Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@H:5]([C@@H:7]([NH2:11])[CH2:8][S:9][CH3:10])[CH2:4][O:3]1.C([BH3-])#N.[Na+].[CH2:17]([O:24][CH2:25][N:26]1[C:34]2[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[N:32][CH:31]=[N:30][C:29]=2[C:28]([CH:40]=O)=[CH:27]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][CH2:25][N:26]1[C:34]2[C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[N:32][CH:31]=[N:30][C:29]=2[C:28]([CH2:40][NH:11][C@H:7]([C@@H:5]2[CH2:4][O:3][C:2]([CH3:12])([CH3:1])[O:6]2)[CH2:8][S:9][CH3:10])=[CH:27]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CSC[C@H](N)[C@@H]1COC(C)(C)O1
Reactant: CC(C)(C)Oc1ncnc2c(C=O)cn(COCc3ccccc3)c12
Agent: [BH3-]C#N
Agent: [Na+]
Product: CSC[C@H](NCc1cn(COCc2ccccc2)c2c(OC(C)(C)C)ncnc12)[C@@H]1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
A mixture of the product from Example 27.4 (0.130 g, 0.68 mmol), sodium cyanoborohydride (0.071 g, 1.13 mmol) and 5-(benzyloxymethyl)-4-tert-butyloxy-5H-pyrrolo[3,2-d]pyrimidin-7-carbaldehyde (0.192 g, 0.57 mmol) were evaporated from methanol (3×). The residue was dissolved in methanol (10 ml) and acetic acid added (5 drops). The reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was evaporated on to silica gel and chromatographed (methanol-triethylamine-DCM, 3:1:96) giving an orange oil (0.272 g, 93%). 1H NMR indicated that the product contained some (co-polar) starting amine. 1H NMR (CDCl3) δ 8.47 (s, 1H), 7.38 (s, 1H), 7.34-7.22 (m, 5H), 5.73 (s, 2H), 4.47 (s, 2H), 4.34 (q, J=6.8 Hz, 1H), 4.10 (Abq, 2H), 4.03 (m, 1H), 3.82 (m, 1H), 2.87 (q, J=5.7 Hz; 1H), 2.72 (dd, J=13.2, 5.7 Hz, 1H), 2.60 (dd, J=13.2, 6.0 Hz, 1H), 2.05 (s, 3H), 1.69 (s, 9H), 1.39 (s, 3H), 1.34 (s, 3H).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH:9]1([CH2:12][NH2:13])[CH2:11][CH2:10]1.[Cl:14][C:15]1[C:16]([N:21]2[C:25]([C:26]3[O:31][C:30](=[O:32])[C:29]4[CH:33]=[CH:34][CH:35]=[C:36]([CH3:37])[C:28]=4[N:27]=3)=[CH:24][C:23]([C:38]([F:41])([F:40])[F:39])=[N:22]2)=[N:17][CH:18]=[CH:19][CH:20]=1>O1CCCC1>[CH:9]1([CH2:12][NH:13][C:30]([C:29]2[C:28]([NH:27][C:26]([C:25]3[N:21]([C:16]4[C:15]([Cl:14])=[CH:20][CH:19]=[CH:18][N:17]=4)[N:22]=[C:23]([C:38]([F:40])([F:39])[F:41])[CH:24]=3)=[O:31])=[C:36]([CH3:37])[CH:35]=[CH:34][CH:33]=2)=[O:32])[CH2:11][CH2:10]1
Reactant: NCC1CC1
Reactant: Cc1cccc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)NCC2CC2)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.49 g of triethylamine was gradually dropwise added to a mixed solution comprising 0.8 g of cyclopropylmethylamine hydrochloride and 40 ml of tetrahydrofuran under cooling with ice, followed by stirring at room temperature for 30 minutes. Then, a mixed solution comprising 1 g of 2-[(1-(3-chloro-2-pyridyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazin-4-one and 10 ml of tetrahydrofuran was gradually dropwise added. After completion of the dropwise addition, the mixed solution was reacted for 4 hours under reflux. After completion of the reaction, the solvent was distilled off under reduced pressure, and to the residue, ethyl acetate and water were added for extraction. The organic layer was washed with water and a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1) to obtain 0.54 g of the desired product having a melting point of 199.4° C.
