Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][N:9]([CH3:20])[C@@H:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[C:6]([CH3:21])[N:5]=[C:4]([C:22]2[C:27]([CH2:28][CH3:29])=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:30][CH3:31])[N:3]=1.CC(N(C)C)=O.[O:38]1[C:42]2([CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[O:41][CH2:40][CH2:39]1.C([O-])(O)=O.[Na+]>CCOC(C)=O>[CH2:28]([C:27]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:30][CH3:31])[C:22]=1[C:4]1[N:3]=[C:2]([N:45]2[CH2:46][CH2:47][C:42]3([O:41][CH2:40][CH2:39][O:38]3)[CH2:43][CH2:44]2)[C:7]([CH2:8][N:9]([CH3:20])[C@@H:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[C:6]([CH3:21])[N:5]=1)[CH3:29]
Reactant: CCc1cccc(CC)c1-c1nc(C)c(CN(C)[C@H]2CCCc3ccccc32)c(Cl)n1
Reactant: C1CC2(CCN1)OCCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCc1cccc(CC)c1-c1nc(C)c(CN(C)[C@H]2CCCc3ccccc32)c(N2CCC3(CC2)OCCO3)n1
Temperature: 85 °C

Procedure:
To a vial containing [4-chloro-2-(2,6-diethyl-phenyl)-6-methyl-pyrimidin-5-ylmethyl]-methyl-(1S)-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine (1.0 mL of a 0.2M DMA solution, 0.2 mmol) is added 1,4-dioxa-8-azaspiro(4,5)decane (1.0 ml of a 1.0M DMA solution, 5.0 eq.) and the resulting solution is vortex heated at 85° C. for 12 h. Once the reaction has cooled to room temperature, EtOAc (1.0 mL) and sat. NaHCO3 (1.0 mL) is added and the organic layer is plated directly onto a SiO2 preparatory chromatography plate and the product is eluted using hexanes:Et2O 1:1, which affords the title compound as a colorless oil. [mass expected (540.74); mass found (540.43)].
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:6][CH:7]=[CH2:8])[C:3](=[O:5])[CH3:4].[BrH:10]>C(Cl)(Cl)Cl.[Fe]>[Br:10][CH:7]([CH3:8])[CH2:6][C:2]([CH3:9])([CH3:1])[C:3](=[O:5])[CH3:4]
Reactant: Br
Reactant: C=CCC(C)(C)C(C)=O
Agent: [Fe]
Solvent: ClC(Cl)Cl
Product: CC(=O)C(C)(C)CC(C)Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
18.9 g (0.15 mole) of 3,3-dimethyl-5-hexen-2-one and 1.6 g (0.0054 mole) of iron-III bromide are dissolved in 150 ml of chloroform. 0.16 mole of hydrogen bromide gas are passed in at 0° C. in the course of 90 minutes. The mixture is subsequently stirred at room temperature for 2 hours and the organic phase is separated off, washed with water, dried over sodium sulphate and concentrated in vacuo. 27 g (87% of theory) of 5-bromo-3,3-dimethyl-2-hexanone of refractive index nD20 =1.4639 are obtained.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][N:3]=1.[ClH:15].N([O-])=O.[Na+].[OH-].[Na+]>O>[Cl:15][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][N:3]=1
Reactant: Cl
Reactant: Nc1ccc(Sc2ccccc2)cn1
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Clc1ccc(Sc2ccccc2)cn1
Temperature: -5 °C

Procedure:
Alternatively, 2-amino-5-(phenylthio) pyridine (30 g., 0.15 moles) is added portionwise to 30 ml. of concentrated hydrochloric acid at 0°. The resultant suspension is cooled to -15° C and 20.7 g. of sodium nitrite in 40 ml. of water is added dropwise while keeping the temperature at -15° to -10° C. After stirring for an additional hour at -5° C, an aqueous 30% sodium hydroxide solution is slowly added to pH7 while not allowing the temperature to exceed 0° C. The resultant mixture is extracted with methylene chloride and the combined extracts are washed with water, dried and evaporated in vacuo to yield 2-chloro-5-(phenylthio) pyridine.
Reaction SMILES: C([O:3][C:4](=[O:12])[C:5]([F:11])([F:10])[CH:6]([OH:9])[CH2:7][CH3:8])C.CO.[OH-].[Na+].Cl>O>[F:10][C:5]([F:11])([CH:6]([OH:9])[CH2:7][CH3:8])[C:4]([OH:12])=[O:3]
Reactant: CCOC(=O)C(F)(F)C(O)CC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC(O)C(F)(F)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.1 %

