Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:19]1[N:23]=[C:22]([C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[O:21][N:20]=1)[CH2:3][CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1.OP(O)(O)=O>CS(C)=O>[O:1]=[C:2]([C:19]1[N:23]=[C:22]([C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[O:21][N:20]=1)[CH2:3][CH2:4][CH2:5][CH:6]1[CH2:7][CH2:8][N:9]([CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:10][CH2:11]1
Reactant: O=[N+]([O-])c1ccc(-c2nc(C(O)CCCC3CCN(Cc4ccccc4)CC3)no2)cc1
Agent: O=P(O)(O)O
Solvent: CS(C)=O
Product: O=C(CCCC1CCN(Cc2ccccc2)CC1)c1noc(-c2ccc([N+](=O)[O-])cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
The mixture of 3-[1-hydroxy-4-(1-benzylpiperidin-4-yl)butyl]-5-(4-nitrophenyl)-1,2,4-oxadiazole (0.28 g), N,N-dicyclohexylcarbodiimide (0.66 g) and o-phosphoric acid (0.31 g) in dimethyl sulfoxide (5 ml) was stirred overnight at ambient temperature and extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica eluting with 3% methanol in chloroform to give 3-[1-oxo-4-(1-benzylpiperidin-4-yl)butyl]-5-(4-nitrophenyl)-1,2,4-oxadiazole as an oil (0.21 g). The oil was dissolved in a solution of fumaric acid (48 mg) in ethanol and the crystals were filtered off to give 3-[1-oxo-4-(1-benzylpiperidin-4-yl)butyl]-5-(4-nitrophenyl)-1,2,4-oxadiazole fumarate (0.18 g).
Reaction SMILES: [C:1]([NH:4][C:5]([NH2:7])=[S:6])(=[O:3])[CH3:2].O.[CH:9](=[C:11]([C:17](=O)[CH2:18]Cl)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:10]>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][CH:10]=[C:9](/[C:11](=[CH:17]/[CH3:18])/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:7]=1)(=[O:3])[CH3:2]
Reactant: CC=C(C(=O)CCl)C(=O)OCC
Reactant: CC(=O)NC(N)=S
Solvent: O
Solvent: CN(C)C=O
Product: C/C=C(\C(=O)OCC)c1csc(NC(C)=O)n1
Temperature: 15 °C
Reaction time: 1 h

Procedure:
14.6 parts by weight of acetylthiourea, 30 parts by volume of water and 50 parts by volume of N,N-dimethylformamide are heated up to 85° C. under nitrogen. 22.9 parts by weight of ethyl 2-ethylidene-4-chloro-3-oxobutyrate are then added at this temperature in the course of 40 minutes. The mixture is stirred at 80° to 85° C. for 1 hour and then cooled to 15° C., and, after 10 minutes, the precipitate which has separated out is filtered off with suction. The precipitate is suspended once in 34.5 parts by volume of water, filtered off with suction again and washed twice more with water. The crude product is dried and then extracted by stirring once in a mixture of 13.8 parts by volume of water and 41.8 parts by volume of ethanol for 10 minutes, filtered off with suction and rinsed with ethanol/water (3/1). After drying, 8.8 parts by weight of a pure product are obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[O:8]1[CH2:10][CH2:9]1>>[O:1]1[CH2:6][CH2:5][CH:4]([O:7][CH2:10][CH2:9][OH:8])[CH2:3][CH2:2]1
Reactant: C1CO1
Reactant: OC1CCOCC1
Product: OCCOC1CCOCC1
Temperature: 0 °C

Procedure:
Into a 50-mL 3-necked round-bottom flask, was placed FeCl3 (800 mg, 4.94 mmol, 0.10 equiv). This was followed by the addition of oxan-4-ol (5 g, 48.96 mmol, 1.00 equiv) at 0° C. To this was added oxirane (20 mL) dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 2×50 mL of ethyl acetate and the organic layers combined. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:30-1:1). Purification afforded 2.25 g (crude) of 2-(oxan-4-yloxy)ethan-1-ol (54.2) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([Br:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([Br:26])[C:3]=1[OH:27].[C:28]([O:33]C)(=[O:32])[C@H:29]([CH3:31])O.BrBr>>[Br:26][C:4]1[CH:5]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([Br:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:7]=[C:2]([Br:1])[C:3]=1[O:27][C@H:29]([CH3:31])[C:28]([OH:33])=[O:32]
Reactant: Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Reactant: COC(=O)[C@H](C)O
Agent: BrBr
Product: C[C@@H](Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br)C(=O)O

