Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[CH2:7][C:6]=2[C:5]([CH3:13])=[C:4]([NH:14][C:15](=[O:21])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:3]=1[CH3:22].[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1>CCCCCC>[CH3:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]([NH:14][C:4]1[C:3]([CH3:22])=[C:2]([O:30][C:27]2[CH:28]=[CH:29][C:24]([CH3:23])=[CH:25][CH:26]=2)[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[CH2:7][C:6]=2[C:5]=1[CH3:13])=[O:21]
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)CC(C)(C)O2
Reactant: Cc1ccc(O)cc1
Solvent: CCCCCC
Product: Cc1ccc(Oc2c(C)c(NC(=O)CC(C)(C)C)c(C)c3c2OC(C)(C)C3)cc1
Yield: 19 %

Procedure:
Using N-(7-bromo-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 343 and 4-methylphenol, the title compound was synthesized in the same manner as in Example 344. Yield: 19%. Melting point: 182-184° C. (hexane).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[C:4]([NH2:12])[CH:3]=1.[OH-].[Na+].S(OC)(O[CH3:19])(=O)=O.S(=O)(=O)(O)O>C(O)=O.O>[CH3:19][NH:12][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[S:8]([OH:11])(=[O:9])=[O:10])[NH2:1]
Reactant: Nc1ccc(S(=O)(=O)O)c(N)c1
Reactant: COS(=O)(=O)OC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: O
Product: CNc1cc(N)ccc1S(=O)(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
97 g of 1,3-diaminobenzene-4-sulfonic acid were stirred with 250 ml of water and, after the addition of 38 ml of 98% w/w formic acid, boiled at 95°-100° C. The mixture was then colled to 30° C., and 65 g of ice were added, the pH being adjusted to 6.5 to 7.0 with 60.5 ml of 50% w/w caustic soda solution. There were then added 45 ml of 50% w/w caustic soda solution and 70 ml of dimethyl sulfate, and stirring was continued for 30 minutes. The mixture was then acidified with 43 ml of 96% w/w sulfuric acid and stirred at 100° C. for 3 hours. The mixture was then cooled, and the precipitated 3-(N-methylamino)aniline-4-sulfonic acid was isolated by filtration.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C@@H:13]([C:17]2[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=2)[CH2:14][CH2:15][CH3:16])=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH2:47]([O:49][C:50](=[O:54])[CH2:51][CH2:52][NH2:53])[CH3:48]>C1COCC1.CCOC(C)=O>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C@@H:13]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([NH:53][CH2:52][CH2:51][C:50]([O:49][CH2:47][CH3:48])=[O:54])=[O:22])=[CH:19][CH:18]=2)[CH2:14][CH2:15][CH3:16])=[CH:4][CH:3]=1
Reactant: CCC[C@H](c1ccc(C(=O)O)cc1)C(c1ccc(OC)cc1)c1ccc(F)c2ccccc12
Reactant: CCOC(=O)CCN
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC[C@H](c1ccc(C(=O)NCCC(=O)OCC)cc1)C(c1ccc(OC)cc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-{(1S)-1-[(4-fluoro-1-naphthyl)(4-methoxyphenyl)methyl]butyl}benzoic acid in THF (5 mL) was added CDI (150 mg, 0.925 mmol) After stirring at room temperature for 30 minutes, β-alanine ethyl ester hydrochloride (150 mg, 0.977 mmol) was added, then the mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc then washed with water, then brine. The organic layer was dried over MgSO4, filtered, then concentrated. The residue was purified by preparative reverse phase HPLC eluting with acetonitrile/water+0.1% TFA to afford the two diastereomers of the title compound.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]1([C:13]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][C:15](O)=[O:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1COCC1>[C:24]1([C:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:14][CH2:15][OH:16])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(O)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 88.3 %

Procedure:
To a magnetically stirred suspension of LAH (8.3 g, 0.219 mol) in dry THF (50 mL) was added a solution of 3,3,3-triphenylpropionic acid (9.5 g, 0.0314 mol) over a period of 30 min at 0° C. The reaction mixture was allowed to stir at RT for 14 h. The reaction mixture was cooled and excess LAH was quenched with 20% NaOH solution (50 mL). The reaction mixture was passed through celite, washed with THF and the filtrate was concentrated under vacuum. The residue was washed with pet. ether and dried which gave the title compound (8 g, >85%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[C:9]([C:24]([CH3:26])=[CH2:25])[N:8]([C@@H:27]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28]3)[C:4]=2[N:5]=[CH:6][N:7]=1>[Pd]>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][CH:12]=3)=[C:9]([CH:24]([CH3:26])[CH3:25])[N:8]([C@@H:27]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH2:28]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C=C(C)c1c(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc2n1[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: [Pd]
Product: CC(C)c1c(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc2n1[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 65 °C

