Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:11]2([C:14](Cl)=[O:15])[CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[CH2:18]([O:25][C:26]1[CH:34]=[CH:33][C:29]([CH2:30][CH2:31][NH2:32])=[CH:28][C:27]=1[O:35][CH3:36])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>C(OCC)(=O)C>[CH2:18]([O:25][C:26]1[CH:34]=[CH:33][C:29]([CH2:30][CH2:31][NH:32][C:14]([C:11]2([C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)[CH2:13][CH2:12]2)=[O:15])=[CH:28][C:27]=1[O:35][CH3:36])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)C1(c2cccc3ccccc23)CC1
Reactant: COc1cc(CCN)ccc1OCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc(CCNC(=O)C2(c3cccc4ccccc34)CC2)ccc1OCc1ccccc1
Reaction time: 64 h
Yield: 101.5 %

Procedure:
A solution of 1-(1-naphthyl)cyclopropane carbonyl chloride (7.1 g, prepared as described in Example CL32) in ethyl acetate (50 ml) was added to a stirred mixture of 4-benzyloxy-3-methoxyphenethylamine hydrochloride (9.29 g) in ethyl acetate (150 ml). Triethylamine (25 ml) was added and the mixture stirred for a further 64 hours. The organic layer was washed with dilute hydrochloric acid, dried over sodium sulphate and the solvent removed in vacuo to yield N-[2-(4-benzyloxy-3-methoxyphenyl)-ethyl]-1-(1-naphthyl)cyclopropane carboxamide (14.1 g).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:26])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])=[C:14]([O:24][CH3:25])[CH:13]=2)[CH2:4][CH2:3]1.[H][H]>CO.[C].[Pd]>[CH3:1][C@@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9](=[O:26])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]([CH3:22])[CH3:23])=[C:14]([O:24][CH3:25])[CH:13]=2)[CH2:6][CH2:7]1
Reactant: [H][H]
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@@H](C)CC2)ccc1OCCN(C)C
Agent: [Pd]
Solvent: CO
Product: COc1cc(CCC(=O)N[C@H]2CC[C@@H](C)CC2)ccc1OCCN(C)C

Procedure:
0.05 g of 10% palladium-carbon was added to a solution of 1 g of N-(cis-4-methylcyclohexyl)-4-(2-dimethylaminoethoxy)-3-methoxycinnamamide (Example 107) in 50 ml of methanol. The solution was vigorously stirred for 16 hours under normal-pressure hydrogen gas. After reaction, the catalyst was filtered out, and the solvent was removed in vacuo from the filtrate. The product obtained was recrystallized from methylene chloride/ether, yielding 0.93 g of N-(cis-4-methylcyclohexyl)-3-[4-(2-dimethylaminoethoxy)-3-methoxyphenyl]propionamide (a compound of the present invention) as white crystal, which had the following physiochemical properties:
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][CH:15]3[CH2:17][CH2:16]3)=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[NH2:19][C:20]([CH2:27][CH3:28])([CH2:25][CH3:26])[C:21]([NH:23][CH3:24])=[O:22]>>[CH2:25]([C:20]([NH:19][C:10]([C:7]1[CH:6]=[C:5]([O:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:12])([C:21](=[O:22])[NH:23][CH3:24])[CH2:27][CH3:28])[CH3:26]
Reactant: O=C(O)c1cc(OCC2CC2)c(C2CC2)cn1
Reactant: CCC(N)(CC)C(=O)NC
Agent: Cl
Product: CCC(CC)(NC(=O)c1cc(OCC2CC2)c(C2CC2)cn1)C(=O)NC

