Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1.[C:17]([C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=1)#[CH:18]>>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2][C:18]#[C:17][C:19]2[CH:28]=[CH:27][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)=[CH:11][CH:12]=1
Reactant: C#Cc1ccc(C(=O)OC)cc1
Reactant: Clc1ccc(-c2ccccc2/C=C/I)cc1
Product: O=C(O)c1ccc(C#CC=Cc2ccccc2-c2ccc(Cl)cc2)cc1
Yield: 42.2 %

Procedure:
In a similar manner to that of Example 1(e), by reaction of 2.40 g (7.0 mmol) of 2-((E)-2-iodovinyl)-4'-chlorobiphenyl obtained in Example 23(b) with 1.03 g (6.4 mmol) of methyl 4-ethynylbenzoate, 970 mg (41%) of the expected compound are obtained in the form of a pale yellow solid with a melting point of 135° C.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7])([O-:3])=[O:2].[C:12](O)(=[O:23])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:12]([O:7][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:23])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22]
Reactant: O=[N+]([O-])c1ccccc1CO
Reactant: C=CCCCCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CCCCCCCCCC(=O)OCc1ccccc1[N+](=O)[O-]

Procedure:
One equivalent of 2-nitrobenzyl alcohol (2.39 g, 15.65 mmol) was combined with one equivalent of undecylenic acid (2.88 g, 15.65 mmol) and 0.1 equivalents of DMAP and dissolved in 50 mL CH2Cl2. DCC (3.23 g, 15.65 mmol) was dissolved in 30 mL CH2Cl2 and slowly added to the mixture while stirring. A white precipitate slowly formed after about 5 minutes. The reaction mixture was stirred at room temperature overnight. The precipitate was filtered off by vacuum filtration and the filtrate was concentrated by rotovap. Silica gel column chromatography with CH2Cl2/MeOH (v/v 50:1) as eluent was used for purification. The product was dried over Na2SO4, solvent removed by rotovap, and dried under vacuum producing a yellow oil. Yield: 3.91 g (78.2%). 1H-NMR (CDCl3) δ (ppm): 8.1 (d, 1H, Ar), 7.7 (t, 1H, Ar), 7.6 (d, 1H, Ar), 7.5 (t, 1H, Ar), 5.8 (m, 1H, CH═CH2), 5.5 (s, 2H, CH2—O) 4.9 (dd, 2H, CH2═CH), 2.4 (t, 2H, CH2—C═O), 2.0 (q, 2H, CH2), 1.6 (m, 2H, CH2), 1.2 (m, 10H, CH2). 13C NMR (CDCl3) δ (ppm): 173.5, 147.9, 139.5, 134.1, 132.7, 129.4, 129.1, 125.4, 114.6, 63.2, 34.5, 34.2, 29.7, 29.6, 29.5, 29.4, 29.3, 25.3. MS (ESI): (M+H)+=320.30 (calc. 320.40).
Reaction SMILES: [CH:1]([O:4][C:5]1[C:6]([O:23][CH3:24])=[CH:7][C:8]([N+:20]([O-:22])=[O:21])=[C:9]([CH:11]([OH:19])[C:12]#[C:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=1)([CH3:3])[CH3:2].[CH3:25][O:26][C:27]1[CH:36]=[CH:35][C:30]([CH2:31][N:32]=[N+:33]=[N-:34])=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[OH:19][CH:11]([C:9]1[CH:10]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[C:6]([O:23][CH3:24])=[CH:7][C:8]=1[N+:20]([O-:22])=[O:21])[C:12]1[N:34]=[N:33][N:32]([CH2:31][C:30]2[CH:35]=[CH:36][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C#CC(O)c1cc(OC(C)C)c(OC)cc1[N+](=O)[O-]
Reactant: COc1ccc(CN=[N+]=[N-])cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C(O)c2cc(OC(C)C)c(OC)cc2[N+](=O)[O-])nnn1Cc1ccc(OC)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