Reaction SMILES: [CH3:1][N+:2]([CH2:5][CH:6]([OH:11])[CH2:7][C:8]([OH:10])=[O:9])([CH3:4])[CH3:3].[Cl-].[CH2:13]([C:17]1[CH:22]=[CH:21][C:20](C(C)C([Cl:26])=O)=[CH:19][CH:18]=1)[CH:14]([CH3:16])[CH3:15]>C(O)(C(F)(F)F)=O>[ClH:26].[CH2:13]([C:17]1[CH:18]=[CH:19][C:20]([CH:5]([N+:2]([CH3:3])([CH3:4])[CH3:1])[C:6]([C:8](=[O:9])[CH2:7][CH3:6])([CH2:7][C:8](=[O:10])[O-:9])[OH:11])=[CH:21][CH:22]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)Cc1ccc(C(C)C(=O)Cl)cc1
Reactant: C[N+](C)(C)CC(O)CC(=O)O
Agent: [Cl-]
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)C(O)(CC(=O)[O-])C(c1ccc(CC(C)C)cc1)[N+](C)(C)C
Product: Cl
Reaction time: 4.5 h
Yield: 65 %

Procedure:
4.95 g (0.025 moles) of D,L-carnitine hydrochloride are dissolved in 8 mls of CF3COOH, and to the solution an excess (16 mls) of p-isobutylphenyl-alpha-methyl acetyl chloride is added and the mixture is kept under stirring at a temperature of 40°-45° C. for 4-5 hours. At the end of this period of time, the mixture is partitioned with H2O--CHCl3, the organic phase is discarded whereas the aqueous phase is concentrated under reduced pressure at a bath temperature of about 50° C. A gelatinous raw material is obtained which is crystallized with isopropanol. The precipitate thus obtained is filtered, rapidly washed with ether because of its hydroscopicity, and dried under vacuum at a temperature not exceeding 50° C.; 6.3 g of a product are obtained (yield 65%) having the following characteristics:
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[N:18]=[C:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH2:5][CH2:4]1.Cl[C:25]1([N:35]([CH2:38][CH3:39])[CH2:36][CH3:37])[N:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26]1.CCN(C(C)C)C(C)C.[OH-].[Na+]>C(#N)CCC.C(OCC)(=O)C>[CH2:38]([N:35]([CH2:36][CH3:37])[C:25]1[N:34]=[C:33]([NH:1][CH2:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]3[N:18]=[C:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:5][CH2:4]2)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1)[CH3:39]
Reactant: CCN(CC)C1(Cl)N=Cc2ccccc2N1
Reactant: CCN(CC)c1nc(N2CCC(CN)CC2)nc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCC#N
Solvent: CCOC(C)=O
Product: CCN(CC)c1nc(NCC2CCN(c3nc(N(CC)CC)c4ccccc4n3)CC2)c2ccccc2n1

Procedure:
A mixture of the compound of Example III (500 mg, 1.8 mmol), 2-chloro-2-diethylaminoquinazoline (467 mg, 2.0 mmol) and Hunig's base (0.4 ml), 2.7 mmol) in 5 ml of butyronitrile was reacted for 12 hours at 120° C. After cooling, ethyl acetate (50 ml) and 50 ml of sodium hydroxide (10%) were added. The phases were separated and the aqueous phase was extracted with ethyl acetate (2×25 ml). The combined organic phases were dried (Na2SO4), concentrated on a rotary evaporator and purified by chromatography on silica gel (eluent: methylene chloride/ethanol/ammonia, 100/10/1) to give the free base as a solid.
