Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6]([O:8]CC)=[O:7])[CH3:2].[OH-].[K+]>C(O)C>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(CC(C)C)C(=O)O
Reaction time: 17 h
Yield: 81.4 %

Procedure:
A total of 21.6 g of isobutylmalonic acid diethyl ester prepared above was dissolved in 100 ml of ethanol and treated dropwise at 0° with a solution of 5.6 g of potassium hydroxide in 100 ml of ethanol. The solution was allowed to stand to neutral pH for 17 hours at 20° and then evaporated under reduced pressure. The residue was dissolved in ice-water and extracted three times with ethyl acetate. The ethyl acetate extracts were rejected. The aqueous phase was acidified with 2-N hydrochloric acid and extracted twice with ethyl acetate. The combined ethyl acetate extracts were washed once with water, dried over magnesium sulfate and evaporated under reduced pressure. There were obtained 15.3 g of colorless isobutylmalonic acid monoethyl ester in the form of a chromatographically pure oil.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6].[OH-].[K+:10]>O>[C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6].[K+:10]
Reactant: C/C=C/C=C/C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: C/C=C/C=C/C(=O)[O-]
Reaction time: 0.5 h

Procedure:
A crude sorbic acid was prepared by decomposing a polyester with hydrochloric acid, which polyester was prepared by a reaction of ketene with crotonaldehyde. A total of 100 g of the crude sorbic acid (moisture content: 20% by weight, tar content: 4% by weight, sorbic acid: 76% by weight) was dissolved at 120° C. in 320 g of a commercially available lubricating oil having a boiling point ranging from 200° C. to 250° C. The solution was heated and evaporated at a pressure of 30 mmHg till a bottom temperature reached 170° C. The vapor was purified with a packed mist separator, was then cooled and condensed with a contact condenser in which water was circulated and was collected as a slurry mixture of water, lubricating oil, and sorbic acid. The slurry mixture was immediately filtered to yield 102 g of a purified sorbic acid wet cake (moisture content: 20% by weight, ethanol: 10% by weight, sorbic acid: 70% by weight). A total of 33 g of water was added to 50 g of the purified sorbic acid wet cake, and the mixture was neutralized with a 49% by weight potassium hydroxide (KOH) aqueous solution. The neutralized solution was allowed to stand to separate and remove the lubricating oil content. To the resulting solution, 1 g of activated carbon (SHIRASAGI A, a product of Takeda Chemical Industries, Ltd.) was added and the mixture was stirred for 30 minutes. The treated mixture was filtered, and the color valency of the filtrate was determined as a light transmittance at a wavelength of 430 nm with a spectrophotometer and was found to be 98.0%. The aqueous solution was dried under reduced pressure (30 mmHg, 55° C.) to yield 46 g of potassium sorbate. The potassium sorbate had a color valency of 98.0% as determined by dissolving 2 g of the potassium sorbate in water to make 10 ml, and determining the light transmittance of the aqueous solution at 430 nm with a spectrophotometer. The potassium sorbate was air-sealed and was left for 6 months, and was then found to have a color valency of 94.5%.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6].C(=O)([O-])[O-].[Zn+2:13].C(=O)=O>C(O)C>[C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6].[Zn+2:13].[C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6]
Reactant: C/C=C/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [Zn+2]
Solvent: CCO
Product: C/C=C/C=C/C(=O)[O-]
Reaction time: 24 h

Procedure:
224 g sorbic acid were added to 1,000 ml ethanol. While stirring, 117 g basic zinc carbonate was added incrementally at room temperature. The mixture formed a readily stirrable suspension. At room temperature, stirring was continued and, after a short delay, the formation of CO2 started which showed that the reaction was occurring. After 24 hours, enough zinc sorbate had formed so that a firm mass had formed. In a rotary evaporator, the ethanol was drawn off at 60° under vacuum. A white mass of zinc disorbate was recovered and ground in a mill.
Reaction SMILES: CC1C(N=C=O)=CC(N=C=[O:10])=CC=1.[CH2:14]([C:16]([CH2:21][OH:22])([CH2:19][OH:20])[CH2:17][CH3:18])[OH:15]>C(OCC)(=O)C>[C:21]([OH:22])(=[O:10])[CH:16]=[CH2:19].[C:21]([OH:22])(=[O:10])[CH:16]=[CH2:19].[C:21]([OH:22])(=[O:10])[CH:16]=[CH2:19].[CH2:14]([C:16]([CH2:21][OH:22])([CH2:19][OH:20])[CH2:17][CH3:18])[OH:15]
Reactant: Cc1ccc(N=C=O)cc1N=C=O
Agent: CCC(CO)(CO)CO
Solvent: CCOC(C)=O
Product: C=CC(=O)O

