52])=[CH:17][CH:18]=1)[OH:12]
Reactant: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(C(O)C(=O)OC)cc2)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(C(O)C(=O)OC)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
Trifluoroacetic acid (0.05 mL) was added to a solution of [4′-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2′-methyl-biphenyl-4-yl]-hydroxy-acetic acid methyl ester (Example 154-(2); 7.0 mg, 0.011 mmol) in dichloromethane (0.28 mL) at room temperature, and the mixture was stirred at room temperature for one hour. The solvent in the reaction solution was distilled off under reduced pressure, and the residue was diluted with diethyl ether. The mixture was adjusted to pH 7 to 8 with aqueous sodium bicarbonate solution, followed by extraction with diethyl ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=3/1) to give the title compound (5.0 mg, 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)(=[O:11])=[O:10])=[C:4]([CH:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[OH:23])[CH:3]=1.[H-].[Na+].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)(=[O:10])=[O:11])[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:4]([CH:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[OH:23])[CH:3]=1
Reactant: COc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(O)c2ccccc2Cl)cc1OC
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CN(c1ccc(Cl)cc1C(O)c1ccccc1Cl)S(=O)(=O)c1ccc(OC)c(OC)c1
Reaction time: 1 h

Procedure:
To 6 g of N-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-3,4-dimethoxybenzenesulfonamide dissolved in 50 ml of DMF at 0° C. is added portionwise 0.674 g of sodium hydride. After 1 hour at 0° C., 1.4 ml of ethyl 2-bromoacetate are introduced and the mixture is left for 18 hours at room temperature. The reaction medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with dichloromethane to give 1.3 g of the expected product.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]1[N:7]=[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:9][C:10]=1[CH:11]=[O:12].C(P(CCCC)CCCC)CCC.[CH3:32][C:33]1[O:37][C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[N:35][C:34]=1[CH2:44][O:45][C:46]1[CH:51]=[CH:50][C:49](O)=[CH:48][CH:47]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]1[N:7]=[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:9][C:10]=1[CH2:11][O:12][C:49]1[CH:48]=[CH:47][C:46]([O:45][CH2:44][C:34]2[N:35]=[C:36]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[O:37][C:33]=2[CH3:32])=[CH:51][CH:50]=1
Reactant: COCOCc1nc(-c2ccccc2)oc1C=O
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COCOCc1nc(-c2ccccc2)oc1COc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Reaction time: 15 h
Yield: 57.1 %

Procedure:
To a mixture of 4-[(methoxymethoxy)methyl]-2-phenyl-1,3-oxazole-5-carbaldehyde (0.45 g), tributylphosphine (0.73 g), 4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenol (0.50 g) and tetrahydrofuran (50 mL) was added 1,1′-(azodicarbonyl)dipiperidine (0.91 g) at room temperature, and the mixture was stirred for 15 hrs. The precipitated crystals were removed by filtration and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give 4-[(methoxymethoxy)methyl]-5-({4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenoxy}methyl)-2-phenyl-1,3-oxazole as colorless crystals (0.52 g, yield 57%) from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 74-75° C.
Reaction SMILES: [C:1]12([CH2:11][C:12](Cl)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:15][C:16]1[C:17]([CH3:24])=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][OH:20]>>[OH:20][CH2:19][C:18]1[C:17]([CH3:24])=[C:16]([NH:15][C:12](=[O:13])[CH2:11][C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]4)[CH2:2]2)[CH2:8]3)[CH:23]=[CH:22][CH:21]=1
Reactant: Cc1c(N)cccc1CO
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Product: Cc1c(CO)cccc1NC(=O)CC12CC3CC(CC(C3)C1)C2
Yield: 27.1 %

Procedure:
Prepared according to the method of Example 1b) from 1-adamantaneacetyl chloride (2.0 g) and 3-amino-2-methylbenzyl alcohol (1.29 g). Silica gel chromatography, eluting with 5% ethylacetate in dichloromethane gave the title compound as a white solid (0.80 g).
Reaction SMILES: [C:1]1([C:7]2([CH:12]=O)[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[OH:15][NH3+:16].N1C=CC=CC=1>C(O)C>[C:1]1([C:7]2([CH:12]=[N:16][OH:15])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CC1(c2ccccc2)CCCC1
Reactant: [NH3+]O
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: CCO
Product: ON=CC1(c2ccccc2)CCCC1
Yield: 66 %

Procedure:
A mixture of the above aldehyde (3.4 g, 20 mmol) and hydroxylammonium chloride (2.9 g, 42 mmol) in a mixture of absolute ethanol (30 ml) and pyridine (3.3 g, 42 mmol) was heated at reflux for 2 h. The solvent was evaporated in vacuo, the residue was treated with absolute ethanol (50 ml) and the suspension filtered. The solvent was evaporated from the filtrate in vacuo and the residue crystallised from a 4/1 mixture of n-heptane and ethyl acetate to give 2.5 g of 1-phenyl-1-cyclopentanecarboxaldehyde oxime.