Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([OH:11])(=O)[C:3]1[C:4](=[CH:6][CH:7]=[CH:8][CH:9]=1)[NH2:5].[CH2:12]([N+:16]([O-:18])=[O:17])/[CH:13]=N\O.C([O-])(=O)C.[K+]>[N+](CC=NC1C=CC=CC=1C(O)=O)([O-])=O.C(OC(=O)C)(=O)C>[N+:16]([C:12]1[CH:13]=[N:5][C:4]2[C:3]([C:2]=1[OH:11])=[CH:9][CH:8]=[CH:7][CH:6]=2)([O-:18])=[O:17]
Reactant: O=[N+]([O-])C/C=N\O
Reactant: Nc1ccccc1C(=O)O
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C(O)c1ccccc1N=CC[N+](=O)[O-]
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1cnc2ccccc2c1O

Procedure:
In general, the novel derivatives 31-47 were synthesized as shown in the scheme depicted in FIG. 1. Condensation of anthranilic acid hydrochloride (1) with methazonic acid (2) resulted in 2-β-nitroethylideneaminobenzoic acid (3), which was dehydrated in acetic anhydride in the presence of potassium acetate to give 3-nitro-4-hydroxyquinoline (5) [Bachman, G. B. et al. Quinoline Derivatives from 3-Nitro-4-hydroxyquinoline, J. Am. Chem. Soc., 1947, 69, 365-371]. 3-Nitro-4-hydroxyquinoline (5) was treated with phosphorous oxychloride to afford 3-nitro-4-chloroquinoline (6). This was converted to 3-nitro-4-aminoquinoline (7) with ammonia, which was subsequently reduced by catalytic hydrogenation to 3,4-diaminoquinoline (8) with 10% palladium on charcoal as catalyst. The next step involved ring-closure, which was carried out in three different ways. For example, Compound 10 was prepared by ring closure of the appropriate carboxylic acid and 3,4-diaminoquinoline (8) in polyphosphoric acid [Young, R. C. et al. Purine Derivatives as Competitive Inhibitors of Human Erythrocyte Membrane Phosphatidylinositol 4-Kinase. J. Med. Chem. 1990, 33, 2073-2080]. Compound 14 was prepared by ring-closure of 2-furoyl chloride with 3,4-diaminoquinoline (8) [Scammells P. J. et al. Substituted 1,3-dipropylxanthines as irreversible antagonists of A1 adenosine receptors. J. Med. Chem. 1994, 37, 2704-2712]. Compound 9 was prepared by ring-closure of 3,4-diaminoquinoline (8) with formic acid in trimethylorthoformate. Oxidation with 3-chloroperoxybenzoic acid afforded 5-oxides 16-22, which subsequently could be converted with phosphorous oxychloride into the 4-chlorides 23-29. Finally, reaction with the appropriate amines afforded the desired compounds 30-47, respectively [Van Galen, P. J. M. et. al. 1-H-imidazo[4,5-c]quinolin-4-amines: Novel Non-Xanthine Adenosine Antagonists. J. Med. Chem. 1991, 34, 1202-1206].
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C@H:13]([N:15]([CH2:25][O:26][CH3:27])[S:16]([CH2:19][CH2:20]/[CH:21]=[CH:22]/[CH2:23][OH:24])(=[O:18])=[O:17])[CH3:14])[CH:9]=[CH:10][C:11]=2[F:12])[CH2:3][CH2:2]1>C(OCC)(=O)C.[C].[Pd]>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C@H:13]([N:15]([CH2:25][O:26][CH3:27])[S:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])(=[O:18])=[O:17])[CH3:14])[CH:9]=[CH:10][C:11]=2[F:12])[CH2:3][CH2:2]1
Reactant: COCN([C@H](C)c1ccc(F)c(OCC2CC2)c1)S(=O)(=O)CC/C=C/CO
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCN([C@H](C)c1ccc(F)c(OCC2CC2)c1)S(=O)(=O)CCCCCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
The (R,E)-N-(1-(3-(cyclopropylmethoxy)-4-fluorophenyl)ethyl)-5-hydroxy-N-(methoxymethyl)pent-3-ene-1-sulfonamide (296 mg) obtained in Reference Example 186 was dissolved in ethyl acetate (5.0 mL). To the solution, 10% palladium-carbon (170 mg) was added, and the reaction mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The precipitate was removed by filtration through a pad of Celite and washed with ethyl acetate (100 mL). Then, the combined filtrate was concentrated under reduced pressure to obtain the title compound (208 mg) as a crude product.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[C:4]1[O:5][CH2:6][C:7](=[O:14])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2].[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][N:24]=2)[C:19]([CH:26]=O)=[CH:18]1.[ClH:28]>C(O)C>[ClH:28].[NH:17]1[C:25]2=[N:24][CH:23]=[CH:22][CH:21]=[C:20]2[C:19]([CH:26]=[C:6]2[O:5][C:4]([N:3]([CH2:1][CH3:2])[CH2:15][CH3:16])=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:7]2=[O:14])=[CH:18]1
Reactant: CCOC(=O)C1=C(N(CC)CC)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1=C(N(CC)CC)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 38 %

