Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=O)[CH3:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:21]>CN(C)C=O>[CH:22]1([C:20]([C:19]2[O:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=3[C:9]=2[CH3:10])=[O:21])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CC(=O)c1c(O)cccc1F
Reactant: O=C(CBr)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)C2CCCCC2)oc2cccc(F)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.6 %

Procedure:
To a solution (50 mL) of 1-(2-fluoro-6-hydroxyphenyl)ethanone (2.5 g) in N,N-dimethylformamide were added potassium carbonate (6.7 g) and 2-bromo-1-cyclohexylethanone (4.0 g) synthesized in Example A51(1) at room temperature, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was allowed to cool to room temperature and filtered through celite. Water was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in N,N-dimethylformamide (50 mL) again, 1,8-diazabicyclo[5.4.0]undec-7-ene (2.6 mL) was added to the solution, and the mixture was stirred at 110° C. for 1 hr with heating. After cooling to room temperature, the reaction mixture was quenched with 1N hydrochloric acid, and the reaction mixture was extracted with diethyl ether. The extract was concentrated under reduced pressure, and the precipitated compound was recrystallized from diisopropyl ether-hexane to give the title object compound (2.6 g, 62%) as a colorless solid.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[N:11]1[CH:15]=[CH:14][N:13]([CH2:16][C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=2)[C:12]1=[S:27].[OH-].[Na+]>>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[N:11]1[CH:15]=[CH:14][N:13]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:25][CH:26]=2)[C:12]1=[S:27]
Reactant: COC(=O)c1ccc(Cn2ccn(C3CCc4ccccc4C3)c2=S)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc(Cn2ccn(C3CCc4ccccc4C3)c2=S)cc1

Procedure:
substituting methyl 4-[3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol -1-ylmethyl]benzoate and sodium hydroxide gave 4-[3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-1-ylmethyl]benzoic acid, m.p. 211°-212° C.;
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:5][C@H:4]1[C:6]#[C:7][C:8]#[C:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([CH3:27])([S:23]([CH3:26])(=[O:25])=[O:24])[C:19](OC)=[O:20])=[CH:12][CH:11]=1.[NH2:28][OH:29].CC(O)=O>C(O)(C)C>[OH:29][NH:28][C:19](=[O:20])[C:18]([CH3:27])([S:23]([CH3:26])(=[O:25])=[O:24])[CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]#[C:8][C:7]#[C:6][C@@H:4]2[CH2:5][C@H:3]2[CH2:2][OH:1])=[CH:11][CH:12]=1
Reactant: NO
Reactant: COC(=O)C(C)(CCc1ccc(C#CC#C[C@@H]2C[C@H]2CO)cc1)S(C)(=O)=O
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC(CCc1ccc(C#CC#C[C@@H]2C[C@H]2CO)cc1)(C(=O)NO)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.6 %

Procedure:
To a stirring solution of methyl 4-(4-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)phenyl)-2-methyl-2-(methylsulfonyl)butanoate (9.7) in isopropanol (1.3 mL) at 0° C. was added hydroxylamine (946 μL, 15.44 mmol, 50% in water) and the reaction was stirred at room temperature overnight. The reaction mixture was neutralized with AcOH (884 μL, 15.44 mmol) and concentrated under reduced pressure to give a crude, which was purified by RP-HPLC (0-30% ACN in water) to yield N-hydroxy-4-(4-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diynyl)phenyl)-2-methyl-2-(methylsulfonyl)butanamide (9, 22.6 mg, 22.6% yield). MS: m/z calcd for C20H23NO5S 389.13. found [M+H]+ 390.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([Cl:15])=[CH:9][C:8]=1[NH2:16])[CH3:2].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:17])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([Cl:15])=[CH:9][C:8]=1[NH:16][S:19]([CH3:18])(=[O:21])=[O:20])[CH3:2]
Reactant: CCOC(=O)/C=C/c1cc(OC)c(Cl)cc1N
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)/C=C/c1cc(OC)c(Cl)cc1NS(C)(=O)=O