Procedure:
The title compound was synthesized in analogy to Example 24d, using 5-Cyclopropyl-4-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42c) and 2-Amino-2-ethyl-N-methyl-butyramide hydrochloride (Example 45c) as starting materials and isolated (23 mg, 71%) as colorless oil; MS (ESI, m/z): 360.6 (M+H+).
Reaction SMILES: COC(C1C(C)=CC(C2C=CC=C(C(F)(F)F)C=2)=CN=1)=O.ClC1C=C([C:30]2[CH:31]=[C:32]([CH3:49])[C:33]([C:36]([N:38]3[CH2:43][CH2:42][CH:41]([N:44]4[CH2:48][CH2:47][CH2:46][CH2:45]4)[CH2:40][CH2:39]3)=[O:37])=[N:34][CH:35]=2)C=CC=1Cl.[CH3:50][O:51][C:52]1[CH:57]=[CH:56][C:55]([C:58]([F:61])([F:60])[F:59])=[CH:54][C:53]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.[Pd](Cl)Cl>[CH3:50][O:51][C:52]1[CH:57]=[CH:56][C:55]([C:58]([F:61])([F:60])[F:59])=[CH:54][C:53]=1[C:30]1[CH:31]=[C:32]([CH3:49])[C:33]([C:36]([N:38]2[CH2:39][CH2:40][CH:41]([N:44]3[CH2:48][CH2:47][CH2:46][CH2:45]3)[CH2:42][CH2:43]2)=[O:37])=[N:34][CH:35]=1
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)cnc1C(=O)N1CCC(N2CCCC2)CC1
Reactant: COc1ccc(C(F)(F)F)cc1B(O)O
Agent: Cl[Pd]Cl
Agent: COC(=O)c1ncc(-c2cccc(C(F)(F)F)c2)cc1C
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(C(F)(F)F)cc1-c1cnc(C(=O)N2CCC(N3CCCC3)CC2)c(C)c1

Procedure:
In analogy to the procedure described for the preparation of intermediate 1A, (5-bromo-3-methyl-pyridin-2-yl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (see example 28) was reacted with 2-methoxy-5-trifluoromethyl-phenyl-boronic acid, (1,1′-bis-diphenylphosphino)-ferrocene)palladium-(II)dichloride (1:1 complex with CH2Cl2) and sodium carbonate in dioxane/water to give the title compound as brown amorphous solid. MS: 448.1 (MH+).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:22][CH2:23][CH3:24])(=[O:21])[CH2:17][C:18]([CH3:20])=[O:19].CN1CCOCC1.O>C(Cl)(Cl)(Cl)Cl.O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl.C(OCC)C>[O:19]=[C:18]([CH:20]=[CH:11][C:10]1[CH:13]=[CH:14][CH:15]=[C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:9]=1)[CH2:17][C:16]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Product: CCOC(=O)CC(=O)C=Cc1cccc(Oc2ccccc2)c1
Reaction time: 0.25 h

Procedure:
A solution of 0.10 moles of titanium tetrachloride in 25 ml of carbon tetrachloride was added with rapid stirring over 15 minutes to 200 ml of cold (0°) tetrahydrofuran. After the mixture was stirred an additional 15 minutes, a solution of 0.05 moles of 3-phenoxybenzaldehyde in 15 ml of tetrahydrofuran was added over 30 minutes. A solution of 0.05 moles of ethyl acetoacetate in 15 ml of tetrahydrofuran was then added. A solution of 22 ml of N-methylmorpholine in 30 ml of tetrahydrofuran was added dropwise over three hours. The reaction mixture was then stirred for 20 hours, after which time 50 ml of water and 50 ml of diethyl ether were added. After the resultant layers were separated, the aqueous layer was extracted with 50 ml of diethyl ether. The diethyl ether extract was combined with the initially separated organic layer, dried over sodium sulfate, filtered, and concentrated in vacuo to an oil. Chromatography on silica gel gave the title compound as an oil. Structure assignment was supported by nmr and infrared spectra and by elemental analysis.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1.Cl.Cl.[NH:22]1[C:26]2[CH2:27][NH:28][CH2:29][C:25]=2[CH:24]=[N:23]1>>[NH:22]1[C:26]2[CH2:27][N:28]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]4[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=4)[N:3]=3)[CH2:29][C:25]=2[CH:24]=[N:23]1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: c1n[nH]c2c1CNC2
Agent: Cl
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3Cc4cn[nH]c4C3)n2)c1

Procedure:
B51 was prepared following the general procedure reported for B10 using A1 and 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole dihydrochloride; yield: 194.9 mg (52%), colorless amorphous solid. 1H NMR (400 MHz, d6-DMSO, 300K) δ 4.23 (s, 2H), 4.58 (s, 2H), 4.64 (s, 2H), 6.83 (s, 2H), 7.00 (d, J=7.7 Hz, 1H), 7.26-7.34 (m, 1H), 7.58 (s, 1H), 7.71-7.78 (m, 1H), 7.86 (s, 1H), 8.27 (s, 1H), 9.73 (s, 1H), 12.73 (s, 1H). MS (ES) C15H16N8O2S requires: 372. found: 373 (M+H)+.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:12])[CH:10]=[CH2:11].[C:18](OOC(=O)C1C=CC=CC=1)(=O)[C:19]1C=CC=CC=1>C(C(C)=O)C(C)C>[CH3:17][CH2:16][CH2:15][CH2:14][O:13][C:9]([CH:10]=[CH2:11])=[O:12].[CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:1]=[CH:2][C:3]1[C:8]([CH:18]=[CH2:19])=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: C=CC(=O)OCCCC
Solvent: CC(=O)CC(C)C
Solvent: C=Cc1ccccc1
Product: C=Cc1ccccc1C=C
Temperature: 90 °C