1.5 N butyl lithium (22.6 ml, 33.8 mmol) was added to a solution of diisopropylamine (5.0 ml, 36.0 mmol) in tetrahydrofuran (75 ml) under an argon atmosphere at −78° C., and the mixture was stirred for one hr. Ethyl propiolate (2.9 ml, 28.2 mmol) and a solution of 5-isopropoxy-4-methoxy-2-nitrobenzaldehyde (4.5g, 18.8 mmol) in tetrahydrofuran (50 ml) were then added thereto in that order, and the mixture was stirred at −78° C. for additional 1.5 hr. A solution of acetic acid (5.9 ml, 102 mmol) in tetrahydrofuran (20 ml) was added to the reaction solution. Water was then added thereto, followed by extraction with ethyl acetate. The organic layer was washed with dilute hydrochloric acid, water, a saturated aqueous sodium hydrogencarbonate solution, and saturated brine solution. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give ethyl 4-(5-isopropoxy-4-methoxy-2-nitrophenyl)-4-hydroxy-2-butynoate (7.27 g). The resultant ethyl 4-(5-isopropoxy-4-methoxy-2-nitrophenyl)-4-hydroxy-2-butynoate was dissolved in toluene (60 ml). 4-Methoxybenzyl azide (9.2 g, 56.4 mmol) was added to the solution. The mixture was heated at 100° C. with stirring overnight. The reaction solution was cooled to room temperature. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:2) to give a 1:1 mixture (7.01 g, 75%) of ethyl 4-(1-hydroxy-(5-isopropoxy-4-methoxy-2-nitrophenyl)methyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-5-carboxylate (a-1: low polar product (LP)) and ethyl 5-(1-hydroxy-(5-isopropoxy-4-methoxy-2-nitrophenyl)methyl)-1-(4-methoxybenzyl)-1H-1,2;3-triazole-4-carboxylate (a-2: high polar product (MP))
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.C([N:18]([CH2:27][CH3:28])[C:19]([C:21]1[CH:25]=[CH:24][O:23][C:22]=1[CH3:26])=[O:20])C.[CH3:29][N:30]([CH3:35])[CH2:31]CC#N.Cl>O1CCCC1.CC(C)=O>[CH3:29][N:30]([CH3:35])[CH2:31][CH2:28][C:27]1[NH:18][C:19](=[O:20])[C:21]2[CH:25]=[CH:24][O:23][C:22]=2[CH:26]=1
Reactant: CCN(CC)C(=O)c1ccoc1C
Reactant: CN(C)CCC#N
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CN(C)CCc1cc2occc2c(=O)[nH]1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
To a solution of 2,2,6,6-tetramethylpiperidine (5.1 ml, 30.4 mmole) in dry tetrahydrofuran (60 ml), cooled at -78° C. (dryice/acetone) under an argon atmosphere, was added dropwise n-butyllithium (17.3 ml, 27.6 mmole). After the addition the reaction was warmed to -10° C. (ice/acetone). To this solution was added N,N-diethyl-2-methylfuran-3-carboxamide (5.0 g, 27.6 mmole) in tetrahydrofuran (15 ml). After stirring this mixture for 1.0 hour, 3-(dimethylamino)propionitrile (3.27 ml, 29.0 mmole) was added dropwise. The reaction was allowed to warm overnight. The reaction was poured into ice/water and acidified to a pH 3.25 with hydrochloric acid. The mixture was then extracted with diethyl ether (3×150 ml). The pH of the aqueous layer was adjusted to 13.0 using sodium hydroxide solution (40%) and this solution was extracted exhaustively using methylene chloride (10×150 ml). The combined extracts were washed with water (2×50 ml), brine (2×100 ml) and dried (MgSO4). After solvent evaporation 8.25 g of an oil was obtained. This was purified by flash chromatography using 15% methanol/chloroform as the eluting solvent to give analytically pure product (4.65 g, 82% yield), mp: 97.5°-98.0° C. Some starting amide (1.05 g) was recovered from the initial diethyl ether extracts.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([N+:10]([O-])=O)[S:7][CH:6]=1)=[O:4]>C(O)(=O)C.[Fe]>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([NH2:10])[S:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1csc([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Product: COC(=O)c1csc(N)c1
Yield: 23.8 %

