Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([Cl:29])[C:13]([CH2:17][N:18]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN>CCO.O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([Cl:29])[C:13]([CH2:17][NH2:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1ccc2c(Cl)c(CN3C(=O)c4ccccc4C3=O)ccc21
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)n1ccc2c(Cl)c(CN)ccc21
Temperature: 100 °C
Yield: 73.2 %

Procedure:
To a stirred suspension of 318 (10.75 g, 0.026 mol) in EtOH (200 mL) was added hydrazine hydrate (2.52 mL, 0.052 mol), and the resulting reaction mixture was heated at 100° C. for 1 h. The cooled reaction mixture was diluted with water and thrice extracted with DCM. The combined organic layers were washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The solid was suspended in hexane (100 mL) and ethyl acetate (5 mL) and filtered. The filtrate was concentrated under reduced pressure to afford 5.34 g (73%) of tert-butyl-5-(aminomethyl)-4-chloro-1H-indol-1-carboxylate (320) as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 7.97 (d, J=8.5 Hz, 1H), 7.73 (s, 1H), 7.50 (d, J=8.5 Hz, 1H), 6.71 (d, J=3.7 Hz, 1H), 2.09 (s, 2H), 1.63 (s, 9H); 2H not seen; MS (ESI) m/z=281.5 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>CN(C=O)C>[Cl:21][C:6]1([C:5]2[CH:17]=[CH:18][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:8]2[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10](=[O:12])[O:11]1
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C1OC(Cl)(c2ccc(Cl)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
Distilled THF (25 mL) was added to 2-(4-chlorobenzoyl)benzoic acid (1 g, 3.8 mmol) followed by thionyl chloride (0.55 mL, 7.6 mmol) and a catalytic amount of DMF (3 drops). The system was stirred under nitrogen for 4 h at room temperature and monitored by TLC. Removal of the solvent gave 3-chloro-3-(4-chlorophenyl)-3H-isobenzofuran-1-one as a colourless oil (1.06 g, 3.8 mmol, 100%).
Reaction SMILES: [Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[NH:7][CH2:6][C:5](=[O:13])[C:4]=2[CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([Mg]Br)=[CH:17][CH:16]=1.CCOCC>C1COCC1>[Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:11])(=[O:12])[NH:7][CH2:6][C:5]([C:18]3[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=3)([OH:13])[C:4]=2[CH:3]=1
Reactant: O=C1CNS(=O)(=O)c2sc(Cl)cc21
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=S1(=O)NCC(O)(c2ccc(Cl)cc2)c2cc(Cl)sc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
6-chloro-2,3-dihydro-4H-thieno[3,2-e][1,2]thiazin-4-one 1,1-dioxide (0.820 g, 3.45 mmol) was dissolved in THF (31 mL) and 1 M of 4-Chlorophenylmagnesium bromide in ether (8.2 mL, 8.2 mmol) was added. The solution was stirred at room temperature overnight. At that time, TLC indicated good conversion. Reaction was quenched by addition of satd NaHCO3 (20 mL) and extracted with EA (3×50 mL). The combined organic extracts were washed with brine (20 mL), dried with MgSO4, filtered and evaporated. The residue was purified using column chromatography on silica gel (80 g Analogix column, gradient 10% EA in hexane to 40% EA in hexane over 20 minutes) to give the product (0.34 g, 26%). LCMS: (FA) ES-348, 350, 352. 1H NMR (400 MHz, d6-DMSO) δ: 8.41 (dd, J=8.75, 5.76 Hz, 1H), 7.49-7.42 (m, 2H), 7.33-7.25 (m, 2H), 6.74 (s, 1H), 6.57 (s, 1H), 3.70-3.60 (m, 2H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([CH3:25])[CH:17]=2)=[N:4][N:3]1[C:26](O)=[O:27].[N-]1C=CN=C1.[CH:34]1([NH2:37])[CH2:36][CH2:35]1>>[CH:34]1([NH:37][C:26]([N:3]2[CH:2]([CH3:1])[CH2:8][C:7]3[CH:9]=[C:10]4[O:15][CH2:14][O:13][C:11]4=[CH:12][C:6]=3[C:5]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([CH3:25])[CH:17]=3)=[N:4]2)=[O:27])[CH2:36][CH2:35]1
Reactant: Cc1cc(C2=NN(C(=O)O)C(C)Cc3cc4c(cc32)OCO4)ccc1[N+](=O)[O-]
Reactant: NC1CC1
Agent: c1c[n-]cn1
Product: Cc1cc(C2=NN(C(=O)NC3CC3)C(C)Cc3cc4c(cc32)OCO4)ccc1[N+](=O)[O-]
Yield: 71 %