Procedure:
40 parts by weight of methyl isobutyl ketone were put into a flask with a stirrer, and heated to 90° C. with stirring in a stream of nitrogen gas. A mixture of 95 parts by weight of styrene, 10 parts by weight of butyl acrylate and 25 parts by weight of benzoyl peroxide was added dropwise over a period of 6 hours to the methyl isobutyl ketone which was maintained at 90° C. Subsequently, the above-mentioned mixture was subjected to polymerization at 90° C. for 10 hours, whereby a styrene-butyl acrylate copolymer solution was obtained.
Reaction SMILES: Br[C:2]1[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[CH3:19][NH:20]C>C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[K+].[K+].[K+].[K+].[Fe+2]>[C:19]([C:2]1[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])#[N:20]
Reactant: COC(=O)c1cccc(Br)c1C
Reactant: CNC
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(C#N)c1C
Temperature: 120 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
To a solution of methyl 3-bromo-2-methylbenzoate (0.646 g, 2.8 mmol) in 4 ml of dimethylamine was added Pd(OAc)2 (0.5 mol %), sodium carbonate (0.3 g, 2.8 mmol), K4[Fe(CN)6].3H2O (0.262 g, 0.62 mmol). The mixture was heated to 120° C. and stirred at this temperature for 4 hours then at RT for 18 hours. The reaction mixture was diluted with 30 ml of ethyl acetate and the resulting slurry was filtered through Celite. The filtrate was washed with water (2×15 ml) then 5% aqueous ammonium hydroxide (1×15 ml). The organic layer was dried over anhydrous sodium sulfate then filtered and concentrated to provide methyl 3-cyano-2-methylbenzoate (0.248 g, 50% yield) (S. Weissman, D. Zewge, C. Chen, J. Org. Chem. 2005, 70, 1508-1510). 1H-NMR (400 MHz, DMSO-d6): 8.09 (d, 1H), 8.04 (d, 1H), 7.53 (t, 1H), 3.87 (s, 3H), 2.66 (s, 3H).
Reaction SMILES: C1(O[C:8](=[O:19])[NH:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([Cl:17])=[CH:12][C:11]=2[CH3:18])C=CC=CC=1.[CH3:20][C:21]([CH3:38])([CH3:37])[CH2:22][CH2:23][NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:28][CH:27]=1.CCCCCC>C1(C)C=CC=CC=1>[CH3:20][C:21]([CH3:38])([CH3:37])[CH2:22][CH2:23][N:24]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:28][CH:27]=1)[C:8]([NH:9][C:10]1[C:11]([CH3:18])=[CH:12][C:13]([Cl:17])=[CH:14][C:15]=1[CH3:16])=[O:19]
Reactant: CC(C)(C)CCNCc1ccc(CC(C)(C)C)cc1
Reactant: Cc1cc(Cl)cc(C)c1NC(=O)Oc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: Cc1cc(Cl)cc(C)c1NC(=O)N(CCC(C)(C)C)Cc1ccc(CC(C)(C)C)cc1

Procedure:
A solution of 825 mg of phenyl-N-(4-chloro-2,6-dimethylphenyl)carbamate and 782 mg of N-(3,3-dimethylbutyl)-4-(2,2-dimethylpropyl)benzenemethanamine in 40 ml of toluene was heated to reflux for 1 hour, cooled, and the solution was washed with 1N sodium hydroxide, brine, dried, and evaporated to dryness to yield a solid. The solid was recystallized from hexane to yield 1-[3,3-dimethylbutyl]-1-[[4-(2,2-dimethylpropyl)phenyl]methyl]-3-[4-chloro-2,6-dimethylphenyl]urea as a white solid, mp 148°-150° C.
Reaction SMILES: [C:1]([Si:3]([CH3:6])([CH3:5])[CH3:4])#[CH:2].Br[C:8]1[C:9]([C:15]#[N:16])=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=1>[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].CN(C=O)C>[Cl:14][C:12]1[CH:13]=[C:8]([C:2]#[C:1][Si:3]([CH3:6])([CH3:5])[CH3:4])[C:9]([C:15]#[N:16])=[N:10][CH:11]=1
Reactant: N#Cc1ncc(Cl)cc1Br
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1cc(Cl)cnc1C#N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 39.9 %