Procedure:
To a solution of 5-nitro-thiophene-3-carboxylic acid methyl ester (0.5 g, 2.67 mmol) in aqueous acetic acid (5 ml) was added iron powder (1.04 g, 18.6 mmol) and the reaction mixture was heated to reflux for 3 hr. The reaction mixture was filtered and triethylamine was added to the filtrate. The compound was extracted with ethyl acetate and the organic layer was washed with water, concentrated and dried to yield crude compound. The compound was purified by silica gel column chromatography, using ethyl acetate/hexane as eluent, to yield 5-amino-thiophene-3-carboxylic acid methyl ester (0.1 g, 24%).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[C:10]([C:12]([OH:14])=O)[C:9]([CH3:15])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:25][CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[C:21]([CH:24]=1)[C:22]#[N:23].C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>O.CN(C)C=O>[C:22]([C:21]1[CH:24]=[C:17]([NH:16][C:12]([C:10]2[C:9]([CH3:15])=[N:8][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:11]=2)=[O:14])[CH:18]=[CH:19][C:20]=1[O:25][CH2:26][C:27]([CH3:29])([CH3:28])[CH3:30])#[N:23]
Reactant: Cc1nn(-c2ccccc2)cc1C(=O)O
Reactant: CC(C)(C)COc1ccc(N)cc1C#N
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1nn(-c2ccccc2)cc1C(=O)Nc1ccc(OCC(C)(C)C)c(C#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.4 %

Procedure:
1-Phenyl-3-methylpyrazole-4-carboxylic acid (2.2 g), 5-amino-2-neopentyloxybenzonitrile (2.2 g), triethylamine (3.3 g) and diethyl cyanophosphate (2.7 g) were added to dimethylformamide (20 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. n-Hexane was added to the residue to allow crystallization. The crystals were recrystallized from hydrous methanol to give the title compound (2.4 g), melting point: 155–156° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[CH2:23][CH2:24][S:25][CH3:26]>CO>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:23][CH2:24][S:25][CH3:26])[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CSCCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CSCCN1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
Piperidin-4-yl-carbamic acid tert-butyl ester (0.70 g, 3.0 mmol), triethylamine (1.46 mL, 10 mmol) and 2-chlorethyl-methylsulfide (0.39 g, 3.0 mmol) were dissolved in methanol (10 mL) and stirred for 16 h at 50° C. Then the solvent was removed and the residue subjected to column chromatography (silica gel, heptane:ethyl acetate gradient=1:1→0:1). [1-(2-Methylsulfanyl-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester was obtained as a light yellow solid (0.46 g, 48%); MS: m/e=275.5 (M+H+).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:15][C:16]1[N:21]=[C:20](S(C)(=O)=O)[CH:19]=[CH:18][N:17]=1>O1CCCC1>[Cl:15][C:16]1[N:21]=[C:20]([O:3][CH2:2][CH2:1][OH:4])[CH:19]=[CH:18][N:17]=1
Reactant: OCCO
Reactant: CS(=O)(=O)c1ccnc(Cl)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCOc1ccnc(Cl)n1
Reaction time: 0.25 h
Yield: 61.1 %

Procedure:
To a suspension of ethylene glycol (865 μL, 15.5 mmol) in tetrahydrofuran (19 mL) was added sodium bis(trimethylsilyl)amide (2.0 M in tetrahydrofuran, 4.66 mL, 4.7 mmol) at room temperature. The mixture was stirred for 15 minutes, then 2-chloro-4-(methylsulfonyl)pyrimidine (747 mg, 3.88 mmol) was added. The reaction mixture was stirred for 1 h at room temperature, concentrated, then purified by column chromatography on silica gel (Biotage 50 G, eluting with 0:100 to 100:0 ethyl acetate:hexanes) to give 2-[(2-chloropyrimidin-4-yl)oxy]ethanol (416 mg, 2.37 mmol, 61% yield) as a white solid. MS ESI: [M+H]+ m/z 175.0.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:4]#[N:5].[C:12]([N:29]=[C:30]=[S:31])([O:14][CH2:15][CH:16]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13].C(N(C(C)C)C(C)C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[NH2:5][C:4]1[S:31][C:30]([NH:29][C:12]([O:14][CH2:15][CH:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]3[C:28]2=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:13])=[N:2][C:3]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Reactant: N#CC(N)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Nc1sc(NC(=O)OCC2c3ccccc3-c3ccccc32)nc1-c1ccccc1
Reaction time: 3 h
Yield: 48 %