Reaction SMILES: C([Li])CCC.[CH2:6]([CH2:9]/[C:10](/[O:17]CC)=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]#[CH:8].[Cl:20][CH:21]([CH2:24][CH3:25])[CH:22]=[O:23].P(O)(O)([O-])=O.[Na+]>CCCCCC.O1CCCC1.O>[O:17]=[C:10]([CH2:9][CH2:6][C:7]#[C:8][CH:22]([OH:23])[CH:21]([Cl:20])[CH2:24][CH3:25])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: C#CCC/C(=C/C(=O)OCC)OCC
Reactant: CCC(Cl)C=O
Agent: O=P([O-])(O)O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CCOC(=O)CC(=O)CCC#CC(O)C(Cl)CC
Temperature: -60 °C
Reaction time: 1 h
Yield: 41.4 %

Procedure:
42.2 ml of 1.4 N butyl lithium in hexane were added with stirring to a solution of 10 g of ethyl γ-propargyl-β-ethoxy-crotonate in 75 ml of tetrahydrofuran cooled to -60°C and after holding the mixture at the said temperature for 2 hours, 6.5 g of α-chlorobutyraldehyde were added thereto. The mixture was held at -60°C for 1 hour and after raising the temperature to 0°C a mixture of 90 g of monosodium phosphate in 110 ml of water was added thereto. The mixture was decanted and the aqueous phase was extracted with ethyl acetate. The extracts were washed with a saturated sodium bicarbonate solution, then with water, was dried and evaporated to dryness. The oil residue was mixed with stirring with 120 ml of ethanol and 60 ml of 2 N hydrochloric acid for 16 hours and was then poured into water. The mixture was extracted with methylene chloride and the extracts were washed with water, dried and evaporated to dryness. The oily residue was chromatographed over silica and was eluted with a 3-1 cyclohexane-ethyl acetate mixture to obtain 5.8 g of ethyl 3-oxo-8-hydroxy -9-chloro-6-undecynoate with a refractive index of nD22 = 1.4855.
Reaction SMILES: [C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][OH:16])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]=[C:24]1[O:28][C:26](=[O:27])[CH2:25]1>C1(C)C=CC=CC=1.CC(C)=O>[C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][O:16][C:26](=[O:27])[CH2:25][C:24]([CH3:23])=[O:28])[CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=C1CC(=O)O1
Reactant: OCCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)OCCCN1CCC(c2ccccc2)(c2ccccc2)CC1

Procedure:
23.6 g of 3-(4,4-diphenylpiperid-1-yl)-propanol were dissolved in 100 ml of absolute toluene, and 16 ml of a 50% strength solution of diketene in acetone were added with stirring. After standing for several days at room temperature (monitored by thin layer chromatography), the mixture was concentrated, and the residue was dried under high vacuum. The pale yellow, viscous oil which remains was employed without further purification for the next stage.
Reaction SMILES: [Br:1]Br.[OH:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH2:21])=[N:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:9]1.[OH-].[NH4+]>C(Cl)(Cl)Cl.CC(O)=O>[Br:1][C:11]1[C:10]([NH:13][C:14]([NH2:21])=[N:15][CH2:16][C:17]([F:20])([F:18])[F:19])=[N:9][N:8]([CH2:7][CH2:6][CH2:5][CH2:4][OH:3])[CH:12]=1
Reactant: BrBr
Reactant: NC(=NCC(F)(F)F)Nc1ccn(CCCCO)n1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: NC(=NCC(F)(F)F)Nc1nn(CCCCO)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
A solution (2.75 ml.) of bromine (80 mg.) in chloroform was added to a solution of 1-(4-hydroxybutyl)-3-[2-(2,2,2-trifluoroethyl)guanidino]pyrazole (140 mg.) in HOAc (2 ml.). After stirring at room temperature for 1 hour the mixture was basified with 6 N aqueous ammonium hydroxide and then extracted with EtOAc (6×10 ml.). The combined extracts were dried (MgSO4) and evaporated to dryness in vacuo to give 4-bromo-1-(4-hydroxybutyl)-3-[2-(2,2,2-trifluoroethyl)guanidino]pyrazole (145 mg., 82%) having the following n.m.r. spectrum in d6DMSO: 7.7 (s, 1H); 4.2 (br t, 2H); 3.9 (t, 2H); 3.3 (t, 2H); 1.5 (br m, 4H).