Procedure:
Into a 10-L glass flask with a dropping funnel, 784 g (purity: 98%, 4.30 mol) of 2,2-difluoro-3-hydroxy-pentanoic acid ethyl ester, 300 mL of methanol and 2400 mL of water were added. The glass flask was cooled with ice water, followed by dropping 515 g (6.18 mol/1.4 eq) of 48% aqueous sodium hydroxide solution into the glass flask over 2 hours. The resulting solution was heated to room temperature and stirred for 1 hour. The completion of the reaction was confirmed by gas chromatography. The solution was washed twice with 800 mL of diisopropyl ether. The glass flask was again cooled with ice water. Then, 717 g (6.88 mmol/1.6 eq) of concentrated hydrochloric acid was dropped into the glass flask. After confirming that the pH of the solution was 1, the solution was stirred for 1 hour at room temperature. Subsequently, the solution was separated into an organic layer and an aqueous layer with the addition of 1000 mL of a mixed solution of diisopropyl ether and ethyl acetate. The aqueous layer was extracted three times with 1000 mL of a mixed solution of diisopropyl ether and ethyl acetate. The thus-obtained organic layers were combined and concentrated under a reduced pressure. With this, 683 g of 2,2-difluoro-3-hydroxy-pentanoic acid was obtained (yield: 98%, purity: 95%).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:6]([CH3:11])=[CH:7][CH:8]=[CH:9][CH:10]=1)=O.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:15]=1C#N.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:3]1[C:5]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:11]=[C:1]([C:20]2[CH:21]=[C:14]([O:13][CH3:12])[CH:15]=[CH:18][C:19]=2[O:22][CH3:23])[N:2]=1
Reactant: COc1ccc(OC)c(C#N)c1
Reactant: CNC(=O)c1ccccc1C
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc(OC)c(-c2cc3ccccc3c(Cl)n2)c1

Procedure:
3-(2,5-Dimethoxyphenyl)isoquinolin-1-one (0.61 g) obtained by reacting N-methyl-o-toluamide (1.64 g) and 2,5-dimethoxybenzonitrile (1.80 g) according to Example 10-1 was reacted with phosphorous oxychloride (10 ml) according to Example 10-2, to give 1-chloro-3-(2,5-dimethoxyphenyl)isoquinoline, which was then reacted with N-ethylpiperazine (15 ml) at 100° C. for 8 hr. The reaction solution was evaporated, and to the resulting residue were added ethyl acetate and water. The resulting organic layer was washed with water and brine, and then dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give the free compound of the title compound as a pale yellow oil.
Reaction SMILES: [C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]1([CH2:22][CH:23]=O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:23][CH2:22][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Nc1ccccc1)N1CCNCC1
Reactant: O=CCc1ccccc1
Product: O=C(Nc1ccccc1)N1CCN(CCc2ccccc2)CC1