Procedure:
A suspension of α-aminophenylacetonitrile hydrochloride (3.19 g, 18.9 mmol) and Fmoc-isothiocyanate (5.31 g, 18.9 mmol) in DCM was treated with ethyldiisopropylamine (3.62 ml, 20.8 mmol) at 0° C. for 1 hr and then at ambient temperature for 3 hr. The mixture was poured into saturated aqueous sodium bicarbonate and extracted three times into ethyl acetate. The combined organic phases were washed with water and brine, and dried over sodium sulfate and concentrated in vacuo. Flash chromatography on silica gel (ethyl acetate/hexanes) yielded 5-amino-2-(Fmoc-amino)-4-phenylthiazole (3.75 g, 48%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([OH:26])=[C:23]([CH:25]=1)[NH2:24]>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([OH:26])=[C:23]([CH:25]=1)[NH:24][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: Nc1cc(Cl)ccc1O
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: Oc1ccc(Cl)cc1Nc1cc(C(F)(F)F)nc(-c2cccnc2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 5-chloro-2-hydroxyaniline (42 mg, 0.290 mmol) similar to Example 117 and isolated as a tan solid (38 mg, 54%). 1H NMR (DMSO-d6): 10.44 (s, 1H), 9.74 (s, 1H), 9.42 (s, 1H), 8.75-8.74 (m, 1H), 8.58-8.54 (m, 1H), 8.29 (s, 1H), 7.48 (s, 1H), 7.61-7.57 (m, 1H), 7.08 (dd, J=2.1, 8.7 Hz, 1H), 6.96 (d, J=9.0 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([C:10](=O)[C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:18])=[C:6]([NH:8]C)[CH3:7])[CH3:2].O.[NH2:22]N>C(O)(=O)C>[CH2:1]([O:3][C:4]([CH:5]1[C:6]([CH3:7])=[N:8][N:22]=[C:10]1[C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:18])=[O:20])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)C(C(=O)c1c(F)cccc1Cl)=C(C)NC
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C1C(C)=NN=C1c1c(F)cccc1Cl

Procedure:
2-(2-Chloro-6-fluoro-benzoyl)-3-methylamino-but-2-enoic acid ethyl ester (500 mg, 1.6 mmol) was taken in acetic acid (10 mL) and was treated with hydrazine hydrate at 150° C. overnight. Acetic acid is removed under reduced pressure and the residue was dissolved in ethyl acetate (20 mL) and washed with water, (2×10 mL), brine (2×10 mL), dried over sodium sulfate, filtered and evaporated to yield the title compound (588 mg, crude).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[CH:48]=[CH:47][N:46]([CH3:49])[C:45](=[O:50])[CH:44]=2)=[CH:38][C:37]=1[CH3:51].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:42][C:41]1[CH:40]=[C:39]([C:43]2[CH:48]=[CH:47][N:46]([CH3:49])[C:45](=[O:50])[CH:44]=2)[CH:38]=[C:37]([CH3:51])[C:36]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: Cc1cc(-c2ccn(C)c(=O)c2)cc(C)c1Br
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6ccn(C)c(=O)c6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydro-benzofuran-3-yl)acetate and 4-(4-bromo-3,5-dimethylphenyl)-1-methylpyridin-2(1H)-one following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 11): tR=1.19 min; Mass spectrum (ESI+): m/z=554 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[C:5]2[CH:18]=[C:19]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:20]=[C:21](N)[C:4]=2[N:3]=1.N([O-])=O.[Na+].[Na+].[Br-:34].C([O-])(O)=O.[Na+]>Br>[Br:34][C:21]1[C:4]2[N:3]=[C:2]([CH3:1])[N:6]([CH2:7][C:8]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH:11]=[CH:10][CH:9]=3)[C:5]=2[CH:18]=[C:19]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:20]=1
Reactant: [Br-]
Reactant: Cc1nc2c(N)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Agent: Br
Agent: O=C([O-])O
Agent: O=N[O-]
Product: Cc1nc2c(Br)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 55 %