Procedure:
4.33 g (10.0 millimoles) of (±)-7,8-dihydro-8-methyl-5-(3-methyl-4-nitro-phenyl)-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepine-7-carboxylic acid-imidazolide are heated to boiling in 30 ml of cyclopropyl amine for 6 hours, whereupon the amine is distilled off in vacuo. The residue is taken up in 75 ml of dichloro methane, washed three times with 30 ml of water each, dried over magnesium sulfate and evaporated in vacuo. The crude product obtained is recrystallized from 40 ml of ethanol and washed with 10 ml of diethyl ether. Thus 3.00 g of the desired compound are obtained, yield 71%, mp.: 171–175° C.
Reaction SMILES: Br.[NH2:2][C:3]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].C(N(CC)CC)C.[C:20]1([CH2:26][C:27](Cl)=O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl.O>[CH2:26]([C:27]1[O:12][C:11]2[C:3](=[C:4]([C:5]([OH:7])=[O:6])[CH:8]=[CH:9][CH:10]=2)[N:2]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Nc1c(O)cccc1C(=O)O
Agent: Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)c1cccc2oc(Cc3ccccc3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
To a mixture of 2-amino-3-hydroxybenzoic acid hydrobromide (0.5 g, 2.14 mmol) and triethylamine (0.90 mL, 6.42 mmol) in dichloromethane (15 mL) was added phenylacetyl chloride (0.28 mL, 2.14 mmol) dropwise, then the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane, and then washed with 2 N HCl. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was dissolved in toluene (8 mL) and the solution was treated with p-toluenesulfonic acid monohydrate (537 mg, 2.83 mmol). The reaction mixture was then heated to reflux for 5 h. The reaction was cooled to room temperature, poured into water and extracted with ethyl acetate. The organic layer was separated, then washed with water (3×100 mL), brine, dried (Na2SO4), filtered and concentrated to afford 2-benzylbenzoxazole-4-carboxylic acid (277 mg, 51%) as a white solid: 1H NMR (500 MHz, DMSO-d6) δ 13.08 (br s, 1H), 7.91 (dd, J=7.1, 1.0 Hz, 1H), 7.85 (dd, J=7.7, 1.0 Hz, 1H), 7.44 (t, J=7.9 Hz, 1H), 7.40-7.34 (m, 4H), 7.31-7.27 (m, 1H), 4.40 (s, 2H); MS (ESI+) m/z 254 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:14][C:13]2[CH:15]=[C:16]([OH:23])[C:17]([C:19]([O:21][CH3:22])=[O:20])=[CH:18][C:12]=2[N:11]=1.OS(O)(=O)=O.[N+:29]([O-])([O-:31])=[O:30].[K+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:14][C:13]2[C:15]([N+:29]([O-:31])=[O:30])=[C:16]([OH:23])[C:17]([C:19]([O:21][CH3:22])=[O:20])=[CH:18][C:12]=2[N:11]=1
Reactant: O=[N+]([O-])[O-]
Reactant: COC(=O)c1cc2nc(Nc3c(Cl)cccc3Cl)[nH]c2cc1O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)c1cc2nc(Nc3c(Cl)cccc3Cl)[nH]c2c([N+](=O)[O-])c1O
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
To a mixture of methyl 2-[(2,6-dichlorophenyl)amino]-6-hydroxy-1H-benzimidazole-5-carboxylate (0.050 g, 0.142 mmol) and conc. H2SO4 (2.0 mL) was added KNO3 (0.014 g, 0.142 mmol) at 10-15° C. The reaction mass was stirred for 30 minutes at the same temperature. The reaction mass was quenched in water and filtered off to afford 0.050 g of the desired product. 1HNMR (DMSO-d6): δ 3.91 (s, 3H), 7.43 (t, J=8.1 Hz, 1H), 7.61-7.77 (m, 3H), 10.80 (s, 1H), 11-12.00 (s, 2H); MS [M+H]+: 397.02.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:17][CH:12]4[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]4)[CH2:9]2)[CH2:15]3)=[CH:4][C:3]=1[C:18]1[CH:23]=[C:22]([C:24]23[CH2:33][CH:28]4[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]4)[CH2:25]2)[CH2:31]3)[CH:21]=[CH:20][C:19]=1[CH3:34].C[C:36]1[CH:41]=[CH:40][C:39]([C:42]23CC4CC(CC(Br)(C4)[CH2:43]2)C3)=[CH:38][C:37]=1[C:53]1C=C(C23CC4CC(CC(Br)(C4)C2)C3)C=C[C:54]=1C>>[CH3:34][C:19]1[CH:20]=[CH:21][C:22]([C:24]23[CH2:25][CH:26]4[CH2:27][CH:28]([CH2:29][C:30]([C:7]5[CH:6]=[C:5]([C:8]#[CH:9])[CH:4]=[C:3]([C:18]#[CH:19])[CH:2]=5)([CH2:32]4)[CH2:31]2)[CH2:33]3)=[CH:23][C:18]=1[C:3]1[CH:4]=[C:5]([C:8]23[CH2:9][CH:10]4[CH2:16][CH:14]([CH2:13][C:12]([C:41]5[CH:40]=[C:39]([C:42]#[CH:43])[CH:38]=[C:37]([C:53]#[CH:54])[CH:36]=5)([CH2:11]4)[CH2:17]2)[CH2:15]3)[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccc(C23CC4CC(CC(Br)(C4)C2)C3)cc1-c1cc(C23CC4CC(CC(Br)(C4)C2)C3)ccc1C
Reactant: Cc1ccc(C23CC4CC(CC(C4)C2)C3)cc1-c1cc(C23CC4CC(CC(C4)C2)C3)ccc1C
Product: C#Cc1cc(C#C)cc(C23CC4CC(C2)CC(c2ccc(C)c(-c5cc(C67CC8CC(CC(c9cc(C#C)cc(C#C)c9)(C8)C6)C7)ccc5C)c2)(C4)C3)c1
Yield: 73.5 %

