Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:15]=[C:14]([CH3:16])[S:13][C:4]=2[NH:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.[CH3:17][N:18]1[CH2:23][CH2:22]N[CH2:20][CH2:19]1>CC(O)C>[CH3:16][C:14]1[S:13][C:4]2[NH:5][C:6]3[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=3[N:8]=[C:2]([N:1]3[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]3)[C:3]=2[CH:15]=1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N
Reactant: CN1CCNCC1
Solvent: CC(C)O
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 80 %

Procedure:
4-Amino-2-methyl-10H-thieno-[2,3-b][1,5]benzodiazepine (50 g, 0.19 mol), N-methylpiperazine (125 mL, 2.5 vol) and 2-propanol (150 mL, 3 vol) were charged into a three-necked round bottom flask, equipped with reflux condenser, overhead stirrer, and thermometer. The reaction mixture was heated to reflux (about 100° C.) slowly under a nitrogen atmosphere and then refluxed overnight. The reaction mixture was allowed to cool slowly to below 40° C. (about 1 h), whereupon solid precipitates out. This precipitate was then isolated by filtration and the resulting light yellow solid was twice washed with 2-propanol (100 mL). The light yellow solid was stirred with water (4 volumes) for 2.5 hours, filtered, and the resulting solid, was washed twice with water (2 volumes) and dried to furnish olanzapine (47 g, 80%).
Reaction SMILES: Br[CH:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH3:3].[Cl-].[Cd+2:14].[Cl-]>CCOCC>[CH3:3][CH:2]([Cd:14][CH:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:2][CH3:3])[CH3:12])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: [Cd+2]
Reactant: CCCCCCCCCC(C)Br
Agent: [Cl-]
Solvent: CCOCC
Product: CCCCCCCCCC(C)[Cd]C(C)CCCCCCCCC

Procedure:
A Grignard reagent is made from 2-bromoundecane and magnesium (II, step (f)) which is treated (II, step (g)) with cadmium chloride to form the corresponding dialkylcadmium, di(2-undecyl)cadmium, (5).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([CH2:18][C:19]([OH:21])=[O:20])[C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O.[C:33](=[O:36])([O-])[O-:34].[Na+].[Na+]>C1C=CC=CC=1>[C:33]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:20][C:19](=[O:21])[CH2:18][C:10]1[C:9]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[N:8][N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([OH:34])=[O:36]
Reactant: O=C(O)Cc1c(-c2ccccc2)nn(-c2ccccc2)c1-c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cc1c(-c2ccccc2)nn(-c2ccccc2)c1-c1ccccc1)Oc1ccccc1C(=O)O
Reaction time: 0.42 h
Yield: 54 %

Procedure:
7.0 grams 1,3,5-triphenyl-pyrazol-4-acetic acid, 3.1 grams phosphorus oxychloride and 40 milliliters benzene were mixed and the mixture was heated to the boiling temperature under reflux for 2 hours. The reaction mixture was then poured on ice, the pH adjusted to 6 by the addition of dilute aqueous sodium carbonate solution. The benzene solution was separated, washed with water, dried over anhydrous magnesium sulfate, and evaporated. The residue, consisting of 1,3,5-triphenyl-pyrazol-4-acetylchloride was taken up in 40 milliliters absolute ether. The ether solution was then added dropwise at 0°-3° C. and within 20 minutes to a solution of 2.8 grams salicyclic acid in a mixture of 20 milliliters ether and 4.2 grams pyridine. The mixture was after stirred for 25 minutes and thereafter poured on a mixture of ice and concentrated aqueous hydrochloric acid. The acid solution was separated, extracted with water, and the ether evaporated. The residue was recrystallized from ethanol. 5.1 grams 1,3,5-triphenyl-pyrazol-4-acetic acid-(2-carboxyphenyl)-ester, melting at 190°-191° C., were obtained representing a yield of 54%.
Reaction SMILES: Br[C:2]1[N:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:9]([O:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[S:27]1(=[O:34])(=[O:33])[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]1.N1C=CC=CC=1C1C=CC=CN=1.O.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>CN(C=O)C.O.[Cu-]=O>[O:33]=[S:27]1(=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[C:2]1[N:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:9]([O:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: COC(=O)c1nc(Br)c2cccnc2c1OS(=O)(=O)c1ccc(C)cc1
Reactant: O=S1(=O)CCCCN1
Agent: O=[Cu-]
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: c1ccc(-c2ccccn2)nc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1nc(N2CCCCS2(=O)=O)c2cccnc2c1OS(=O)(=O)c1ccc(C)cc1
Temperature: 118 °C

