Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[N:11]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:10][CH:9]([CH2:16][OH:17])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:21]1[C:26]([C:27]#[N:28])=[CH:25][CH:24]=[CH:23][N:22]=1.O>CN(C)C=O>[C:1]1([CH:7]2[N:11]([C:12]([CH3:13])([CH3:14])[CH3:15])[CH2:10][CH:9]([CH2:16][O:17][C:21]3[C:26]([C:27]#[N:28])=[CH:25][CH:24]=[CH:23][N:22]=3)[O:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)N1CC(CO)OC1c1ccccc1
Reactant: N#Cc1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)N1CC(COc2ncccc2C#N)OC1c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To S -2-phenyl-3-tert. butyl-5-hydroxymethyloxazolidine (7 grams, 0.03 moles) in 35 ml. of N,N-dimethylformamide (DMF) is added 1.3 grams (0.03 moles of sodium hydride (57% dispersion in mineral oil). This mixture is heated 5 minutes over steam and then is allowed to stir 15 minutes at room temperature. 4.1 grams (0.03 moles) of 2-chloro-3-cyanopyridine in 20 ml of DMF is then added and the resultant reaction mixture is stirred four hours at room temperature. Water is then added and an oil separates. This oil is extracted three times with 25 ml of chloroform each time. This chloroform exrract is dried over sodium sulfate and concentrated under reduced pressure (20 mm) over steam to yield the product, S -2-phenyl-3-tert. butyl-5-(3-cyano-2-pyridyloxymethyl)oxazolidine, as an oil. This oil is then suspended in 1N HCl (50 ml), heated 5 minutes over steam and then is stirred for 15 minutes at room temperature. The solution obtained is then extracted twice with 25 ml of diethylether each time. The extracted aqueous layer is made basic by addition of saturated aqueous sodium carbonate solution. This aqueous solution is then extracted with ethyl acetate (3 × 25 ml) and the ethylacetate solution is dried over sodium sulfate. The dried ethyl acetate solution is then concentrated under reduced pressure (20 mm) over steam to yield an oil. This oil is chromatographed on alumina. The chromatographic fractions are concentrated to yield an oil which is dissolved in diethyl ether. Ethanolic HCl (saturated solution) is added to this ether solution until solid separation is substantially complete. The separated semi-solid is recrystallized from isopropanol/ether (ether added to isopropanol to the point of turbidity) to yield 1 gram of S -2-(3-tert. butylamino-2-hydroxypropoxy)-3-cyanopyridine hydrochloride, melting at 161°-163° C.
Reaction SMILES: [SH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[CH3:12][S:13]S(C)(=O)=O>O.C(O)C>[CH3:12][S:13][S:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1
Reactant: CSS(C)(=O)=O
Reactant: O=C(O)c1ccc(CS)cc1
Solvent: O
Solvent: CCO
Product: CSSCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
4-(mercaptomethyl)benzoic acid (36, 500 mg, 2.97 mmol) was dissolved in water (10 mL) and cooled in an ice bath. The cooled solution stirred as methyl methanethiolsulfonate (413 mg, 3.27 mmol) dissolved in ethanol (5.00 mL) was added. Following addition, the cooling bath was removed and the reaction was stirred overnight at room temperature. After proceeding overnight, the reaction was diluted with saturated sodium chloride and extracted with ether. The combined extracts were washed with sodium chloride, dried over anhydrous sodium sulfate and concentrated in vacuo. The product was isolated using silica flash chromatography eluting with a gradient of 40-60% ethyl acetate in hexanes containing 1% acetic acid over 20 min. to give 482 mg of the desired product, 4-((methyldisulfanyl)methyl)benzoic acid (37b), in 73.5% yield. 1H NMR (CDCl3) δ 2.121 (3H, s), 3.938 (2H, s), 7.457 (2H, d, J=8.4 Hz), 8.068 (2H, d, J=8 Hz).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:10]([CH:21]([CH:25]([CH3:27])[CH3:26])[C:22]([OH:24])=O)[C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Cl.[CH2:39]([O:46][NH2:47])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[N:10]([CH:21]([CH:25]([CH3:27])[CH3:26])[C:22]([NH:47][O:46][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:24])[C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NOCc1ccccc1
Reactant: COc1ccc(C2CN(Cc3ccccc3)C(=O)N2C(C(=O)O)C(C)C)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2CN(Cc3ccccc3)C(=O)N2C(C(=O)NOCc2ccccc2)C(C)C)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.5 %

