Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[CH3:16])[N:3]=1.[NH2:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][N:22]=[CH:21]2>>[Cl:8][C:6]1[N:5]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[CH3:16])[N:3]=[C:2]([NH:17][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][N:22]=[CH:21]3)[N:7]=1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: Cc1ccc(Cl)cc1-c1nc(Cl)nc(Cl)n1
Product: Cc1ccc(Cl)cc1-c1nc(Cl)nc(Nc2ccc3[nH]ncc3c2)n1
Yield: 7 %

Procedure:
The reaction of 2,4-dichloro-6-(5-chloro-2-methyl-phenyl)-[1,3,5]triazine and 5-aminoindazole using the method described in Example 37 provided the title compound (7% yield). 1H NMR (DMSO-d6) 12.95 (s, 1H), 9.52 (br s, 1H), 8.25 (s, 1H), 7.94 (s, 1H), 7.75 (m, 1H), 7.52 (m, 2H), 7.35-7.45 (m, 3H), 7.30 (m, 1H), 7.12)br s, 2H), 2.50 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)#[N:2].[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:23]([C:24]3[CH:25]=[CH:26][C:27]4[N:28]([C:30](I)=[CH:31][N:32]=4)[CH:29]=3)=[CH:22][N:21]([C:34]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:20]=2)=[CH:15][CH:14]=1>>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:23]([C:24]3[CH:25]=[CH:26][C:27]4[N:28]([C:30]([C:7]5[CH:8]=[C:3]([CH:4]=[CH:5][CH:6]=5)[C:1]#[N:2])=[CH:31][N:32]=4)[CH:29]=3)=[CH:22][N:21]([C:34]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:20]=2)=[CH:15][CH:14]=1
Reactant: Fc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(I)n3c2)cc1
Reactant: N#Cc1cccc(B(O)O)c1
Product: N#Cc1cccc(-c2cnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cn23)c1
Yield: 87.8 %

Procedure:
46 mg 3-cyanophenylboronic acid and 161 mg 6-[3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]-3-iodoimidazo[1,2-a]pyridine (compound in Production Example 39) were reacted in the same manner as in Example 3, to give 136 mg 3-{6-[3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]imidazo[1,2-a]pyridin-3-yl} benzonitrile as colorless crystals. This product was subjected to deprotection of the trityl group and converted into the corresponding hydrochloride by the same method as in Example 68, to give 90 mg of the title compound as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[N:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1.[CH:21](=[O:25])[CH:22]([CH3:24])[CH3:23].O>O1CCCC1.O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]2[C:5]=1[NH:11][CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1)[C:22]([CH3:24])([CH3:23])[CH:21]2[OH:25])=[O:20]
Reactant: CC(C)C=O
Reactant: COC(=O)c1cc(Cl)ccc1N=Cc1cccc(Br)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(Br)c1)C(C)(C)C2O
Temperature: 25 °C
Reaction time: 5 h
Yield: 100.5 %

Procedure:
To a mixture of 2-{[1-(3-bromo-phenyl)-methylidene]-amino}-5-chloro-benzoic acid methyl ester (5.3 g, 15 mmol) and ytterbium(III) triflate hydrate (0.93 g, 1.5 mmol) in dry tetrahydrofuran (10 mL) at 25° C. was added isobutyraldehyde (1.08 g, 15 mmol) and water (0.27 mL, 15 mmol) dropwise. The reaction mixture was stirred at 25° C. for 5 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×100 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-bromo-phenyl)-6-chloro-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (6.4 g, 100%) as a light yellow oil: LC/MS m/e calcd for C19H19BrClNO3 M+: 424.7, observed: 408.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2].[CH:23]([NH:26][CH3:27])([CH3:25])[CH3:24].C(N(CC)CC)C>CS(C)=O>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:26]([CH:23]([CH3:25])[CH3:24])[CH3:27])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CNC(C)C
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)N(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F