Procedure:
To a slurry of methyl 5-bromo-8-{[(4-methylphenyl)sulfonyl]oxy}-1,6-naphthyridine-7-carboxylate (7.55 g, 17.27 mmol) in degassed DMF (20 mL) in a pressure tube was added 1,2-thiazinane-1,1-dioxide (2.8 g, 20.7 mmol, prepared as in White et al, J. Org Chem. 1987, 52: 2162) followed by 2,2′-bipyridine (3.24 g, 20.7 mmol) and copper (I) oxide powder (2.96 g, 20.7 mmol). The pressure tube was closed and heated to 118 degrees C. overnight. Celite (0.5 g) was added to the resulting slurry and this was filtered through a plug of DMF wetted celite. The solids were washed with more DMF (10 mL) and the filtrate transferred to a large Erlenmeyer flask (1L) fitted with a 2 inch stirring bar. The volume was brought up to 200 mL with chloroform and a solution of ethylenediaminetetraacetic acid monohydrate (13.3 g, 35.7 mmol) in 140 mL of water was added. The biphasic mixture was vigorously stirred, open to the air, for 3 hours. The organic phase was separated and retreated with another solution of ethylenediaminetetraacetic acid monohydrate (13.3 g, 35.7 mmol) in 140 mL of water overnight (16 hrs). The organic was separated and washed with water and dried over Na2SO4, filtered, and reduced to a small volume in vacuo. The product solidified during solvent reduction. The solid was broken up and dried to afford the desired product.
Reaction SMILES: [CH2:1]([CH:3]1[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH2:6][CH2:5][NH:4]1)[CH3:2].[CH3:12][N:13]=[C:14]=[S:15]>C(#N)C.C(O)C>[CH2:1]([CH:3]1[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH2:6][CH2:5][N:4]1[C:14](=[S:15])[NH:13][CH3:12])[CH3:2]
Reactant: CCC1NCCc2[nH]cnc21
Reactant: CN=C=S
Solvent: CCO
Solvent: CC#N
Product: CCC1c2nc[nH]c2CCN1C(=S)NC
Yield: 69.7 %

Procedure:
A solution of 2.9 g of 4-ethyl-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine (Farmaco, Ed. Sci. 1967, 22, 821) and 3 g of methyl isothiocyanate in 32 ml of acetonitrile and 8 ml of ethanol is refluxed for 8 h. The solution is evaporated in vacuo, and the residue crystallized from diethyl ether to give 3 g of 4-ethyl-5-(N-methyl-thiocarbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine, m.p. 230°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([Br:11])=[N:8][C:7]=1[CH2:12]Br)=[O:5])[CH3:2].[CH2:14]([O:16][C:17](=[O:31])[CH2:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([Br:11])=[N:8][C:7]=1[CH2:12][N:19]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:18][C:17]([O:16][CH2:14][CH3:15])=[O:31])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(Br)nc1CBr
Reactant: CCOC(=O)CNCc1ccc(OC)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(Br)sc1C(=O)OCC
Temperature: 25 °C
Reaction time: 17 h
Yield: 96.3 %