Procedure:
(E)-3-(2-Amino-4-chloro-5-methoxyphenyl)-acrylic acid ethyl ester (250 mg; 0.98 mmol) in pyridine (2 ml) was treated with methanesulfonyl chloride (0.15 ml; 2 mmol) for 15 min. at room temperature. The reaction mixture was poured on water and extracted with TBME three times. The combined organic phases were evaporated to dryness and purified via chromatography (SiO2; acetone/hexanes 2/8) to yield the title compound as slightly yellow crystals (216 mg; 66%)
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][C@H:10]1O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:43])=O>C1C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][CH:10]1[Cl:43])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O[C@@H]1O[C@@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: c1ccccc1
Product: ClC1O[C@@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1

Procedure:
Method B--2,3,4,6-Tetra-O-benzyl-α-L-glucopyranose (400 mg.) was dissolved in dry benzene (25 ml.) in a round-bottomed flask equipped with a calcium chloride drying tube and an inlet for nitrogen. To the magnetically stirred solution was added zinc chloride (1.1 g.) followed by thionyl chloride (0.55 ml.) care being taken to exclude atmospheric moisture. The reaction, which was monitored by t.l.c. (Solvent D), was complete after approximately 45 minutes. The solution was then filtered through a 3 cm. thickness of silica gel on a sintered glass funnel and the residue washed with dry benzene. The filtrate was then concentrated under reduced pressure to a colourless syrup which was co-evaporated with benzene (40 ml.) at 30° bath to remove traces of thionyl chloride. The colourless syrup (0.31 g.) was homogeneous on t.l.c. (benzene/diethyl ether 10:1 v/v) and had [α]D -62.5° (c 2.1, chloroform) and the following p.m.r. data: τ2.7 (20 aromatic protons), τ3.9 (1 proton, H-1, doublet with J1,2 ≃3 Hz.), τ5.1-6.6 (15 protons, ring protons and benzylic --CH2 --). The corresponding D-isomer has [α]D +109° (c 1, benzene), +62° (c 1, chloroform) as found by Grob et al [Carbohyd. Res. 10 595 (1964)] and [α]D +95° (c 4.0, benzene), +66° (c 6.3, benzene) as found by Austin et al [J. Chem. Soc., 2128 (1964)].
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:38]1([CH2:44][CH2:45][CH2:46][C:47]#[N:48])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:41]3[CH2:42][CH2:43][N:38]([CH2:44][CH2:45][CH2:46][C:47]#[N:48])[CH2:39][CH2:40]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: N#CCCCN1CCNCC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCC#N)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 4-piperazin-1-yl-butyronitrile (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C37H45Cl2N6O2 [(M+H)+] 675.2976, observed 675.2972.
Reaction SMILES: N[C:2]1[S:3][C:4]2[C:9](=[O:10])[N:8]=[C:7]([S:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:14]=3)[NH:6][C:5]=2[N:26]=1.N(OC(C)(C)C)=O>O1CCCC1>[O:19]([C:15]1[CH:14]=[C:13]([CH2:12][S:11][C:7]2[NH:6][C:5]3[N:26]=[CH:2][S:3][C:4]=3[C:9](=[O:10])[N:8]=2)[CH:18]=[CH:17][CH:16]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1nc2[nH]c(SCc3cccc(Oc4ccccc4)c3)nc(=O)c2s1
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Product: O=c1nc(SCc2cccc(Oc3ccccc3)c2)[nH]c2ncsc12
Reaction time: 3.5 h