Procedure:
The title compound was prepared from (5-chloro-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example B5) (4.00 g, 11.7 mmol), N-isopropyl-methyl-amine (3.67 ml, 35.2 mmol) and triethylamine (5.73 ml, 41.1 mmol) in DMSO (30 mL) at 50° C. according to the general procedure C. Obtained as a yellow solid (3.27 g, 74%).
Reaction SMILES: C1(C[O:8][C:9]2[C:14]([O:15]CC3C=CC=CC=3)=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]2[CH:31]=[C:32]([CH:36]=[C:37]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH:38]=2)[C:33]([OH:35])=[O:34])C=CC=CC=1.[H][H]>[Pd].C1COCC1>[OH:8][C:9]1[C:14]([OH:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH:38]=1)[C:33]([OH:35])=[O:34]
Reactant: CCCCCCCCCCCCCCOc1cc(OCCCCCCc2cccc(OCc3ccccc3)c2OCc2ccccc2)cc(C(=O)O)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1cc(OCCCCCCc2cccc(O)c2O)cc(C(=O)O)c1
Reaction time: 4 h
Yield: 91.5 %

Procedure:
A mixture of 1.66 g of 3-[[6-[2,3-bis(phenylmethoxy)phenyl]hexyl]oxy]-5-(tetradecyloxy)benzoic acid and 0.3 g of 10% palladium on carbon in 75 ml of THF was stirred in a hydrogen atmosphere until uptake ceased after 4 hours. The usual workup followed by trituration with hexane and filtration gave 1.14 g (91% yield, mp 92°-94°) of 3-[[6-(2,3-dihydroxyphenyl)hexyl]oxy]-5-(tetradecyloxy) benzoic acid.
Reaction SMILES: [C:1]1([S:7]([NH:10][N:11]=[C:12](Cl)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Br:19])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>O1CCCC1>[C:1]1([S:7]([NH:10][N:11]=[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Br:19])[N:25]2[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(NN=C(Cl)c1ccccc1Br)c1ccccc1
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Product: CN1CCN(C(=NNS(=O)(=O)c2ccccc2)c2ccccc2Br)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 124.8 %

Procedure:
To a stirred solution, under nitrogen, of a-chloro-2-bromobenzaldehyde phenylsulfonylhydrazone (271.1 g; 720 mmol) in tetrahydrofuran (THF; 2 L), was added dropwise N-methylpiperazine (159.7 g; 1600 mmol). The reaction was stirred at ambient temperature for three hours, and then permitted to stand at ambient temperature for 16 hours. The reaction was chilled in an ice bath, and then filtered to remove the piperazine hydrochloride that was formed. The filtrate was concentrated to yield a brown gum. The gum was triturated with hot acetonitrile, the mixture was cooled in an ice bath, and when cold, was filtered to remove unwanted side product. The filtrate was then concentrated to afford 392.9 g of a brown gum of crude 1-[[(phenylsulfon-yl)hydrazono]-(2-bromophenyl)methyl]-4-methylpiperazine.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH2:2]1.[N+:12]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O)([O-:14])=[O:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[N+:12]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[C:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]1=[O:11])([O-:14])=[O:13]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: O=C1CC=Cc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1C(=Cc2cccc([N+](=O)[O-])c2)CCc2ccccc21

Procedure:
A mixture of 3,4-dihydro-1)(2H)-naphthalenone (21.9 g), 3-nitrobenzaldehyde (22.6 g) and p-toluenesulphonic acid monohydrate (50 mg) in toluene (250 ml) was stirred at reflux with separation of water for 4.5 hours. The brown solution was allowed to cool overnight. The resulting yellow-orange deposited solid was filtered off, washed well with toluene and dried in vacuo yielding 2-(3-nitrobenzylidene)-3,4-dihydro-1(2H)-naphthalenone as crisp yellow needles.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14]>C(N(CC)CC)C>[CH3:12][Si:13]([C:16]#[C:17][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1)([CH3:15])[CH3:14]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)c1ccc(Br)cc1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(C#C[Si](C)(C)C)cc1
Temperature: 67.5 °C
Reaction time: 20 h