Procedure:
A mixture of 2-bromo-4-bromomethyl-thiazole-5-carboxylic acid ethyl ester (3.57 g, 10.91 mmole), (2,4-dimethoxy-benzylamino)-acetic acid ethyl ester (2.76 g, 10.91 mmole) and potassium carbonate (2.26 g, 16.36 mmole) in anhydrous dimethylformamide (25 ml) was stirred at room temperature for 17 h before it was quenched with water, extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a yellow oil (5.27 g): MS: (+) m/z 523.11, 525.04 (M+Na+, 79Br/81Br)
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:13][C:14]([O:16]C(C)(C)C)=[O:15])[N:5]=1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:13][C:14]([OH:16])=[O:15])[N:5]=1)(=[O:3])[NH2:2]
Reactant: CC(C)(C)OC(=O)Cn1nc(C(N)=O)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1nn(CC(=O)O)c2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl 2-(3-carbamoyl-1H-indazol-1-yl)acetate (3.42 g, 12.4 mmol) in CH2Cl2 (20 mL) was added TFA (10 mL, 130 mmol) and the resulting mixture was stirred at RT for 16 h. The reaction mixture was concentrated in vacuo, the residual solid was suspended in methanol and concentrated again in vacuo to give the title compound. MS (LC/MS): 220 [M+H]+; tR (HPLC conditions k): 1.79 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.O.[C:15](Cl)(Cl)=[S:16]>C(Cl)(Cl)Cl>[N:1]([C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:11])[F:12])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1)=[C:15]=[S:16]
Reactant: N#Cc1ncc(N)cc1C(F)(F)F
Reactant: S=C(Cl)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: N#Cc1ncc(N=C=S)cc1C(F)(F)F
Temperature: 22 °C
Reaction time: 2 h

Procedure:
5-Amino-3-(trifluoromethyl)pyridine-2-carbonitrile 8 (1.141 g, 6.1 mmol) is mixed with chloroform (5 ml) and water (40 ml) to give a white suspension. Thiophosgene (0.701 ml, 9.15 mmol) is added and the reaction stirred for 2 hours at 22° C. to give a clear biphasic system. Chloroform (20 ml) is added and the phases are separated. The aqueous layer is extracted with chloroform (30 ml) and the combined organic is washed with saturated aqueous NaHCO3 and water, dried over MgSO4 and the solvent is removed under reduced pressure. The crude 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile 9 is dried under vacuum and used as such in the next step, for example, in the step described in Example 8 below.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][CH2:10][CH2:11][CH2:12][C:13](Cl)=[O:14].Cl>C1(C)C(C)=CC=CC=1>[Cl:9][CH2:10][CH2:11][CH2:12][C:13]([O:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:14]
Reactant: Cc1ccc(O)cc1
Reactant: O=C(Cl)CCCCl
Agent: Cl
Solvent: Cc1ccccc1C
Product: Cc1ccc(OC(=O)CCCCl)cc1
Temperature: 130 °C
Yield: 95.1 %