Procedure:
To a solution of ethyl 2-(diethylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.034 g, 0.15 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.022 g, 0.15 mmol) in ethanol (1.0 mL), 2M hydrochloric acid in ethanol (0.16 mL, 0.32 mmol) was added at ambient temperature. The mixture was refluxed for 3 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and diisopropyl ether then dried to afford the titled compound (0.023 g, y. 38%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH2:8].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])(=O)C.[K+].[O:48]1[CH2:53][CH2:52][CH:51]([CH2:54][CH:55]=O)[CH2:50][CH2:49]1>CC(N(C)C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:48]1[CH2:53][CH2:52][CH:51]([C:54]2[C:2]3[C:3](=[CH:4][N:5]=[CH:6][CH:7]=3)[NH:8][CH:55]=2)[CH2:50][CH2:49]1
Reactant: Nc1cnccc1Cl
Reactant: O=CCC1CCOCC1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CC(=O)N(C)C
Product: c1cc2c(C3CCOCC3)c[nH]c2cn1
Temperature: 120 °C
Yield: 99.5 %

Procedure:
4-Chloro-3-aminopyridine (200 mg, 1.56 mmol) was dissolved in DMA (4 mL) and Pd2(dba)3 (71.2 mg, 0.08 mmol), X-Phos (74.2 mg, 0.16 mmol), potassium acetate (458 mg, 4.67 mmol) and (tetrahydro-pyran-4-yl)-acetaldehyde (598 mg, 4.67 mmol) were added under nitrogen. The reaction mixture was heated at 120° C. overnight, cooled to r.t. and partitioned between water (100 mL) and DCM (100 mL). The aqueous fraction was concentrated in vacuo and the residue was dissolved in DCM (100 mL), dried (MgSO4) and concentrated in vacuo to give the crude title compound as an orange/brown solid (314 mg, 99.8%). LCMS (ES+): 203.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[Br:14].Cl[C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([I:29])[CH:27]=2)[N:22]=[CH:21][N:20]=1>C(O)(C)C>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([I:29])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[CH:9][C:8]=1[Br:14]
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Br)c1
Reactant: Clc1ncnc2ccc(I)cc12
Solvent: CC(C)O
Product: Fc1cccc(COc2ccc(Nc3ncnc4ccc(I)cc34)cc2Br)c1
Yield: 98.2 %

