Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=[S:12])[C:7]2[CH:13]=[CH:14][CH:15]=[N:16][C:6]=2[O:5]1.[CH3:17][NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[CH3:11][N:9]1[C:8](=[S:12])[C:7]2[CH:13]=[CH:14][CH:15]=[N:16][C:6]=2[O:5][CH:4]([CH2:3][CH2:2][N:18]([CH3:17])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:10]1
Reactant: CNc1ccccc1
Reactant: CN1CC(CCCl)Oc2ncccc2C1=S
Solvent: Cc1ccccc1
Product: CN1CC(CCN(C)c2ccccc2)Oc2ncccc2C1=S
Reaction time: 48 h

Procedure:
To a suspension of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-thione in 100 ml of toluene was added 11.49 g (0.11 mole) N-methylaniline and the mixture heated to reflux with stirring for 2 days (after approx. 6 hr, 23.0 g (0.22 mole) additional N-methylaniline was added). Toluene was removed by rotary evaporation (90° C., water aspirator). The N-methylaniline was removed also by rotary evaporation (90° C., vacuum pump). The residue was taken up in 100 ml of chloroform and washed with 3×30 ml dilute aqueous sodium hydroxide. The organic layer was dired over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation (80° C., water aspirator). More N-methylaniline was removed with the vacuum pump at 90° C. for several hours. To the residue was added 150 ml of ethyl acetate at which point some product crystallized out. However, since much remained in solution, preparative HPLC on a silica gel column eluting with 60% hexane/40% ethyl acetate was effected. After concentrating the flasks containing the product, crystallization was effected induced by seeding. The chromatographed product was recrystallized from ethyl acetate/isopropyl alcohol and amounted to 1.1 g m.p. 164°-5° C. Approximately 2 g additional was collected by recrystallization of crude product, m.p. 163°-4° C. The combined yield was 3.1 g (26%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:12][C:13]([F:16])([F:15])[F:14])[CH:11]=1)[C:6](Cl)=[O:7])#[N:2].[BH4-].[Na+].CO.Cl>C1COCC1>[OH:7][CH2:6][C:5]1[CH:4]=[C:3]([CH:11]=[C:10]([O:12][C:13]([F:14])([F:15])[F:16])[CH:9]=1)[C:1]#[N:2]
Reactant: N#Cc1cc(OC(F)(F)F)cc(C(=O)Cl)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1cc(CO)cc(OC(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 59.9 %

Procedure:
3-Cyano-5-(trifluoromethoxy)benzoyl chloride (844 mg, 3.38 mmol) was dissolved in THF (10 mL) and cooled to 0° C. Sodium borohydride (320 mg, 8.45 mmol) was added, followed by methanol (2 mL) and the reaction was stirred for 20 min at 0° C. before it was allowed to warm to room temperature. After 2 h, the reaction mixture was acidified to pH 3 with 1.0 M HCl. The aqueous mixture was extracted with ethyl acetate and the combined extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (440 mg). LCMS m/z=218.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:18]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=2)[NH2:29])[CH2:22][CH2:21]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:19][N:20]1[CH2:21][CH2:22][N:23]([C:26]2[CH:27]=[C:28]([NH:29][C:2]3[N:18]=[C:5]4[C:6]([NH:10][CH2:11][C:12]5[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=5)=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)[CH:30]=[CH:31][CH:32]=2)[CH2:24][CH2:25]1
Reactant: Clc1nc2c(NCc3cccnc3)cccn2n1
Reactant: CN1CCN(c2cccc(N)c2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2cccc(Nc3nc4c(NCc5cccnc5)cccn4n3)c2)CC1