Procedure:
Prepared from of 2,6-dibromo-4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11-yl)-phenol (Example 21) and commercially available (S)-lactic acid, methyl ester. White solid: mp 131-133 ° C.: NMR (CDCl3);δ8.37 (d, J=9 Hz, 1 H), 7.84 (d, J=8 Hz, 1 H), 7.71-7.65 (m, 3 H), 7.57-7.50(m, 2 H), 7.45 (ddd, J=8, 7, 1 Hz, 1 H), 7.18 (ddd, J=8,7, 1 Hz, 1 H), 6.73 (d, J=8 Hz, 1 H), 5.36 (q, J=7 Hz, 1 H), 1.82 (d, J=7 Hz, 3 H); MS (EI): [M-H]+, 3 bromine isotope pattern, 631 (14%), 633 (44 %), 635 (42%), 637 (16%); Anal. Calc. for C25H15Br3O3S: C, 47.27, H, 2.38, N, 0.00. Found: C, 47.57, H, 2.33, N, 0.03.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([S:19]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)(=[O:21])=[O:20])[CH2:15][CH2:14]3)=[O:12])[NH:8]2)=[CH:4][C:3]=1[O:28][CH:29]1[CH2:34][CH2:33][N:32]([CH:35]([CH3:37])[CH3:36])[CH2:31][CH2:30]1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH:49]([CH3:51])[CH3:50])(=O)=O.C(=O)(O)[O-].[Na+]>C(#N)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:14][CH2:15][N:16]([S:19]([N:22]4[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]4)(=[O:21])=[O:20])[CH2:17][CH2:18]3)=[O:12])[N:8]2[CH:49]([CH3:51])[CH3:50])=[CH:4][C:3]=1[O:28][CH:29]1[CH2:30][CH2:31][N:32]([CH:35]([CH3:37])[CH3:36])[CH2:33][CH2:34]1
Reactant: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCN(S(=O)(=O)N5CCCCC5)CC4)[nH]c3cc2Br)CC1
Reactant: CC(C)OS(C)(=O)=O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCN(S(=O)(=O)N5CCCCC5)CC4)n(C(C)C)c3cc2Br)CC1
Temperature: 25 °C
Yield: 55.3 %

Procedure:
To a solution of 100 mg (0.17 mmol) [6-bromo-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-[4-(piperidine-1-sulfonyl)-piperazin-1-yl]-methanone (example 1) in 3 mL acetonitrile were added 109 mg (0.33 mmol) cesium carbonate and 46 mg (0.33 mmol) isopropyl methanesulfonate. The reaction was stirred under reflux for 18 h. After cooling to room temperature, the reaction mixture was poured into 10% aqueous sodium bicarbonate solution; the phases were separated and the aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel with a gradient of dichloromethane:methanol (100:0 to 50:50) as eluant, to afford 60 mg (56%) of the product as a light-yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:13])=[CH:4][C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[N:6][CH:7]=1.[C:14](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[C:3]([CH3:13])=[CH:4][C:5]([N:8]([CH3:14])[S:9]([CH3:12])(=[O:10])=[O:11])=[N:6][CH:7]=1
Reactant: Cc1cc(NS(C)(=O)=O)ncc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1cc(N(C)S(C)(=O)=O)ncc1Br

Procedure:
The product from step (i) (2.23 g), potassium carbonate (2.33 g) and methyl iodide (0.7 ml) were stirred in DMF (20 ml) for 20 h. The reaction was quenched with water, extracted with EtOAc, dried (MgSO4) and evaporated. The residue was purified by chromatography on silica eluting with 30% EtOAc/isohexane. Yield 1.5 g. Carried forward to step (ii) without characterisation.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[NH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[OH:20].C([O-])([O-])=O.[Na+].[Na+]>N1C=CC=CC=1>[OH:20][C:19]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[NH:13][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: Nc1cnccc1O
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: O=C(Nc1cnccc1O)c1cccc([N+](=O)[O-])c1
Reaction time: 1 h
Yield: 79.3 %