Procedure:
The title compound was prepared from piperazine-1-carboxylic acid phenylamide and phenylacetaldehyde. 1H NMR (400 MHz, CDCl3): 7.37-7.19 (m, 9H), 7.06-7.02 (m, 1H), 6.31 (s, 1H), 3.55-3.53 (m, 4H), 2.85-2.81 (m, 2H), 2.67-2.56 (m, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:12]([NH2:13])=[C:11]([CH3:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[O:29]1[CH2:34][CH2:33][CH:32]([C:35](Cl)=[O:36])[CH2:31][CH2:30]1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:12]([NH:13][C:35]([CH:32]2[CH2:33][CH2:34][O:29][CH2:30][CH2:31]2)=[O:36])=[C:11]([CH3:19])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(OCc2ccccc2)cc([N+](=O)[O-])c1N
Reactant: O=C(Cl)C1CCOCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(OCc2ccccc2)cc([N+](=O)[O-])c1NC(=O)C1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.22 g (0.85 mmol) 4-(benzyloxy)-2-methyl-6-nitroaniline were placed in 5 mL DCM. 0.17 mL (1.00 mmol) DIPEA and 0.10 mL (1.00 mmol) tetrahydro-2H-pyran-4-carbonyl chloride were added and the mixture was stirred for 2 h at RT. A further 0.10 mL (1.00 mmol) tetrahydro-2H-pyran-4-carbonyl chloride were added and the mixture was stirred overnight at RT. The reaction mixture was diluted with DCM and washed with water. The organic phase was evaporated down i.vac.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[CH:21]=O.O>O1CCCC1>[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[CH:21]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
To a mixture of sodium hydride (0.84 g: 55% dispersion in mineral oil) and tetrahydrofuran (40 ml) was dropwise added a solution of ethyl diethylphosphonoacetate (4.33 g) in tetrahydrofuran (20 ml) with ice-cooling of 6° to 12° C. over a 12 minutes period. After stirring at room temperature for 30 minutes, to the mixture thus obtained was dropwise added a solution of 3,5-dichlorobenzaldehyde (3.07 g) in tetrahydrofuran (20 ml) with ice-cooling of 8° to 11° C. over a 10 minutes period. After stirring at room temperature for 4 hours, the reaction mixture was poured into water and extracted twice with ethyl acetate. The combined extract was washed with water, dried and concentrated. The residue was purified by flash column chromatography through silica gel (100 g). Fractions eluted with a 99:1 mixture of hexane and ethyl acetate were collected and worked up to afford the title compound (3.33 g), melting at 71°-73° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][N:3]=1.O.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[C:24](#[N:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>[Cu]Br>[Br:8][C:6]1[CH:5]=[CH:4][N:3]2[N:31]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:1]=[C:2]2[CH:7]=1
Reactant: Nc1cc(Br)ccn1
Reactant: N#Cc1ccccc1
Agent: [Cu]Br
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: O
Product: Brc1ccn2nc(-c3ccccc3)nc2c1
Temperature: 130 °C
Yield: 75 %

Procedure:
A mixture of 2-amino-4-bromopyridine (10.0 g, 56.6 mmol), copper (I) bromide (400 mg, 2.70 mmol), 1,10-phenanthroline monohydrate (560 mg, 2.80 mmol) and benzonitrile (130 mL) was heated in a 350 mL 4-necked flask to 130° C. During 45 h a gentle flow of O2/N2 (5:95) was bubbled through the reaction mixture (>99% conversion, HPLC method see below). The dark brown suspension was then cooled to 0-5° C. and filtered. The filter cake was washed with TBME (50 mL) and dried to yield crude 7-bromo-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine (11.6 g, 75%) as a green solid with 100% purity (HPLC area-%, HPLC method see below).
Reaction SMILES: [C:1]([C:4]([NH:9][C:10]([C:12]1[C:21]([C:22]([OH:24])=[O:23])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1)=O)([CH3:8])[CH:5]([CH3:7])[CH3:6])(=[O:3])[NH2:2].[OH-].[Na+].Cl>O>[CH:5]([C:4]1([CH3:8])[C:1](=[O:3])[NH:2][C:10]([C:12]2[C:21]([C:22]([OH:24])=[O:23])=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[N:9]1)([CH3:7])[CH3:6]
Reactant: CC(C)C(C)(NC(=O)c1nc2ccccc2cc1C(=O)O)C(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)C1(C)N=C(c2nc3ccccc3cc2C(=O)O)NC1=O

Procedure:
A solution of 2-[(1-carbamoyl-1,2-dimethylpropyl)carbamoyl]-3-quinolinecarboxylic acid (0.152 mol), in water (50 ml) containing sodium hydroxide (0.06 mol) is heated at 75° to 80° C. for 2 hours. The solution is cooled in an ice bath and acidified with concentrated hydrochloric acid, added in small increments. The resulting precipitate is filtered, washed with water, air dried, and recrystallized from acetone to afford the 2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-3-quinolinecarboxylic acid, mp 239°-243.5° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.Br[C:38]1[C:46]2[O:45][C:44]([CH2:47][CH3:48])=[N:43][C:42]=2[C:41]([O:49][CH:50]([F:52])[F:51])=[CH:40][CH:39]=1.[C]=[O:54].C1[CH2:59][O:58]CC1.O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:51][CH:50]([F:52])[O:49][C:41]1[C:42]2[N:43]=[C:44]([CH2:47][CH3:48])[O:45][C:46]=2[C:38]([C:59]([OH:58])=[O:54])=[CH:39][CH:40]=1
Reactant: [C]=O
Reactant: C1CCOC1
Reactant: CCc1nc2c(OC(F)F)ccc(Br)c2o1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: CCc1nc2c(OC(F)F)ccc(C(=O)O)c2o1
Temperature: 25 °C