Procedure:
2-(3-Benzyl-5-(4-methoxyphenyl)-2-oxoimidazolidin-1-yl)-3-methylbutyric acid (150 mg; 0.39 mmol) was introduced into DMF (10 ml) and cooled to 0° C. Then N,N-diisopropylethylamine (202 mg; 1.56 mmol), O-benzylhydroxylamine hydrochloride (125 mg, 0.78 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU; 223 mg; 0.58 mmol) were added, and the mixture was stirred at 0° C. for 2 h. The reaction solution was then concentrated and partitioned between dilute HCl solution/EtOAc and extracted with EtOAc (2×). The combined organic phases were dried over MgSO4, and the solvent was removed in a rotary evaporator. Purification by chromatography resulted in 2-(3-benzyl-5-(4-methoxyphenyl)-2-oxoimidazolidin-1-yl)-N-benzyloxy-3-methylbutyramide (116 mg; 0.24 mmol). MS: 488.25 (M+H); Rt: 3.50 min (method: gradient 95% H2O (0.05% TFA) to 95% acetonitrile over 3.5 min, 95% acetonitrile for 1.0 min, 5% acetonitrile 1.0 min; flow rate 0.5 ml/min; column 1 μL (Merck Purospher 5μ 2×55 mm); 30° C.)
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl(O)(=O)=O.[CH2:12](O)[CH3:13]>>[CH2:12]=[CH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:12]=[CH2:13]
Reactant: CCO
Reactant: Cc1ccccc1
Agent: [O-][Cl+2]([O-])O
Product: C=C
Product: C=Cc1ccccc1

Procedure:
5 ml (50 μmol of Ti) of toluene solution in which the metallocene was dissolved were added thereto while vigorously agitating. After agitating for 2 hours, 10 wt % of chloric acid-ethanol solution was added to terminate a reaction and the reactant was filtered, washed with ethanol and dried in a vacuum oven of 50° C. to obtain a final styrene/ethylene copolymer.
Reaction SMILES: BrC[N:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]1[CH3:14].[CH2:15]([NH2:17])[CH3:16].[C:18](#N)C>>[CH3:14][C:4]1[NH:3][C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:18][NH:17][CH2:15][CH3:16])[CH:10]=2)[N:5]=1
Reactant: Cc1nc2ccccc2c(=O)n1CBr
Reactant: CC#N
Reactant: CCN
Product: CCNCc1ccc2nc(C)[nH]c(=O)c2c1
Reaction time: 4 h

Procedure:
A mixture of 6 bromomethyl 3,4 dihydro-2-methylquinazolin-4-one (prepared as described in Example 3; 10 g), anhydrous ethylamine (7.9 ml) and acetonitrile (250 ml) was stirred rapidly at laboratory temperature for 4 hours. The mixture was evaporated to dryness, the residue was dissolved in water, filtered and the filtrate was evaporated. The residue was triturated in acetone to give N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl) N-ethylamine, as its hydrobromide salt (8.5 g), m.p. >260° C.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[CH2:7]([O:9][N:10]=[C:11]([C:15]1[N:19]=[C:18]([NH2:20])[S:17][N:16]=1)[C:12](O)=[O:13])[CH3:8]>C(Cl)Cl>[ClH:2].[CH2:7]([O:9][N:10]=[C:11]([C:15]1[N:19]=[C:18]([NH2:20])[S:17][N:16]=1)[C:12]([Cl:2])=[O:13])[CH3:8]
Reactant: CCON=C(C(=O)O)c1nsc(N)n1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCON=C(C(=O)Cl)c1nsc(N)n1
Product: Cl
Temperature: -20 °C
Yield: 169.3 %