Reaction SMILES: N1[CH:6]=[CH:5][C:4]([C:7]2[CH:11]=[CH:10][O:9][CH:8]=2)=[CH:3][CH:2]=1.BrC1C=C[C:16]([C:17]#[N:18])=CC=1.O1C=CC(B(O)O)=C1>>[C:17]([C:16]1[CH:6]=[CH:5][C:4]([C:7]2[CH:11]=[CH:10][O:9][CH:8]=2)=[CH:3][CH:2]=1)#[N:18]
Reactant: c1cc(-c2ccoc2)ccn1
Reactant: N#Cc1ccc(Br)cc1
Agent: OB(O)c1ccoc1
Product: N#Cc1ccc(-c2ccoc2)cc1

Procedure:
As described in Example 1(d) for the preparation of 3-(pyridin-4-yl)furan, 4-bromobenzonitrile (4.00 g, 22.0 mmol) was coupled to 3-furanboronic acid to furnish in high yield crude 3-(4-cyanophenyl)-furan as a brown solid, mp 55-7° C., which was used immediately without further purification. 1H NMR (CDCl3): δ 7.82 (bs, 1H), 7.67 (d, 2H, J=8.4 Hz), 7.59 (d, 2H, J=8.4 Hz), 7.52 (t, 1H, J=1.9 Hz), 6.72 (bs, 1H). IR (KBr): 2214, 1608, 1160, 796 cm−1. Anal. Calculated for C11H7NO•0.1 C6H6: C, 78.72; H, 4.33; N, 7.91. Found: C, 78.32; H, 4.60; N, 7.65.
Reaction SMILES: F[C:2]1[C:7]([I:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[S:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[NH:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[I:8][C:7]1[C:2]([O:25][C:22]2[CH:21]=[CH:20][C:19]([NH:18][C:10]3[S:9][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[N:11]=3)=[CH:24][CH:23]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Reactant: Fc1ncccc1I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Ic1cccnc1Oc1ccc(Nc2nc3ccccc3s2)cc1
Temperature: 80 °C

Procedure:
A mixture of 2-fluoro-3-iodopyridine (4.93 g, 22.11 mmol), 4-(benzo[d]thiazol-2-ylamino)phenol (6.16 g, 25.4 mmol), and cesium carbonate (10.81 g, 33.2 mmol) in DMSO (50 mL) was heated at 80° C. overnight. The reaction was cooled to rt and poured into water (200 mL). The solution was extracted with EtOAc (3×) and the combined organic layers were washed with brine, evaporated onto silica gel and purified by flash chromatography (Isco (240 gram)) eluting with EtOAc:hexanes (0:1→1:1) to give a white crystalline solid. MS (ESI, pos. ion) m/z: 445.8 (M+1).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4](C(O)=O)[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[F:22].C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:30])=CC=1.C([N:42]([CH2:45]C)CC)C>CC(O)(C)C>[F:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]2[NH:42][C:45](=[O:30])[N:14]([C:15]3[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=3[F:22])[C:3]=12
Reactant: CCN(CC)CC
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1cc2scnc2c(F)c1Nc1ccc(I)cc1F
Solvent: CC(C)(C)O
Product: O=c1[nH]c2cc3scnc3c(F)c2n1-c1ccc(I)cc1F
Temperature: 25 °C
Yield: 94 %

Procedure:
To a solution of 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxylic acid (75 mg, 0.17 mmol) in t-BuOH (3 mL) was added DPPA (82 mg, 0.29 mmol) followed by triethylamine (36 mg, 0.36 mmol). The mixture was heated under reflux for 3 h and allowed to slowly warm to room temperature. The solvent was removed in vacuo and the resultant crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 2:1, v/v). The corresponding product was obtained (70 mg, 94.0% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.78 (s, 1H), 8.66 (s, 1H), 7.95 (d, 1H), 7.74 (d, 1H), 7.47 (t, 1H), 7.33 (s, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5]C(=O)[CH2:3][CH2:2]1.[CH:8]([O:13][CH3:14])([O:11][CH3:12])OC.[I:15]I>>[I:15][CH:3]1[C:8]([O:11][CH3:12])([O:13][CH3:14])[CH2:5][CH2:6][O:1][CH2:2]1