Procedure:
A mixture of (R)-tert-butyl 3-(4-amino-5-(4-phenoxyphenyl)-6-(prop-1-en-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (116) (218 mg, 0.43 mmol) and 10% Pd/C (200 mg) was purged with H2 before heated at 65° C. overnight. The reaction was monitored by LCMS until all starting material converted to the product. After cooled down to r.t., the reaction mixture was filtered through celite pad and concentrate under reduced pressure to afford (R)-tert-butyl 3-(4-amino-6-isopropyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (117) as a yellow solid. LC-MS (ESI): m/z (M+1) 514.1
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:9])=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:10]([O:9][C:3]1[C:2]([Cl:1])=[CH:7][NH:6][C:5](=[O:8])[CH:4]=1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=c1cc(O)c(Cl)c[nH]1
Reactant: O=C(Cl)c1ccccc1
Product: O=C(Oc1cc(=O)[nH]cc1Cl)c1ccccc1
Yield: 37 %

Procedure:
Using 1.00 g of 5-chloro-4-hydroxy-2-pyridone and 0.96 ml of benzoyl chloride and following the general procedure of Example 9, 0.64 g of the title compound was produced in a yield of 37%. M.p. 196°-197° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][C:9]=2[S:18]C#N)=[CH:4][CH:3]=1.[BH4-].[Na+].[OH-].[K+].C(P(CCCC)CCCC)CCC.Cl[CH:39]([F:41])[F:40]>CC(O)C.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:12][C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][C:9]=2[S:18][CH:39]([F:41])[F:40])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(SC#N)c(-c2ccc(Cl)cc2)[nH]1
Reactant: FC(F)Cl
Agent: CCCCP(CCCC)CCCC
Agent: [BH4-]
Agent: [Cl-]
Solvent: O
Solvent: CC(C)O
Product: CCOC(=O)c1cc(SC(F)F)c(-c2ccc(Cl)cc2)[nH]1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
A solution of ethyl 5-(p-chlorophenyl)-4-thiocyanatopyrrole-2-carboxylate (76.7 mg, 0.25 mmol) in 2-propanol is treated with sodium borohydride (11.0 mg, 0.29 mmol) under nitrogen, heated to 70° C. for ten minutes, cooled to room temperature, treated with a solution of potassium hydroxide (16.8 mg, 0.30 mmol) in 2-propanol, treated with tributylphosphine (81.2 mg, 0.4 mmol), heated to 65°-70° C. and treated with excess chlorodifluoromethane for one hour. Additional tributylphosphine (81.2 mg, 0.4 mmol) is added to the reaction mixture and the addition of chlorodifluoromethane is continued for 30 minutes. The mixture is then poured into brine and extracted with ethyl acetate. The combined organic extracts are washed with water, dried over anhydrous soidum sulfate and concentrated in vacuo to obtain a liquid. Flash chromatography of the liquid using silica gel and a 1:10 ethyl acetate/hexanes solution gives the title product as a white solid (42.6 mg, mp 113°-117° C.) which is identified by 1HNMR and 13CNMR spectral analyses.
Reaction SMILES: [Br:1][C:2]1[NH:6][C:5]([Br:7])=[N:4][C:3]=1[Br:8].C([O-])([O-])=O.[K+].[K+].Cl[CH2:16][O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[CH2:18]([O:17][CH2:16][N:4]1[C:3]([Br:8])=[C:2]([Br:1])[N:6]=[C:5]1[Br:7])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Brc1nc(Br)c(Br)[nH]1
Reactant: ClCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1nc(Br)n(COCc2ccccc2)c1Br
Reaction time: 18 h