Procedure:
A stirred mixture of 3.05 g (14.31 mmol) of 4-tert-butyl-bromobenzene (Compound 20), 1.41 g (14.39 mmol) of trimethylsilylacetylene (Compound 16), 139 mg (0.13 mmol) of cuprous iodide, 293 mg (0.42 mmol) of bis(triphenyophosphine)palladium (II) chloride and 3 ml of triethylamine was flushed with nitrogen and then heated under nitrogen at 65-70 degrees C. for 20 hours. The reaction mixture was stirred at room temperature for a further 4 hours and the triethylamine then removed under vacuum. The residue was purified by flash chromatography (silica; hexanes) to give the title compound as a colorless oil. PMR (CDCl3): & 0.26 (9H, s), 1.31 (9H, s), 7.32 (2H, d, J~8.2 Hz), 7.42 (2H, d, J~8.2 Hz).
Reaction SMILES: [CH2:1]([NH:13][CH:14]1[CH2:19][C:18]([CH3:21])([CH3:20])[NH:17][C:16]([CH3:23])([CH3:22])[CH2:15]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[N:24]1[C:31](Cl)=[N:30][C:28](Cl)=[N:27][C:25]=1[Cl:26].C(=O)([O-])[O-].[K+].[K+]>C1(C)C(C)=CC=CC=1>[Cl:26][C:25]1[N:24]=[C:31]([N:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:14]2[CH2:15][C:16]([CH3:22])([CH3:23])[NH:17][C:18]([CH3:21])([CH3:20])[CH2:19]2)[N:30]=[C:28]([N:13]([CH:14]2[CH2:15][C:16]([CH3:23])([CH3:22])[NH:17][C:18]([CH3:20])([CH3:21])[CH2:19]2)[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[N:27]=1
Reactant: CCCCCCCCCCCCNC1CC(C)(C)NC(C)(C)C1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: CCCCCCCCCCCCN(c1nc(Cl)nc(N(CCCCCCCCCCCC)C2CC(C)(C)NC(C)(C)C2)n1)C1CC(C)(C)NC(C)(C)C1
Reaction time: 1.5 h

Procedure:
A solution of 35.7 g of 4-dodecylamino-2,2,6,6-tetramethylpiperidine in 50 ml of xylene was added dropwise at 20°-25° C. to a solution of 9.2 g of cyanuric chloride in 250 ml of xylene. The mixture was stirred for 1.5 hours at the same temperature and then for 5 hours at 50°-55° C. At the end of this time, the reaction mixture was neutralised with an aqueous solution of potassium carbonate, and the xylene layer was separated and dried over anhydrous potassium carbonate. The xylene was distilled off and the resulting oil was purified by column chromatography through silica gel eluted with a 20:20:3:1 by volume mixture of ethyl acetate, benzene, ethanol and triethylamine to give the title compound as an oil. The Rf value of this compound on thin layer chromatography was 0.28, using silica gel and using, as developing solvent, a 20:20:3:1 by volume mixture of ethyl acetate, benzene, ethanol and triethylamine.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH2:7][C:8]2[S:9][CH:10]=[CH:11][C:12]=2[S:13](N2C=CC=C2)(=[O:15])=[O:14])=[CH:4][CH:3]=1.[K].S(Cl)([Cl:27])(=O)=O>>[CH3:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH2:7][C:8]2[S:9][CH:10]=[CH:11][C:12]=2[S:13]([Cl:27])(=[O:15])=[O:14])=[CH:4][CH:3]=1
Reactant: Cc1ccc(CCc2sccc2S(=O)(=O)n2cccc2)cc1
Reactant: O=S(=O)(Cl)Cl
Agent: [K]
Product: Cc1ccc(CCc2sccc2S(=O)(=O)Cl)cc1
Yield: 51 %