Procedure:
A pressure vessel was charged with TEA (7.65 mL, 55.2 mmol), ethynyltrimethylsilane (2.32 mL, 16.6 mmol), copper (I) iodide (0.263 g, 1.380 mmol), palladium (0) tetrakis(triphenylphosphine) (0.558 g, 0.483 mmol), 3-bromo-5-chloropicolinonitrile (3.0 g, 13.8 mmol), and DMF (50 ml). The vessel was flushed with argon, sealed, stirred at ambient temperature for 15 minutes, and then heated at 50° C. for 4 hours. The solution was diluted with water and extracted with EtOAc. The combined organic layers were concentrated, and the residue was purified by silica-gel chromatography, eluting 0-50% ethyl acetate in hexane, to afford the title compound (1.3 g, 5.5 mmol). MS m/z=235 (M+H)+.
Reaction SMILES: C([O:4][C@H:5]1[O:22][C@H:21]([CH2:23][N:24]=[N+:25]=[N-:26])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.C(N)C1C=CC=CC=1>C1COCC1>[C:8]([O:7][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@@H:21]([CH2:23][N:24]=[N+:25]=[N-:26])[O:22][C@@H:5]1[OH:4])(=[O:10])[CH3:9]
Reactant: CC(=O)O[C@H]1O[C@H](CN=[N+]=[N-])[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Solvent: NCc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](O)O[C@H](CN=[N+]=[N-])[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1,2,3,4-tetra-O-acetyl-6-azido-6-deoxy-α-D-glucopyranose (IV, 850 mg, 2.78 mmol) in THF (12 mL) was added benzylamine (0.23 mL) and the mixture was stirred at rt overnight. Solvents were removed under the reduced pressure and the resulting residue was dissolved in dichloromethane (50 mL) and washed with water, saturated ammonia chloride, brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography, eluting with 1:1 hexane-ethyl acetate, to give V (640 mg, 85%) as a white foam. 1H NMR (500.1 MHz) (CD3Cl) δ: 5.50 (m, 2H), 5.03 (t, J=10.5 Hz, 1H), 4.90 (m, 1H), 4.24 (m, 1H), 3.35 (m, 2H), 2.12 (s, 3H), 2.05 (s, 3H), 2.02 (s, 3H). 13C NMR (125.8 MHz) (CDCl3) δ: 170.26, 170.23, 169.78, 89.98, 71.09, 69.71, 68.34, 51.05, 20.68, 20.62, 20.58.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:3]=1.[CH2:20]([N:27]1[CH2:32][CH2:31][NH:30][C@@H:29]([CH:33]([CH3:35])[CH3:34])[CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:20]([N:27]1[CH2:32][CH2:31][N:30]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=3)[N:5]=[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[OH:19])[N:3]=2)[C@@H:29]([CH:33]([CH3:35])[CH3:34])[CH2:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)[C@H]1CN(Cc2ccccc2)CCN1
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CCN(Cc4ccccc4)C[C@@H]3C(C)C)nc(-c3ccccc3O)nc2c1
Temperature: 85 °C
Yield: 64 %

Procedure:
To a solution of 2-(4-chloro-7-methylquinazolin-2-yl)phenol (200 mg, 0.74 mmol) in 10 mL DMF was added (S)-1-benzyl-3-isopropylpiperazine followed by the addition of triethylamine (206 μL). The reaction was heated at 85° C. for two hours. The reaction was quenched with water after cooling it to room temperature. The aqueous layer was extracted twice with CH2Cl2, and the combined extracts were dried over MgSO4, filtered, and concentrated. The reaction was purified via silica gel chromatography using 1:1 hexanes:CH2Cl2 solvent system to yield 2-(4-((S)-4-benzyl-2-isopropylpiperazin-1-yl)-7-methylquinazolin-2-yl)phenol (230 mg, 64%). LC/MS: m/z 453.5 (M+H)+ at 2.61 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[C:5]1[C:11]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:10]=2[CH2:9][CH2:8][C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]1=2.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1>>[Cl:16][C:14]1[CH:13]=[CH:12][C:11]2[C:5](=[CH:4][CH2:3][OH:2])[C:6]3[CH:20]=[CH:19][CH:18]=[CH:17][C:7]=3[CH2:8][CH2:9][C:10]=2[CH:15]=1
Reactant: COC(=O)C=C1c2ccccc2CCc2cc(Cl)ccc21
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: OCC=C1c2ccccc2CCc2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
Dissolve (2-chloro-10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidene)acetic acid methyl ester (1 equivalent) in a suitable dry solvent and cool to 0° C. under a dry atmosphere. Add 1M diisobutylaluminum hydride solution in toluene (3 equivalents) dropwise and stir the mixture for one hour. Quench with aqueous citric acid solution and partition between water and ethyl acetate. Dry and evaporate the organic layer to obtain the title compound in 87% yield.
Reaction SMILES: [CH3:1]N(C)C=O.[OH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[CH:17]=[O:18].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(OC)(=O)=O)=CC=1>O>[CH3:1][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[CH:17]=[O:18]
Reactant: CN(C)C=O
Reactant: O=Cc1c(O)ccc2ccccc12
Agent: COS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1ccc2ccccc2c1C=O
Temperature: 50 °C

