Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([CH:19]3[CH2:21][CH2:20]3)=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)C1C=CC=CC=1.[Cl:22]C(OC(Cl)C)=O>C1(C)C=CC=CC=1>[ClH:22].[CH:19]1([C:17]2[CH:16]=[N:15][C:13]3[CH2:14][NH:8][CH2:9][CH2:10][O:11][C:12]=3[N:18]=2)[CH2:21][CH2:20]1
Reactant: c1ccc(CN2CCOc3nc(C4CC4)cnc3C2)cc1
Reactant: CC(Cl)OC(=O)Cl
Solvent: Cc1ccccc1
Product: Cl
Product: c1nc2c(nc1C1CC1)OCCNC2
Temperature: 100 °C
Reaction time: 3 h
Yield: 16 %

Procedure:
To a solution of 8-benzyl-3-cyclopropyl-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine (79.9 mg) in toluene (3 mL) was added 1-chloroethyl chloroformate (0.033 mL), and the mixture was stirred at 100° C. for 3 hr. The reaction mixture was cooled to room temperature, and concentrated. To the obtained residue was added methanol (3 mL) and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was cooled to room temperature, and concentrated. The concentrate was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (solvent gradient; 10→100% ethyl acetate/hexane). To a solution of the obtained oil in methanol (1 mL) was added 0.1 N hydrochloric acid (0.6 mL), and the mixture was concentrated under reduced pressure. The obtained crude crystals were purified by recrystallization (ethanol-diisopropyl ether) to give the title compound (10.2 mg, 16%) as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:35])([CH2:31][CH2:32][C:33]#[N:34])[C:3]([F:30])([F:29])[C:4]([F:28])([F:27])[C:5]([F:26])([F:25])[C:6]([F:24])([F:23])[C:7]([F:22])([F:21])[C:8]([F:20])([F:19])[C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12].N.[H][H]>[Co].O1CCCC1>[F:1][C:2]([F:35])([CH2:31][CH2:32][CH2:33][NH2:34])[C:3]([F:29])([F:30])[C:4]([F:27])([F:28])[C:5]([F:25])([F:26])[C:6]([F:24])([F:23])[C:7]([F:21])([F:22])[C:8]([F:20])([F:19])[C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12]
Reactant: N#CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: [H][H]
Agent: [Co]
Agent: N
Solvent: C1CCOC1
Product: NCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 110 °C
Yield: 94.3 %

Procedure:
A one liter Hastelloy pressure vessel was charged with 126.1 g (0.22 mol) of 3-(perfluorodecyl)propionitrile (Du Pont), 20 g of Rainey cobalt, 50 g of anhydrous ammonia and 300 mL of tetrahydrofuran. The vessel was pressured to 800 psi with hydrogen and heated to 110° C. The hydrogen pressure was adjusted to 1500 psi and maintained for 20 hours. The vessel was cooled to room temperature and vented. The solution was decanted and the reaction vessel was rinsed with tetrahydrofuran. The combined solutions were filtered through Celite® and concentrated on a rotary evaporator at 50° C. The product was distilled through a Vigreux column to give 119.8 g of product, bp 78-80° C. at 1.2 mm as a waxy solid which melted at 53-55° C. The product was redistilled through an 8 in. Vigreux column to give 107.7 g of a center cut, bp 70° C. at 1.8 mm.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:17][CH:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:15]=[CH:14][C:10]([C:11]([NH:17][CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:12])=[CH:9][CH:8]=1
Reactant: CCOC(=O)C(N)C(=O)OCC
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(NC(=O)c1ccc(-c2ccccc2)cc1)C(=O)OCC
Reaction time: 3 h
Yield: 95 %

Procedure:
4-Phenylbenzoyl chloride (4.3 g) was added little by little to a chloroform (80 mL) solution of diethyl aminopropanedioate hydrochloride (4.3 g) and TEA (8.4 mL) under ice cooling, and the mixture was stirred for 3 hours at the same temperature. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, and the desiccant was filtered out. Then, the solvent was distilled off under reduced pressure, and the resulting residue was purified by OH type silica gel column chromatography (chloroform/methanol=20/1) to obtain diethyl [(biphenyl-4-ylcarbonyl)amino]propanedioate (white solid) (6.7 g, 95%).
Reaction SMILES: [CH3:1][SiH2:2][O:3][Si:4]([CH3:7])([CH3:6])[CH3:5].[C:8]([O:13][CH2:14][CH:15]=C)(=[O:12])[C:9](C)=[CH2:10].[CH:17]1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>>[CH3:5][Si:4]([CH2:7][CH2:15][CH2:14][O:13][C:8](=[O:12])[CH:9]=[CH2:10])([CH3:6])[O:3][SiH:2]([CH3:17])[CH3:1]
Reactant: C[SiH2]O[Si](C)(C)C
Reactant: C=CCOC(=O)C(=C)C
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C=CC(=O)OCCC[Si](C)(C)O[SiH](C)C
Reaction time: 3 h