Procedure:
From the obtained 2,2′-dimethyl-5,5′-bis(1-adamantyl)-biphenyl 10 g, the same method as in Synthesis Example 7 was used to synthesize 2,2′-dimethyl-5,5′-bis(3-bromo-1-adamantyl)biphenyl 4.5 g, then the same method as in Synthesis Example 3 was used to obtain 2,2′-dimethyl-5,5′-bis(3-(3,5-diethynylphenyl)-1-adamantyl)biphenyl 3.8 g.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10](=[O:24])[N:11]([CH2:16][O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:12]=[N:13]2)=[CH:8][C:7]=1[O:25][CH3:26].[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:15]=[C:14]3[C:9]([C:10](=[O:24])[N:11]([CH2:16][O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:12]=[N:13]3)=[CH:8][C:7]=2[O:25][CH3:26])[CH2:30][CH2:29]1
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCCBr
Reactant: CN1CCNCC1
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCCN1CCN(C)CC1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 83 %

Procedure:
A suspension of 7-(3-bromopropoxy)-6-methoxy-3-((pivaloyloxy)methyl) -3,4-dihydroquinazolin-4-one (36.7 g, 86 mmol) in 1-methylpiperazine (370 ml) was stirred at 100° C. for 90 minutes. After removal of the volatiles under vacuum, the residue was partitioned between methylene chloride and aqueous ammonium chloride. The organic layer was separated, washed with water, brine, dried (MgSO4) and evaporated. The solid was triturated with ether, filtered, washed with ether and dried under vacuum to give 7-(3-(4-methylpiperazin-1-yl)propoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (31.9 gr, 83%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)=[N:4][C:3]=1[CH2:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1.O1CCCC1.CO.[BH4-].[Na+]>O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)=[N:4][C:3]=1[CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][OH:24])=[CH:25][CH:26]=1
Reactant: Cc1oc(-c2ccc3ccccc3c2)nc1COc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccc3ccccc3c2)nc1COc1ccc(CO)cc1
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
To a mixture of 4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]benzaldehyde (6.00 g), tetrahydrofuran (80 mL) and methanol (20 mL) was gradually added sodium borohydride (330 mg) at room temperature. After stirring for 30 min., water was added to the reaction mixture, and the precipitated crystals were collected by filtration and recrystallized from acetone-methanol to give colorless prism crystals (5.76 g, 95%) of 4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]benzyl alcohol. melting point: 181-182° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:11]O)[CH:5]=[C:6]([F:10])[C:7]=1[S:8][CH3:9].CS([Cl:17])(=O)=O.Cl>ClCCl>[Cl:17][CH2:11][C:4]1[CH:5]=[C:6]([F:10])[C:7]([S:8][CH3:9])=[C:2]([F:1])[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CSc1c(F)cc(CO)cc1F
Agent: Cl
Solvent: ClCCl
Product: CSc1c(F)cc(CCl)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.7 %