Procedure:
A mixture of 4-methylphenol (54 g) and 4-chlorobutyryl chloride (77.5 g) was dissolved in xylene (250 ml). The mixture was heated gently until, at about 130° C., a vigorous reaction occurred. After the reaction had subsided, the mixture was heated at reflux for approximately 40 minutes, until the evolution of hydrogen chloride had ceased. The xylene was then removed in vacuo, and the residue was distilled to give 4-methylphenyl 4-chlorobutyrate (101 g), b.p. 116°-118° C./0.2 mm Hg.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]=[C:12]([NH:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[NH:13][C:14]1[C:23]([CH3:24])=[C:22]2[C:17]([CH:18]=[CH:19][CH:20]=[N:21]2)=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C:37]1C(C)=C2C(C=CC=N2)=CC=1.C(N=C(S)N(C(OCC1C=CC=CC=1)=O)C(OCC1C=CC=CC=1)=O)C>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]=[C:12]([NH:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[NH:13][C:14]1[C:23]([CH2:24][CH3:37])=[C:22]2[C:17]([CH:18]=[CH:19][CH:20]=[N:21]2)=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(N)ccc2cccnc12
Reactant: Cc1c(NC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)ccc2cccnc12
Agent: CCN=C(S)N(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1c(NC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)ccc2cccnc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7-[N2,N3-Bis(benzyloxycarbonyl)guanidino]-8-methylquinoline. To a pale yellow solution of 500 mg of 7-amino-8-methylquinoline in 20 mL of tetrahydrofuran are added 1.18 g of ethyl N,N-bis(benzyloxy-carbonyl)pseudothiourea and 1.01 g of mercuric acetate and the mixture is stirred at room temperature for 1 hour. The suspension is diluted with ethyl acetate and the organic layer is washed with water followed by brine. The aqueous layers are extracted with ethyl acetate; the combined organic layers are dried over magnesium sulfate, filtered and rotary evaporated. The residue is purified by flash column chromatography on silica gel, eluting with 50% ethyl acetate/hexanes and recrystallization from hexanes/methylene chloride to provide 1.257 g of 7-[N2,N3-bis(benzyloxycarbonyl)guanidino]-8-ethylquinoline as a white solid.
Reaction SMILES: [N:1]1([C:15](=[O:18])[CH2:16][CH3:17])[C@H:10]2[C@@H:5]([CH2:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9]2)[CH2:4][CH2:3][CH2:2]1.[N+:19]([O-])([OH:21])=[O:20].O.S(=O)(=O)(O)O>[N+](C)([O-])=O>[N+:19]([C:13]1[CH:12]=[CH:11][C:8]2[CH2:9][C@@H:10]3[C@H:5]([CH2:4][CH2:3][CH2:2][N:1]3[C:15](=[O:18])[CH2:16][CH3:17])[CH2:6][C:7]=2[CH:14]=1)([O-:21])=[O:20]
Reactant: CCC(=O)N1CCC[C@@H]2Cc3ccccc3C[C@H]21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C[N+](=O)[O-]
Product: CCC(=O)N1CCC[C@@H]2Cc3cc([N+](=O)[O-])ccc3C[C@H]21
Reaction time: 1.5 h
Yield: 91.2 %

Procedure:
2.5 g trans-1-(3,4,4a,5,10,10a-Hexahydro-2H-benzo[g]quinolin-1-yl)-propan-1-one (10.27 mmol) were dissolved in 25 ml nitromethane. At −5° C. to −10° C., a mixture of 0.71 ml of nitric acid (10.27 mmol), 1.5 ml of water, and 9.5 ml of sulphuric acid (170 mmol) were added within 30 minutes. Stirring continued for 1.5 h under cooling conditions before the mixture was poured onto crushed ice. The aqueous phase was extracted twice with ethyl acetate, the combined organic layer was dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure to yield 2.7 g of the nitrated product as a mixture of several nitro-isomers, which was used in the subsequent reaction without further separation.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1.O>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:9](=[O:11])[C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:13][CH:12]=2)=[N:16][CH:17]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: Nc1ccc(Br)cn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(=O)Nc2ccc(Br)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.5 %

Procedure:
To a solution of 4-methanesulfonylbenzoic acid (100 mg, 0.50 mmol) and 2-amino-5-bromopyridine (104 mg, 0.60 mmol) in dry dichloromethane (10 mL) was added 4-(dimethylamino)pyridine (67 mg, 0.55 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (105 mg, 0.55 mmol). The mixture was stirred at room temperature overnight under N2, diluted with water (10 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/ethyl acetate=3/1) to give the title compound as a white crystal (56 mg, yield 32%).
Reaction SMILES: C1(C)C=CC=CC=1.[N:8]1[CH:13]=[CH:12][C:11]([CH:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][N:15]2[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:10][CH:9]=1.[N:29]12CC[CH:32]([CH2:33][CH2:34]1)[CH:31](O)[CH2:30]2.[H-].[Na+]>C(O)C>[N:8]1[CH:9]=[CH:10][C:11]([CH:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][N:15]2[C:24]([O:26][CH:27]2[CH:32]3[CH2:33][CH2:34][N:29]([CH2:30][CH2:31]3)[CH2:28]2)=[O:25])=[CH:12][CH:13]=1
Reactant: OC1CN2CCC1CC2
Reactant: CCOC(=O)N1CCc2ccccc2C1c1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(OC1CN2CCC1CC2)N1CCc2ccccc2C1c1ccncc1
Temperature: 25 °C
Yield: 89.2 %