Procedure:
Palladium(II) acetate (54 mg), 1,3-bis(diphenylphosphino)propane (198 mg) and triethylamine (3.3 ml) were added to a solution of 7-bromo-4-difluoromethoxy-2-ethylbezooxazole (0.7 g) in THF/water (30 ml/15 ml). The mixture was heated at 90° C. under 100 psi of carbon monoxide for 4 days. The reaction mixture was allowed to cool to room temperature and the pressure released. The THF was removed in vacuo and the residue diluted with water (10 ml) and washed with ethyl acetate (50 ml). The aqueous layer was acidified to pH 3 with 2N hydrochloric acid and extracted with ethyl acetate (150 ml). Separation of the organic layer, drying over magnesium sulphate, filtering and removal of the solvent in vacuo afforded the title compound as an off-white solid (0.47 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([NH2:13])[CH:9]=2)=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:16]=1[C:17](Cl)=[O:18]>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:16]=1[C:17]([NH:13][C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[O:12][N:11]=1)=[O:18]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: Nc1cc(-c2ccc(Cl)cc2)on1
Solvent: Cc1ccccc1
Product: O=C(Nc1cc(-c2ccc(Cl)cc2)on1)c1c(Cl)cccc1Cl
Temperature: 25 °C

Procedure:
5-(4-Chlorophenyl)-3-aminoisoxazole (25 grams) was placed in a 500 ml. 3-necked flask under an atmosphere of nitrogen. Following the addition of 150 ml. of toluene, the reaction mixture was stirred continuously and treated in rapid fashion (15 minutes), with 2,6-dichlorobenzoylchloride (60 grams). The mixture was then heated to reflux for 18 hours and allowed to gradually cool to room temperature. When the reaction mixture was further cooled to approximately 0° C. the final product precipitated. The product was filtered and recrystallized from acetone to yield 28 grams, m.p. 228°-229° C.
Reaction SMILES: O1CCOCC1.Cl.[NH2:8][C:9]([NH2:11])=[NH:10].[OH-].[Na+].[CH2:14]([O:21][C:22](Cl)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O>[C:22]([NH:10][C:9]([NH2:11])=[NH:8])([O:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:23]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N=C(N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: N=C(N)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1,4-Dioxane (20 ml) is added to a solution of guanidine hydrochloride (0.96 g, 10 mmol) and sodium hydroxide (0.8 g, 20 mmol) in water (10 ml) and the resulting mixture is cooled to 0° C. Benzyloxycarbonyl chloride (1.1 ml, 7.7 mmol) is added dropwise with vigorous stirring over a period of 10 min. After the addition is completed, the ice-bath is removed and stirring is continued for 1 h at room temperature. The mixture is concentrated in vacuo to one third of its original volume and extracted three times with ethyl acetate (20 ml each). The combined extracts are washed with brine (20 ml) and dried with anhydrous sodium sulfate. After filtering and removal of the solvent under reduced pressure N-Cbz-guanidine (1.31 g, 88%) is obtained as a white powder: mp: 120-122° C.; 1H NMR (360 MHz, DMSO-d6) δ 7.35-7.25 (m, 5H), 6.88 (br s, 4H), 4.95 (s, 2H); Electrospray-MS m/e 194 (M+H+).
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([N+]([O-])=O)=[CH:9][C:8]=1[CH3:16])[CH2:3][C:4]([OH:6])=[O:5].CC1C=C([N+:26]([O-:28])=[O:27])C=CC=1C=O.C(O)(=O)CC(O)=O.C([O-])(=O)C.[NH4+]>C(O)C>[NH2:1][CH:2]([C:7]1[CH:12]=[C:11]([N+:26]([O-:28])=[O:27])[CH:10]=[CH:9][C:8]=1[CH3:16])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: Cc1cc([N+](=O)[O-])ccc1C(N)CC(=O)O
Reactant: Cc1cc([N+](=O)[O-])ccc1C=O
Agent: CC(=O)[O-]
Agent: O=C(O)CC(=O)O
Agent: [NH4+]
Solvent: CCO
Product: Cc1ccc([N+](=O)[O-])cc1C(N)CC(=O)O
Yield: 45 %