Procedure:
2-Amino-5-[[(3-phenoxyphenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7(4H)-one (0.3 g) (product of Example 5) was added over 90 minutes to a solution of t-butyl nitrite (0.17 mL) in tetrahydrofuran (3 mL) at 65° C. After a further 3.5 hours at 65° C., the solvent was evaporated and the residue chromatographed on silica eluting with methanol/dichloromethane mixtures to give the title compound. Yield 0.071 g.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8](Cl)=[O:9])[C:4]([CH3:11])=[N:3]1.[CH3:12][O:13][C:14]([C:23]1[C:29]([CH2:30][CH2:31][CH3:32])=[CH:28][C:26]([NH2:27])=[C:25]([CH3:33])[CH:24]=1)([C:19]([F:22])([F:21])[F:20])[C:15]([F:18])([F:17])[F:16].C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C>[CH3:12][O:13][C:14]([C:23]1[C:29]([CH2:30][CH2:31][CH3:32])=[CH:28][C:26]([NH:27][C:8]([C:5]2[C:4]([CH3:11])=[N:3][N:2]([CH3:1])[C:6]=2[CH3:7])=[O:9])=[C:25]([CH3:33])[CH:24]=1)([C:15]([F:16])([F:17])[F:18])[C:19]([F:20])([F:22])[F:21]
Reactant: Cc1nn(C)c(C)c1C(=O)Cl
Reactant: CCCc1cc(N)c(C)cc1C(OC)(C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1cc(NC(=O)c2c(C)nn(C)c2C)c(C)cc1C(OC)(C(F)(F)F)C(F)(F)F
Yield: 77.3 %

Procedure:
1,3,5-Trimethylpyrazole-4-carbonyl chloride (172 mg, 1 mmol), 4-[1-methoxy-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]-2-methyl-5-n-propylaniline (329 mg, 1 mmol) and triethylamine (303 mg, 3 mmol) were dissolved in tetrahydrofuran (10 ml), and the mixture was heated under reflux for 3 hr. The reaction mixture was diluted with ethyl acetate, and washed with water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:2) to give the desired compound (360 mg).
Reaction SMILES: C(Cl)(=O)/C=C/C1C=CC=CC=1.C1(O)C=CC=CC=1.C(N(CC)CC)C.[C:26]1([O:32][C:33](=[O:42])/[CH:34]=[CH:35]/[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO.O.C1COCC1>[C:26]1([O:32][C:33](=[O:42])[CH:34]=[CH:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(/C=C/c1ccccc1)Oc1ccccc1
Agent: O=C(Cl)/C=C/c1ccccc1
Solvent: CO
Solvent: Oc1ccccc1
Solvent: O
Product: O=C(C=Cc1ccccc1)Oc1ccccc1

Procedure:
To a 1-L three-neck flask, under a nitrogen gas stream, trans-cinnamic acid chloride (100 g, 0.60 mol), phenol (59.3 g, 0.63 mol), and THF (500 ml) were fed, and a THF solution (100 ml) of triethylamine (63.8 g, 0.63 mol) were added dropwise using a dripping funnel while being chilled with ice. After the completion of dropwise addition, 12-hour stirring was performed at room temperature, and the reaction solution was poured into water. The obtained white precipitate was filtered and dried under reduced pressure, and thereafter the yield was 135.5 g (yield rate of 99.9%). This was dissolved into approximately 200 ml of methanol by heating, and then cooled. As a result, white crystal was obtained (112.6 g, yield rate of 83.8%). Note that, the obtained crystal was confirmed to be a target trans-cinnamic acid phenyl ester by NMR structural analysis.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:22])=[CH:8][C:9]=2[NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])[S:4][C:3]=1[C:23]1[CH:24]=[N:25][N:26](C(OC(C)(C)C)=O)[CH:27]=1.CC1(C)C(C)(C)OB([C:43]2[CH:44]=[C:45]([N:49]3[CH2:53][CH2:52][CH2:51][CH2:50]3)[CH:46]=[CH:47][CH:48]=2)O1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.CN(C=O)C>[Cl:21][C:17]1[CH:16]=[C:15]([S:12]([NH:11][C:9]2[CH:8]=[C:7]([CH3:22])[N:6]=[C:5]3[S:4][C:3]([C:23]4[CH:27]=[N:26][NH:25][CH:24]=4)=[C:2]([C:47]4[CH:48]=[CH:43][CH:44]=[C:45]([N:49]5[CH2:50][CH2:51][CH2:52][CH2:53]5)[CH:46]=4)[C:10]=23)(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: CC1(C)OB(c2cccc(N3CCCC3)c2)OC1(C)C
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(Br)c(-c3cnn(C(=O)OC(C)(C)C)c3)sc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(-c3cccc(N4CCCC4)c3)c(-c3cn[nH]c3)sc2n1
Temperature: 120 °C
Yield: 100.7 %