Procedure:
To a solution of phosphorus pentachloride (54.6 g) in methylene chloride (500 ml) was added 2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)-acetic acid (syn isomer) (54.0 g) under stirring and cooling at -20° C. The mixture was stirred for 30 minutes at -15° to -12° C. and for 2 hours at -5° C. To the mixture containing precipitates of an object compound was added diisopropyl ether (500 ml) at -5° C. and the mixture was stirred for 30 minutes at -5° to 10° C. The resulting precipitates were collected by filtration, washed with diisopropyl ether and dried to give 2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetyl chloride hydrochloride (syn isomer) (60.17 g), mp. 125° to 127° C. (dec.).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:6](O)=[O:7])[CH:3]([CH3:5])[CH3:4].CN1CCOCC1.[NH:23]1[CH2:31][CH2:30][CH2:29][C@H:24]1[C:25]([O:27][CH3:28])=[O:26].[ClH:32]>C1COCC1>[NH2:1][C@H:2]([C:6]([N:23]1[CH2:31][CH2:30][CH2:29][C@H:24]1[C:25]([O:27][CH3:28])=[O:26])=[O:7])[CH:3]([CH3:5])[CH3:4].[ClH:32]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)C(C)C
Temperature: -15 °C
Reaction time: 8 h

Procedure:
Boc-Val-OH (3.00 g, 13.8 mmol) was dissolved in 10 ml of dry THF and cooled down to −15° C. To the mixture CAIBE (1.80 ml, 13.8 mmol) and NMM (1.52 ml, 13.8 mmol) where added and the solution was stirred until the formation of the mixed anhydride was complete. Then the mixture was brought to −10° C. and NMM (1.52 ml, 13.8 mmol) was added followed by H-Pro-OMe.HCl (2.29 g, 13.8 mmol). The mixture was allowed to reach room temperature and left overnight. After removing the solvent and the usual workup the resulting ester 1 was taken without further characterisation. The ester 1 was dissolved in HCl/HOAc (5 ml, 6N) and left at 0° C. until the removal of the Boc-group was complete. The solvent was then removed and the resulting oil was treated with diethylether to give a white solid 2.
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.Cl[CH2:27][CH2:28][S:29](Cl)(=[O:31])=[O:30].O>C(Cl)Cl>[CH:28]([S:29]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2][CH2:3]1)(=[O:31])=[O:30])=[CH2:27]
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: O=S(=O)(Cl)CCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CS(=O)(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Temperature: -15 °C
Yield: 42.8 %

Procedure:
A mixture of 11 g (50 mmol) of benzyl 1-piperazinecarboxylate and 16.1 g (125 mmol) of DIPEA in 200 mL CH2Cl2 was cooled to −15° C. and 6.3 mL (9.8 g, 60 mmol) of 2-chloroethanesulfonyl chloride was added slowly over 15 min. The mixture was allowed to warm to 0° C. over 30 min and water was then added. The organic layer was separated and washed successively with dil. HCl and aq. NaHCO3. After drying, the solvent was removed and the residue was chromatographed on silica, eluting with CH2Cl2/EtOAc 95:5, to give an oil, which was recrystallized from CH2Cl2/hexanes to give 6.64 g (43% yield) of benzyl 4-(vinylsulfonyl)-1-piperazinecarboxylate: mp (CH2Cl2/hexanes) 85-87° C.; 1H NMR (CDCl3) δ 7.39-7.30 (m, 5H), 6.40 (dd, J=16.6, 9.8 Hz, 1H), 6.25 (d, J=16.6 Hz, 1H), 6.06 (d, J=9.8 Hz, 1H), 5.14 (s, 2H), 3.61 (m, 4H), 3.14 (m, 4H); Anal. Calcd. for C14H18N2O4S: C, 54.2; H, 5.85; N, 9.0. Found: C, 54.1; H, 5.7; N, 9.1%.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][C@H:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[NH:2]1.C(N(CC)CC)C.[C:26](=[S:28])=[S:27].[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Cl)=[CH:32][CH:31]=1>C(O)C>[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][S:27][C:26]([N:2]2[C@@H:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:4][C:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[NH:12][C:13]=3[CH2:1]2)=[S:28])=[CH:32][CH:31]=1
Reactant: S=C=S
Reactant: CCOC(=O)[C@H]1Cc2c([nH]c3ccccc23)CN1
Reactant: ClCc1ccc(Cl)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H]1Cc2c([nH]c3ccccc23)CN1C(=S)SCc1ccc(Cl)cc1
Yield: 69 %