Procedure:
An oleophilic component was prepared by dissolving 4.24 g of adduct having tolylene diisocyanate to trimethylolpropane ratio (molar ratio) of 3:1 (manufactured by Nippon Polyurethane Industry Co., Ltd. Brand name: Colonate L, containing 25% by mass ethyl acetate), as a microcapsule shell forming material, 1.12 g of trimethylolpropane triacrylate (manufactured by Kyoei Sya Chemical, Ltd.) and 0.93 g of near infrared ray absorption coloring matter (manufactured by Nippon Kayaku Co., Ltd., “Kayasorb IR-820B”) in 21.7 g of glycidyl methacrylate uniformly.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[C:19]4[C:14](=[CH:15][C:16]([F:20])=[CH:17][CH:18]=4)[NH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4]CC1.O1C2(CCC(C3C4C(=CC=CC=4)NC=3)CC2)OCC1>>[F:20][C:16]1[CH:15]=[C:14]2[C:19]([C:11]([CH:8]3[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]3)=[CH:12][NH:13]2)=[CH:18][CH:17]=1
Reactant: Fc1ccc2c(C3CCC4(CC3)OCCO4)c[nH]c2c1
Agent: c1ccc2c(C3CCC4(CC3)OCCO4)c[nH]c2c1
Product: O=C1CCC(c2c[nH]c3cc(F)ccc23)CC1
Yield: 60 %

Procedure:
The title compound was prepared according to the procedure of Example 1, Step 3 except that 3-(1,4-dioxa-spiro[4.5]dec-8-yl)-6-fluoro-1H-indole was used instead 3-(1,4-Dioxa-spiro[4.5]dec-8-yl)-1H-indole. Yield: 60%; MS (ES) m/z (relative intensity): 429 (M++H, 100).
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([O:14][CH3:15])[CH:10]=[CH:9][CH:8]=2)=[O:4].[OH-].[K+]>CCO>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH:13]=[C:5]([C:3]([OH:4])=[O:2])[NH:6]2
Reactant: COC(=O)c1cc2c(OC)cccc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc2[nH]c(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
A mixture of 4-methoxy-1H-indole-2-carboxylic acid methyl ester (0.448 g, 2.18 mmol) in potassium hydroxide (0.612 g, 10.9 mmol) and EtOH (111 mL) was stirred at ambient temperature for about 16 h. The reaction mixture was concentrated in vacuo and the residue portioned between water (10 mL) and Et2O (10 mL). The aqueous portion was separated and acidified by the addition of 1N aqueous HCl, then extracted with Et2O (2×10 mL). The combined organic extracts were washed with brine (10 mL), dried over MgSO4, filtered, and concentrated in vacuo to give 4-methoxy-1H-indole-2-carboxylic acid (0.371 g, 89%) as a white solid which was used in subsequent reactions without further purification. 1H NMR (d6 DMSO, 400 MHz) 12.84 (1H, s), 11.74 (1H, s), 7.15 (1H, t), 7.00-7.03 (2H, m), 6.52 (1H, d), and 3.87 (3H, s).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH:9]1[C:17]2[C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[S:14][C:13]=2[C:12]([N:22]2[C:34]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:28]3[C:23]2=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:11][CH:10]=1>CN(C=O)C.C(Cl)Cl>[Br:1][C:31]1[CH:32]=[CH:33][C:34]2[N:22]([C:12]3[C:13]4[S:14][C:15]5[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=5[C:17]=4[CH:9]=[CH:10][CH:11]=3)[C:23]3[C:28]([C:29]=2[CH:30]=1)=[CH:27][CH:26]=[CH:25][CH:24]=3
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc2c(c1)sc1c(-n3c4ccccc4c4ccccc43)cccc12
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Brc1ccc2c(c1)c1ccccc1n2-c1cccc2c1sc1ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.1 %