Procedure:
A mixture of 1,1-dimethylethyl 4-(3-bromo-4-{[(3-chlorophenyl)sulfonyl]amino}-6-methylthieno[2,3-b]pyridin-2-yl)-1H-pyrazole-1-carboxylate (Description 75) (200 mg, 0.343 mmol), 1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidine (140 mg, 0.514 mmol), potassium carbonate (142 mg, 1.03 mmol), tetrakis(triphenylphosphine)palladium(0) (39.6 mg, 0.034 mmol) and bis(triphenylphosphine)palladium(II) chloride (24.04 mg, 0.034 mmol) were weighed into a microwave vial. 1,4-Dioxane (3.0 mL), DMF (1.5 mL) and water (0.75 mL) were added and the mixture heated in a microwave at 120° C. for 30 min. At this point, the four reaction mixtures were combined and concentrated. The residue was passed through an SCX cartridge, eluting with MeOH (250 mL) and then 2M NH3 in MeOH (300 mL). The basic methanolic solution was concentrated and purified by normal phase chromatography eluting with 0-10% 2M NH3 in MeOH in DCM. Further purification by normal phase chromatography eluting with 0-100% ethyl acetate in cyclohexane followed by MDAP (acidic conditions), afforded the title compound (190 mg).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[BH4-].[ClH:18]>>[Cl:18][CH:6]1[C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[CH:10]=[CH:9][C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]1=2
Reactant: O=c1c2ccccc2ccc2ccccc12
Reactant: Cl
Agent: [BH4-]
Product: ClC1c2ccccc2C=Cc2ccccc21

Procedure:
Certain of these prior art methods are described in U.S. Pat. No. 3,372,196 of Edward L. Engelhardt and in a publication of Engelhardt et al., J. Med. Chem., 11, 326-332 (1968). One such typical method begins with 5H-dibenzo[a,d]cycloheptene-5-one and first converts the ketone to the corresponding 5-hydroxy compound by reduction with borohydride followed by treatment with dry hydrogen chloride to produce the corresponding 5-chloro-5H-dibenzo[a,d]cycloheptene. This compound is then coupled with a Grignard reagent derived from dimethylaminopropyl chloride to produce the desired N,N-dimethyl-5H-dibenzo[a,d]cycloheptene-5-propylamine which is demethylated to the corresponding N-methyl derivative. Another method, disclosed in the above-mentioned patent, to prepare compounds of the type described involves the reaction of a 5H-dibenzo[a,d]cycloheptene-5-one with an alkoxypropyl magnesium halide to produce the corresponding 5-alkoxypropyl-5-hydroxy-5H-dibenzo[a,d]cycloheptene and reducing this compound using hydrogen iodide in acetic anhydride to produce a 5-(3-iodopropyl)-5H-dibenzo[a,d]cycloheptene in low yield. This compound is then reacted with ammonia or a lower alkyl or dialkyl amine to produce the corresponding 5-(3-aminopropyl, 3-alkylaminopropyl, or 3-dialkylaminopropyl)-5H-dibenzo[a,d]cycloheptene. Compounds of this type have tetrabenazine antagonist activity and are useful in the treatment of humans affected by depression as reported in the above-noted J. Med. Chem. article or as disclosed in the above-noted U.S. Pat. No. 3,372,196 of Engelhardt or are useful as intermediates in the preparation of such compounds.
Reaction SMILES: C(N=C(SC)NCCCOC1C=CC=C(CN2CCCCC2)C=1)#N.O.NN.[N:28]1([CH2:34][C:35]2[CH:36]=[C:37]([CH:49]=[CH:50][CH:51]=2)[O:38][CH2:39][CH2:40][CH2:41][N:42]2[C:46]([NH2:47])=[N:45][C:44]([NH2:48])=[N:43]2)[CH2:33]CCC[CH2:29]1.N>C(O)(C)C.O.C(OCC)(=O)C>[CH3:29][N:28]([CH2:34][C:35]1[CH:36]=[C:37]([CH:49]=[CH:50][CH:51]=1)[O:38][CH2:39][CH2:40][CH2:41][NH:42][C:46]1[NH:47][N:43]=[C:44]([NH2:48])[N:45]=1)[CH3:33]
Reactant: Nc1nc(N)n(CCCOc2cccc(CN3CCCCC3)c2)n1
Agent: CSC(=NC#N)NCCCOc1cccc(CN2CCCCC2)c1
Agent: N
Agent: NN
Solvent: O
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CN(C)Cc1cccc(OCCCNc2nc(N)n[nH]2)c1