Procedure:
To a solution of [3,5-difluoro-4-(methylthio)-phenyl]-methanol (24.0 g, 0.126 mol) in dichloromethane (300 mL) cooled in an ice bath was added methanesulfonylchloride (16.9 g, 0.147 mol) in portions followed by disopropyl-ethylamine in portions. The mixture was allowed to warm to room temperature, and stirred for 18 hours. 4-dimethyl-aminopyridine was added and the mixture was heated to reflux for 2 hours, cooled, and stirred at room temperature for 18 hours. The mixture was poured into dilute HCl and extracted with dichloromethane once (75 mL) after separating. The combined extracts were washed with dilute sodium chloride, dried using magnesium sulfate, and concentrated. Purification by silica gel chromatography using 5% ethyl acetate in hexanes gave 5-(chloromethyl)-1,3-difluoro-2-(methylthio)benzene as a clear colorless liquid (24.9 g, 95%). 1H NMR (CDCl3/400 MHz) 6.92-6.96 (m, 2H), 4.49 (s, 2H), 2.44 (s, 3H). HRMS m/z 207.9893 (M+, calcd 207.9925).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[N:17][NH:18]C(OCC)=O)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.O=[S:25](Cl)Cl>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:25][N:18]=[N:17][C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)NN=C(Cc1ccc(OC)cc1)c1ccccc1
Reactant: O=S(Cl)Cl
Product: COc1ccc(-c2snnc2-c2ccccc2)cc1
Temperature: 60 °C
Yield: 82.3 %

Procedure:
The acylhydrazone 9 (4.6 g, 14.8 mol), was added to SOCl2 (25 ml) at 0° C. The reaction was stirred to 60° C. and was complete (by TLC) after 1.5 hour. SOCl2 was evaporated under reduced pressure and the crude oil was chromatographed on SiO2 (150 g), eluting with CH2Cl2 to afford 8 (3.25 g, 82.3%), m.p. 56.5°-58° C.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[Na+].[C:8]([O:11][CH2:12][CH2:13][CH2:14][S:15]([O-:18])(=O)=[O:16])(=[O:10])[CH3:9]>>[C:8]([O:11][CH2:12][CH2:13][CH2:14][S:15]([Cl:2])(=[O:18])=[O:16])(=[O:10])[CH3:9]
Reactant: CC(=O)OCCCS(=O)(=O)[O-]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Product: CC(=O)OCCCS(=O)(=O)Cl
Reaction time: 2.5 h

Procedure:
A 100 g (0.48 mol) portion of phosphorus pentachloride is added to a flask containing 82.0 g (0.4 mol) of the above sulfonic acid salt. When the initial reaction subsides, the mixture is heated on the steam bath for 1 hr and 25 g of phosphorus pentachloride is added. Heating is continued for another 2.5 hr and another 10 g of phosphorus pentachloride is added and heating continued for 30 min. The dark reaction mixture is cooled and filtered and the filtrate distilled. The clear distillate is redistilled to give 42.3 g of 3-acetyloxy-1-propanesulfonyl chloride; bp 69°-81°/0.03 mm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7]([C:13](OC)=[O:14])=[C:6]2[C:17]([O:19]C)=O.O.[NH2:22][NH2:23]>C(O)C>[Cl:12][C:11]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[C:6]3[C:17](=[O:19])[N:23]=[N:22][C:13](=[O:14])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: COC(=O)c1[nH]c2cc(Cl)c(OC)cc2c1C(=O)OC
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1cc2c3c([nH]c2cc1Cl)C(=O)N=NC3=O
Temperature: 25 °C
Yield: 30.3 %