Procedure:
N-bromosuccinimide (0.31 g, 1.74 mmol) in 5 mL DMF was added slowly to 9-(dibenzo[b,d]thiophen-4-yl)-9H-carbazole (0.6 g, 1.72 mmol) in 50 mL of DCM at 0° C. The reaction was allowed to warm to room temp and stirred overnight. The reaction mixture was extracted with DCM and dried over MgSO4 and the solvent was evaporated. The residue was purified by column chromatography using DCM:hexane (1:4, v/v) as the eluent to obtain 0.45 g of product.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[C:21]1[N:22]([CH3:33])[C:23](=[O:32])[C:24]([CH3:31])=[CH:25][C:26]=1[C:27]([O:29][CH3:30])=[O:28]>C1COCC1>[F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:21]1[N:22]([CH3:33])[C:23](=[O:32])[C:24]([CH3:31])=[CH:25][C:26]=1[C:27]([O:29][CH3:30])=[O:28]
Reactant: Nc1ccc(I)cc1F
Reactant: COC(=O)c1cc(C)c(=O)n(C)c1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)c(=O)n(C)c1Nc1ccc(I)cc1F
Temperature: -78 °C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
An oven dried three-necked flask was charged with 2-fluoro-4-iodoaniline (2.08 g, 8.79 mmol) and dry THF (40 mL). The mixture was cooled at −78° C. and LiHMDS (17.79 mL, 1.0 M, THF) was added dropwise. The reaction was stirred an additional hour at this temperature and methyl 2-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylate (1.89 g, 8.79 mmol) previously dissolved in dry THF (30 mL) was added. The mixture was slowly warmed to room temperature and stirred an additional 2 hours and quenched with 2N aq. HCl. The resulting mixture was further diluted with EtOAc and the organic layer was washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The brown residue was purified by flash chromatography (Biotage system) using a gradient of EtOAc (0-25%) in hexane to afford the title product (2.9 g, 79%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6][NH2:7].[S:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=S.CCN(C(C)C)C(C)C>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][CH2:6][NH:7][C:12]2[S:11][CH2:17][C:15](=[O:16])[N:14]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: NCCc1cccc(F)c1
Reactant: O=C1CSC(=S)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1CSC(NCCc2cccc(F)c2)=N1
Temperature: 0 °C
Reaction time: 48 h
Yield: 76.6 %

Procedure:
To a solution of 3-fluoro phenethylamine (3.06 g, 22 mmol) and Rhodanine (2.66 g, 20 mmol) in acetonitrile (70 mL) was added DIPEA (7.66 mL, 44 mmol) at room temperature. Then, this solution was cooled to 0° C. and mercuric chloride (5.97 g, 22 mmol) was added in two portions within 10 min. After addition, the suspension was allowed to warm to room temperature and stirred for 2 days. The resulting black solids were filtered through a plug of celite and washed with acetonitrile (1.0 L) and ethyl acetate (500 mL). The combined solvents were removed under the vacuum and the crude residue was dissolved in ethyl acetate (100 mL) and water (100 mL). The two layers were separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined extracts were washed with brine solution and dried over anhydrous magnesium sulfate. After filtration of the drying agent, the filtrate was removed under the vacuum and the crude residue was dissolved in acetonitrile (25 mL) at hot condition. After cooling in the refrigerator overnight, the solids were collected by filtration and washed with acetonitrile. After drying in air, 3.65 g (76.6% yield) of 2-[2-(3-fluoro-phenyl)-ethylamino]-thiazol-4-one was isolated as a white solid: HRES(+) m/e calcd for C11H11FN2OS (M+H)+ 239.0649. found 239.0647.
Reaction SMILES: [Na].[CH2:2]([OH:14])[CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][OH:13].C1(S(O[CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][OH:33])(=O)=O)C=CC=CC=1.C1(S([O-])(=O)=O)C=CC=CC=1.[Na+]>>[CH2:12]([OH:13])[CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][O:14][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][OH:33]
Reactant: O=S(=O)(OCCOCCOCCO)c1ccccc1
Reactant: OCCOCCOCCOCCO
Agent: O=S(=O)([O-])c1ccccc1
Agent: [Na+]
Agent: [Na]
Product: OCCOCCOCCOCCOCCOCCOCCO