Procedure:
In the same manner as described in Example 53, ethyl (3R)-1,2,3,4-tetrahydro-β-carboline-3-carboxylate (2.00 g), triethylamine (1.07 g), carbon disulfide (0.65 ml), ethanol (60 ml) and 4-chlorobenzyl chloride (1.72 g) are reacted and treated. The product is recrystallized from ethyl acetate-n-hexane to give the title compound (2.75 g, 69%) as pale yellow needles, m.p. 198°-199° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([Cl:12])[C:7]([S:10][CH3:11])=[N:8][CH:9]=1)(=[O:3])[CH3:2].[BH4-].[Na+].Cl>C(O)C.O>[Cl:12][C:6]1[C:7]([S:10][CH3:11])=[N:8][CH:9]=[C:4]([CH:1]([OH:3])[CH3:2])[CH:5]=1
Reactant: CSc1ncc(C(C)=O)cc1Cl
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CSc1ncc(C(C)O)cc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.6 %

Procedure:
5-Acetyl-3-chloro-2-methylthiopyridine (24.1 g, 0.12 mol) was slurried in absolute ethanol (200 mL) and sodium borohydride (4.5 g, 0.118 mol) added in portions. The reaction mixture was stirred at room temperature for 48 hours and acidified to pH 2 with 2N hydrochloric acid. This was then diluted with water (200 mL) and the bulk of the ethanol evaporated under reduced pressure, the temperature of the mixture being maintained below 50° C. The reaction mixture was diluted with water (200 mL) and extracted twice with dichloromethane (15 mL). The combined organic extracts were washed with water (200 mL) and saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulphate, and evaporated to dryness to give the desired product (21.9 g, 90%) as an orange oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([OH:12])=[CH:7]2.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][CH:21]=1.O>CN1C(=O)CCC1.C(Cl)Cl>[CH3:31][O:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[O:32][CH3:33])[N:23]=[CH:22][CH:21]=[C:20]2[O:12][C:6]1[CH:7]=[C:8]2[C:3](=[CH:4][CH:5]=1)[C:2]([NH2:1])=[CH:11][CH:10]=[CH:9]2
Reactant: Nc1cccc2cc(O)ccc12
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc4c(N)cccc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-amino-2-naphthol (711 mg, 4.47 mmol) in NMP (3 ml), Cs2CO3 (4.37 g, 13.41 mmol) was added and the reaction was stirred at RT for 15 min. To the mixture, 4-chloro-6,7-dimethoxy-quinoline (500 mg, 2.23 mmol) was added and the vessel was sealed/clamped shut. The reaction was placed in the microwave and heated at 160° C. for 15 min, then 10 additional min with pre-stirring for 60 sec. The mixture was taken up into water and CH2Cl2, and filtered through Celite. The aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with water, 1N NaOH, and brine, dried with Na2SO4, filtered and concentrated in vacuo. The 6-(6,7-dimethoxy-quinolin-4-yloxy)-naphthalen-1-ylamine was purified by column chromatography using 0-10% MeOH in CH2Cl2.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6](Br)[C:5]([Cl:9])=[CH:4][N:3]=1.[C:10]([C:14]1[NH:18][N:17]=[C:16]([NH2:19])[CH:15]=1)([CH3:13])([CH3:12])[CH3:11].O.CC(=O)OCC>CCO>[Br:1][C:2]1[N:7]=[C:6]([NH:19][C:16]2[CH:15]=[C:14]([C:10]([CH3:13])([CH3:12])[CH3:11])[NH:18][N:17]=2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: CC(C)(C)c1cc(N)n[nH]1
Reactant: Clc1cnc(Br)nc1Br
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)c1cc(Nc2nc(Br)ncc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.6 %