Procedure:
2-[(4-methyl)phenethyl]thiophene-3-sulfonylchloride was prepared, as described in Example 64E, using N-{2-[(4-methyl)phenethyl]thiophene-3-sulfonyl}pyrrole by basic hydrolysis (KOH/ethanol) of the sulfonamide to this potassium salt followed by conversion of salt to the corresponding sulfonyl chloride in 51% yield.
Reaction SMILES: Cl[CH:2](P(=O)(OCC)OCC)[C:3]1[CH:12]=[CH:11][C:10]2[C:9]([CH3:14])([CH3:13])[CH2:8][CH2:7][C:6]([CH3:16])([CH3:15])[C:5]=2[CH:4]=1.[C:25]([C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1)([OH:27])=[O:26].S(=O)(=O)(O)O>CS(C)=O>[CH3:13][C:9]1([CH3:14])[CH2:8][CH2:7][C:6]([CH3:16])([CH3:15])[C:5]2[CH:4]=[C:3]([C:2]#[C:32][C:31]3[CH:34]=[CH:35][C:28]([C:25]([OH:27])=[O:26])=[CH:29][CH:30]=3)[CH:12]=[CH:11][C:10]1=2
Reactant: CCOP(=O)(OCC)C(Cl)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: CS(C)=O
Product: CC1(C)CCC(C)(C)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
22.6 g (0.06 mole) of diethyl 1-chloro-1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphth-2-yl)-methylphosphonate (about 85% strength) and 9 g of 4-carboxybenzaldehyde in 190 ml of dry dimethyl sulfoxide were initially taken. 21 g (0.185 mole) of potassium tert.-butylate in 65 ml of dimethyl sulfoxide were added dropwise to the stirred mixture at room temperature. Stirring was continued for 1 hour, after which the reaction mixture was poured onto 1 liter of ice water and acidified with 20% strength sulfuric acid. The resulting precipitate was filtered off under suction, washed with water and recrystallized from isopropanol to give 14 g (70%) of the title compound. Carrying out recrystallization twice more gave 6 g of pure material of melting point 263°-264° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:9]([CH2:19][CH:20](OCC)OCC)[S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[C:13]1([S:10]([N:9]2[C:4]3[C:5](=[CH:6][C:7]([CH3:8])=[C:2]([Br:1])[CH:3]=3)[CH:20]=[CH:19]2)(=[O:11])=[O:12])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(CN(c1ccc(C)c(Br)c1)S(=O)(=O)c1ccccc1)OCC
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cc2ccn(S(=O)(=O)c3ccccc3)c2cc1Br
Temperature: 25 °C
Yield: 50 %

Procedure:
Under a nitrogen stream, a solution of N-(3-bromo-4-methylphenyl)-N-(2,2-diethoxyethyl)benzenesulfonamide (5.16 g, 11.66 mmol) in toluene (118 mL) and a solution of titanium tetrachloride (1.92 mL, 17.51 mmol) in toluene (118 mL) were simultaneously added dropwise over 25 minutes to toluene (315 mL) which was heated to reflux. After heating to reflux for 1 hour, the reaction mixture was cooled to room temperature and then saturated aqueous sodium hydrogen carbonate was added thereto. The resultant mixture was extracted with ethyl acetate. After drying (anhydrous potassium carbonate), solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solution=ethyl acetate:n-hexane (1:4)), to thereby obtain the titled compound (2.04 g, 50%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:17]#[N:18])=[N:4][C:5]([C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[CH:6][N+:7]=1[O-].P(Cl)(Cl)([Cl:21])=O.O>COCCOC>[NH2:1][C:2]1[C:3]([C:17]#[N:18])=[N:4][C:5]([C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[C:6]([Cl:21])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(-c2c[n+]([O-])c(N)c(C#N)n2)cn1
Solvent: COCCOC
Solvent: O
Product: COc1ccc(-c2nc(C#N)c(N)nc2Cl)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.3 %