Procedure:
Dissolve one equivalent of sodium in at least 5 equivalents of tetraethylene glycol and then add one equivalent of triethylene glycol monobenzenesulfonate. Heat the resulting solution at 100° to 150°C until the elimination of sodium benzene sulfonate is substantially complete. Remove the insoluble sulfonate salt by filtration and fractionally distill the resulting product in vacuo to obtain heptaethylene glycol as the higher boiling fraction.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:29])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].Cl>CN(C)C1C=CN=CC=1.ClCCl>[C:18]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:29])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CCCCCCCCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCC(=O)Oc1ccc(C(=O)O)cc1

Procedure:
12.7 Grams (0.0917 mol) of p-hydroxybenzoic acid was added to 150 ml of dichloromethane, and to this suspension was added 10.2 g (0.0917 mol) of triethylamine. The mixture was stirred until a homogeneous solution was formed. 19.7 Grams (0.096 mol) of undecanoyl chloride was added to the solution at such a rate that the dichloromethane was not refluxed. Then, 1.0 g (0.0085 mol) of 4-dimethylaminopyridine was added, and the mixture was stirred at room temperature overnight. 1N Hydrochloric acid was added to the reaction mixture and the mixture was subjected to extraction with ether. The ether was distilled off, and the resultant crude product was washed with hexane.
Reaction SMILES: [C:1]1([N:7]2[N:11]=[C:10]([CH2:12][C:13]#[N:14])[C:9]([CH2:15][CH3:16])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:19][C:20]([C:22]1[N:26]([CH3:27])[N:25]=[C:24]([CH3:28])[C:23]=1[CH3:29])=O)C.CCCCCCC.CC(C)([O-])C.[K+]>COCCOCCOC>[C:1]1([N:7]2[N:11]=[C:10]([CH:12]([C:20]([C:22]3[N:26]([CH3:27])[N:25]=[C:24]([CH3:28])[C:23]=3[CH3:29])=[O:19])[C:13]#[N:14])[C:9]([CH2:15][CH3:16])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1c(C)c(C)nn1C
Reactant: CCc1nn(-c2ccccc2)nc1CC#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: COCCOCCOC
Product: CCc1nn(-c2ccccc2)nc1C(C#N)C(=O)c1c(C)c(C)nn1C
Temperature: 92.5 °C
Yield: 68 %

Procedure:
In a 2 L-reaction flask equipped with a rectification column, 106 g (0.5 mol) of 2-phenyl-4-cyanomethyl-5-ethyl-1,2,3-triazole, 91 g (0.5 mol) of 1,3,4-trimethylpyrazol-5-carboxylic acid ethyl ester, 530 g of heptane, and 106 g of diethylene glycol dimethyl ether were added, then azeotropic dehydration was carried out by heating at 90 to 95° C. Thereafter 61.7 g (0.55 mol) of potassium-tert-butoxide was carefully added under nitrogen atmosphere, then the resulting solution was heated at 95° C. and reacted for 15 hours while removing the eluent from the rectification column. After cooling to 30° C. or less, 3000 g of water was added to separate out heptane phase, and the resulting aqueous phase was further washed with 600 g of heptane to separate into phases. A quantitative analysis of the obtained aqueous phase with liquid chromatography showed that the aqueous phase contained 118.5 g (yield 68%) of 2-(2-phenyl-5-ethyl-1,2,3-triazol-4-yl)-3-(1,3,4-trimethyl-5-pyrazolyl)-3-oxopropionitrile. The aqueous solution was warmed at 40° C., pH was adjusted to 1 by adding 35% hydrochloric acid with stirring. The crystal obtained by cooling to 15° C. over 2 hours was filtered. The crystal cake was washed three times with 200 ml of water and then dried to obtain 116 g (yield 66.5%) of 2-(2-phenyl-5-ethyl-1,2,3-triazol-4-yl)-3-(1,3,4-trimethyl-5-pyrazolyl)-3-oxopropionitrile (melting point 119° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[OH-].[Na+].[S].CC(C)=O>O.CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(CCOc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Na+]
Agent: [OH-]
Agent: [S]
Solvent: O
Solvent: CO
Solvent: CC(C)=O
Product: Cc1ccc(CCOc2ccc(N)cc2)cc1
Yield: 96.8 %