Procedure:
Tribromoimidazole (2.0 g, 6.6 mmol) in 25 mL of DMF solution was treated with powdered K2CO3 (12.7 g, 91.6 mmol). To the vigorously stirring suspension was added dropwise benzyl chloromethyl ether (1.4 g, 9.2 mmol). After 18 hours, the reaction mixture was filtered. The filtrate was concentrated in vacuo. The residue was chromatographed as described previously. The product was used immediately in Example 39.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([NH:8][C:9]2[C:14](=[O:15])[N:13]([CH3:16])[CH:12]=[C:11]([C:17]3[C:22]([CH:23]=[O:24])=[C:21]([N:25]4[CH2:37][CH2:36][C:35]5[N:34]6[C:29]([CH2:30][CH2:31][CH2:32][CH2:33]6)=[CH:28][C:27]=5[C:26]4=[O:38])[N:20]=[CH:19][CH:18]=3)[CH:10]=2)=[N:3]1.[BH4-].[Na+]>CO>[CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([NH:8][C:9]2[C:14](=[O:15])[N:13]([CH3:16])[CH:12]=[C:11]([C:17]3[CH:18]=[CH:19][N:20]=[C:21]([N:25]4[CH2:37][CH2:36][C:35]5[N:34]6[C:29]([CH2:30][CH2:31][CH2:32][CH2:33]6)=[CH:28][C:27]=5[C:26]4=[O:38])[C:22]=3[CH2:23][OH:24])[CH:10]=2)=[N:3]1
Reactant: Cc1cc(Nc2cc(-c3ccnc(N4CCc5c(cc6n5CCCC6)C4=O)c3C=O)cn(C)c2=O)nn1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(Nc2cc(-c3ccnc(N4CCc5c(cc6n5CCCC6)C4=O)c3CO)cn(C)c2=O)nn1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 67.1 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 242b (150 mg, 0.29 mmol, 1.0 eq.), NaBH4 (55 mg, 1.46 mmol, 5.0 eq.), and methanol (10 mL). The resulting mixture was stirred at room temperature for 20 min. It was then filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 242 (100 mg, 66%) as a white solid. MS-ESI: [M+H]+ 514.3. 1H NMR (500 MHz, DMSO-d6) δ 8.47 (d, J=5.5 Hz, 1H), 8.04-8.03 (m, 2H), 7.42 (d, J=2.0 Hz, 1H), 7.30 (d, J=5.0 Hz, 1H), 6.05 (s, 1H), 5.90 (s, 1H), 4.87-4.85 (m, 1H), 4.43-4.35 (m, 2H), 4.18-4.12 (m, 1H), 3.98-3.93 (m, 1H), 3.84-3.78 (m, 2H), 3.59 (s, 3H), 3.58 (s, 3H), 3.06-2.92 (m, 2H), 2.75-2.68 (m, 2H), 2.18 (s, 3H), 1.94-1.92 (m, 2H), 1.79-1.73 (m, 2H).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[CH2:14]([CH2:16][NH2:17])[OH:15]>>[OH:15][CH2:14][CH2:16][NH:17][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3]
Reactant: NCCO
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Product: O=C(O)c1cccc(S(=O)(=O)NCCO)c1

Procedure:
Procedure H was performed to couple 3-(chlorosulfonyl)benzoic acid with ethanolamine to produce 3-(2-hydroxyethylsulfamoyl)benzoic acid which was purified by reverse phase HPLC.
Reaction SMILES: [C:1]([C:5]1[C:10](=[O:11])[CH:9]=[C:8]([CH3:12])O[C:6]=1[CH3:13])([O:3][CH3:4])=[O:2].[Cl:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:14][C:15]1[CH:21]=[CH:20][C:18]([N:19]2[C:8]([CH3:12])=[CH:9][C:10](=[O:11])[C:5]([C:1]([O:3][CH3:4])=[O:2])=[C:6]2[CH3:13])=[CH:17][CH:16]=1
Reactant: COC(=O)c1c(C)oc(C)cc1=O
Reactant: Nc1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1c(C)n(-c2ccc(Cl)cc2)c(C)cc1=O
Yield: 46.8 %

Procedure:
40 g of 3-carbomethoxy-2,6-dimethylpyr-4-one and 30.2 g of 4-chloroaniline are dissolved in 400 ml of toluene along with 400 mg of p-toluenesulfonic acid monohydrate. The reaction mixture is refluxed for four hours. The solvent is removed and the product crystallized from ether to yield 30 g of N-(4-chlorophenyl)-3-carbomethoxy-2,6-dimethylpyrid-4-one (m.p. 189°-90°).
Reaction SMILES: CN(C=O)C.Cl.[N:7]1[C:16]2[CH2:15][NH:14][CH2:13][CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.[C:17]([O:21][C:22](=[O:25])[CH2:23]Br)([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C>CCOC(C)=O>[C:17]([O:21][C:22](=[O:25])[CH2:23][N:14]1[CH2:15][C:16]2[N:7]=[CH:8][CH:9]=[CH:10][C:11]=2[CH2:12][CH2:13]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: c1cnc2c(c1)CCNC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1CCc2cccnc2C1
Yield: 100 %