Procedure:
N(2)-[3-(4-Methyl-piperazin-1-yl)-phenyl]-N(8)-pyridin-3-ylmethyl-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-pyridin-3-ylmethyl-amine (75.0 mg, 0.289 mmol) and 3-(4-methylpiperazin-1-yl)aniline (61.0 mg, 0.319 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (33.0 mg, 0.0604 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a pale yellow foam (0.017 g, 14%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.66 (s, 1H), 8.56 (d, J=4.6 Hz, 1H), 7.85 (d, J=6.6 Hz, 1H), 7.72 (d, J=7.9 Hz, 1H), 7.31-7.25 (m, 1H), 7.24-7.18 (m, 2H), 7.06 (d, J=7.9 Hz, 1H), 6.75 (s, 1H), 6.68 (t, J=7.3 Hz, 1H), 6.57 (d, J=8.3 Hz, 1H), 6.32 (d, J=7.8 Hz, 1H), 5.18 (t, J=5.5 Hz, 1H), 4.51 (d, J=5.7, 2H), 3.28-3.23 (m, 4H), 2.61-2.56 (m, 4H), 2.36 (s, 3H). MS=415 (MH)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:14][F:15])([CH2:12][F:13])[CH:9]=[C:8](OS(C(F)(F)F)(=O)=O)[C:7]=2[CH:24]=1)#[N:2].C[Sn](C)(C)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Li+]>CCOCC.O1CCCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:12][F:13])([CH2:14][F:15])[CH:9]=[C:8]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[C:7]=2[CH:24]=1)#[N:2]
Reactant: C[Sn](C)(C)c1ccccn1
Reactant: N#Cc1ccc2c(c1)C(OS(=O)(=O)C(F)(F)F)=CC(CF)(CF)O2
Agent: [Cl-]
Agent: [Li+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: N#Cc1ccc2c(c1)C(c1ccccn1)=CC(CF)(CF)O2
Yield: 82.5 %

Procedure:
A mixture of 120 mg of 6-cyano-4-trifluoromethanesulfonyloxy-2,2-bisfluoromethyl-2H-1-benzopyran, 87 mg of 2-trimethylstannylpyridine, 25.4 mg of tris-dibenzylidene acetone chloroform dipalladium (O), 12.8 mg of triphenylphosphine, 110 mg of lithium chloride and 6 ml of dry tetrahydrofuran was refluxed for 6.5 hours. After cooling, ether was added and the mixture was filtered using Celite. After the organic layer of the mother liquor was washed with water and dried, the solvent was distilled off. The resultant residue was purified using silica gel column chromatography (developing solution, CH2Cl2) to obtain 80 mg of oily 6-cyano-2,2-bisfluoromethyl-4-(2-pyridyl)-2H-1-benzopyran represented by the following formula.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.ON1C2C=CC=CC=2N=N1.[CH2:28]([N:35]1[CH2:39][C@@H:38]2[C@@H:40]([NH2:43])[CH2:41][CH2:42][C@@H:37]2[CH2:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N=C=NCCCN(C)C)C>ClCCl>[CH2:28]([N:35]1[CH2:39][C@@H:38]2[C@@H:40]([NH:43][C:14](=[O:16])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH:11]([CH3:12])[CH3:13])[CH2:41][CH2:42][C@@H:37]2[CH2:36]1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
N-(tert-Butoxycarbonyl)-L-leucine (0.374 g, 1.617 mmol), 1-hydroxybenzotriazole hydrate (0.248 g, 1.617 mmol), and (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine from Step A of Example 33 (0.318 g, 1.470 mmol) were combined in dichloromethane (3.0 mL). After 20 minutes, N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.286 mL, 1.617 mmol) was added, and the reaction was stirred at room temperature overnight. The reaction was quenched with water and extracted with of dichloromethane (2×2 mL), and the extracts were applied directly to a 25 g silica gel cartridge and purified with a gradient of 5-40% acetone/hexanes over 30 minutes to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.61-8.64 (m, 1H), 7.96-7.99 (m, 1H), 7.42-7.44 (m, 2H), 7.36 (t, J=7.4 Hz, 2H), 7.28 (d, J=7.3 Hz, 1H), 4.65-4.73 (m, 1H), 4.37-4.45 (m, 1H), 3.59 (d, J=13.1 Hz, 1H), 3.43 (d, J=13.1 Hz, 1H), 2.81-2.84 (m, 1H), 2.55-2.58 (m, 1H), 2.44-2.54 (m, 2H), 2.24-2.36 (m, 2H), 2.02-2.13 (m, 1H), 1.78-1.94 (m, 4H), 1.53-1.66 (m, 1H), 1.50 (s, 9H), 1.26-1.43 (m, 1H), 0.87 (d, J=5.5 Hz, 3H), 0.83-0.85 (m, 3H); MS (ES+) m/z 430 (M+H)+.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[C:5](#[N:8])[CH:6]=[CH2:7].Cl>CO>[CH2:1]([O:4][CH2:7][CH2:6][C:5]#[N:8])[CH2:2][O:3][CH2:7][CH2:6][C:5]#[N:8]
Reactant: OCCO
Reactant: C=CC#N
Agent: Cl
Solvent: CO
Product: N#CCCOCCOCCC#N
Temperature: 25 °C
Reaction time: 60 h
Yield: 39.9 %