Procedure:
Similarly prepared from N'-cyano-N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-carbamimidothioic acid, methyl ester (14.1 g) and hydrazine hydrate (10 ml) was N3 -[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-1H-1,2,4-triazole-3,5-diamine (10.4 g) m.p. 100°-101.5°. TLC silica; ethyl acetate:water:isopropanol:0.088 ammonia 25:8:15:2; Rf 0.4.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[CH:10][C:9]([O:12][C@@H:13]3[CH2:17][CH2:16][NH:15][C:14]3=[O:18])=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.Br[C:20]1[C:28]([F:29])=[C:27]2[C:23]([CH2:24][CH2:25][CH:26]2[OH:30])=[C:22]([F:31])[CH:21]=1>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[CH:10][C:9]([O:12][C@@H:13]3[CH2:17][CH2:16][N:15]([C:20]4[C:28]([F:29])=[C:27]5[C:23](=[C:22]([F:31])[CH:21]=4)[CH2:24][CH2:25][CH:26]5[OH:30])[C:14]3=[O:18])=[CH:8][CH:7]=2)[CH2:2][CH2:3]1
Reactant: O=C1NCC[C@H]1Oc1ccc(OCC2CC2)nc1
Reactant: OC1CCc2c(F)cc(Br)c(F)c21
Product: O=C1[C@H](Oc2ccc(OCC3CC3)nc2)CCN1c1cc(F)c2c(c1F)C(O)CC2

Procedure:
Following Typical Procedure 1 (R)-3-((6-(cyclopropylmethoxy)pyridin-3-yl)oxy)pyrrolidin-2-one was reacted with 6-bromo-4,7-difluoro-2,3-dihydro-1H-inden-1-ol to provide the subtitle compound. MS ESI+: m/z=417 [M+H]+.
Reaction SMILES: [ClH:1].Cl.[Cl:3][C:4]1[C:13]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][N:7]1[CH2:21][C:20](=[O:22])[NH:19][C:8]1=[N:9]2>CO.[Pd]>[ClH:3].[ClH:1].[N:14]1([C:13]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]2[NH:19][C:20](=[O:22])[CH2:21][N:7]2[CH2:6]3)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C1CN2Cc3c(ccc(N4CCCC4)c3Cl)N=C2N1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: O=C1CN2Cc3cc(N4CCCC4)ccc3N=C2N1
Yield: 61.9 %

Procedure:
1.5 g of 6-chloro-7-pyrrolidino-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one dihydrochloride was dissolved in 50 ml of methanol and catalytically reduced in the presence of 250 mg of 10% palladium-on-charcoal at ambient temperature under atmospheric pressure. After completion of the reaction, the catalyst was removed by filtration, and the filtrate was dried to a solid under reduced pressure to obtain 0.84 g of 7-pyrrolidino-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one dihydrochloride (melting point: above 280° C.).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+]([C:17]1[CH:18]=[C:19]([C:25]#[N:26])[C:20](=[CH:23][CH:24]=1)[C:21]#[N:22])([O-])=O.C(=O)([O-])[O-].[K+].[K+]>Cl>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([O:13][C:17]3[CH:18]=[C:19]([C:25]#[N:26])[C:20](=[CH:23][CH:24]=3)[C:21]#[N:22])=[CH:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: N#Cc1ccc(Oc2ccc(-c3ccccc3)cc2)cc1C#N
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 88.7 %