Procedure:
A DMF solution (8 mL) of 5,6,7,8-Tetrahydro-[1,7]naphthyridinehydrochloride (Preparation 233, 400 mg, 1.93 mmol), bromo-acetic acid tert-butyl ester (414.1 mg, 2.12 mmol) and triethylamine (1.64 mL, 11.92 mmol) was heated at 80° C. for 16 hours. The reaction mixture was diluted with EtOAc (40 mL), washed with water (3×25 mL), brine (20 mL), dried over Na2SO4 and evaporated to dryness in vacuo to afford the title compound as colorless sticky solid in 100% yield, 480 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[CH2:6][NH:7][C:8]1[C:9]2[C:14]([N:15]=[C:16]3[C:21]=1[C:20](=[O:22])[CH2:19][CH2:18][CH2:17]3)=[CH:13][CH:12]=[CH:11][CH:10]=2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[CH2:6][NH:7][C:8]1[C:9]2[C:14]([N:15]=[C:16]3[C:21]=1[CH:20]([OH:22])[CH2:19][CH2:18][CH2:17]3)=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: COc1cccc(CNc2c3c(nc4ccccc24)CCCC3=O)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc(CNc2c3c(nc4ccccc24)CCCC3O)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3,4-Dihydro-9-(3-methoxybenzylamino)acridin-1(2H)-one (4.0 g) was dissolved in 75 ml of dry THF, the solution was chilled with ice-water, and 1M lithium aluminum hydride (6.5 ml) was added dropwise through a syringe. After 30 minutes TLC showed that the reaction was complete, so the reaction was quenched by the successive addition of 0.4 ml of water, 0.4 ml of 15% sodium hydroxide, and 1.2 ml of water. The inorganic salts were filtered off and the organic phase was evaporated to an oil. Trituration with ether gave a solid that was filtered off and then recrystallized from ether-pentane to give 2.2 g of analytically pure product, mp 123°-125° C.
Reaction SMILES: Cl.C[O:3][C:4](=O)[CH2:5][NH2:6].[OH-].[Na+].CO[C:12](=[NH:17])[CH2:13][CH2:14][CH2:15][CH3:16]>CO.ClC1C=CC=CC=1>[CH2:13]([C:12]1[NH:17][C:4](=[O:3])[CH2:5][N:6]=1)[CH2:14][CH2:15][CH3:16]
Reactant: COC(=O)CN
Reactant: CCCCC(=N)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccccc1
Solvent: CO
Product: CCCCC1=NCC(=O)N1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
31.71 g (0.25 mol) of glycine methyl ester hydrochloride was added to a solution of 10.1 g (0.25 mol) of sodium hydroxide in methanol at 0° C. After 15 minutes, 126.5 g of a 22.8 percent solution of pentanimidic acid methyl ester in chlorobenzene was instilled for 5 minutes to a white suspension. The light yellow suspension was stirred for 4 hours at room temperature and diluted with chlorobenzene (100 ml). The methanol was distilled off at a temperature of 26° C. and a pressure of 30 to 50 mbar, and the orange suspension was diluted with methylene chloride (100 ml) and then filtered. After removal of the solvent from the filtrate, 34.08 g (97 percent) of the title compound (content >95 percent, according to GC and 1H-NMR) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][O:11][C:12](=[O:16])[C:13]([CH3:15])=[CH2:14])=[CH:4][C:3]=1[N:17]1[N:21]=[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]2=[N:18]1.[CH3:26][O-:27].[Na+].CO>C1(C)C(C)=CC=CC=1>[N:18]1[N:17]([C:3]2[C:2]([OH:1])=[C:7]([CH2:2][C:7]3[CH:6]=[C:5]([CH3:8])[CH:4]=[C:3]([N:17]4[N:18]=[C:19]5[CH:25]=[CH:24][CH:23]=[CH:22][C:20]5=[N:21]4)[C:26]=3[OH:27])[CH:6]=[C:5]([CH2:8][CH2:9][CH2:10][O:11][C:12](=[O:16])[C:13]([CH3:15])=[CH2:14])[CH:4]=2)[N:21]=[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=12
Reactant: C[O-]
Reactant: C=C(C)C(=O)OCCCc1ccc(O)c(-n2nc3ccccc3n2)c1
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CO
Product: C=C(C)C(=O)OCCCc1cc(Cc2cc(C)cc(-n3nc4ccccc4n3)c2O)c(O)c(-n2nc3ccccc3n2)c1
Temperature: 25 °C
Yield: 71 %