Procedure:
A mixture of 2,4-dibromo-5-chloropyrimidine (500 mg, 1.85 mmol) and 5-tert-butyl-1H-pyrazol-3-amine (216 mg, 2.2 mmol, 1.2 eq) in EtOH (100 mL) was stirred at rt for 2 h. After addition of water and extraction with EA (3×), the combined organic layers were dried (Na2SO4), filtered, concentrated and purified by silica gel chromatography (EA/PE 1:2) to afford 2-bromo-N-(5-tert-butyl-1H-pyrazol-3-yl)-5-chloropyrimidin-4-amine (450 mg, 85%). LC-MS (m/z)=288 [M+H]+
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[C:13]2[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([N:27]1[CH:31]=[CH:30][N:29]=[CH:28]1)(N1C=CN=C1)=[O:21].NCCN1C[CH2:39][O:38][CH2:37][CH2:36]1.C(=O)(O)[O-].[Na+]>O1CCCC1.C(O)(=O)C.CCOCC>[N:29]1([CH2:30][CH2:31][NH:27][C:20](=[O:21])[O:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([CH:9]3[CH2:10][CH2:11][CH2:12][N:8]3[CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:14]=2)[CH2:28][CH2:39][O:38][CH2:37][CH2:36]1
Reactant: NCCN1CCOCC1
Reactant: Oc1cccc(C2CCCN2Cc2ccccc2)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(NCCN1CCOCC1)Oc1cccc(C2CCCN2Cc2ccccc2)c1
Reaction time: 48 h
Yield: 54 %

Procedure:
To a solution of 3-[1-phenylmethyl-2-pyrrolidinyl]phenol (0.64 g) in dry tetrahydrofuran (20 ml) was added 1,1'-carbonyldiimidazole (0.61 g) at ambient temperature, under nitrogen. The reaction mixture was stirred for 48 hrs, glacial acetic acid (0.50 ml) was added followed by a solution of 4-(2-aminoethyl)morpholine (0.43 ml) in tetrahydrofuran (1.0 ml) and glacial acetic acid (0.20 ml). After 3 hrs, the reaction mixture was poured into saturated sodium bicarbonate solution and ether. The layers were separated, and the aqueous phase was extracted with ether (2 times). The combined organic extracts were washed with saturated sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by radial chromatography, using ether as the eluent. The appropriate fractions were collected and concentrated to give 0.56 g (54%) of product. Recrystallization from ether/petroleum ether gave the analytical sample, mp 74°-77° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[C:18]([O:20]CC)=[O:19])=[CH:5][CH:4]=1.[CH3:23][O:24][C:25]1[CH:40]=[CH:39][C:28]([CH2:29]C(C(=O)C)C(OCC)=O)=[CH:27][CH:26]=1.[OH-:41].[Na+].[Cl-].C1([N+]#N)C=CC=CC=1>CCOC(C)=O.O>[CH2:23]1[O:24][C:25]2[CH:40]=[CH:39][C:28]([CH2:29][N:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)=[C:10]3[C:18]([OH:20])=[O:19])=[CH:27][C:26]=2[O:41]1
Reactant: [OH-]
Reactant: CCOC(=O)C(Cc1ccc(OC)cc1)C(C)=O
Reactant: CCOC(=O)c1[nH]c2ccccc2c1-c1ccc(OC)cc1
Agent: N#[N+]c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2c(C(=O)O)n(Cc3ccc4c(c3)OCO4)c3ccccc23)cc1
Temperature: 25 °C
Yield: 27 %