Procedure:
To a solution of ethanol (15 ml) and dimethyl 5-methoxy-6-chloroindole-2,3-dicarboxylate (0.67 g, 2.30 mM), was added hydrazine hydrate (3.45 g, 0.69 mM). The resulting heterogeneous mixture was refluxed for 5 hr and then cooled to room temperature. The ethanol was removed under reduced pressure, acetic acid (15 ml) was added, and the resulting mixture refluxed for 2 hr. The reaction was cooled to room temperature, filtered, and dried. This afforded the titled compound as a white solid (0.18 g, 30%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C:16]([O:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH3:31])(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[OH:19]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[C:16]([O:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH3:31])=[O:24]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CC/C=C\CCOC(=O)c1ccccc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: CC/C=C\CCOC(=O)c1ccccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (112 mg), (Z)-3-hexenyl salicylate (440 mg), and 4-dimethylaminopyridine (244 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120° C. overnight. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (130 mg, yield 64%).
Reaction SMILES: [CH3:1][CH:2]1[C:7]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[C:6](=[O:12])[CH2:5][CH2:4][CH2:3]1.[CH3:13][Mg]I>>[CH3:13][C:6]1([OH:12])[CH2:5][CH2:4][CH2:3][CH:2]([CH3:1])[C:7]21[CH2:11][CH2:10][CH2:9][CH2:8]2
Reactant: CC1CCCC(=O)C12CCCC2
Reactant: C[Mg]I
Product: CC1CCCC(C)(O)C12CCCC2
Yield: 82 %

Procedure:
10-methyl-spiro[4.5]decan-6-one was alkylated by means of methyl-magnesium iodide under the reaction conditions commonly used in a Grignard reaction. 6,10-dimethyl-spiro[4.5]-decan-6-ol was thus obtained with an yield of 82 %.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5](C2(O)CCN(CCCC([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=O)CC2)=[CH:4][CH:3]=1.ClC1C=CC(C2(O)CCN(CCCC(C3C=CC=C(C4C=CC=CC=4)C=3)=O)CC2)=CC=1.C1(C(C2CC2)=O)CC1.C1(C2C=CC=CC=2)C=CC=CC=1.C1(C2C=CC=CC=2)C=CC=CC=1.C1C(C(CCCN2CCC(O)(C3C=CC(Cl)=CC=3)CC2)=O)=CC=C(F)C=1>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[C:20]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:19]=1.[CH3:6][CH2:7][CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=C(CCCN1CCC(O)(c2ccc(Cl)cc2)CC1)c1ccccc1-c1ccccc1
Agent: O=C(C1CC1)C1CC1
Agent: O=C(CCCN1CCC(O)(c2ccc(Cl)cc2)CC1)c1ccc(F)cc1
Agent: O=C(CCCN1CCC(O)(c2ccc(Cl)cc2)CC1)c1cccc(-c2ccccc2)c1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CCCCCC
Yield: 12 %

Procedure:
This example describes the synthesis of both 4-(4-(p-chlorophenyl)-4-hydroxypiperidinyl)-2'-phenylbutyrophenone (UCSF51) and 4-(4-(p-chlorophenyl)-4-hydroxypiperidinyl)-3'-phenylbutyrophenone (UCSF52). The ortho and meta biphenyl analogs of halopeddol were prepared from the opening of the cyclopropyl ring of the corresponding biphenyl cyclopropyl ketone (875 mg of the ortho isomer and 500 mg of the meta isomer) by 4-(4 chlorophenyl)4-hydroxy pipeddine by refluxing the two reagents in xylene for 5 days. The reaction was worked up as described for the synthesis of para-biphenyl haloperidol. The products were separated by flash chromatography using a slow gradient from 100% CH2Cl2 to 100% ethyl acetate to 10% methanol in ethyl acetate as eluent. Pooling of the fractions containing product followed by evaporation of the solvent resulted in an orange liquid for the ortho isomer, and a tan solid for the meta. In ethyl acetate, the Rf 's are 0.17 for o-biphenyl haldol, UCSF51, and 0.26 for the meta derivative, UCSF52. Both products were recrystallized from hexane yielding approximately 200 mg (12% yield), and 350 mg (35% yield), of the ortho and meta isomers respectively. A melting point of 96°-97° C. was determined for 4-(4-(p-chlorophenyl)-4-hydroxypiperidinyl)-2'-phenylbutyrophenone, and a melting point of 99°-100° C. was determined for 4-(4-(p-chlorophenyl)-4-hydroxypiperidinyl)-3'-phenylbutyrophenone. Spectral data supported the assigned structures for both products.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]([CH2:13][N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([N+:24]([O-])=O)[CH:20]=4)[CH2:15]3)=[N:11][CH:10]=[N:9]2)=[CH:5][CH:4]=1>CO.[Pd]>[NH2:24][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[CH2:15][N:14]([CH2:13][C:12]1[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:28][CH:27]=3)[N:9]=[CH:10][N:11]=1)[CH2:23][CH2:22]2
Reactant: COc1ccc(Cn2ncnc2CN2CCc3cc([N+](=O)[O-])ccc3C2)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(Cn2ncnc2CN2CCc3cc(N)ccc3C2)cc1
Yield: 87 %