Procedure:
To a solution of 2-methyl-6-(4-morpholinyl)-1-(1-naphthalenylmethyl)-1H-benzimidazol-4-amine (prepared following the same procedure as for Example 2, 1.1 g, 3 mmol) in aqueous HBr (50 mL) was added aqueous NaNO2 (214 mg, 3.1 mmol) solution dropwise at 0-5° C. After addition the mixture was stirred at 0° C. for 5 minutes, it was added to another solution of NaBr (927 mg, 9 mmol) in aqueous HBr (50 mL) dropwise at 60° C. The resulting mixture was then heated to 80° C. for 30 minutes and then cooled to room temperature. The solution pH was neutralized with aqueous NaHCO3 (600 mL) and extracted with DCM (500 mL×3). The combined organic layers were concentrated in vacuum and the residue was purified by silica gel chromatography eluted with petroleum ether:EtOAc=1:1 to give the desired product (725 mg, 55%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 2.55 ppm (s, 3H), 3.05 (t, 4H, J=4.8 Hz), 3.79 (t, 4H, J=4.8 Hz), 5.73 (s, 2H), 6.50 (dd, 1H, J=1.2, 7.5 Hz), 6.53 (d, 1H, J=1.8 Hz), 7.15 (d, 1H, J=1.8 Hz), 7.28 (t, 1H, J=7.5 Hz), 7.60-7.67 (m, 2H), 7.81 (d, 1H, J=8.4 Hz), 7.96 (d, 1H, J=7.5 Hz), 8.06 (d, 1H, J=8.4 Hz); LC-MS: m/e=436 [M+1]+.
Reaction SMILES: [H-].[Na+].[NH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([Cl:13])[C:9](Cl)=[N:10][CH:11]=1.[OH:14][CH2:15][CH:16]1[O:20]C(C2C=CC=CC=2)[N:18]([CH:27]([CH3:29])[CH3:28])[CH2:17]1>COCCOC>[NH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([Cl:13])[C:9]([O:14][CH2:15][CH:16]([OH:20])[CH2:17][NH:18][CH:27]([CH3:29])[CH3:28])=[N:10][CH:11]=1
Reactant: CC(C)N1CC(CO)OC1c1ccccc1
Reactant: NCCc1cnc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)NCC(O)COc1ncc(CCN)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
12 g of sodium hydride dispersion (55% strength) are added in portions to 44 g of 5-(2'-aminoethyl)-2,3-dichloro-pyridine and 55 g of 5-hydroxymethyl-3-isopropyl-2-phenyl-oxazolidine, dissolved in 500 ml of 1,2-dimethoxyethane, whilst cooling with ice at 0°-10° C. The reaction mixture is then stirred for 2 hours at room temperature and 16 hours under reflux. Working up gives crude 5-(2'-aminoethyl)-3-chloro-2-[3'-isopropyl-2'-phenyl-oxazolidinyl-(5')]-methoxy-pyridine, which is hydrolysed without further purification, analogously to Example 37), to give 5-(2'-aminoethyl)-3-chloro-2-(3'-isopropylamino-2'-hydroxy-propoxy)-pyridine (boiling point 165°-185° C./0.06 mm Hg).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])=[CH:5][CH:4]=1)=O.Cl.[NH2:20][CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[NH:20]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=1)[CH2:1][C:3]1[CH:18]=[CH:17][C:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(C(=O)OCc2ccccc2)cc1
Reactant: COC(=O)c1ccc(CN)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CNCc2ccc(C(=O)OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 54 %