Reactant: II
Reactant: COC(OC)OC
Reactant: O=C1CCOCC1
Product: COC1(OC)CCOCC1I
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a mixture of tetrahydro-4H-pyran-4-one (18.52 mL, 200 mmol) and trimethyl orthoformate (100 mL, 914 mmol) at 0° C. was added Iodine (49.2 mL, 200 mmol) slowly over 10 min. When the addition was complete, the reaction mixture was allowed to stir at 0° C. for 30 min. and was then allowed to come to RT and stir until TLC indicated all starting material had been consumed (approx. 1 h). The reaction was then cooled to 0° C. and quenched by the slow addition of sat. aqu. sodium thiosulfate (300 mL). The resulting mixture was extracted with EtOAc (3×75 mL). The combined organic layers were washed with brine (100 mL), dried over MgSO4, filtered and concentrated in vacuo. Purification by flash chromatography (Silica, EtOAc/Hexanes) gave 3-iodo-4,4-dimethoxytetrahydro-2H-pyran (43.95 g, 162 mmol, 81% yield) as a yellow oil. 1H NMR (500 MHz, CDCl3) δ ppm 4.25 (1H, q, J=2.44 Hz), 3.93-4.01 (1H, m), 3.84-3.93 (2H, m), 3.57 (1H, td, J=11.75, 2.44 Hz), 3.19-3.30 (6H, m), 2.34 (1H, ddd, J=14.34, 12.21, 4.88 Hz), 1.80 (1H, dq, J=14.34, 2.44 Hz).
Reaction SMILES: [C:1]([C:3]1[C:4]([OH:13])=[CH:5][C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1)#[N:2].S(Cl)([Cl:17])(=O)=O>C(#N)C>[Cl:17][C:12]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([OH:13])[C:3]=1[C:1]#[N:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: N#Cc1cc2c(cc1O)CCCC2
Solvent: CC#N
Product: N#Cc1c(O)cc2c(c1Cl)CCCC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a 100 mL round-bottom flask was placed 5,6,7,8-tetrahydro-3-cyano-2-naphthol (1.0 g, 5.77 mmol, 1 eq, from Method II-2) in 20 mL of dry acetonitrile under argon. Sulfuryl chloride (6.09 mL, 28.85 mmol, 5.0 eq) was added dropwise. The reaction was stirred at rt for 18 h. The reaction mixture was concentrated and purified on silica gel (flash column chromatography) eluting with 20% ethyl acetate-hexane. A 1:1 diastereomeric mixture of 4-Chloro-3-hydroxy-5,6,7,8-tetrahydro-naphthalene-2-carbonitrile and 1-Chloro-3-hydroxy-5,6,7,8-tetrahydro-naphthalene-2-carbonitrile was obtained as a yellow liquid (887 mg, 66.6%, isomer ratio:1:1). 1H-NMR (CD3CN) δ 7.81 (s, 1H), 3.24 (m, 1H), 2.66 (m, 1H), 2.33 (m, 1H), 2.07(m, 2H), 1.88 (m, 2H), 1.43 (m, 1H). GC-MS (M+=207)
Reaction SMILES: [O:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]([NH2:17])=[S:16])=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:19][CH:20]=O>CN(C=O)C>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]2[S:16][CH:19]=[CH:20][N:17]=2)=[N:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CCCl
Reactant: NC(=S)Nc1ccc(Oc2ccccc2)cn1
Solvent: CN(C)C=O
Product: c1ccc(Oc2ccc(Nc3nccs3)nc2)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