Procedure:
Following the General Procedure of Description 3, 3-amino-3-(2-methyl-4-nitro-phenyl)propanoic acid (2c) was prepared from 2-methyl-4-nitro-benzaldehyde (2b) (800 mg, 5.0 mmol), malonic acid (520 mg, 5.0 mmol), and ammonium acetate (NH4OAc) (578 mg, 7.5 mmol) in ethanol (EtOH) (10 mL) at reflux for 48 h (oil bath). The reaction was followed by LC/MS to completion. Filtrative work-up afforded 510 mg (45% yield) of the target compound (1c) as a near colorless solid which was of sufficient purity to be used directly in the next step without further purification and isolation. 1H NMR (300 MHz, D2O): δ 8.01-7.97 (m, 2H), 7.46 (d, J=8.4 Hz, 1H), 4.83 (t, J=7.2 Hz, 1H), 2.70-2.65 (m, 2H), 2.33 (s, 3H) ppm. LC/MS: Rt=1.274 min; ESI (pos.) m/z=225.1 (M+H+)+.
Reaction SMILES: [CH2:1]([N:8]([CH3:12])[CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20](F)[C:17]=1[C:18]#[N:19]>CN(C=O)C.CCOCC>[CH2:1]([N:8]([CH2:9][CH2:10][O:11][C:20]1[CH:21]=[CH:22][CH:23]=[C:16]([Cl:15])[C:17]=1[C:18]#[N:19])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1c(F)cccc1Cl
Reactant: CN(CCO)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CN(CCOc1cccc(Cl)c1C#N)Cc1ccccc1
Temperature: 25 °C

Procedure:
A solution of N-benzyl-N-methylethanolamine (145 g) in dry DMF (500 ml) was added dropwise to a stirred suspension of sodium hydride (35.15 g of a 60% dispersion in mineral oil) in dry DMF (1000 ml) over 20 minutes under nitrogen. The mixture was heated on a steam bath for 30 minutes to give a solution. The solution was cooled to ambient temperature and a solution of 2-chloro-6-fluorobenzonitrile (136.7 g) in dry DMF (300 ml) was added over 30 minutes with stirring. The mixture was heated on a steam bath for 3 hours with stirring and distilled at approximately 13 mbar to remove 1 liter of DMF. The residue was cooled to ambient temperature and poured into ice (2 l), basified with 5M sodium hydroxide solution to pH 14 and extracted with dichloromethane to give an oil. This oil was dissolved in ether (2 l) and washed with water (4×200 ml). The ether solution was extracted with 2M hydrochloric acid (500 ml) which gave three layers in the separating funnel. The bottom two layers were run off and the top ether layer was extracted with 2M hydrochloric acid (2×250 ml). The combined acidic layers were basified with concentrated sodium hydroxide solution with cooling and then extracted with dichloromethane to give 2-[2-(N-benzyl-N-methylamino)ethoxy]-6-chlorobenzonitrile as an oil.
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].C[O-].[Na+].[C:8]([C:10]1[CH:11]=[C:12]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[O:22][CH:21]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:20]/[C:19]/3=[N:32]\[C:33]#[N:34])[CH:13]=[CH:14][CH:15]=1)#[N:9]>CO>[NH2:34][C:33]1[N:3]([CH3:2])[O:4][C:19]2([C:18]3[C:23](=[CH:24][CH:25]=[C:16]([C:12]4[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=4)[C:8]#[N:9])[CH:17]=3)[O:22][CH:21]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[CH2:20]2)[N:32]=1
Reactant: N#C/N=C1\CC(c2cccnc2)Oc2ccc(-c3cccc(C#N)c3)cc21
Reactant: CNO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN1OC2(CC(c3cccnc3)Oc3ccc(-c4cccc(C#N)c4)cc32)N=C1N
Reaction time: 0.17 h
Yield: 3.1 %