Procedure:
4-(3-fluorobenzyloxy)-3-bromobenzenamine (1.48 g, 5 mmol) and 4-chloro-6-iodo-quinazoline (1.45 g, 5 mmol) were dissolved in isopropanol (50 ml). The reaction mixture was refluxed for 12 hours. The solid product was collected by filtration, washed with cold isopropanol (10 mL) and ether (20 mL), and air dried to afford 2.7 g of the clean desired material.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Na+].[I-].Cl[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=[O:17].[CH3:25][CH:26]([CH3:42])[C:27]([NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH:31]=1)=[O:28]>>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:16](=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][N:39]2[CH2:40][CH2:41][CH:36]([C:32]3[CH:31]=[C:30]([NH:29][C:27](=[O:28])[CH:26]([CH3:25])[CH3:42])[CH:35]=[CH:34][CH:33]=3)[CH2:37][CH2:38]2)=[CH:19][CH:20]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCCCCCl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCC(=O)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme E using K2CO3 instead of Na2CO3 and NaI instead of KI and 7-chloro-1-(4-fluorophenyl)-1-heptanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 453.2 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]3[CH:21]=2)=[CH:8][CH:7]=1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[CH3:29][S:30]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]3[CH:21]=2)=[CH:10][CH:11]=1)(=[O:32])=[O:31]
Reactant: Cc1ccn2cc(-c3ccc(CCCCO)cc3)nc2c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccn2cc(-c3ccc(CCCCOS(C)(=O)=O)cc3)nc2c1
Temperature: 0 °C
Yield: 125.6 %

Procedure:
The product of Step A (0.33 g) in dichloromethane (20 mL) was treated with triethylamine ( 0.36 g) and cooled to 0° C. The cold solution was treated with methanesulfonyl chloride (0.338 g) and allowed to stir and warm to ambient temperature over 18 hours. The reaction mixture was washed with water (50 mL), saturated sodium bicarbonate solution (25 mL), water (50 mL), dried over sodium sulfate, filtered and evaporated to give the crude title compound (0.53 g). The crude product was used, Step C, without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[CH2:12][NH:11][CH:10]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]2([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[F:27])[C:18]#[N:19])[CH:5]=[CH:6][CH:7]=1.C([O-])(O)=O.[Na+].[C:34](Cl)([Cl:36])=[O:35]>ClCCl>[Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[CH2:12][N:11]([C:34]([Cl:36])=[O:35])[CH:10]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]2([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[F:27])[C:18]#[N:19])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)CC1NCC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)CC1N(C(=O)Cl)CC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
To a solution of rac-(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-2-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile prepared in Example 3 (0.3 g, 0.71 mmol) in dichloromethane (5 mL) was added saturated aqueous NaHCO3 solution (5 mL). The temperature of the mixture was lowered to 0° C., and a solution of phosgene (Aldrich, 20% in toluene, 0.67 mL, 1.28 mmol) was added dropwise via a syringe. The reaction mixture was stirred at room temperature for 30 min, then diluted dichloromethane. The organic layer was separated, the aqueous layer was extracted with dichloromethane (2×). The combined organic layers were washed with water, brine, dried over MgSO4, and concentrated to give crude rac-(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl chloride as a light yellow oil (0.34 g, 100%).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[O:17])[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2].[OH:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH2:1]([NH:3][C:4]1[C:5]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([N:33]4[CH2:34][CH2:35][N:30]([CH2:29][CH2:28][OH:27])[CH2:31][CH2:32]4)=[O:23])=[CH:25][CH:26]=3)=[O:17])[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: OCCN1CCNCC1
Reactant: CCNc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cc2)CC1
Product: CCNc1cccnc1N1CCN(C(=O)c2ccc(C(=O)N3CCN(CCO)CC3)cc2)CC1
Yield: 76 %

Procedure:
By the same procedure as described in the example 19, synthesis was carried out starting with 4-[1-[3-(ethylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoic acid and using 1-(2-hydroxyethyl)piperazine. Then, the product was recrystallized using ethyl acetate and hexane to give the desired compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH2:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:21]1[N:26]=[C:25]([NH2:27])[C:24]([F:28])=[CH:23][N:22]=1>>[F:28][C:24]1[C:25]([NH2:27])=[N:26][C:21]([NH:19][CH2:18][CH:15]2[CH2:14][CH2:13][N:12]([S:9]([CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:10])=[O:11])[CH2:17][CH2:16]2)=[N:22][CH:23]=1
Reactant: NCC1CCN(S(=O)(=O)CCc2ccccc2)CC1
Reactant: Nc1nc(Cl)ncc1F
Product: Nc1nc(NCC2CCN(S(=O)(=O)CCc3ccccc3)CC2)ncc1F