Procedure:
Small scale: Ethylene glycol (1 g, 16.1 mmol) was mixed with Triton B (40% in MeOH, 0.22 g, 0.53 mmol) and cooled in an ice-bath while acrylonitrile (1.71 g, 32.2 mmol) was added. The mixture was stirred at room temperature for 60 hours after which it was neutralized with 0.1M HCl (0.6 cm3) and extracted with CH2Cl2 (80 cm3). The extracts were concentrated under reduced pressure and the residue was Kugelrohr-distilled to give 3,3′-(ethane-1,2-diylbis(oxy))dipropanenitrile (1.08 g, 39.9%) as a light coloured oil, by 150-170° C./20 Torr.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:10])[CH:9]=1)[CH:5]=O.[C@@H:11]1([NH2:21])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:10])[CH:9]=1)[CH2:5][NH:21][C@@H:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: Cc1cc(C)cc(C=O)c1
Reactant: N[C@H]1CCCc2ccccc21
Product: Cc1cc(C)cc(CN[C@H]2CCCc3ccccc32)c1

Procedure:
3,5-Dimethylbenzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [C:1]([C:5]1[C:13]2[S:12][C:11]([NH2:14])=[N:10][C:9]=2[C:8]([O:15][CH3:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>>[C:1]([C:5]1[C:13]2[S:12][C:11]([NH:14][C:22](=[O:23])[C:21]3[CH:25]=[CH:26][C:18]([F:17])=[CH:19][CH:20]=3)=[N:10][C:9]=2[C:8]([O:15][CH3:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1ccc(C(C)(C)C)c2sc(N)nc12
Product: COc1ccc(C(C)(C)C)c2sc(NC(=O)c3ccc(F)cc3)nc12

Procedure:
Using 7-tert-butyl-4-methoxy-benzothiazol-2-ylamine and 4-fluoro-benzoyl chloride the title compound was obtained as a white solid (75% yield), MS: m/e=258.1 (M+H+).
Reaction SMILES: [NH2:1][C@H:2]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:3]([NH:5][CH:6]1[CH2:15][C:14]2[C:9](=[C:10]([N:16]3[CH2:20][CH2:19][CH2:18][C:17]3=[O:21])[CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:22][C:23]2[CH:27]=[CH:26][S:25][CH:24]=2)[C:7]1=[O:28])=[O:4].[C:33]([O:37][C:38]([NH:40][C@@:41]([CH3:47])([CH2:45][CH3:46])[C:42](O)=[O:43])=[O:39])([CH3:36])([CH3:35])[CH3:34]>>[CH3:47][C@:41]([NH:40][C:38](=[O:39])[O:37][C:33]([CH3:36])([CH3:35])[CH3:34])([CH2:45][CH3:46])[C:42]([NH:1][C@H:2]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:3](=[O:4])[NH:5][CH:6]1[CH2:15][C:14]2[C:9](=[C:10]([N:16]3[CH2:20][CH2:19][CH2:18][C:17]3=[O:21])[CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:22][C:23]2[CH:27]=[CH:26][S:25][CH:24]=2)[C:7]1=[O:28])=[O:43]
Reactant: CC[C@](C)(NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)C[C@@H](N)C(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Product: CC[C@](C)(NC(=O)OC(C)(C)C)C(=O)N[C@H](CC(C)C)C(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Yield: 102.1 %