Procedure:
A solution of 3-nitrobenzoyl chloride (3.339 g, 18.0 mmol) in pyridine (54.0 mL) was added dropwise to a solution of 3-amino-4-hydroxypyridine (2.376 g, 21.6 mmol) in pyridine (36.0 mL) at 10° C. and the resultant mixture was stirred overnight. Na2CO3 (1.145 g, 10.8 mmol) was added and the mixture was stirred for 1 h. The solid was collected by filtration, washed with 10% HOAc (30 mL×3) and water (30 mL×3), and dried under vacuo to afford N-(4-hydroxypyridin-3-yl)-3-nitrobenzamide as yellow solid (3.70 g, yield: 66%). 1H-NMR (400 MHz, DMSO-dB6B) δ: 6.34 (1H, d, J=7.2 Hz), 7.74 (1H, d, J=8.0 Hz), 7.84 (1H, t, J=8.0 Hz), 8.34 (1H, d, J=7.2 Hz), 8.44 (1H, t, J=8.0 Hz), 8.66 (1H, s), 8.73 (1H, s), 9.66 (1H, s), 11.65 (1H, br s); MS (ESI) calcd. for C12H9N3O4 (m/z): 259, found: 260 [M+1]+.
Reaction SMILES: [C:1]([N:4]1[CH2:49][CH2:48][CH2:47][C@H:5]1[C:6]([NH:8][C@H:9]([C:11]([N:13]1[CH2:46][CH2:45][CH2:44][C@H:14]1[C:15]([NH:17][N:18]([C:20]([O:22][CH:23]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:24][CH2:25][CH2:26][CH2:27][NH:28]C(OCC1C=CC=CC=1)=O)=[O:21])[CH3:19])=[O:16])=[O:12])[CH3:10])=[O:7])(=[O:3])[CH3:2].[ClH:50].[H][H]>[Pd]>[ClH:50].[C:1]([N:4]1[CH2:49][CH2:48][CH2:47][C@H:5]1[C:6]([NH:8][C@H:9]([C:11]([N:13]1[CH2:46][CH2:45][CH2:44][C@H:14]1[C:15]([NH:17][N:18]([C:20]([O:22][CH:23]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:24][CH2:25][CH2:26][CH2:27][NH2:28])=[O:21])[CH3:19])=[O:16])=[O:12])[CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C(CCCCNC(=O)OCc1ccccc1)OC(=O)N(C)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(C)=O
Agent: [Pd]
Agent: Cl
Product: CCOC(=O)C(CCCCN)OC(=O)N(C)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(C)=O

Procedure:
A mixture of 0.01 moles of 5-benzyloxycarbonylamino1-ethoxycarbonylpentyl acetylprolylalanylprolyl-2-azaalaninate and 0.2 gm of 10% Pd/C in 200 ml of 1.0 N-ethanolic hydrogen chloride is hydrogenated at room temperature. When the required amount of hydrogen has been taken up the reaction mixture is filtered and concentrated in vacuo to give 5-amino-1-ethoxycarbonylpentyl acetylprolylalanylprolyl-2-azaalaninate hydrochloride.
Reaction SMILES: I[CH2:2][C:3]1([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.[NH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>CN1CCCC1=O.C([O-])(O)=O.[Na+]>[C:22]([O:21][C:20]([NH:19][CH2:18][CH:15]1[CH2:14][CH2:13][N:12]([CH2:2][C:3]2([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:17][CH2:16]1)=[O:26])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Reactant: COC(=O)C1(CI)CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COC(=O)C1(CN2CCC(CNC(=O)OC(C)(C)C)CC2)CCCC1
Temperature: 120 °C
Reaction time: 24 h
Yield: 67.2 %