Procedure:
500 ml of a dimethylformamide solution containing 103.2 g (0.6 mole) of 2-hydroxy-1-naphthaldehyde and 107.6 g (0.78 mole) of anhydrous potassium carbonate was stirred with heating at 50° C. To the solution was added dropwise 145 g (0.78 mole) of methyl p-toluenesulfonate. After the completion of the dropwise addition, the mixture was stirred at 60° C. for 2 hours. The reaction mixture was added to 1.5 liters of water, and the precipitated crystals were collected by filtration. The crude crystals were recrystallized from a solvent mixture of n-hexane and ethyl acetate (5/1 by volume) to obtain 93.8 g (0.504 mole) of 2-methoxy-1-naphthaldehyde.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][OH:5])[CH3:2].C(=O)CCC>>[CH2:1]([C:3](=[CH:6][CH2:7][CH2:8][CH3:9])[CH:4]=[O:5])[CH3:2]
Reactant: CCCCC(CC)CO
Solvent: CCCC=O
Product: CCCC=C(C=O)CC

Procedure:
The production of 2-ethylhexanol (2EH) from normal butyraldehyde (NBD) is being industrially conducted on a large scale. This process is constituted of an NBD condensation step in which two molecules of NBD undergo aldol condensation and dehydration to give 2-ethylhexenal (ethylpropylacrolein, EPA), an EPA hydrogenation step in which the EPA obtained is reacted with hydrogen to obtain crude 2EH, and a 2EH purification step in which the crude 2EH is purified to a desired purity to obtain a 2EH product. The purification of crude 2EH is conducted mainly by distillation.
Reaction SMILES: [N:1]1([C:6]2[CH:18]=[CH:17][C:9]([O:10][C@@H:11]3[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[CH2:20][C:21]1[CH:29]=[CH:28][C:24]2[O:25][CH2:26][O:27][C:23]=2[CH:22]=1.C([O-])([O-])=O.[K+].[K+].N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1>CN(C=O)C.C(OCC)(=O)C.CO>[N:1]1([C:6]2[CH:18]=[CH:17][C:9]([O:10][C@@H:11]3[CH2:16][CH2:15][CH2:14][N:13]([CH2:20][C:21]4[CH:29]=[CH:28][C:24]5[O:25][CH2:26][O:27][C:23]=5[CH:22]=4)[CH2:12]3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: ClCc1ccc2c(c1)OCO2
Reactant: c1cn(-c2ccc(O[C@@H]3CCCNC3)cc2)cn1
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CO
Product: c1cn(-c2ccc(O[C@@H]3CCCN(Cc4ccc5c(c4)OCO5)C3)cc2)cn1
Temperature: 50 °C

Procedure:
(3R)-3-[4-(Imidazol-1-yl)phenoxy]piperidine (150 mg, 0.61 mmol) was dissolved in DMF (2 mL) and was added to a solution of 5-chloromethyl-1,3-benzodioxole (0.16 ml in 50% methylene chloride, 1.0 eq.) in DMF, followed by the addition of K2CO3 (2.5 eq.) and Nal (0.1 eq.). The resulting mixture was heated at 50° C. for 1 hour. The solvent was evaporated and flash column chromatography on silical gel with 3% methanol in methylene chloride gave a crude product (112 mg). Additional flash chromatography with 3% methanol in ethyl acetate afforded (3R)-3-[4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)methyl]piperidine (70 mg), 1H NMR (CDCl3) 7.75 (s, 1), 7.30 (d, 2), 7.20 (d, 2), 7.00 (d, 2), 6.85 (s, 1), 6.75 (d, 2), 5.90 (s, 2), 4.40 (m, 1), 3.50 (s, 2), 3.00 (m, 1), 2.70 (m, 1), 2.20 (m, 3), 1.85 (m, 1), 1.50 (m, 2) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](Cl)(=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>>[C:2]1([NH:1][C:8](=[O:15])[CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CCCCCCC(=O)Cl
Product: CCCCC=CC(=O)Nc1ccccc1
Yield: 94 %