Procedure:
Into a 1000 mL round bottom flask, equipped with a Teflon-coated stir bar and located in a water bath at room temperature, is added tetramethyldisiloxane (134 grams, 1 mole) and allyl methacrylate (126 grams, 1 mole). A reaction is initiated by the addition of Karstedt's catalyst (0.5 mL) and the charge is stirred for 3 hours. At this point PPh3 (10 mL) is added and the charge is vacuum distilled (0.1 millibar) at 50° C. The product, 112 grams of colorless liquid, is rectified on a spinning band column (75 plates, 0.3 mbar) to yield 41 grams (16%) of SiH-MA. The boiling point is determined to be 62° C.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][C:6]([CH3:13])([CH3:12])[C:7](=[O:11])[CH:8]([OH:10])[CH3:9].N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:6]([C:7]1[O:11][C:1](=[O:2])[O:10][C:8]=1[CH3:9])([CH3:13])([CH3:12])[CH3:5]
Reactant: CC(O)C(=O)C(C)(C)C
Reactant: O=C(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1oc(=O)oc1C(C)(C)C
Reaction time: 20 h

Procedure:
Forty-four g of a 12.5% solution of phosgene in toluene is added over 30 min to a well stirred solution of 4,4-dimethyl-2-hydroxy-3-pentanone (4.85 g, 37.3 mmol) in toluene, 90 ml, at 0°-5° C. Following this addition, a solution of pyridine, 11.4 ml, in toluene, 25 ml, is then added to the cooled reaction mixture over 30 min. After stirring at 20°-25° C. for 20 hours, the reaction mixture is washed with 3N HCl and water saturated with NaCl. The toluene extract is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. After addition of p-toluenesulfonic acid hydrate, 100 mg, to the residue, it is stirred neat at 160° C for 24 hours. The resulting black liquid is dissolved in ethyl acetate, washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution and dried over anhydrous sodium sulfate. After filtering and concentrating under reduced pressure, the residue is distilled to give 3.5 g of product, bp 82°-4° C. at 3mm.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Cl[CH2:14][C:15]1[NH:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1.C(N(CC)CC)C>CN(C=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH2:14][C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH2:11][CH2:12]1
Reactant: ClCc1nc2ccccc2[nH]1
Reactant: c1ccc(N2CCNCC2)nc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: c1ccc(N2CCN(Cc3nc4ccccc4[nH]3)CC2)nc1
Reaction time: 16 h
Yield: 85.2 %

Procedure:
To a rapidly stirred solution of 1-(2-pyridyl)piperazine (5.9 g, 36 mmol) in DMF (15 mL) in a large round bottom flask in a water bath at 20° C. was added 2-chloromethylbenzimidazole powder (6 g, 36 mmol) over 2 minutes. Triethylamine (7.5 mL, 1.5 eq) was added, and the reaction was stirred for 16 hours, until TLC indicated complete consumption of starting material. The reaction was then treated with 5 mL of triethylamine followed by the slow dropwise addition of water (70 mL). After one hour, the precipitate was collected by suction filtration and washed with 400 mL of water and dried to give 9 grams of product. The solid was recrystallized twice from boiling n-butanol to give 7.6 grams (72% yield purified) of the title compound as a buff powder. mp 220-221° C. 1H NMR (d6-DMSO, 300 MHz) δ 2.55 (4H, J=4.5 Hz), 3.52 (4H, J=4.5 Hz), 3.77 (s, 2H), 6.62 (1H, J=6.6, 4.5 Hz), 6.81 (1H, J=8.7 Hz), 7.14 (2H, m), 7.41-7.58 (3H, m), 8.09 (1H, J=4.5, 1.8 Hz). MS (DCI/NH3) m/z 294 (M+H)+. Anal. Calcd for C17H19N5: C, 69.60; H, 6.53; N, 23.87. Found: C, 69.47; H, 6.58; N, 23.87.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2[C:8](=[O:15])[NH:9][C:10](SC)=[N:11][CH:12]=2)=[CH:4][CH:3]=1.[CH3:18][C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH2:24][S:25][CH2:26][CH2:27][NH2:28]>>[CH3:18][C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH2:24][S:25][CH2:26][CH2:27][NH:28][C:10]1[NH:9][C:8](=[O:15])[C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:17][CH:16]=2)=[CH:12][N:11]=1
Reactant: CSc1ncc(Cc2ccc(Cl)cc2)c(=O)[nH]1
Reactant: Cc1[nH]cnc1CSCCN
Product: Cc1[nH]cnc1CSCCNc1ncc(Cc2ccc(Cl)cc2)c(=O)[nH]1