Procedure:
EXAMPLE 95 was prepared from C-[1-(2-phenyl-ethanesulfonyl)-piperidin-4-yl]-methylamine and 2-chloro-5-fluoro-pyrimidin-4-ylamine: MS (m+1)=394.5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:29])[C:5]2[N:10]=[C:9]([C:11]3[N:15]([C:16]4[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=4)[N:14]=[C:13]([C:23]([F:26])([F:25])[F:24])[CH:12]=3)[O:8][C:7](=[O:27])[C:6]=2[CH:28]=1.O.[NH2:31][NH2:32].O1CCCC1.O>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:29])[C:5]([NH:10][C:9]([C:11]2[N:15]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[N:14]=[C:13]([C:23]([F:26])([F:25])[F:24])[CH:12]=2)=[O:8])=[C:6]([C:7]([NH:31][NH2:32])=[O:27])[CH:28]=1
Reactant: NN
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Cl)cc(C(=O)NN)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.2 %

Procedure:
A mixture of 0.44 g of 6-chloro-2-[1-(3-chloro-2-pyridinyl)-3-trifluoromethyl-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazine-4-one, 0.05 g of hydrazine monohydrate and 10 ml of tetrahydrofuran was stirred at room temperature for 2 hours. After the reaction mixture was mixed with water and ethyl acetate, layers were separated. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 0.10 g of N-[4-chloro-2-(hydrazinocarbonyl)-6-methylphenyl]-1-(3-chloro-2-pyridinyl)-3-trifluoromethyl-1H-pyrazole-5-carboxamide of the formula:
Reaction SMILES: [CH3:1][N:2]1[C@@H:6]2[CH2:7][CH:8]([OH:10])[CH2:9][C@H:3]1[CH2:4][CH2:5]2.Cl.[CH3:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([CH3:22])[CH:21]=1)[C:16]([Cl:18])=[O:17].Cl.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:22][C:20]1[CH:19]=[C:15]([C:16]([O:10][CH:8]2[CH2:9][C@H:3]3[N:2]([CH3:1])[C@H:6]([CH2:5][CH2:4]3)[CH2:7]2)=[O:17])[CH:14]=[C:13]([CH3:12])[CH:21]=1.[ClH:18]
Reactant: CN1[C@@H]2CC[C@H]1CC(O)C2
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cc(C)cc(C(=O)OC2C[C@H]3CC[C@@H](C2)N3C)c1
Yield: 58.8 %

Procedure:
A stirred mixture of tropine hydrochloride (5.27 g) and 3,5-dimethylbenzoyl chloride (5 g) is heated at 130°-140° C. for 30 minutes during which time the mixture liquifies, evolves hydrogen chloride gas and resolidifies. A solution of the cooled solid in water is basified with a solution of potassium carbonate and the base extracted with ethyl acetate. The ethyl acetate solution is washed several times with water, dried over magnesium sulphate, and evaporated to yield the free base which is converted to the hydrochloride by the addition of ethereal hydrogen chloride. Recrystallization of the precipitated solid from ethanol yields tropyl 3,5-dimethylbenzoate hydrochloride (5.4 g) m.p. 260° C.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][SH:3].[CH:8]([C:10]1[CH:18]=[CH:17][C:13]2[O:14][CH2:15][O:16][C:12]=2[CH:11]=1)=[CH2:9]>>[O:14]1[C:13]2[CH:17]=[CH:18][C:10]([CH2:8][CH2:9][S:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])=[CH:11][C:12]=2[O:16][CH2:15]1
Reactant: CCOC(=O)CS
Reactant: C=Cc1ccc2c(c1)OCO2
Product: CCOC(=O)CSCCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 14 h
Yield: 69.1 %