Procedure:
The procedure described in Example 1 is repeated, but in section a) aniline is used in place of n-pentylamine and n-heptanoyl chloride is used in place of caproyl chloride. N-Phenyl-n-heptenamide (m.p. 50° C.) is obtained in 94% yield. This is reacted with PCl5 as in Example 1, section b), and gives in quantitative yield N-phenyl-heptaneiminoyl chloride as a yellowish oil which is converted according to section c) into the desired product and purified by chromatography on silica gel in hexane/ether=1:1. M.p. 83°-84° C. UV (EtOH): 320 nm (ε=19502).
Reaction SMILES: Cl.[Br:2][C:3]1[C:4]([O:9][CH:10]2[CH2:13][CH:12]([NH2:14])[CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.Cl[C:16]1[S:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1.CCN(C(C)C)C(C)C.O>CN1C(=O)CCC1>[Br:2][C:3]1[C:4]([O:9][CH:10]2[CH2:11][CH:12]([NH:14][C:16]3[S:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)[CH2:13]2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: Clc1nc2ccccc2s1
Reactant: NC1CC(Oc2ncccc2Br)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: Brc1cccnc1OC1CC(Nc2nc3ccccc3s2)C1
Temperature: 180 °C
Yield: 60 %

Procedure:
A mixture of 3-((3-bromopyridin-2-yl)oxy)cyclobutanamine hydrochloride (242 mg, 1 mmol), 2-chloro-benzothiazole (169 mg, 1 mmol) and DIEA (286 mg, 2 mmol) in NMP (10 mL) was heated to 180° C. for 2 hours in microwave. The reaction mixture was added water, extracted with EtOAc (40 mL), washed with brine and dried over Na2SO4. The organic layers were concentrated and purified by column chromatography to give N-(3-((3-bromopyridin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine (225 mg, 0.6 mmol, yield 60%). ESI-MS (M+1): 376 calc. for C16H14BrN3OS 375.
Reaction SMILES: [CH3:1][N:2]([CH3:37])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH2:11][N:12]([CH2:25][C:26]1[N:27]([S:31]([N:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])[CH:28]=[CH:29][N:30]=1)[C:13]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH2:21][NH:20][CH2:19][CH2:18]2)=[O:14])(=[O:5])=[O:4].[CH2:38]([N:41]([CH2:49][CH2:50][CH3:51])[CH:42]1[CH2:47][CH2:46][C:45](=O)[CH2:44][CH2:43]1)[CH2:39][CH3:40]>>[CH3:35][N:34]([CH3:36])[S:31]([N:27]1[CH:28]=[CH:29][N:30]=[C:26]1[CH2:25][N:12]([CH2:11][C:7]1[N:6]([S:3]([N:2]([CH3:37])[CH3:1])(=[O:4])=[O:5])[CH:10]=[CH:9][N:8]=1)[C:13]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH2:21][N:20]([CH:45]1[CH2:46][CH2:47][CH:42]([N:41]([CH2:49][CH2:50][CH3:51])[CH2:38][CH2:39][CH3:40])[CH2:43][CH2:44]1)[CH2:19][CH2:18]2)=[O:14])(=[O:33])=[O:32]
Reactant: CN(C)S(=O)(=O)n1ccnc1CN(Cc1nccn1S(=O)(=O)N(C)C)C(=O)c1ccc2c(c1)CCNC2
Reactant: CCCN(CCC)C1CCC(=O)CC1
Product: CCCN(CCC)C1CCC(N2CCc3cc(C(=O)N(Cc4nccn4S(=O)(=O)N(C)C)Cc4nccn4S(=O)(=O)N(C)C)ccc3C2)CC1
Yield: 75.2 %

Procedure:
The same operation as in Example 2 was performed, except for using the compound (150 mg) obtained in Example 31 and 4-(dipropylamino)cyclohexanone (269 mg), and then the obtained crude product was purified by silica gel chromatography (dichrolomethane:methanol:28% aqueous ammonia=1:0:0→80:10:1) to obtain the title compound (150 mg) having the following physical properties.