Procedure:
To a solution of methylhydroxylamine HCl salt (17 mg, 0.2 mmol) in anhydrous MeOH (2 mL) was added NaOMe (25% in MeOH (Wt. %), 0.10 mL, 0.2 mmol), followed by (E)-N-(6-(3-cyanophenyl)-2-(pyridine-3-yl)chroman-4-ylidene)cyanamide (70 mg, 0.2 mmol). After stirring for 10 mins, the solvent was removed in vacuo. The resulting residue was redissolved in DCM (5 mL). The mixture was filtered, and the solvent was removed to give the residue, which was purified by preparative TLC and preparartive HPLC to give 3-(3′-amino-2′-methyl-2-(pyridine-3-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazole]-6-yl)benzonitrile (2.5 mg, 3%). 1H-NMR (MeOD): 2.40-2.47 (t, 1H), 2.92-3.16 (m, 1H), 3.46 (s, 3H), 5.61-5.69 (m, 1H), 7.21 (m, 1H), 7.64-7.67 (m, 1H), 7.75 (d, 1H), 7.81-7.88 (m, 2H), 7.96-8.00 (t, 1H), 8.04-8.10 (t, 2H), 8.40 (m, 1H), 8.43 (m, 1H), 8.75 (s, 1H).
Reaction SMILES: [C@@H:1]1([N:9]2[CH:16]=[CH:15][C:13]([NH2:14])=[N:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.[CH3:17][C:18]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])[CH3:19]>N1C=CC=CC=1>[Si:21]([O:7][CH2:6][C@H:5]1[O:8][C@@H:1]([N:9]2[CH:16]=[CH:15][C:13]([NH2:14])=[N:12][C:10]2=[O:11])[CH2:2][C@@H:3]1[OH:4])([C:18]([CH3:20])([CH3:19])[CH3:17])([CH3:23])[CH3:22]
Reactant: Nc1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(N)nc2=O)C[C@@H]1O
Temperature: 25 °C
Reaction time: 20 h
Yield: 83.9 %

Procedure:
To a stirred solution of 2′-deoxycytidine 47 (1.00 g; 4.40 mmol) in dry pyridine (37 mL), TBDMSCl (814 mg; 5.39 mmol) was added. The mixture was stirred at room temperature for 20 h. After evaporation, the residue was purified by flash column chromatography using CH3OH—CH2Cl2 (1:10) as the eluent to afford 48 as white solid (1.26 g; 84% yield): 1H NMR (400 MHz, CD3OD) δ 8.03 (d, J=7.5 Hz, 1H, 6-H), 6.23 (t, J=6.3 Hz, 1H, 1′-H), 5.86 (d, J=7.5 Hz, 1H, 5-H), 4.35 (m, 1H, 3′-H), 3.91-3.98 (m, 2H, 4′-H and one of 5′-H), 3.85 (dd, J=2.5, 11.3 Hz, 1H, one of 5′-H), 2.36-2.43 (ddd, J=4.1, 6.1, 13.5 Hz, 1H, one of 2′-H), 2.05-2.13 (m, 1H, one of 2′-H), 0.94 (s, 9H, C(CH3)3), 0.14 (s, 3H, one of SiCH3), 0.13 (s, 3H, one of SiCH3); 13C NMR (100 MHz, CD3OD) δ 167.1, 157.6, 142.1, 95.6, 88.7, 87.4, 71.7, 64.1, 42.7, 26.5, 19.3, −5.2, −5.3; HRMS (FAB+) calcd for C15H28O4N3Si (M+H+): 342.1849, found: 342.1844.
Reaction SMILES: [Na].[C:2]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=1.[CH2:15]([O:17][C:18](=[O:28])[CH:19](Br)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH3:16]>C(O)C>[CH2:15]([O:17][C:18](=[O:28])[CH:19]([O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)=[CH:13][CH:12]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH3:16]
Reactant: CCCCCCCC(Br)C(=O)OCC
Reactant: Oc1ccc(C2=CCCCC2)cc1
Agent: [Na]
Solvent: CCO
Product: CCCCCCCC(Oc1ccc(C2CCCCC2)cc1)C(=O)OCC

Procedure:
To a solution of 2.4 g of sodium in 100 ml of absolute ethanol are added initially 15 g of p-(1-cyclohexenyl)-phenol in a small amount of absolute ethanol at room temperature under anhydrous conditions and with stirring. 34 Grams of α-bromo-nonanoic acid ethyl ester are then added dropwise and the reaction mixture is stirred for 24 hours at 50° C. The ethanol is subsequently stripped off in vacuo and the residue is partitioned between water and ice-cold N sodium hydroxide solution. The organic phase is washed until neutral, dried over sodium sulphate and concentrated in vacuo. The residue yields the crude α-[p-(1-cyclohexyl)-phenoxy]-nonanoic acid ethyl ester of the formula ##STR15## in the form of an oil.