Procedure:
4-[2-(4-Methylphenyl)ethoxy]nitrobenzene (VI) (5.14 g, 0.02 mole), sodium hydroxide powder (3.0 g) and sulfur (1.6 g, 0.05 mole) were added to a mixture of acetone (20 ml) and methanol (20 ml), followed by heating under reflux for 5 hours. After cooling, the reaction mixture was diluted with water, extracted with ether and treated in the same manner as in Example 18 to obtain 4.4 g of 4-[2-(4-methylphenyl)ethoxy]aniline (V) (yield, 96.9%).
Reaction SMILES: [OH-].[Na+].Cl[O-].[Na+].[NH2:6][C:7]1[C:16]([CH3:17])=[CH:15][C:14](Br)=[CH:13][C:8]=1[C:9]([NH:11][CH3:12])=[O:10].C1(C)C=C(C)C=C(C)C=1.[C-]#N.[Na+].[CH2:31]([N:35]1C=CN=C1)CCC>[Cu]I.O>[NH2:6][C:7]1[C:16]([CH3:17])=[CH:15][C:14]([C:31]#[N:35])=[CH:13][C:8]=1[C:9]([NH:11][CH3:12])=[O:10]
Reactant: CNC(=O)c1cc(Br)cc(C)c1N
Reactant: CCCCn1ccnc1
Agent: [Cu]I
Agent: [C-]#N
Agent: [Na+]
Solvent: Cc1cc(C)cc(C)c1
Solvent: O
Product: CNC(=O)c1cc(C#N)cc(C)c1N
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A 500-mL four-necked flask equipped with a mechanical stirrer, thermocouple, condenser, side-arm addition funnel and sodium hydroxide/sodium hypochlorite scrubber was charged with 2-amino-5-bromo-N,3-dimethylbenzamide (prepared by the method of Reference Example 1) (24.6 g, 0.10 mol, 99% purity) and mesitylene (100 g) while maintaining an atmosphere of nitrogen through a gas inlet line connected to the condenser. The reaction mixture was stirred at room temperature, and granular sodium cyanide (Alfa Aesar®, 7.7 g, 0.15 mol, assuming 95% purity), copper(I) iodide (2.9 g, 0.015 mol, 98% purity) and 1-butyl-1H-imidazole (10.8 g, 0.085 mol, 98% purity) were added to the reaction mixture, after which time the nitrogen inlet line was attached directly to the reaction flask. The reaction mixture was heated at reflux (about 166-170° C.) for 6 h, while venting through the scrubber and then allow to cool overnight. Water (100 mL) was added to the reaction mixture and stirring was continued for 45 minutes. More water (25 mL) was added to the reaction mixture and stirring continued for an additional 15 minutes. The mixture was filtered, and the solid collected was washed with water (3×50 mL), mesitylene (50 g) and dried to a constant weight in a vacuum-oven at 55° C. to give the title compound as a light yellow solid (16.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18]Br.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:18][C:17]3[CH:20]=[CH:21][CH:22]=[C:15]([O:14][CH3:13])[CH:16]=3)[CH:8]=2)[N:3]=1
Reactant: Oc1ccc2nc(Cl)ccc2c1
Reactant: COc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1cccc(COc2ccc3nc(Cl)ccc3c2)c1
Yield: 44.5 %