Procedure:
3.24 g of ethyl thioglycolate was added to 6 g of 5-ethenyl-1,3-benzodioxole and the mixture was stirred at room temperature for 14 h. The reaction product was purified according to silica gel column chromatography (benzene:ethyl acetate=40:1) to obtain 5 g of the intended compound in the form of a colorless oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[H-].[Na+].[CH2:11](Cl)/[CH:12]=[C:13](/[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])\[CH3:14].O>CN(C=O)C>[CH3:14][C:13]([CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:12][CH2:11][CH:2]([O:1][CH:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[CH2:11][CH:12]=[C:13]([CH3:14])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: OCc1ccccn1
Reactant: CC(C)=CCC/C(C)=C/CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)=CCCC(C)=CCC(OC(CC=C(C)CCC=C(C)C)c1ccccn1)c1ccccn1
Reaction time: 8 h

Procedure:
To a mixture of 18.6 g. (0.20 moles) 2-hydroxymethylpyridine in dry DMF is added, in small portions, 8.8 g. of sodium hydride (60% in oil), and the mixture is stirred for one hour at 60° C. Then 34.6 g. (0.2 moles) geranylchloride is added and the reaction mixture is stirred overnight at 50°-60° C. 200 ml. of water is added to the reaction mixture, which then is extracted with ethyl ether. After separation the organic layer is washed with a 10% KOH solution and then with water until neutral. The extract is dried over anhydrous Na2SO4, and the solvent is removed in vacuo. The yield was 36.5 g. of the crude ether, which was purified on silica gel as described below. The actual compound have nD24 : 1.5048.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[CH:13])[CH:10]=2)[S:5][CH2:4][CH2:3]1.C([Li])CCC.Cl[C:21]1[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][N:22]=1>O1CCCC1.CCCCCC.[Cl-].[Cl-].[Zn+2]>[CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][N:22]=3)[CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCS2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCS3)nc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Reaction vessels used in this procedure were flame dried under vacuum and all operations carried out in an oxygen-free, argon or nitrogen atmosphere. To a solution of 465.7 mg (2.3019 mmol) of 4,4-dimethyl-6-ethynyl-thiochroman in 4 ml of dry tetrahydrofuran at 0° C. was added dropwise 1.5 ml of 1.6M (2.4 retool) n-butyllithium in hexane. This was stirred at 0° C. for 10 minutes and at room temperature for 10 minutes, cooled again to 0° C. and then treated with a solution of 330 mg (2.4215 retool) of fused ZnCl2 in 4 ml dry tetrahydrofuran using a double ended needle. Thereafter the solution was stirred at 0° C. for 30 minutes, then at room temperature for 10 minutes. A solution of 426.3 mg (2.2967 mmol) of ethyl 6-chloronicotinoate (from Example 5) in 4 ml dry tetrahydrofuran was transferred by double ended needle into a suspension of 430 mg (0.37 retool) of tetrakistriphenylphosphine palladium in 4 ml dry tetrahydrofuran and stirred at room temperature for 10 minutes, then treated by double ended needle with the solution of the alkynylzinc prepared above. This mixture was stirred at room temperature for 18 hours, then quenched with 100 ml water. Product was recovered by extraction with 3×75 ml ether. Ether fractions were combined and washed with saturated NaCl solutions and dried (MgSO4). Solvent was removed in vacuo and the residue purified by flash chromatography (silica; 5% ethyl acetate in hexane) followed by HPLC (Whatman Partisil M-9 10/50; 4% ethyl acetate in hexane) to give the title compound as a white solid.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>CCOCC>[CH3:12][N:9]1[CH2:10][CH2:11][CH:6]([CH2:4][OH:3])[CH2:7][CH2:8]1
Reactant: CCOC(=O)C1CCN(C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CN1CCC(CO)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
A solution of ester 21 (10.1 g, 59.0 mmol) in Et2O (40 mL) was added dropwise to a suspension of LiAlH4 (2.46 g, 64.9 mmol) in Et2O (200 mL) at 0° C. Then, the reaction mixture was allowed to warm to room temperature and was then stirred for 4 h at this temperature. Water (10 mL) was added slowly and stirring was continued for a further 30 min. The formed white precipitate was separated by filtration and washed thoroughly with Et2O (250 mL). After removal of the solvent under reduced pressure the resulting oil was purified by distillation (bp. 108° C., 14 mbar) to give alcohol 22 (6.40 g, 84%) as a colorless oil. −Rf=0.53 (CH2Cl2/MeOH, 5:1, 5% NEt3, PMA: dark blue). 1H NMR (300 MHz, CDCl3): δ=1.28 (dq, J=12.2, 3.7 Hz, 2 H, 3-Hax, 5-Hax), 1.38-1.55 (m, 1 H, 4-H), 1.68-1.79 (m, 2 H, 3-Heq, 5-Heq), 1.93 (dt, J=11.8, 2.3 Hz, 2 H, 2-Hax, 6-Hax), 2.26 (s, 3 H, NMe), 2.82-2.92 (m, 2 H, 2-Heq, 6-Heq), 3.12 (sbr, 1 H, OH), 3.46 (d, J=6.4 Hz, 2 H, CH2OH) ppm. —13C NMR (75.5 MHz, CDCl3): δ=28.8 (C-3, C-5), 37.9 (C-4), 46.3 (NMe), 55.5 (C-2, C-6), 67.4 (CH2OH) ppm. −MS (70 eV, EI): m/z (%)=129 (55) [M]+, 128 (100) [M−H]+, 112 (10) [M-OH]+, 98 (21) [M-CH2OH]+. —C7H15NO (129.20).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH:10]2[CH3:15])=[CH:5][CH:4]=1.[BrH:16]>O>[BrH:16].[BrH:16].[CH3:15][CH:10]1[CH2:11][NH:12][CH2:13][CH2:14][N:9]1[C:6]1[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=1
Reactant: COc1ccc(N2CCNCC2C)cc1
Agent: Br
Solvent: O
Product: CC1CNCCN1c1ccc(O)cc1
Yield: 97 %