Procedure:
3-Amino-6-(6-methoxy-3-pyridyl)-2-pyrazinecarbonitrile 4-oxide (6.65 g) was dissolved in DME (133 ml). To the solution was added phosphorus oxychloride (12.6 g) at 25° C. The mixture was stirred at ambient temperature for 2 hours. To the mixture was added water (520 ml). The solution was stirred at 20-25° C. for 15 hours. The precipitated crystals were collected by filtration and dried in vacuo, to give 3-amino-5-chloro-6-(6-methoxy-3-pyridyl)-2-pyrazinecarbonitrile as powder (4.6 g). The filtrate was extracted with EtOAc. The organic solution was washed with brine, dried over MgSO4. Evaporation of solvent in vacuo gave oily residue. The residue was purified by chromatography on silica gel (EtOAc:n-Hexane=1:1, v/v) to give 3-amino-5-chloro-6-(6-methoxy-3-pyridyl)-2-pyrazinecarbonitrile as powder (1.0 g).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:14]([O:16]CC)=[O:15])=[N:4][O:5][C:6]=1[CH:7]1[CH2:12][CH:11]=[CH:10][CH:9]([CH3:13])[O:8]1.[OH-].[Na+]>CO.C1COCC1>[CH3:1][C:2]1[C:3]([C:14]([OH:16])=[O:15])=[N:4][O:5][C:6]=1[CH:7]1[CH2:12][CH:11]=[CH:10][CH:9]([CH3:13])[O:8]1
Reactant: CCOC(=O)c1noc(C2CC=CC(C)O2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C(=O)O)noc1C1CC=CC(C)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 4-methyl-5-(6-methyl-3,6-dihydro-2H-pyran-2-yl)isoxazole-3-carboxylate (14 mg, 0.056 mmol) in MeOH (0.2 mL) and THF (0.3 mL) was added 2M NaOH (aq) (27.9 μl, 0.056 mmol). The reaction mixture was stirred at room temperature for 3 hours. The resulting mixture was concentrated under reduced pressure and 2M NaOH (aq) (1 mL) and water (1 mL) added. The aqueous was extracted with DCM (×3) and the combined organic extracts passed through a phase separating cartridge. The eluent was concentrated under reduced pressure to afford the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([OH:19])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[F:28][C:29]1[CH:30]=[C:31]([N+:36]([O-:38])=[O:37])[CH:32]=[CH:33][C:34]=1F>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:34]3[CH:33]=[CH:32][C:31]([N+:36]([O-:38])=[O:37])=[CH:30][C:29]=3[F:28])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: COc1cc2c(O)ccnc2cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCc1ccccc1
Temperature: 40 °C
Reaction time: 0.75 h

Procedure:
To a stirred suspension of 7-(benzyloxy)-6-methoxyquinolin-4-ol (4.0 g, 14.2 mmol) and Cs2CO3 (11.5 g, 35.5 mmol) in DMF (40 mL) at 40° C. under N2 was added 3,4-difluoronitrobenzene (1.6 mL, 14.2 mmol). The suspension stirred at 40° C. for 45 min. Solvent was removed under reduced pressure and the residue was partitioned between CH2Cl2 (150 mL) and 1 N NaOH (50 mL). The organic layer was washed with water (50 mL) and brine (25 mL) and purified on silica gel yielding the title compound. Calc'd Mass for C23H17FN2O5, 420, MS (M+1) 421.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:5]=[CH:6][CH:7]=1.[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]=[C:35]=[O:36]>>[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34][C:35]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:5]=[CH:6][CH:7]=1)=[O:36]
Reactant: O=C=Nc1ccccc1Cl
Reactant: CCOC(=O)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(N)c1
Product: CCOC(=O)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(NC(=O)Nc2ccccc2Cl)c1

Procedure:
The title compound was prepared from ethyl 4-(3-aminophenyl)-8-(trifluoromethyl)quinoline-3-carboxylate and 2-chlorophenyl isocyanate according to the procedure of Example 65. MS (ES) m/z 511.9.
Reaction SMILES: [CH3:1][Si:2]([CH3:10])([CH3:9])[O:3]/[C:4](/[CH2:7][CH3:8])=[CH:5]\[CH3:6].[C:11]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:14])[CH:12]=[O:13].C(=O)([O-])O.[Na+]>C(Cl)Cl>[OH:13][CH:12]([CH:7]([CH3:8])[C:4]([O:3][Si:2]([CH3:10])([CH3:9])[CH3:1])=[CH:5][CH3:6])[C:11]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14]
Reactant: C/C=C(/CC)O[Si](C)(C)C
Reactant: CCCCOC(=O)C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC=C(O[Si](C)(C)C)C(C)C(O)C(=O)OCCCC
Reaction time: 0.5 h
Yield: 63 %