Procedure:
To a 50 ml toluene suspension containing 720 mg of ethyl 1-(4-pyridyl)-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate and 973 mg of 3-quinuclidinol, 102 mg of sodium hydride (60%) was added at room temperature. The resulting mixture was heated under reflux for 5 hours and 40 minutes while the resulting ethanol was removed together with toluene. The reaction mixture was cooled to room temperature, followed by addition of 20 ml of water. The resulting mixture was extracted with chloroform. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol:28% aqueous ammonia=100:2:1), thereby 827 mg of 3-quinuclidinyl 1-(4-pyridyl)-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate were obtained as yellow oil. The resulting oil was dissolved in 5 ml of ethyl acetate, 2 ml of a 4N hydrogen chloride in ethyl acetate solution was added. The solvent was then removed under reduced pressure. Ethanol and ether were added to the residue, and the crude crystals thus obtained was recrystallized from ethanol and ether, thereby 402 mg of 3-quinuclidinyl 1-(4-pyridyl)-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate dihydrochloride was obtained as pale yellow crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]1([CH2:17][CH2:18][NH2:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CS(C)=O>O>[C:11]1([CH2:17][CH2:18][NH:19][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(NCCc2ccccc2)cc1

Procedure:
A mixture of 50 g. of 1-chloro-4-nitrobenzene, 76 g. of 2-phenylethylamine, and 30 ml. of dimethylsulfoxide is heated for 18 hours at 150°C. The resultant reaction mixture is poured into 3 liters of water. The precipitate formed is recovered by filtration and recrystallized from ether to yield the product, N-(2-phenylethyl)-p-nitroaniline; m.p. 57°-59°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][C@@H:11]([CH:19]([NH:21]C(=O)OC(C)(C)C)[CH3:20])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][C@@H:11]([CH:19]([NH2:21])[CH3:20])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(NC(=O)OC(C)(C)C)[C@@H]1Cc2ccccc2[C@H](c2ccc(Cl)c(Cl)c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(N)[C@@H]1Cc2ccccc2[C@H](c2ccc(Cl)c(Cl)c2)C1
Reaction time: 1 h
Yield: 88.5 %

Procedure:
To a solution of the above tert-butyl 1-((2S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-2-yl)ethylcarbamate 50b (50 mg, 0.12 mmol) in CH2Cl2 (3 mL) was added TFA (2 mL). The reaction mixture was stirred for 1 h before being concentrated. The residue was subjected to reverse phase column chromatography (CH3CN/H2O/0.1% formic acid=5% to 100%) to give 51 (34 mg, 90%). 1HNMR (400 MHz, CDCl3) δ 7.36 (d, J=8.0 Hz, 1 H), 7.26 (d, J=2.0 Hz, 1 H), 7.12 (m, 2 H), 7.03 (m, 1 H), 7.00 (dd, J=1.6, 8.0 Hz, 1 H), 6.71 (d, J=8.0 Hz, 1 H), 4.04 (dd, J=5.2, 12.0 Hz, 1 H), 2.92 (m, 2 H), 2.72 (dd, J=12.4, 16.0 Hz, 1 H), 2.22 (m, 2 H), 1.85 (m, 1 H), 1.48 (q, J=12.0 Hz, 1H), 1.20 (d, J=6.0 Hz, 3 H); 13CNMR (100 MHz, CDCl3) δ 147.45, 138.65, 136.88, 132.65, 130.87, 130.69, 130.46, 129.54, 129.43, 128.43, 126.02, 126.26, 77.45, 51.35, 40.70, 41.77, 37.10, 32.94, 20.25; ESI MS m/z 320.0.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][OH:11])=[CH:5][CH:4]=1.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.[OH-].[Na+]>O>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1
Reactant: BrCCCCCBr
Reactant: CSc1ccc(CCO)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSc1ccc(CCOCCCCCBr)cc1
Yield: 76.1 %