Procedure:
A mixture of 43 parts of 1-(4-methoxyphenyl)-2-methylpiperazine and 375 parts of a hydrobromic acid solution 48% in water was stirred and refluxed overnight. The reaction mixture was evaporated and the residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 72 parts (97%) of 4-(2-methyl-1-piperazinyl)phenol dihydrobromide (77).
Reaction SMILES: [CH3:1][S:2]([O:5][C@@H:6]1[C@@H:12]([NH:13][C:14](=[O:26])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22](=[O:24])[CH3:23])[C:16]=2[CH3:25])[CH2:11]OC(C)(C)[O:8][CH2:7]1)(=[O:4])=[O:3].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:5][C@H:6]([C@@H:12]1[CH2:11][O:26][C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22](=[O:24])[CH3:23])[C:16]=2[CH3:25])=[N:13]1)[CH2:7][OH:8])(=[O:3])=[O:4]
Reactant: CC(=O)Oc1cccc(C(=O)N[C@H]2COC(C)(C)OC[C@@H]2OS(C)(=O)=O)c1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cccc(C2=N[C@H]([C@H](CO)OS(C)(=O)=O)CO2)c1C
Temperature: 25 °C

Procedure:
(5R,6S)-N-(5-Methanesulfonyloxy-2,2-dimethyl1,3-dioxepan-6-yl)-3-acetoxy-2-methylbenzamide (compound [9], 34.2 g, 82.3 mmol) was dissolved in dichloromethane (340 ml) and boron trifluoride-diethyl ether complex (30.4 ml, 247 mmol) was added over 5 minutes with stirring at room temperature. The mixture was stirred for 40 hours at room temperature. Triethylamine (34.5 ml, 247 mmol) was added at not more than 15° C. and the solvent was distilled away under reduced pressure to 1/5 volume. The residue was diluted with ethyl acetate (340 ml) and washed successively with 10% brine (340 ml), 10% brine (340 ml) containing citric acid (17 g), and saturated brine (340 ml). After drying over magnesium sulfate, the solution was concentrated to 36 g to give a crude product of (2R)-2-methanesulfonyloxy-2-((4S)-2-(3-acetoxy-2-methylphenyl)-4,5-dihydrooxazol-4-yl)ethanol (compound [10]).