Procedure:
A mixture of Methyl 1-(iodomethyl)cyclopentanecarboxylate (5.52 g, 0.0206 mol, Step 1), tert-butyl (piperidin-4-ylmethyl)carbamate (8.83 g, 0.0412 mol) and iPr2NEt (10.76 mL, 0.0618 mol) in N-methylpyrrolidone (70 mL) was stirred at 120° C. for 24 h. After cooling, the reaction mixture was diluted with sat. NaHCO3 aq. (200 mL), extracted with AcOEt (200 mL) for three times, and the combined organic layer was washed with water (200 mL) and brine (200 mL). The organic layer was dried over Na2SO4, filtered and concentrated. Removal of the solvent gave a residue, which was chromatographed on a column of silica gel eluting with EtOAc/hexane (1:1) to give 4.91 g (67%) of title compound as a yellow syrup.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.Cl[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1>CC(O)C>[NH:6]1[CH:5]=[C:4]([CH2:3][CH2:2][NH:1][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[N:8]=[CH:7]1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: NCCc1c[nH]cn1
Solvent: CC(C)O
Product: O=[N+]([O-])c1ccc(NCCc2c[nH]cn2)cc1

Procedure:
1.45 g (13.1 mmol) of histamine and 2.06 g (13.1 mmol) of 1-chloro-4-nitrobenzene are brought to reflux in 20 ml of 2-propanol for 3 days. The cooled reaction mixture is filtered, evaporated and chromatographed on a first column of silica gel, using a chloroform/methanol (99/1) mixture, and then on a second column, using a chloroform/methanol (9/1) mixture. The pure fractions were evaporated and the resulting solid was treated with oxalic acid in ethanol. Addition of ether provided the title compound in the form of an oxalate salt, M.p.: 185°-186° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:34][CH3:35])[C:4]([C:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([C:20]3[C:21]4[C:26]([CH:27]=[C:28]5[C:33]=3[CH:32]=[CH:31][CH:30]=[CH:29]5)=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:19])[CH2:14][CH2:13]2)[CH:7]=1)=[O:5])[CH3:2]>CO.[Pd]>[CH2:34]([N:3]([CH2:1][CH3:2])[C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH:12]2[CH2:13][CH2:14][N:15]([C:18]([C:20]3[C:33]4[C:28]([CH:27]=[C:26]5[C:21]=3[CH2:22][CH2:23][CH2:24][CH2:25]5)=[CH:29][CH:30]=[CH:31][CH:32]=4)=[O:19])[CH2:16][CH2:17]2)[CH2:7]1)=[O:5])[CH3:35]
Reactant: CCN(CC)C(=O)C1=CN(C2CCN(C(=O)c3c4ccccc4cc4ccccc34)CC2)CCC1
Agent: [Pd]
Solvent: CO
Product: CCN(CC)C(=O)C1CCCN(C2CCN(C(=O)c3c4c(cc5ccccc35)CCCC4)CC2)C1
Temperature: 25 °C
Reaction time: 42 h
Yield: 33.8 %

Procedure:
1′-(Anthracene-9-carbonyl)-5,6,1′,2′,3′,4′,5′,6′-octahydro-4H-[1,4′]bipyridinyl-3-carboxylic acid diethylamide (0.033 mmol, 15.5 mg) was dissolved in methanol (˜20 mL), 10% palladium on carbon (10% w/w) (30 mg) was added and the suspension was shaken under a hydrogen atmosphere (45 psi) for 42 h at room temperature in a Parr shaker. The catalyst was filtered off, the solvent evaporated and the residue was purified by chromatography on silica gel eluting with a 1%-5% methanol-dichloromethane gradient to give the title compound (5.3 mg, 34%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[OH:63][N:64]1[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:67]1[CH2:68][CH2:69][N:64]([OH:63])[CH2:65][CH2:66]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: ON1CCNCC1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2cc(C(=O)N3CCN(O)CC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 4-hydroxy-piperazine in DMSO at ambient temperature.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][CH2:9][CH2:10][Cl:11]>>[Cl:11][CH2:10][CH2:9][CH2:8][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: ClCCCBr
Reactant: C1COCCN1
Product: ClCCCN1CCOCC1