Procedure:
4-(methylthio)benzeneethanol (7.44 g) and 1,5 dibromopentane (30.48 g) were stirred rapidly at room temperature with TAB (1.0 g) and 12.5M aqueous sodium hydroxide (35 ml) for 64 h. The mixture was diluted with water (170 ml), extracted with ER (3×200 ml), and the combined organic extracts were washed consecutively with water (170 ml) and brine (170 ml), dried and evaporated. The residual oil (29.29 g) was purified by FCC eluting with ER-CX (0:100→3:97) to give the title compound as a colourless oil (10.68 g). T.l.c. (ER-CX 1:79) Rf 0.08.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([NH:18][C:19]3[CH:24]=[C:23]([O:25]CC4C=CC=CC=4)[C:22]([CH3:33])=[CH:21][C:20]=3[F:34])=[N:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[O:35][CH3:36])(=[O:3])[CH3:2].[H][H]>[Pd].C(OCC)(=O)C>[C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([NH:18][C:19]3[CH:24]=[C:23]([OH:25])[C:22]([CH3:33])=[CH:21][C:20]=3[F:34])=[N:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[O:35][CH3:36])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: COc1cc2c(Nc3cc(OCc4ccccc4)c(C)cc3F)ncnc2cc1OCCOC(C)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc2c(Nc3cc(O)c(C)cc3F)ncnc2cc1OCCOC(C)=O
Yield: 14.8 %

Procedure:
A mixture of 7-(2-acetoxyethoxy)-4-(5-benzyloxy-2-fluoro-4-methylanilino)-6-methoxyquinazoline (133 mg, 0.27 mmol) and 10% palladium-on-charcoal catalyst (50 mg) in ethyl acetate (8 ml) was stirred under 1 atmosphere of hydrogen at ambient temperature for 18 hours. The catalyst was removed by filtration through diatomaceous earth and most of the solvent removed by evaporation and hexane added to the residue. The resulting precipitated product was collected by filtration and dried to give 7-(2-acetoxyethoxy)-4-(2-fluoro-5-hydroxy4-methylanilino)-6-methoxyquinazoline (16 mg, 15%).
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][C:8]([OH:14])=[CH:7][C:6]=1[CH:15]([CH3:17])[CH3:16])(=[O:3])[CH3:2].Cl[CH2:19][C:20]([CH3:22])=[CH2:21].C(O)(=O)C>ClCCl.[Cl-].[Zn+2].[Cl-]>[C:1]([O:4][C:5]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][C:8]2[O:14][C:20]([CH3:22])([CH3:21])[CH2:19][C:7]=2[C:6]=1[CH:15]([CH3:17])[CH3:16])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C(C)C)cc(O)cc1C(C)C
Reactant: C=C(C)CCl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)Oc1c(C(C)C)cc2c(c1C(C)C)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 72 h
Yield: 87.5 %

Procedure:
Under argon atmosphere, 294 mg of 4-acetoxy-3,5-diisopropylphenol was dissolved in 10 ml of anhydrous dichloromethane, 2.25 g of 3-chloro-2-methyl-1-propene, 202 mg of anhydrous zinc chloride and 0.5 ml of acetic acid were added, and the mixture was stirred at room temperature for 3 days. After the reaction was quenched with water, the reaction solution was extracted with hexane. The organic layers were washed with a saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (in n-hexane containing 1% ethyl acetate) to give 316 mg of 5-acetoxy-2,2-dimethyl-4,6-diisopropyl-2,3-dihydrobenzofuran as a yellow oil (yield 88%).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[C@H:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4]1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:1][CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[C@H:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4]1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1N[C@H](CO)C[C@H]1Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@@H]1C[C@@H](Cc2ccccc2)C(=O)N1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the crude product from Step 2, in 5 ml of methylene chloride cooled to 0° C. was added triethylamine (42 mg, 0.41 mmol) and methanesulfonyl chloride (47 mg, 0.41 mmol). The reaction was slowly allowed to warm to room temperature and was stirred for 18 hr after which time it was diluted with 30 ml of methylene chloride, washed with 30 ml of 10% citric acid solution, dried filtered and concentrated to afford the product as an oil.