Procedure:
The procedure of Example 14(a) was repeated, except that (2R)-2-amino-4-methyl-N-[2-oxo-8-(2-oxopyrrolidin-1-yl)-1-(thiophen-3-ylmethyl)-1,2,3,4-tetrahydroquinolin-3-yl]pentanamide (600 mg) and (S)-2-(tert-butoxycarbonylamino)-2-methylbutanoic acid (320 mg) were used, whereby tert-butyl (2S)-2-methyl-1-[(2R)-4-methyl-1-oxo-1-[2-oxo-8-(2-oxopyrrolidin-1-yl)-1-(thiophen-3-ylmethyl)-1,2,3,4-tetrahydroquinolin-3-ylamino]pentan-2-ylamino]-1-oxobutan-2-ylcarbamate (881 mg) was yielded. Subsequently, the procedure of Example 25(a) was repeated, except that the compound prepared as described above was used, whereby the title compound (241 mg) was yielded.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([O:18][CH3:19])[C:12]=2[C:11]([C:20]2[CH:25]=[CH:24][C:23]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:22][CH:21]=2)=[N:10]1.C(N(CC)CC)C.[C:39](Cl)(=[O:41])[CH3:40].C(=O)([O-])O.[Na+]>C1COCC1>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([O:18][CH3:19])[C:12]=2[C:11]([C:20]2[CH:25]=[CH:24][C:23]([CH:26]3[CH2:31][CH2:30][N:29]([C:39](=[O:41])[CH3:40])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)=[N:10]1
Reactant: COc1nccc2c1c(-c1ccc(C3CCNCC3)cc1)nn2-c1c(F)cccc1F
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1nccc2c1c(-c1ccc(C3CCN(C(C)=O)CC3)cc1)nn2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(2,6-difluorophenyl)-4-methoxy-3-(4-(piperidin-4-yl)phenyl)-1H-pyrazolo[4,3-c]pyridine (120 mg), triethylamine (0.080 mL) and N,N-dimethylaminopyridine (1.7 mg) in THF (4 mL) was added acetyl chloride (0.080 mL). The reaction mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution at 0° C., and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (117 mg).
Reaction SMILES: [C:1]([N:8]([CH2:12][CH2:13][OH:14])[CH2:9][CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.Cl[C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[C:1]([N:8]1[CH2:9][CH2:10][O:11][C:23](=[O:25])[O:14][CH2:13][CH2:12]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N(CCO)CCO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCOC(=O)OCC1

Procedure:
The procedure of Example 1 was followed using N-boc diethanolamine (3 g, 14.6 mmol), triethylamine (4.1 mL, 29.2 mmol), dry dichloromethane (100 mL) and triphosgene (1.4 g, 4.9 mmol). The filtrate was concentrated yielding only oligomeric compounds.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[C:5]([C:15]#[N:16])=[C:4](S(C)=O)[N:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][NH2:27]>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[C:5]([C:15]#[N:16])=[C:4]([NH:27][CH2:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccccc2F)c1C#N
Reactant: NCc1ccccn1
Solvent: COCCOC
Product: N#Cc1c(NCc2ccccn2)nc(N)nc1-c1ccccc1F

Procedure:
From 2-amino-4-(2-fluoro-phenyl)-6-methanesulfinyl-pyrimidine-5-carbonitrile and 2-picolylamine in DME. ES-MS m/e (%): 321 (M+H+, 100).
Reaction SMILES: [H-].[K+].[CH3:3][C@H:4]1[C@H:9]2[C@H:10]3[C@H:20]([CH2:21][CH2:22][C@:7]2([CH3:8])[C@@H:6]([OH:24])[CH2:5]1)[C@:18]1([CH3:19])[C:13]([NH:14][C:15](=[O:23])[CH2:16][CH2:17]1)=[CH:12][CH2:11]3.[CH2:25](Br)[CH:26]=[CH2:27].Cl>>[CH3:3][C@H:4]1[C@H:9]2[C@H:10]3[C@H:20]([CH2:21][CH2:22][C@:7]2([CH3:8])[CH:6]([O:24][C:26](=[CH2:25])[CH3:27])[CH2:5]1)[C@:18]1([CH3:19])[C:13]([NH:14][C:15](=[O:23])[CH2:16][CH2:17]1)=[CH:12][CH2:11]3
Reactant: C[C@@H]1C[C@H](O)[C@@]2(C)CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@H]12
Reactant: C=CCBr
Agent: Cl
Agent: [H-]
Agent: [K+]
Product: C=C(C)OC1C[C@@H](C)[C@H]2[C@@H]3CC=C4NC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 1 h