Procedure:
Morpholine and 1-bromo-3-chloropropane are reacted using the procedure for Example OO to afford 4-(3-chloropropyl)morpholine.
Reaction SMILES: [CH2:1]([SiH:5]([CH:9]([CH3:11])[CH3:10])[CH:6]([CH3:8])[CH3:7])[CH:2]([CH3:4])C.C([SiH](C(C)C)Cl)(C)C>>[CH:1]1([SiH:5]([CH:6]([CH3:7])[CH3:8])[CH:9]([CH3:10])[CH3:11])[CH2:2][CH2:4]1
Reactant: CC(C)C[SiH](C(C)C)C(C)C
Agent: CC(C)[SiH](Cl)C(C)C
Product: CC(C)[SiH](C(C)C)C1CC1

Procedure:
The procedure of synthesizing Compound 40a was repeated, except that diisopropylchlorosilane (4.10 mL, 96.0 mmol) and cyclopropylmagnesium bromide THF solution (1.0M, 100 mL) were employed, whereby the Compound 44a was obtained as a colorless liquid (boiling point; 35 mmHg, 86 to 89° C. fraction, 1.84 g, 50%).
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])(C)(C)C.Br[C:20]1[CH:21]=[C:22]([S:26]([CH2:29][CH2:30][OH:31])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:18])=[C:10]([C:16]#[C:17][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([S:26]([CH2:29][CH2:30][OH:31])(=[O:28])=[O:27])[CH:21]=2)[CH:11]=1
Reactant: O=S(=O)(CCO)c1cccc(Br)c1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: O=C(O)COc1ccc(Cl)cc1C#Cc1cccc(S(=O)(=O)CCO)c1

Procedure:
Following the general method as outlined in Example 10, starting from tert-butyl(4-chloro-2-ethynylphenoxy)acetate (Intermediate 3) and 2-(3-bromo-benzenesulfonyl)-ethanol (Intermediate 7), the title compound was obtained as a beige solid after purification by preparative HPLC.
Reaction SMILES: [CH3:1][C@H:2]1[N:7]([CH2:8][C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[N:12]=[N:11][N:10]=2)[CH2:6][CH2:5][NH:4][C:3]1=[O:24].I[CH2:26][CH3:27].[H-].[Na+]>CN(C)C=O>[CH2:26]([N:4]1[CH2:5][CH2:6][N:7]([CH2:8][C:9]2[N:13]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=3)[N:12]=[N:11][N:10]=2)[C@H:2]([CH3:1])[C:3]1=[O:24])[CH3:27]
Reactant: CCI
Reactant: C[C@@H]1C(=O)NCCN1Cc1nnnn1-c1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1CCN(Cc2nnnn2-c2ccc(C(F)(F)F)cc2)[C@H](C)C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (3R)-3-methyl-4-({1-[4-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)-2-piperazinone (100 mg, 0.294 mmol, intermediate 18), in N,N-Dimethylformamide (DMF) (1 mL) was added iodoethane (0.026 mL, 0.323 mmol) and sodium hydride (23.5 mg, 0.588 mmol). The resulting reaction mixture was stirred at room temperature for 24 hours.
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:15]=[CH:14][N+:13]([O-])=[CH:12][CH:11]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1.C[Si]([C:21]#[N:22])(C)C.C(N(CC)CC)C>C(#N)C>[N:1]1([CH:6]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:21]#[N:22])[CH:11]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCCC(c1cc[n+]([O-])cc1)n1ccnc1
Reactant: C[Si](C)(C)C#N
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCC(c1ccnc(C#N)c1)n1ccnc1
Reaction time: 22 h
Yield: 89.9 %