Procedure:
2-Chloro-6-hydroxy-quinoline (CAS RN 577967-89-6, 0.6 g, 3 mMol) and 3-methoxybenzylbromid (0.56 mL, 0.004 Mol) were dissolved in a slurry of potassium carbonate (0.55 g, 4 mMol) in 15 mL acetone and heated to reflux for 3 hr. Then water was added and the mixture extracted with ethyl acetate (3×20 mL). The combined organic phases were dried on sodium sulfate, filtered and evaporated. The residue was subjected to column chromatography on silica gel (heptane/ethyl acetate 10:0→9:1→4:1 gradient) to yield 2-chloro-6-(3-methoxy-benzyloxy)-quinoline (0.40 g, 40%) as a colorless solid; MS: m/e=300.3 (M+H+).
Reaction SMILES: Br[C:2]1[O:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][CH:6]=1.C(N(CC)CC)C.O.[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22]>CN(C)C=O>[CH2:10]([O:9][C:7]([C:4]1[O:3][C:2]([C:25]#[C:24][Si:21]([CH3:23])([CH3:22])[CH3:20])=[CH:6][CH:5]=1)=[O:8])[CH3:11]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)c1ccc(Br)o1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#C[Si](C)(C)C)o1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of the compound obtained in Example 29 (1) (0.5 g) in N,N-dimethylformamide (5 ml), trimethylsilylacetylene (0.65 ml), bistriphenylphosphine palladium dichloride (0.16 g), cuprous iodide (0.04 g) and triethylamine (0.64 ml) were added successively and the mixture was stirred in a sealed tube at 100° C. for 2 hours. After cooling, the reaction solution was poured into water, extracted with ethyl acetate, washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 0.3782 g of the desired product as a brown oil.
Reaction SMILES: Br[C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[N:10][C:9]2[NH:8][C:7](=[O:16])[CH2:6][S:5][C:4]=2[CH:3]=1.[CH3:17][Sn](C)(C)C>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:17][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[N:10][C:9]2[NH:8][C:7](=[O:16])[CH2:6][S:5][C:4]=2[CH:3]=1
Reactant: C[Sn](C)(C)C
Reactant: COC(=O)c1nc2c(cc1Br)SCC(=O)N2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1nc2c(cc1C)SCC(=O)N2
Yield: 84.8 %

Procedure:
Methyl 7-bromo-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylate (Example 304b) (1.50 g, 4.95 mmol), tetramethyltin (1.71 mL, 12 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.84 g, 1.2 mmol) in dimethylformamide (30 mL) were heated at 120° C. for 24 h. The mixture was filtered through Kieselguhr, washed through with ethyl acetate and evaporated. Chromatography on silica gel (10-50% ethyl acetate/petroleum ether) gave the title compound (1.0 g, 85%).
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([CH:8]([CH3:10])[CH3:9])=[N:5][CH:4]=1.BrCC1CCCCO1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2([C:31]3=[CH:32][C:33]4[O:37][CH2:36][O:35][C:34]=4[CH:38]=[C:30]3[O:29][CH2:28]2)[C:20]1=[O:39]>>[CH:8]([C:6]1[O:7][C:3]([CH2:2][N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]3([C:31]4=[CH:32][C:33]5[O:37][CH2:36][O:35][C:34]=5[CH:38]=[C:30]4[O:29][CH2:28]3)[C:20]2=[O:39])=[CH:4][N:5]=1)([CH3:10])[CH3:9]
Reactant: CC(C)c1ncc(CCl)o1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: BrCC1CCCCO1
Product: CC(C)c1ncc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)o1

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 5-chloromethyl-2-isopropyloxazole to replace 2-(bromomethyl)tetrahydro-2H-pyran, and spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-[(2-isopropyl-1,3-oxazol-5-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one was obtained (11%) as a colorless solid: mp 75-77° C.; 1H NMR (300 MHz, CDCl3) δ7.42 (s, 1H), 7.26 (dd, J=7.4, 7.4 Hz, 1H), 7.15 (d, J=7.3 Hz, 1H), 7.07-7.00 (m, 2H), 6.48 (s, 1H), 6.15 (s, 1H), 5.83 (d, J=4.2 Hz, 2H), 4.83 (ABq, 2H), 4.78 (ABq, 2H), 3.10-2.95 (m, 1H), 1.30 (d, J=7.0 Hz, 6H); 13C NMR (75 MHz, DMSO-d6) δ177.3, 169.4, 155.8, 148.9, 142.3, 141.8, 135.3, 135.1, 132.2, 128.9, 123.8, 123.5, 119.5, 109.6, 103.1, 101.5, 93.6, 80.3, 58.2, 36.6, 28.5, 20.4, 20.3; MS (ES+) m/z 405.4 (M+1).