Procedure:
An intimate mixture of 5-(4-chlorobenzyl)-2-methylthio-4-pyrimidone (17.7 g) and 2-(5-methyl-4-imidazolylmethylthio)ethylamine (11.4 g) was heated at 145°-150° for 5 hours. After cooling, the reaction mixture was triturated with water to give the free base, which was separated by decantation and recrystallised from methanol to give 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(4-chlorobenzyl)-4-pyrimidone m.p. 204.5°-206°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].N1C=CC=CC=1.Cl[C:19](OCC)=[O:20].Cl>O.C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:19](=[O:20])[NH:9][C:7](=[O:8])[C:6]=2[CH:10]=1
Reactant: NC(=O)c1cc(Cl)ccc1O
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: c1ccncc1
Product: O=c1[nH]c(=O)c2cc(Cl)ccc2o1
Temperature: 95 °C
Reaction time: 0.5 h
Yield: 85.3 %

Procedure:
A solution of 10 g of 5-chloro-2-hydroxybenzamide (58.0 mmol), pyridine (22 ml) and acetonitrile (25 ml) was stirred in an ice bath. Ethyl chloroformate (6.1 ml, 0.0638 mol) was added dropwise. The pink solution was stirred for 30 minutes at <10° C. The ice bath was replaced with an oil bath. The reaction mixture was heated to 95° C. and the volatiles were distilled off (43 ml). The reaction was cooled to room temperature, causing a white solid to form. The mixture was poured into water (100 ml) and acidified with concentrated aqueous hydrochloric acid. The resulting solid was filtered and recrystallized in hot ethanol to give 9.77 g of 6-chloro-2H-1,3-benzoxazine-2,4(3H)-dione.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14]O)=[C:12]([CH:16]([CH3:18])[CH3:17])[O:11][N:10]=1.[CH3:19][O:20][C:21]([C:23]1[C:31]2[C:26](=[CH:27][C:28]([C:32]3[CH:37]=[CH:36][C:35](O)=[CH:34][C:33]=3[CH3:39])=[CH:29][CH:30]=2)[NH:25][CH:24]=1)=[O:22].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=[O:43].C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH3:19][O:20][C:21]([C:23]1[C:27]2[C:26](=[CH:31][CH:30]=[CH:29][C:28]=2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:43][CH:9]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])[C:13]3[CH:14]=[N:10][O:11][C:12]=3[CH:16]([CH3:18])[CH3:17])[C:33]=2[CH3:39])[NH:25][CH:24]=1)=[O:22]
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CO
Reactant: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Reactant: COC(=O)c1c[nH]c2cc(-c3ccc(O)cc3C)ccc12
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)c1c[nH]c2cccc(-c3cccc(OC(c4cnoc4C(C)C)c4c(Cl)cccc4Cl)c3C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
To a mixture of [3-(2,6-dichloro-phenyl)-5-isopropyl-isoxazol-4-yl]-methanol (112 mg, 0.391 mmol) and 6-(4-hydroxy-2-methyl-phenyl)-1H-indole-3-carboxylic acid methyl ester (100 mg, 0.355 mmol) and toluene (7 mL) is added 1,1′-(azodicarbonyl)dipiperidine (99 mg, 0.39 mmol) followed by tri-n-butylphosphine (105 μL, 0.426 mmol). The mixture is allowed to stir overnight at room temperature. The reaction mixture is concentrated and purified via chromatography cluting with CH2Cl2 to give 85 mg (40%) of the title compound. ES/MS m/e 549.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16]([OH:26])[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=2)=[N:6]1.[CH2:31](O)[CH2:32][CH3:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16]([O:26][CH2:31][CH2:32][CH3:33])[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=2)=[N:6]1
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(O)c21
Reactant: CCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCOc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2c1C(C)(C)C(=O)N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under argon, 80 mg (0.20 mmol) of the compound from example 109, 13 mg (16 μl, 0.22 mmol) of n-propanol and 57 mg (0.22 mmol) of triphenyl phosphine were suspended in 0.8 ml THF, mixed for 10 min in the ultrasonic bath and finally 44 mg (43 μl, 0.22 mmol) of diisopropyl azodicarboxylate was added and it was stirred for 1 h at RT. The reaction mixture was purified by preparative HPLC (Reprosil C18, gradient of acetonitrile/0.01% aq. formic acid). Yield: 48 mg (55% of theor.)
Reaction SMILES: [N:1]1[N:2]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][CH2:20][CH2:19][C:18]3=[O:22])=[CH:13][CH:12]=2)[CH:3]=[C:4]2[CH2:10][CH2:9][NH:8][CH2:7][CH2:6][C:5]=12.C(=O)([O-])[O-].[K+].[K+].I[CH2:30][CH3:31]>C(O)C>[CH2:30]([N:8]1[CH2:9][CH2:10][C:4]2=[CH:3][N:2]([C:11]3[CH:12]=[CH:13][C:14]([N:17]4[CH2:21][CH2:20][CH2:19][C:18]4=[O:22])=[CH:15][CH:16]=3)[N:1]=[C:5]2[CH2:6][CH2:7]1)[CH3:31]
Reactant: CCI
Reactant: O=C1CCCN1c1ccc(-n2cc3c(n2)CCNCC3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCN1CCc2cn(-c3ccc(N4CCCC4=O)cc3)nc2CC1