Procedure:
0.109 g of 4-[1-(1-imidazolyl)-butyl]pyridine-N-oxide is dissolved in 2 ml of acetonitrile, 0.150 g of trimethylsilyl cyanide and 0.101 g of triethylamine are added to it. The reaction is left for 22 hours at 110° C. The mixture is concentrated by evaporation in a vacuum and then distilled on a bulb tube, boiling point: 210°-220° C./0.035 mbar. 0.102 g of 4-[1-(1-imidazolyl)-butyl]-2-cyanopyridine is obtained as brownish oil.
Reaction SMILES: [NH2:1][CH:2]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][N:10]=1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.C(N(CC)CC)C.[C@:23]12([CH3:35])[C:29]([CH3:31])([CH3:30])[CH:26]([CH2:27][CH2:28]1)[CH2:25][CH:24]2[C:32](Cl)=[O:33]>ClCCl>[C@:23]12([CH3:35])[C:29]([CH3:30])([CH3:31])[CH:26]([CH2:27][CH2:28]1)[CH2:25][CH:24]2[C:32]([NH:1][CH:2]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][N:10]=1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1)=[O:33]
Reactant: NC(Cn1ccnc1)c1ccc(Cl)cn1
Reactant: CC1(C)C2CC[C@@]1(C)C(C(=O)Cl)C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CC[C@@]1(C)C(C(=O)NC(Cn1ccnc1)c1ccc(Cl)cn1)C2
Reaction time: 1.5 h

Procedure:
To a solution of 0.38 g of 1-amino-1-(5-chloro-2-pyridyl)-2-(1H-imidazol-1-yl)ethane (racemic compound, see A) above) in 4 ml of dry dichloromethane is added 0.26 g (0.36 ml) of triethylamine. The mixture is stirred and cooled to -79°. Then 0.44 g of (1S)(-)-camphanic acid chloride are added in such a way that the temperature does not exceed -74°. Stirring is continued for additionally 90 minutes without further cooling. For working up the mixture is poured onto ice-water, extracted three times with dichloromethane and washed with brine. After drying with sodium sulfate the solvent is evaporated. A mixture of the two diastereomeric amides is obtained which is separated by chromatography over silica gel (dichloromethane/methanol/heptane=10/1/5). The two compounds are obtained as white crystals:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:21]2[CH:20]=[C:19]([C:22](=[O:24])[CH3:23])[CH:18]=[CH:17][C:16]=2[S:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:26].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CN(C)C=O.CCOCC>[C:22]([C:19]1[CH:18]=[CH:17][C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([OH:26])=[O:1])[C:21]=2[CH:20]=1)(=[O:24])[CH3:23]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: CC(=O)c1ccc2c(c1)N(CCCCCCO)c1ccccc1S2
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2c(c1)N(CCCCCC(=O)O)c1ccccc1S2
Temperature: 25 °C
Reaction time: 12 h
Yield: 23.4 %

Procedure:
A solution of 41 mg (0.12 mmol) of 1-[10-(6-hydroxyhexyl)-10H-phenothiazin-2-yl]ethanone in 0.16 mL of N,N-dimethylformamide is treated with 158 mg (0.42 mmol) of pyridinium dichromate and stirred at room temperature for 12 hours. The mixture is diluted with ether and filtered through a pad of celite with the aid of 100 mL of ether. The filtrate is washed successively with 10% sodium bisulfate solution and saturated sodium chloride solution, then dried over magnesium sulfate and concentrated in vacuo to give 10 mg (23%) of 2-acetyl-10H-phenothiazine-10-hexanoic acid as a dark residue. The 1 H NMR (300 MHz, CDCl3) is consistent with the desired product. MS (CI) m/e 323 (M+ +H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:21]=1.O>COCCOC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:15])[CH:9]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:21]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Reactant: ClCc1cccc(Oc2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(Cc1cccc(Oc2ccccc2)c1)C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
To a solution of ethyl 3-(4-fluorophenyl)-3-oxopropionate (7.2 g, 34.3 mmol) in 1,2-dimethoxyethane (50 ml) was added sodium hydride (60% in oil, 1.37 g, 34.3 mmol) under ice-cooling and the mixture was stirred at room temperature for 30 min. To the reaction solution was dropwise added a solution of 1-(chloromethyl)-3-(phenyloxy)benzene (9.0 g, 41.6 mmol) in 1,2-dimethoxyethane (50 ml) and the reaction solution was heated under reflux overnight. The reaction solution was poured into water (200 ml) and extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene:hexane=1:1-toluene) to give ethyl 3-(4-fluorophenyl)-3-oxo-2-((3-(phenyloxy)phenyl)methyl)propionate (10.2 g, crude, 76%).