Procedure:
Potassium hydride (40% oil dispersion, 114 mg, 2 mmol) was added to a 5 mL round bottomed flask fitted with a stirrer bar and a rubber septum. The potassium hydride dispersion was washed with dry hexane (2×5 ml) to remove the mineral oil and 3 mL of dry dimethylformamide was added to the flask. Azasteroid (11) (158 mg, 0.5 mmol) was added to the dispersion and the solution stirred at 0° under nitrogen for 1 h. Then allyl bromide (183 mg, 1.5 mmol) was syringed into the solution and the mixture stirred for 2 h at room temperature. The entire solution was poured into 5 mL of 1N HCl and the mixture extracted with 5×2 mL of dichloromethane. The pooled organic layer was washed with 3×5 mL of saturated brine. The product was flash chromatographed with 3/1 dichloromethane/ethyl acetate. Recovered product (78 mg, 0.2 mmol, 44%) δH (CDCl3) 0.89 (s, 3H), 0.99 (d, J=7 Hz,), 1.06 (s, 3H), 3.60 (m, J=7 Hz, 1H), 3.95 (dd, J=12 Hz, J=5 Hz), 4.64 (dd, J=12 Hz, J=5 Hz), 5.1 (m, 2H), 5.79 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16]O)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[OH-].[K+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[CH2:8][NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:16][C:4]=2[CH:3]=1
Reactant: OCc1ccccc1NCc1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: Clc1ccc2c(c1)Cc1ccccc1NC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
2-[[(4-chlorophenyl)methyl]amino]benzenemethanol (6.7 g) (prepared as described in J. Chem. Soc. Chem. Commun., 1989 (1), 44-5) was cooled under a N2 atmosphere to -40° C. Sulfuric acid (35 ml) was added dropwise keeping the temperature at about -10° C. and the mixture was stirred at room temperature for 1 hour. The mixture was poured into ice water and basified carefully with KOH. The mixture was filtered off and the precipitate was washed with water and CH2Cl2. The filtrate and the washings were extracted, dried with Na2SO4, filtered off and evaporated, yielding 5.8 g (95%) of 9-chloro-6,11-dihydro-5H-dibenz-[b,e]azepine (interm. 27).
Reaction SMILES: C(=O)([O-])O.[Na+].[N+:6]([C:9]1[CH:10]=[C:11]([OH:16])[C:12](=[CH:14][CH:15]=1)[OH:13])([O-:8])=[O:7].[CH2:17]([CH:19]1[O:21][CH2:20]1)Cl>CN(C=O)C.O>[N+:6]([C:9]1[CH:15]=[CH:14][C:12]2[O:13][CH2:17][CH:19]([CH2:20][OH:21])[O:16][C:11]=2[CH:10]=1)([O-:8])=[O:7]
Reactant: ClCC1CO1
Reactant: O=[N+]([O-])c1ccc(O)c(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(c1)OC(CO)CO2
Yield: 39.9 %

Procedure:
3.0 g of sodium hydrogen carbonate was suspended in 90 mL DMF. At 0° C. a solution of 5.15 g of 4-nitrocatechol was added dropwise over 15 min. Subsequently, 3.9 g of epichlorohydrin in 10 mL DMF were added over 15 min. Stirring was continued at room temperature, then at 80° C. overnight. The mixture was diluted with water and extracted three times with ethyl acetate, dried (anhyd. Na2SO4), filtered and concentrated under vacuum to give a yellow oil. The oil was purified by column chromatography on silica gel using EtOAc-hexanes (0-100% gradient) to give the product (2.8 g) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:14]([OH:15])=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([CH2:6][CH2:7][C:8](O)=[O:9])=O.O.[NH2:17][NH2:18]>>[Cl:1][C:2]1[C:14]([OH:15])=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]1[CH2:6][CH2:7][C:8](=[O:9])[NH:17][N:18]=1
Reactant: NN
Reactant: O=C(O)CCC(=O)c1cccc(O)c1Cl
Solvent: O
Product: O=C1CCC(c2cccc(O)c2Cl)=NN1

Procedure:
3-(2-chloro-3-hydroxybenzoyl)propionic acid was cyclised with hydrazine hydrate in a similar manner to that described in Example 3(i) to give 6-(2-chloro-3-hydroxyphenyl)-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][OH:4].S(=O)(=O)(O)O.[F:10][C:11]1[CH:25]=[CH:24][C:14]([CH:15](O)[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[F:10][C:11]1[CH:12]=[CH:13][C:14]([CH:15]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[O:4][CH2:3][CH2:2][Cl:1])=[CH:24][CH:25]=1
Reactant: OC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: OCCCl
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: Fc1ccc(C(OCCCl)c2ccc(F)cc2)cc1
Yield: 59.5 %