Procedure:
To a solution of 1-[4-(5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl)phenyl]-2-pyrrolidinone (may be prepared as described in Description 22) (50 mg, 0.17 mmol) in ethanol (5 ml) was added potassium carbonate (70 mg, 0.51 mmol) and iodoethane (53 mg, 0.34 mmol). The resulting mixture was heated at reflux, under argon, for 18 hours. A further 3 eq. of potassium carbonate in ethanol (2 ml) was added, and stirring continued over the weekend. Reaction was removed from heat and ethanol (˜20 ml) was added. Reaction was purified by SCX, eluting with methanol and then with 2M ammonia/methanol. The basic fractions were combined and solvent evaporated in vacuo. The resulting crude product was purified further by column chromatography on silica gel eluting with a mixture of methanol in dichloromethane (100:1-10:1) to afford the title compound (E18). MS (ES+) m/e 325 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH:11]2[C:24]3[CH:23]=[CH:22][C:21]4[C:16](=[N:17][CH:18]=[CH:19][CH:20]=4)[C:15]=3[NH:14][S:13](=[O:26])(=[O:25])[N:12]2[CH3:27])=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:50][N:51]([CH3:55])[CH2:52][CH2:53][NH2:54].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:50][N:51]([CH3:55])[CH2:52][CH2:53][NH:54][C:4](=[O:5])[C:3]1[CH:7]=[C:8]([CH:11]2[C:24]3[CH:23]=[CH:22][C:21]4[C:16](=[N:17][CH:18]=[CH:19][CH:20]=4)[C:15]=3[NH:14][S:13](=[O:26])(=[O:25])[N:12]2[CH3:27])[CH:9]=[CH:10][C:2]=1[F:1]
Reactant: CN(C)CCN
Reactant: CN1C(c2ccc(F)c(C(=O)O)c2)c2ccc3cccnc3c2NS1(=O)=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCNC(=O)c1cc(C2c3ccc4cccnc4c3NS(=O)(=O)N2C)ccc1F
Yield: 14.6 %

Procedure:
In a similar fashion, using route 37 general procedure 90, 2-fluoro-5-(2-methyl-3,3-dioxo-1,2,3,4-tetrahydro-3λ*6*-thia-2,4,5-triaza-phenanthren-1-yl)-benzoic acid 424 (60 mg, 0.15 mmol), TBTU (50 mg, 0.15 mmol), N,N-dimethylethane-1,2-diamine (16.9 μl, 0.15 mmol) and DIPEA (25.6 μl, 0.15 mmol) in DCM (1 ml) gave the title compound (10 mg, 14%) after purification by preparative HPLC (acidic conditions 1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[NH2:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[C:25]([CH3:30])[CH:24]=[CH:23]2.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8]([NH:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]=[C:25]([CH3:30])[CH:24]=[CH:23]3)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc2cc(N)ccc2n1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc2cc(NS(=O)(=O)c3cccc(Cl)c3C)ccc2n1
Reaction time: 0.08 h
Yield: 67.5 %