Procedure:
Ten grams (30.9 mmols) of crude 2-(3'-N,N-diethylaminomethyl-2'-hydroxy-5'-methylphenyl)-2H-benzotriazole obtained following the procedures of Synthesis Example 1 and 10.5 g (31.1 mmols) of 2-(2'-hydroxy-5'-methacryloyloxypropylphenyl)-2H-benzotriazole were dissolved in 64 ml of xylene, and 1.5 ml of a 28% sodium methylate-methanol solution were added thereto. The mixture was then refluxed in a nitrogen stream for 10 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature. Yellow crystals precipitated at this point were separated through filtration, and recrystallized from chloroform to obtain 12.8 g of 6-(2H-benzotriazol-2-yl)-4-methacryloyloxypropyl-2-[3'-(2H-benzotriazol-2-yl)-2'-hydroxy-5'-methylphenyl]methylphenol (hereinafter abbreviated as "RUVA-3") as white crystals (yield 71.0%, purity 98.6%).
Reaction SMILES: [S:1]1[CH2:5][CH2:4][S:3][C:2]1=[C:6]([C:13]([O:15]C(C)C)=[O:14])[C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8].[OH-].[K+]>C(O)(C)C>[S:1]1[CH2:5][CH2:4][S:3][C:2]1=[C:6]([C:13]([OH:15])=[O:14])[C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8]
Reactant: CC(C)OC(=O)C(C(=O)OC(C)C)=C1SCCS1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC(C)OC(=O)C(C(=O)O)=C1SCCS1

Procedure:
Diisopropyl 2-(1,3-dithiolan-2-ylidene)malonate was treated with a solution of potassium hydroxide in isopropyl alcohol. The resultant solid was isolated and purified by the same method as in Example 1 to afford the titled compound as a white solid. (64%).
Reaction SMILES: O1CCCC1.[CH3:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9](Cl)=[O:10].[F:16][C:17]([F:30])([F:29])[O:18][C:19]1[CH:28]=[CH:27][C:22]([O:23][CH2:24][CH2:25][NH2:26])=[CH:21][CH:20]=1>C(N(CC)CC)C>[F:16][C:17]([F:29])([F:30])[O:18][C:19]1[CH:28]=[CH:27][C:22]([O:23][CH2:24][CH2:25][NH:26][C:9](=[O:10])[C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[CH3:6])=[CH:21][CH:20]=1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: NCCOc1ccc(OC(F)(F)F)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)NCCOc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A tetrahydrofuran (5 ml) solution of 2-methylbenzoyl chloride (0.77 g) was added dropwise under ice-cooling and stirring to a tetrahydrofuran (20 ml) solution of 2-(4-trifluoromethoxyphenoxy)ethylamine (1.10 g) and triethylamine (0.51 g) and the mixture was further stirred at room temperature for one hour.
Reaction SMILES: [CH3:1][C:2]([NH:14]C(=O)C)([CH3:13])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH3:12])[CH3:11])=[CH:6][CH:5]=1.[ClH:18]>O>[ClH:18].[ClH:18].[CH3:12][N:10]([CH3:11])[C:7]1[CH:8]=[CH:9][C:4]([CH2:3][C:2]([NH2:14])([CH3:13])[CH3:1])=[CH:5][CH:6]=1
Reactant: CC(=O)NC(C)(C)Cc1ccc(N(C)C)cc1
Agent: Cl
Solvent: O
Product: CN(C)c1ccc(CC(C)(C)N)cc1
Reaction time: 16 h

Procedure:
A solution of 3.5 of N-[α, α-dimethyl-β-(4-dimethylaminophenyl) ethyl]acetamide in a mixture of 25 ml of water and 25 ml of concentrated hydrochloric acid is reluxed for 16 hours. The solution is then evaporated under reduced pressure and the residue is recrystallized twice from methanol isopropyl ether. Yield: 1.1 g, m.p. 239,5°-240,5°.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)[CH:9]=[C:10]([C:11](=[O:13])[CH3:12])[N:6]2[N:5]=[CH:4][N:3]=1.[F:21][C:22]([F:40])([F:39])[C:23]1[N:28]=[C:27]([NH:29][C:30](=O)[O:31]C2C=CC=CC=2)[CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>CN(C=O)C.CS(C)=O>[C:11]([C:10]1[N:6]2[C:7]([C:2]([NH2:1])=[N:3][CH:4]=[N:5]2)=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:30]([NH:29][C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([C:22]([F:39])([F:21])[F:40])[N:28]=3)=[O:31])=[CH:16][CH:15]=2)[CH:9]=1)(=[O:13])[CH3:12]
Reactant: O=C(Nc1cccc(C(F)(F)F)n1)Oc1ccccc1
Reactant: CC(=O)c1cc(-c2ccc(N)cc2)c2c(N)ncnn12
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: CC(=O)c1cc(-c2ccc(NC(=O)Nc3cccc(C(F)(F)F)n3)cc2)c2c(N)ncnn12
Reaction time: 8 h
Yield: 61.3 %