Procedure:
Benzyl 4-formylbenzoate (618 mg, 2.57 mmol) and methyl 4-(aminomethyl)benzoate hydrochloride (622 mg, 3.09 mmol) were dissolved in 20 mL of toluene and 2.0 mL of methanol, and the solvent was evaporated under reduced pressure. The resulting white solid was dissolved in 15 mL of 2-propanol, sodium triacetoxyborohydride (1.64 g, 7.72 mmol) was added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous sodium hydrogencarbonate solution and saturated sodium chloride solution. The organic layer was dried with anhydrous magnesium sulfate, then the solvent was evaporated under reduced pressure, and the resulting yellow oily substance was purified by silica gel chromatography (n-hexane:ethyl acetate, 90:10→80:20, v/v) to give the title compound (0.54 g; yield, 54%) as a white solid.
Reaction SMILES: Cl.[C:2]1([C:8]23[CH2:13][CH:12]2[CH2:11][NH:10][CH2:9]3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:18]([Cl:22])(=[O:21])[CH2:19][CH3:20]>ClCCl>[ClH:22].[C:8]12([C:2]3[CH:3]=[CH:4][C:5]([C:18](=[O:21])[CH2:19][CH3:20])=[CH:6][CH:7]=3)[CH2:13][CH:12]1[CH2:11][NH:10][CH2:9]2
Reactant: c1ccc(C23CNCC2C3)cc1
Reactant: CCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC(=O)c1ccc(C23CNCC2C3)cc1

Procedure:
A mixture of 5.6 g. of 1-phenyl-3-azabicyclo[3.1.0]hexane hydrochloride, 12.9 g. of aluminum chloride and 6.2 g. of propionyl chloride in 55 ml. of dichloromethane is reacted as described in Example 57, to give 4.5 g. of the desired product, m.p. 191°-193° C.
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]([CH3:22])[C:16]([C:19](Cl)=[O:20])=[CH:17][N:18]=3)[S:13][C:6]=12.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>C(Cl)Cl>[F:1][C:2]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]([CH3:22])[C:16]([C:19]([N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)=[O:20])=[CH:17][N:18]=3)[S:13][C:6]=12
Reactant: C1CCNC1
Reactant: Cn1c(C(=O)Cl)cnc1-c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Solvent: ClCCl
Product: Cn1c(C(=O)N2CCCC2)cnc1-c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A suspension of the acyl chloride 219 (700 mg, 1.617 mmol) and pyrrolidine (0.3 mL, 3.63 mmol) in DCM (50 mL) was stirred at room temperature overnight. The reaction mixture was concentrated. The residue was triturated with ether to give title compound 220 (756 mg, 1.617 mmol, 100% yield) as beige solid. MS: 468.3 (MH+).
Reaction SMILES: [OH:1][C:2]([CH2:5][CH2:6][CH2:7][C@H:8]([C@@H:10]1[C@:28]2([CH3:29])[C@H:13]([C@H:14]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C:17]([CH2:18][C@H:19]([CH2:21][CH2:22]2)[OH:20])=[CH:16][CH2:15]3)[CH2:12][CH2:11]1)[CH3:9])([CH3:4])[CH3:3].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[OH:1][C:2]([CH2:5][CH2:6][CH2:7][C@H:8]([C@@H:10]1[C@:28]2([CH3:29])[C@H:13]([C@H:14]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C:17](=[CH:18][C:19](=[O:20])[CH:21]=[CH:22]2)[CH2:16][CH2:15]3)[CH2:12][CH2:11]1)[CH3:9])([CH3:3])[CH3:4]
Reactant: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C

Procedure:
The 25-hydroxycholesterol was dissolved in dioxane and boiled with 2,3-dichloro-5,6-dicyanobenzo-quinone (DDQ) to obtain 25-hydroxycholesta-1,4-diene-3-one. This latter compound was subjected to dehydrogenation with chloroanil in the presence of the reduced derivative of DDQ-hydroquinone (2HDDQ) to obtain 25-hydroxy-cholesta-1,4,6-triene-3-one. Alternatively, 25-hydroxy-cholesta-1,4,6-trien-3-one can be obtained by DDQ oxidation of 25-hydroxycholesterol (J. J. Partridge et al., Helv. Chim. Acta 57, 764 (1974) which was converted from 6β-methoxy-25-hydroxy-3α,5-cyclo-5α-cholestane.