Procedure:
To a solution of 3-chloro-2-methylbenzenesulphonyl chloride (149 mg, 0.664 mmol) in dichloromethane (4 mL) was added pyridine (130 μL, 1.58 mmol) and the mixture was stirred under N2 for 5 min, after which time 6-amino-2-methylquinoline (100 mg, 0.632 mmol) was added. The resulting mixture was stirred for 90 min at room temperature, then saturated NaHCO3 solution (10 mL) was added and the mixture was extracted into ethyl acetate (20 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford an off-white solid (148 mg, 68%), single spot at Rf 0.64 (ethyl acetate). mp 178.1-178.4° C., HPLC purity 99+% (tR 2.27 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 7.93-7.89 (3H, m), 7.53 (1H, d, J=8.2 Hz), 7.44 (1H, d, J=2.5 Hz), 7.31-7.24 (2H, m), 7.18 (1H, t, J=8.1 Hz), 2.73 (3H, s), 2.69 (3H, s). LCMS: 345.17 (M−). FAB-MS (MH+, C17H15CIN2O2S): calcd 347.0621, found 347.0622.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18](Cl)/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C.CCOC(C)=O>[C:21]1(/[CH:20]=[CH:19]/[CH2:18][O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[N+:9]([O-:11])=[O:10])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ClC/C=C/c1ccccc1
Reactant: O=[N+]([O-])c1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)ccc1OC/C=C/c1ccccc1
Temperature: 60 °C

Procedure:
4-Fluoro-2-nitrophenol (13.5 g, 86 mmol) was dissolved in anhydrous DMF (100 mL) under an N2 atmosphere and treated sequentially with K2CO3 (23.7 g, 172 mmol) and trans-cinnamyl chloride (13.4 g, 87.6 mmol) and heated to 60° C. for 12 h. Upon completion, the reaction was diluted with EtOAc (500 mL), and washed with H2O (3×300 mL) and sat. aq. NaCl (500 mL). The organic layer was dried with MgSO4, filtered and concentrated to yield a yellow solid which was easily recrystallized from EtOAc/hexanes to provide pure 4-fluoro-2-nitrophenyl (2E)-3-phenylprop-2-enyl ether (5-1). 1H NMR (300 MHz, CDCl3) δ 7.61 (dd, J=7.5, 2.5 Hz, 1H), 7.41 (app d, J=7.0 Hz, 2H), 7.34 (t, J=7.5 Hz, 2H), 7.27 (m, 2H), 7.12 (dd, J=9.0, 4.0 Hz, 1H), 6.76 (d, J=16.0 Hz, 1H), 6.37 (dt, J=16.0, 5.5 Hz, 1H), 4.83 (dd, J=5.5, 1.0 Hz, 2H).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[C:11]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])[CH3:12].Br[C:20]1[CH:25]=[C:24]([Br:26])[N:23]=[C:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[C:21]=1[CH2:34]Br>C1COCC1>[Br:26][C:24]1[N:23]=[C:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[C:21]([CH2:34][CH2:12][C:11]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:20][CH:25]=1
Reactant: Clc1ccccc1-c1nc(Br)cc(Br)c1CBr
Reactant: CC(=O)OC(C)(C)C
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCc1ccc(Br)nc1-c1ccccc1Cl
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To 25 mL of THF at −78° C. was added 26.6 mL of a 1.0M solution of lithium hexamethyldisilazane in THF. t-Butyl acetate (4.47 mL) was added dropwise to the cold solution, and the mixture was stirred for 10 min at −78° C. 4,6-Dibromo-3-(bromomethyl)-2-(2-chlorophenyl)pyridine (9.74 g) in 25 mL of THF was added dropwise over 15 min. The mixture was stirred 20 min at −78° C., then quenched by addition of 5 mL of saturated aqueous NaHCO3. The mixture was warmed to rt, diluted with 200 mL of saturated aqueous NaHCO3, and extracted with 3×100 mL of EtOAc. The combined organics were washed with 100 mL of brine, and dried over MgSO4. The residue was purified by flash chromatography on a Biotage 65M column, eluting with a gradient system of 95:5 to 90:10 hexanes-Et2O to yield the title compound as a white solid. Mass spectrum (ESI) 476 (M+1).
Reaction SMILES: [CH:1](NC(C)C)(C)C.[C:8]1(=O)[O:21][C:14](C)([CH:15]([CH2:18][CH3:19])CC)[O:13][C:11](=[O:12])[CH2:10][CH2:9]1.C([C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=2)[N:28]([CH3:37])[C:27]=1[CH3:38])(=O)C.Cl>O1CCCC1.C([Li])CCC.C(Cl)(Cl)Cl>[CH3:37][N:28]1[C:29]2[C:34](=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[C:26](/[C:18](=[C:15]2/[C:14]([O:13][C:11](=[O:12])[C:10]/2=[C:9]([CH3:8])[CH3:1])=[O:21])/[CH3:19])=[C:27]1[CH3:38]
Reactant: CCC(CC)C1(C)OC(=O)CCC(=O)O1
Reactant: CC(C)NC(C)C
Reactant: COc1ccc2c(c1)c(C(C)=O)c(C)n2C
Agent: Cl
Agent: [Li]CCCC
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(/C(C)=C1/C(=O)OC(=O)C1=C(C)C)c(C)n2C
Reaction time: 0.5 h
Yield: 5 %