Procedure:
To a solution of 21.6 mg (0.05 mmol) of a chiral titanium complex, (R)-1, in 3 ml of methylene chloride were added 157 mg (1 mmol) of Z-3-(trimethylsilyl)oxy-2-pentene and subsequently a solution of 130 mg (1 mmol) of freshly distilled butyl glyoxylate in 0.5 ml of methylene chloride at 0° C. After stirring for 30 minutes at that temperature, the resultant mixture was poured into 10 ml of a saturated sodium hydrogencarbonate aqueous solution at 0° C. The solution was filtered through a pad of Celite, and the filtrate was extracted three times with a 5 ml portion of diethyl ether. The combined organic layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. Separation by silica gel chromatography (eluent: hexane/ethyl acetate=15/1 by volume) gave 181 mg (0.63 mmol; yield 63%) of butyl 2-hydroxy-3-methyl-4-(trimethylsilyl)oxy-4-hexenoate.
Reaction SMILES: [CH2:1](O)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH2:20]([N:22]([CH2:48][CH3:49])[C:23](=[O:47])[C:24]1[CH:29]=[CH:28][C:27]([CH:30]([C:37]2[CH:38]=[CH:39][CH:40]=[C:41]3[C:46]=2[N:45]=[CH:44][CH:43]=[CH:42]3)[N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:26][CH:25]=1)[CH3:21].[OH-].[Na+]>C(Cl)Cl>[CH2:48]([N:22]([CH2:20][CH3:21])[C:23](=[O:47])[C:24]1[CH:29]=[CH:28][C:27]([CH:30]([N:31]2[CH2:32][CH2:33][N:34]([CH2:1][C:2]3[O:6][CH:5]=[CH:4][CH:3]=3)[CH2:35][CH2:36]2)[C:37]2[CH:38]=[CH:39][CH:40]=[C:41]3[C:46]=2[N:45]=[CH:44][CH:43]=[CH:42]3)=[CH:26][CH:25]=1)[CH3:49]
Reactant: CCN(CC)C(=O)c1ccc(C(c2cccc3cccnc23)N2CCNCC2)cc1
Reactant: OCc1ccco1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc(C(c2cccc3cccnc23)N2CCN(Cc3ccco3)CC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 54.4 %

Procedure:
To a 0° C. solution of furfurylalcohol (0.19 ml; 2.24 mmol) and triethylamine (0.52 ml; 3.73 mmol) in methylene chloride (4 ml) was added methanesulfonyl chloride (0.17 ml; 2.24 mmol). The mixture was stirred 1 hour at 0° C., then compound 1 (300 mg; 0.75 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred overnight, then heated to 45° C. and stirred for 1½ hours. The reaction mixture was allowed to cool to room temperature and NaOH 2N was added untill pH was basic. The mixture was extracted with methylene chloride (3×). The combined methylene chloride extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by reverse phase using 10%-25% CH3CN/H2O (TFA as the buffer) gave 197 mg of desired product (TFA salt).
Reaction SMILES: [CH2:1]([NH:8][C:9](=O)[CH2:10][C:11]1[C:12]([CH2:17][OH:18])=[N:13][CH:14]=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B>C1COCC1>[CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[C:12]([CH2:17][OH:18])=[N:13][CH:14]=[CH:15][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cc1cccnc1CO)NCc1ccccc1
Agent: B
Solvent: C1CCOC1
Product: OCc1ncccc1CCNCc1ccccc1
Temperature: 50 °C
Yield: 23.7 %

Procedure:
To a solution of N-benzyl-2-[2-(hydroxymethyl)-pyridin-3-yl]-acetamide (357 mg, 1.5 mmol) in THF (2 mL) was added borane in THF (5 mL of a 1.0 M solution, 5 mmol) and the mixture heated at 50° C. for 3 h. The reaction was cooled, quenched with MeOH (5 mL) and heated at 50° C. for 1 h. The resultant mixture was cooled, concentrated under reduced pressure, diluted with 3 N HCl (5 mL) and heated at 80° C. for 6 h. After cooling, an aqueous 15% NaOH solution was added until a basic pH (pH=13) was obtained and the mixture was extracted with CH2Cl2 (3×10 mL). The phases were separated and the combined organic fractions were dried (Na2SO4), concentrated under reduced pressure and purified by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 100:10:1) to afford benzyl-2-[2-(hydroxymethyl)-pyridin-3-yl]-ethylamine (86 mg, 41%) as a yellow oil. 1H NMR (CDCl3) 2.75 (t, 2H, J=6.8 Hz), 2.88 (t, 2H, J=6.8 Hz), 4.75 (s, 2H), 7.18-7.34 (m, 6H), 7.50 (d, 1H, J=7.8 Hz), 8.43 (d, 1H, J=4.9 Hz). ES-MS m/z 243 (M+H).