Procedure:
Ethyl 3-(4-methoxyphenyl)indole-2-carboxylate. To a solution of ethyl 2-(4-methoxybenzyl)-3-oxobutyrate (1.0 g, 4 mmol) in EtOAc (6 mL) stirred at ice bath temperature under an argon atmosphere was added a solution of NaOH (0.48 g, 12 mmol) in H2O (2 mL). This was immediately followed by the addition of an aqueous solution of benzenediazonium chloride (4.2 mmol) [prepared from aniline, (0.39 g, 4.2 mmol) in 6N HCl (0.5 mL) and NaNO2 (0.29 g, 4.2 mmol)]. After 10 min the mixture was partitioned between EtOAc (50 mL) and H2O (25 mL). The aqueous layer was washed with EtOAc (15 mL). The combined organic extracts were washed with saturated aqueous NaCl solution, dried (Na2SO4) and the solvent was removed in vacuo. The residue was dissolved in EtOH (10 mL) and the solution was saturated with HCl gas. This was refluxed for 1 h then cooled to room temperature and partitioned EtOAc (50 mL) and saturated aqueous NaHCO3 solution (50 mL). The aqueous layer was washed with EtOAc (15 mL). The combined organic extract was washed with H2O then saturated aqueous NaCl solution, dried (Na2SO4) and the solvent was removed in vacuo. Chromatography (silica gel, gradient elution from 25% Et2O/hexanes to 45% Et2O/hexanes) followed by crystallization from EtOAc/hexanes to afford the title compound (0.32 g, 27%); m.p. 109°-111° C.
Reaction SMILES: C1(C)C=C(C)C=C(C)C=1S(O[NH2:13])(=O)=O.[C:15]([SiH2:19][O:20][C:21]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([C:28]#[C:29][CH3:30])[CH:23]=1)([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[C:15]([SiH2:19][O:20][C:21]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:22]1[CH:27]=[CH:26][N:25]2[N:13]=[C:29]([CH3:30])[CH:28]=[C:24]2[CH:23]=1)([CH3:16])([CH3:17])[CH3:18]
Reactant: CC#Cc1cc(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)ccn1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cc2cc(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)ccn2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
A solution of O-mesitylenesulfonylhydroxylamine (18.6 g, 77.8 mmol, 5.0 equiv) in chloroform (50 ml) is added at 0-10° C. to a solution of 4-(tert-butyl-diphenyl-silanyloxymethyl)-2-prop-1-ynyl-pyridine in chloroform (50 ml). The resulting mixture is stirred at room temperature overnight. The solvent is removed in vacuo, and N,N-dimethylformamide (50 ml) is added to the residue. Potassium carbonate (4.30 g, 31.1 mmol, 2.0 equiv) is added, and the mixture is stirred at room temperature for 2 hours. The reaction mixture is diluted with water and extracted three times with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification via flash chromatography (gradient from hexane/EtOAc 100:0 to 30:70) affords the title compound (2.6 g, 42%). 1H NMR (400 MHz, d6-DMSO): δ=8.42 (d, J=7.1 Hz, 1H), 7.60-7.58 (m, 4H), 7.43-7.35 (m, 7H), 6.64 (dd, J=7.3/1.9 Hz, 1H), 6.27 (s, 1H), 4.71 (s, 2H), 2.30 (s, 3H), 0.99 (s, 9H). MS (ES+): 401 (M+H)+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[O:12][CH3:13].[CH2:14]([Mg]Br)[CH3:15]>O1CCCC1.[Ni](Cl)Cl.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:14]([C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[O:12][CH3:13])[CH3:15]
Reactant: COc1cc(OC)c(C#N)nc1Br
Reactant: CC[Mg]Br
Agent: Cl[Ni]Cl
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1nc(C#N)c(OC)cc1OC
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Impure 6-bromo-3,5-dimethoxy-pyridine-2-carbonitrile (462 mg; <1.9 mmol) was dissolved in tetrahydrofuran (20 mL) under nitrogen, and to the solution was added 1,3-bis(diphenylphosphino)propane nickel (II) chloride (105 mg; 0.19 mmol). The solution was cooled to 0° C., and a solution of ethyl magnesium bromide (1.0 molar in THF; 2.7 mL; 1.4 eq.) was slowly added. The reaction was stirred for five minutes, and quenched with saturated aqueous ammonium chloride (10 mL). To the reaction was added ethyl acetate (40 mL) and water (40 mL). The organic layer was isolated, dried over sodium sulfate, evaporated, and purified by column chromatography to give 6-ethyl-3,5-dimethoxy-pyridine-2-carbonitrile (114 mg; 0.6 mmol).
Reaction SMILES: [F:1][C:2]1[CH2:7][CH2:6][C:5]([OH:18])([C:8]([O:10]CC2C=CC=CC=2)=[O:9])[CH2:4][CH:3]=1.O.[OH-].[Na+].Cl>C1COCC1>[F:1][C:2]1[CH2:7][CH2:6][C:5]([OH:18])([C:8]([OH:10])=[O:9])[CH2:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)C1(O)CC=C(F)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1(O)CC=C(F)CC1
Reaction time: 1.5 h

Procedure:
Benzyl 4-fluoro-1-hydroxycyclohex-3-ene-1-carboxylate (0.554 g, 2.21 mmol) was dissolved in 27.5 mL of a 4:1 solution of THF:deionized water. A solution of 1 N NaOH was added to the reaction mixture. After stirring for 1.5 hours, the reaction mixture was acidified with 6 N HCl and extracted with EtOAc three times. The organic extracts were combined, washed with water, dried over sodium sulfate, filtered and concentrated to give 4-fluoro-1-hydroxycyclohex-3-ene-1-carboxylic acid as an oil.