Procedure:
2-[2-(4-Methoxybenzyl)-2H-[1,2,4]triazol-3-ylmethyl]-6-nitro-1,2,3,4-tetrahydro-isoquinoline (0.5 g, 1.3 mmol) was hydrogenated in methanol (25 mL) over 10% Pd/C (0.25 g) at 50 psi (about 345 kPa) for three hours. The reaction mixture was filtered and the solvent was evaporated in vacuo. Ethyl acetate and water were added and the pH was adjusted to 10 with solid sodium carbonate. The layers were separated and the aqueous layer was extracted with additional ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo to an oil; 0.4 g, 87% yield. 1H NMR (CDCl3) δ 7.86 (s, 1), 7.18 (d, 2), 6.79 (m, 3), 6.48 (m, 2), 5.42 (s, 2), 3.76 (s, 3), 3.73 (s, 2), 3.50 (s, 2), 2.80 (m, 2), 2.69 (m, 2). IR (KBr) 1613, 1587, 1513 cm-1. Mass spectrum: m/z: 348 (M+ -1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[C:13]2[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:12]=2[N:11]([C:19]([NH:21][C@@H:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:23](NC)=[O:24])=[O:20])[N:10]=1.N[C@H](CO)C(C)(C)C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[C:13]2[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:12]=2[N:11]([C:19]([NH:21][C@@H:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:23][OH:24])=[O:20])[N:10]=1
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2cc(F)ccc2F)c2c1CCN(C)C2)C(C)(C)C
Agent: CC(C)(C)[C@H](N)CO
Product: CN1CCc2c(c(-c3cc(F)ccc3F)nn2C(=O)N[C@H](CO)C(C)(C)C)C1

Procedure:
Compound 66 was prepared according to the procedure described for the synthesis of compound 64 by replacing tert-leucine methylamide with tert-leucinol. LCMS (+ESI) m/z=393.3 [M+H]+.
Reaction SMILES: [I:1][C:2]1[C:7]2[C:8](=[O:19])[C:9]3[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][OH:18])[C:10]=3[CH2:11][CH2:12][C:6]=2[CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4]>[I:1][C:2]1[C:7]2[C:8](=[O:19])[C:9]3[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=[O:18])[C:10]=3[CH2:11][CH2:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2cccc(CO)c2CCc2cccc(I)c21
Agent: [Mn+4]
Agent: [O-2]
Product: O=Cc1cccc2c1CCc1cccc(I)c1C2=O

Procedure:
150 mg of the mixture of 6-iodo-5-oxo-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-1-ylmethanol and 4-iodo form prepared in Example 6-a was oxidized by the procedure of Example 1-f using manganese dioxide, to give 120 mg of a mixture of the title compound with a 4-iodo form as a colorless powder.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][C:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:3]1.[BH4-].[Na+].[CH4:15]>CO.[Cl-].[Na+].CCOCC>[CH3:1][N:2]1[CH:6]=[N:5][C:4]([C:7]2[CH2:8][N:9]([CH3:15])[CH2:10][CH2:11][CH:12]=2)=[N:3]1
Reactant: C
Reactant: Cn1cnc(-c2cccnc2)n1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: CN1CCC=C(c2ncn(C)n2)C1
Temperature: -10 °C
Reaction time: 3 h

Procedure:
A suspension of 6.3 g (0.020 mol) of the methiodide of 57 (prepared from 57 by the procedure described in Example 1) in 75 ml of methanol was cooled to -10° C., and 1.0 g (0.026 mol) of sodium borohydride was added. When the gas evolution had ceased, the mixture was stirred for 3 h at room temperature. Evaporation in vacuo give a red oil which was dissolved in 100 ml of a saturated sodium chloride solution. Extraction with 4×100 ml of dichloromethane, drying of the organic phase over magnesium sulfate, and evaporation in vacuo gave a red oil. The oil was dissolved in 50 ml of ether and stirred with charcoal. Filtration and evaporation gave the base of 59 as a colorless oil, 58. Yield: 1.6 g (0.009 mol, 45%). A 0.5 g portion of 58 was converted to the title compound. M.P. 181°-183° C. Anal. (C11H16N4O2) C, H, N.