Procedure:
A mixture of 1-[4-amino-5-(4-aminophenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]ethanone (50.0 mg, 0.19 mmol), phenyl [6-(trifluoromethyl)pyridin-2-yl]carbamate (105.6 mg, 0.37 mmol,), and triethylamine (0.10 mL, 0.75 mmol) in DMF (2 mL) was stirred overnight resulting in formation of a precipitate. The mixture was diluted with DMSO (1 mL) and then the solid was collected by filtration, washed with MeOH, and air-dried to give 53.0 mg (62%) of the title compound. 1H-NMR (DMSO-d6) δ 9.87 (s, 1H), 9.71 (s, 1H), 9.60 (d, J=3.2 Hz, 1H), 8.34 (d, J=3.3, 1H), 8.10 (s, 1H), 8.04-8.02 (m, 4H), 7.76 (s, 1H), 7.59 (d, J=8.7 Hz, 2H), 7.52-7.50 (m, 1H), 2.64 (s, 3H); MS [M+H]+=456.1; LCMS RT=3.25 min.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:22])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([F:20])[C:13]=1[F:21])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.C(Cl)Cl.Cl.[NH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].C([O-])(O)=O.[Na+]>O>[CH2:33]([O:32][C:30]([CH2:29][CH2:28][NH:27][CH:4]=[C:5]([C:11](=[O:22])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([F:20])[C:13]=1[F:21])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:31])[CH3:34]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(F)c1F
Reactant: CCOC(=O)CCN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CCNC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(F)c1F
Reaction time: 3 h

Procedure:
6.4 g of ethyl 3-ethoxy-2-(2,3,4,5-tetrafluoro-benzoyl)acrylate are initially introduced into 30 ml of methylene chloride. A solution of 3.1 g of ethyl 3-amino-propionate hydrochloride in 12 ml of water is added to this. A solution of 1.7 g of NaHCO3 in 20 ml of water is added dropwise to the two-phase mixture with vigorous stirring. After the dropwise addition is complete, the mixture is stirred for a further 3 hours. The phases are then separated, and the organic phase is washed with water and dried over Na2SO4. After concentration, 7.8 g of the title compound remain. Melting point: 96°-97° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:10])[CH:3]([C@H:5]1[CH2:9][CH2:8][NH:7][CH2:6]1)[NH2:4].[Cl:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][C:15]([F:20])=[C:14](Cl)[N:13]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.CCOC(C)=O.O.C([O-])(O)=O.[Na+]>[NH2:4][C@H:3]([C@@H:5]1[CH2:9][CH2:8][N:7]([C:14]2[C:15]([F:20])=[CH:16][C:17]([C:18]#[N:19])=[C:12]([Cl:11])[N:13]=2)[CH2:6]1)[CH:2]([CH3:10])[CH3:1]
Reactant: CC(C)C(N)[C@H]1CCNC1
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)[C@H](N)[C@@H]1CCN(c2nc(Cl)c(C#N)cc2F)C1
Temperature: 130 °C
Yield: 86.2 %

Procedure:
A mixture of 2-methyl-1-[(3S)-pyrrolidin-3-yl]propan-1-amine (310 mg, 1.98 mmol), 2,6-dichloro-5-fluoro-pyridine-3-carbonitrile (378.7 mg, 1.98 mmol) and DIPEA (512.6 mg, 690.8 μL, 3.97 mmol) in NMP (3 mL) was heated at 130° C. for 20 minutes under microwave conditions. After this time, the reaction mixture was allowed to cool to ambient temperature and diluted with EtOAc, water and saturated aqueous NaHCO3. The organic layer was separated and washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude mixture was purified by column chromatography (ISCO Companion™, 40 g column, eluting with MeOH/DCM) to give the sub title compound as an oil (506.3 mg, 86% Yield).