Procedure:
2-Chloroethanol (2) (4.1 g, 51 mmol) was added to a 500 ml three neck round bottom flask containing 250 ml of toluene and sulfuric acid(1 ml, 18 mmol). A solution of 4,4'-difluorobenzhydrol (1) (9.16 g, 41.6 mmol) in 50 ml of toluene was then added dropwise over 30 minutes. Once addition was complete the resulting mixture was heated to reflux for 3 hours. At the end of this time the mixture was washed with 10% sodium carbonate (150 ml), water (150 ml), and dried over anhydrous magnesium sulfate. The mixture was then filtered and the solvents were evaporated under reduced pressure to afford a clear yellow liquid. The material was distilled on a Kugelrohr distillation apparatus at 140° C., 0.5 mm Hg to afford the desired product (3) (7.0 g, 60%) as a clear and colorless liquid which crystallized slowly upon standing.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][O:27]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[O:27]1[CH2:28][CH2:29][CH2:30][CH2:31][CH:26]1[O:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][O:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: BrCCCCCCOC1CCCCO1
Reactant: COC(=O)c1cccc(-c2cccc(O)c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2cccc(OCCCCCCOC3CCCCO3)c2)n1
Temperature: 70 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
To a solution of methyl 6-(3′-hydroxyphenyl)-pyridine-2-carboxylate (7) (250 mg, 1.1 mmol, 1.0 eq.) and 2-(6′-bromohexyloxy)tetrahydropyran (420 mg, 0.36 mL, 1.6 mmol, 1.5 eq.) in DMF (3 mL) was added K2CO3 (460 mg, 3.3 mmol, 3.0 eq.). The mixture was stirred vigorously overnight at 70° C. and then concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with NaH2PO4 buffer (pH 5, 1M) and brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography on silica using ethyl acetate:hexanes to provide 300 mg (65%) of 12. TLC Rf=0.5 (ethyl acetate:hexanes 1:1), MS m/z 330 (fragment after elimination of the THP group) [M+H]+
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6]([NH2:15])=[CH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:2][CH3:3].[OH:16][CH:17]=[C:18]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[C:19](OCC)=O>C1C=CC=CC=1>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([C:18]2[C:17](=[O:16])[C:7]3[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=4[CH:14]=[C:5]([O:4][CH2:1][CH2:2][CH3:3])[C:6]=3[NH:15][CH:19]=2)=[CH:25][CH:26]=1
Reactant: CCOC(=O)C(=CO)c1ccc(OC)cc1
Reactant: CCCOc1cc2ccccc2cc1N
Solvent: c1ccccc1
Product: CCCOc1cc2ccccc2c2c(=O)c(-c3ccc(OC)cc3)c[nH]c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 42.4 %

Procedure:
To a benzene solution (50 ml) containing 3-propoxynaphthalen-2-ylamine (2.05 g, 10.18 mmol) and ethyl α-(hydroxymethylene)-4-methoxyphenylacetate (2.29 g, 10.3 mmol) was added 350 mg of Amberlyst 15 (Sigma-Aldrich). The resulting mixture was heated under reflux for 21 hours using a Dean-Stark trap. The reaction mixture was then cooled to room temperature, filtered to remove resin, and then the filtrate was concentrated under reduced pressure. Diphenyl ether (2.2 ml) was added to the residue, and the mixture was then heated with a mantle heater and stirred for 1.5 hours under reflux. The resulting reaction mixture was cooled to room temperature, and then directly purified using silica gel column chromatography (dichloromethane:methanol=100:1→60:1). The purified product was concentrated under reduced pressure to recrystallize the residue from ethyl acetate-n-hexane, giving a pale yellow powder of 2-(4-methoxyphenyl)-5-propoxy-4H-benzo[f]quinolin-1-one (1.55 g, yield: 42%).
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1)[OH:4])#[CH:2].[CH2:19]([NH:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=1)[CH3:20]>>[CH2:19]([NH:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([C:2]#[C:1][CH:3]([OH:4])[C:5]2[CH:14]=[CH:13][C:12]3[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=3[CH:6]=2)=[CH:25][CH:24]=1)[CH3:20]
Reactant: C#CC(O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CCNC(=O)c1ccc(I)cc1
Product: CCNC(=O)c1ccc(C#CC(O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
Following the basic procedure of Example 11(d), by reacting 1.21 g (5 mmol) of α-ethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanol with 1.37 g (5.1 mmol) of N-ethyl-4-iodobenzamide, 596 mg (31%) of the expected amide, with a melting point of 153°-154° C., were obtained.