Procedure:
To a solution obtained by dissolving 76 g of diisopropylamine in 750 ml of tetrahydrofuran, 350 ml of n-butyllithium was added at low temperatures (-10°~-40° C.), and 91 g of diethylisopropylidene succinate obtained in Reference Example 1 (4) and 81 g of 3-acetyl-5-methoxy-1,2-dimethylindole were added dropwise thereto in 30 minutes with stirring. After reacting for further 8 hours with stirring, the reaction solution was made acidic by pouring 1050 ml of 10% HCl thereinto, followed by extraction with 1.5 liters of ethyl acetate. The resulting organic layer was concentrated. To the residue, 1.85 liters of 5 w/v% ethanolic potassium hydroxide was added to carry out the reaction for 15 hours under reflux. After the reaction, the reaction solution was made acidic with HCl. A precipitate produced was dissolved in chloroform. After removing the solvent from the resulting chloroform solution by distillation, acetyl chloride was added to the residue to carry out a ring closing reaction. The residue was purified by column chromatography (filler: Wakogel C-300, eluent: a mixed solvent of n-hexane and ethyl acetate) to give pale yellow crystals of 2-[(E)-1-(1,2-dimethyl-5-methoxy-3-indolyl)ethylidene]-3-isopropylidene succinic anhydride of the formula: ##STR30## wherein Me is methyl, in yield of 5%.
Reaction SMILES: [N:1]1[C:8]([NH2:9])=[N:7][C:5]([NH2:6])=[N:4][C:2]=1[NH2:3].[H][H].[CH2:12]([OH:18])[CH2:13][O:14][CH2:15][CH2:16]O>>[NH2:3][C:2]1[N:4]=[C:5]([NH2:6])[N:7]=[C:8]([NH:9][CH2:16][CH2:15][O:14][CH2:13][CH2:12][OH:18])[N:1]=1
Reactant: Nc1nc(N)nc(N)n1
Reactant: OCCOCCO
Reactant: [H][H]
Product: Nc1nc(N)nc(NCCOCCO)n1
Reaction time: 2 h
Yield: 2 %

Procedure:
In a stainless steel autoclave of an inner volume of 100 ml, 1.26 g (10 mmol) of melamine, 250 mg of CuO—Cr2O3—NiO—BaO catalyst (T-4364, manufactured by Nissan Girdler Catalyst Co., Ltd.), and 30 ml of diethylene glycol were charged. After the inside of the reaction system was sufficiently substituted with nitrogen gas, 10 kg/cm2 of hydrogen gas was introduced under pressure at normal temperature. Then, the temperature was elevated while stirring, and after the temperature reached 260° C., the reaction was carried out at the same temperature for further 2 hours. After cooling, the reaction mixture was taken out and quantitative analysis of the reaction product was performed under the above analytical conditions. As a result, the reaction conversion rate of the starting material melamine was 11% and it was confirmed that there were produced only about 2% of 2,4-diamino-6-(5-hydroxy-3-oxapentylamino)-1,3,5-triazine together with many byproducts and an obvious decrease in activity as compared with the mixed catalyst systems was confirmed.