Procedure:
A 1 L round 3-necked round-bottomed flask was charged with 4-phenylphenol (45.7 g, 0.27 mole), 4-nitrophthalonitrile (50 g, 0.29 mole), potassium carbonate (51.9 g, 0.38 mole), and dimethylformide (470 mL). The resulting solution was heated under nitrogen with stirring to 90° C. for 1.5 hour (progress of reaction can be monitored by TLC). The dark brown reaction mixture was then poured into 2M aqueous HCl solution (300 mL) with stirring. The product precipitated out as a pale brown powder. The powder was collected by filtration and dried in a vacuum oven at 150° C. to give the desired product (71 g, 94% yield). 1H NMR (δ, D6-DMSO): 8.13 (d, 1H), 7.87 (d, 1H), 7.80 (d, 2H), 7.70 (d, 2H), 7.55-7.35 (m, 4H), 7.30 (d, 2H).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH3:18])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:4][C:3]=1[CH3:19].[N+:20]([O-])([O-:22])=[O:21].[Na+]>S(=O)(=O)(O)O>[OH:1][C:2]1[C:3]([CH3:19])=[CH:4][C:5]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH3:18])=[CH:15][C:14]([N+:20]([O-:22])=[O:21])=[CH:13][CH:12]=3)=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(-c2[nH]c3ccccc3c2C)cc(C)c1O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1cc(-c2[nH]c3ccc([N+](=O)[O-])cc3c2C)cc(C)c1O
Temperature: 0 °C

Procedure:
5.0 g of 2-(4-hydroxy-3,5-dimethylphenyl)-3-methylindole was added to 100 ml of concentrated sulfuric acid, and the mixture was stirred at 0° C. Then, a solution of 1.76 g of sodium nitrate in 50 ml of concentrated sulfuric acid was added dropwise, and the mixture was stirred for 15 minutes. The reaction mixture was poured into ice-water, and extracted with ether. The resulting crude product was purified by silica gel column chromatography. Recrystallization from ether-hexane gave 2-(4-hydroxy-3,5-dimethylphenyl)-3-methyl-5-nitroindole.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]2([C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH2:21][CH:22]4[CH2:25][C:24](C(O)=O)([C:26]([OH:28])=[O:27])[CH2:23]4)[CH:19]=3)[N:14]([C:32]([O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])=[O:33])[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[OH-].[Na+].Cl>O1CCCC1.C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]2([C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH2:21][CH:22]4[CH2:25][CH:24]([C:26]([OH:28])=[O:27])[CH2:23]4)[CH:19]=3)[N:14]([C:32]([O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])=[O:33])[CH2:13]2)[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC2(C1)CN(C(=O)OCC[Si](C)(C)C)c1ccc(CC3CC(C(=O)O)(C(=O)O)C3)cc12
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(C1)CN(C(=O)OCC[Si](C)(C)C)c1ccc(CC3CC(C(=O)O)C3)cc12
Reaction time: 1.5 h
Yield: 98.8 %

Procedure:
3-((1′-(tert-Butoxycarbonyl)-1-((2-(trimethylsilyl)ethoxy)carbonyl)spiro[indoline-3,3′-pyrrolidin]-5-yl)methyl)cyclobutane-1,1-dicarboxylic acid (19.0 mg, 0.033 mmol) was dissolved in tetrahydrofuran (1 mL). Thereafter, carbonyldiimidazole (6.0 mg, 0.037 mmol) was added to the above obtained solution at room temperature, and the thus obtained mixture was then stirred for 1.5 hours. Thereafter, the reaction solution was concentrated in vacuo, and the obtained reaction mixture was then dissolved in ethanol (1 mL). Subsequently, an 8 N aqueous solution of sodium hydroxide (0.5 mL) was added to the above obtained solution under cooling on ice, and the thus obtained mixture was then stirred at room temperature for 18 hours. Thereafter, a 1 N aqueous solution of hydrochloric acid was added to the reaction solution. The thus obtained mixture was neutralized, and was then extracted with chloroform. The organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo, so as to obtain 3-((1′-(tert-butoxycarbonyl)-1-((2-(trimethylsilyl)ethoxy)carbonyl)spiro[indoline-3,3′-pyrrolidin]-5-yl)methyl)cyclobutanecarboxylic acid (17.3 mg, 99%) in the form of a brown oily product.