8.4 (5-Phenoxy-pyridine-2-yl)-thiourea (0.3 mmol) is dissolved in DMF (1 ml) and chloro-acetaldehyde (1.1 eq., 55% in water) is added and stirred 2 h at 70° C. After cooling to RT the precipitate is filtered, washed with water and dried 16 h in vacuo at 40° C. (5-Phenoxy-pyridine-2-yl)thiazole-2-yl-amine is obtained as colourless powder in a yield of 66%; mp. 161.4-162.4° C.; HPLC (method C): 1.69 min; LC-MS (method A): 1.559 min, 270.15 (M+H+); 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] 11.248 (s, 1H), 8.114 (d, 1H, J=2.7 Hz), 7.523 (dd, 1H, J=9.0 Hz, J=2.7 Hz), 7.387-7.355 (m, 3H), 7.151 (d, 1H, J=9.0 Hz), 7.107 (t, 1H, J=7.1 Hz), 6.997-6.967 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][OH:22])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.[C:25]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][OH:22])[CH:17]=3)[N:12]([CH3:25])[CH:11]=2)=[O:9])=[CH:23][CH:24]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(CO)cc2c1O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CO)ccc21
Temperature: 25 °C
Yield: 49 %

Procedure:
A solution of N-(4-chlorobenzyl)-4-hydroxy-6-(hydroxymethyl)-3-quinolinecarboxamide from Preparation No. 9 (300 mg,), K2CO3 (485.1 mg), and CH3I (0.11 mL) in 4 mL anhydrous DMF is heated at 90° C. for 3 h. The reaction is cooled to room temperature and diluted with H2O to dissolve any salts and precipitate the product. The crude product is adsorbed onto silica and chromatographed eluting with 3% MeOH in CH2Cl2. Fractions homogenous by TLC are combined and condensed to afford 154.2 mg (49%) of the title compound as a white solid.
Reaction SMILES: C[N:2]([CH3:17])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=1)=O.N[C:19]1[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=C[NH:21][N:20]=1>C(O)(=O)C>[CH3:16][O:15][C:9]1[CH:8]=[C:7]([C:5]2[N:21]3[N:20]=[CH:19][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:17]3[N:2]=[CH:3][CH:4]=2)[CH:12]=[CH:11][C:10]=1[O:13][CH3:14]
Reactant: COc1ccc(C(=O)C=CN(C)C)cc1OC
Reactant: CCOC(=O)c1c[nH]nc1N
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn2c(-c3ccc(OC)c(OC)c3)ccnc12

Procedure:
A mixture of 2.35 g. of 3-dimethylamino-3',4'-dimethyoxyacrylophenone and ethyl 3-aminopyrazole-4-carboxylate in 25 ml. of glacial acetic acid is refluxed for 20 hours and worked up to give the product, m.p. 148°-149° C.
Reaction SMILES: C=CC.[CH3:4][NH:5][CH3:6].CC1C=CC(S(O[C@@H:18]2[CH2:27][C@H:26]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)(=O)=O)=CC=1>>[CH:28]1([C@@H:26]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][C@@H:18]([N:5]([CH3:6])[CH3:4])[CH2:27]2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[CH:28]1([C@@H:26]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH2:27]2)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2Cc3ccccc3[C@@H](C3CCCCC3)C2)cc1
Reactant: CNC
Solvent: C=CC
Product: C1=Cc2ccccc2[C@@H](C2CCCCC2)C1
Product: CN(C)[C@@H]1Cc2ccccc2[C@@H](C2CCCCC2)C1
Temperature: 83 °C

Procedure:
(Bosse K, Marineau J, Nason D M, Fliri A J, Segelstein B E, Desai K, and Volkmann R A (2006) Expanding the medicinal chemistry toolbox: stereospecific generation of methyl group-containing propylene linkers. Tetrahedron Letters 47:7285-7287) Dimethylamine (40% in H2O, 6 mL) and (2R,4R)-4-cyclohexyl-1,2,3,4-tetrahydronaphthalen-2-yl 4-methylbenzenesulfonate 3a (0.19 g, 0.5 mmol) were placed in a tube, sealed, and heated at 83° C. for 24 hours. The solvent was removed and the crude material was purified by column chromatography (Si-gel) to give 4a in a 70% yield and 5a, (30%, (R)-1-cyclohexyl-1,2-dihydronaphthalene). After bench chromatography, 4a was examined using chiral (RegisCell™, EtOH(15):hexanes(85)) HPLC technology to indicate ee above 98% by UV trace. 1H NMR (CDCl3) 1.00-1.31 (m, 5H), 1.39-1.47 (m, 1H), 1.57-1.85 (m, 6H), 2.48-2.52 (m, 1H), 2.72-2.77 (m, 1H), 2.80 (s, 6H), 3.03 (dd, J=9.0, 16.6 Hz, 1H), 3.34 (dd, J=6.8, 16.0 Hz, 1H), 3.72-3.75 (m, 1H), 7.09-7.29 (m, 4H). 13C NMR (CDCl3) 26.5, 26.8, 27.3, 30.2, 31.8, 32.3, 41.6, 41.9, 43.5, 56.8, 124.9, 125.7, 129.1, 129.2, 136.0, 139.7. HRMS m/z Calcd for C18H27N 258.2216 [M+H]+. Found 258.2220. For pharmacological studies, the free base was converted to the HCl salt; MP: 174-176° C. Anal. Calcd for C18H27N+HCl+H2O: C, 69.32; H, 9.70; N, 4.49. Found: C, 69.48; H, 9.98; N, 4.34.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.[I-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)C.[CH2:29]([N:36]1[CH2:41][CH2:40][CH:39]([N:42]([CH2:51][CH3:52])[C:43]2[C:48]([CH:49]=O)=[CH:47][CH:46]=[CH:45][N:44]=2)[CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([N:36]1[CH2:41][CH2:40][CH:39]([N:42]([CH2:51][CH3:52])[C:43]2[C:48]([CH:49]=[C:2]([CH3:3])[CH3:1])=[CH:47][CH:46]=[CH:45][N:44]=2)[CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: [Li]CCCC
Reactant: CCN(c1ncccc1C=O)C1CCN(Cc2ccccc2)CC1
Agent: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Product: CCN(c1ncccc1C=C(C)C)C1CCN(Cc2ccccc2)CC1

Procedure:
Following the general procedure of EXAMPLE 16 and making non-critical variations but starting with n-butyl lithium (1.6M, 4.3 ml, 6.8 mmol), isopropyltriphenylphosphonium iodide (2.9 g, 6.8 mmol), and 1-benzyl-4-[N-ethyl-N-(3-(formyl)-2-pyridinyl)amino]piperidine (XXI, EXAMPLE 12, 1.1 g, 3.4 mmol), the title compound is obtained, NMR (300 MHz, CDCl3) 1.08, 1.71-1.80, 1.90, 1.90-2.00, 2.01, 2.98-3.03, 3.30-3.45, 3.43, 3.57, 6.18, 6.89, 7.32-7.45, 7.46 and 8.24δ.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3]([OH:5])=[O:4].[CH2:8](O)[C:9]([CH3:12])([CH3:11])[CH3:10].S(=O)(=O)(O)O.O>C1(C)C=CC=CC=1>[C:1]([O:7][CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])(=[O:6])[CH2:2][C:3]([O:5][CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:4]
Reactant: CC(C)(C)CO
Reactant: O=C(O)CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)COC(=O)CC(=O)OCC(C)(C)C
Yield: 94.8 %

Procedure:
Malonic acid (40 g, 0.38 mol) and neopentyl alcohol (77.5 g, 0.88 mol) in 110 ml of toluene in the presence of 0.2 ml of concentrated sulfuric acid are refluxed for 3 hours in a reactor equipped with Dean-Stark apparatus. The water formed is removed azeotropically. The organic phase is washed 3 times with water and dried over sodium sulfate. After filtration and evaporation of the solvent under vacuum, 88 g (yield: 94%) of dineopentyl malonate are obtained in the form of a colorless oil and used without further purification in the next step.