Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[Cl-:12].[NH2:13][N:14]1[CH:18]=[CH:17][N+:16]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=2)=[C:15]1[CH2:30][CH3:31]>C(O)(=O)C>[Cl-:12].[CH2:30]([C:15]1[N:14]([N:13]=[CH:7][C:6]2[CH:9]=[CH:10][C:3]([N:2]([CH3:11])[CH3:1])=[CH:4][CH:5]=2)[CH:18]=[CH:17][N+:16]=1[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=1)[CH3:31]
Reactant: CCc1n(N)cc[n+]1NCc1ccc(N(C)C)cc1
Reactant: CN(C)c1ccc(C=O)cc1
Agent: [Cl-]
Solvent: CC(=O)O
Product: CCc1n(N=Cc2ccc(N(C)C)cc2)cc[n+]1NCc1ccc(N(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.5 g (3.38 mmol) of p-dimethylaminobenzaldehyde is added to a solution of 1.0 g (3.38 mmol) of 3-amino-1-[[p-(dimethylamino)benzyl]amino]-2-ethylimidazolium chloride in 15 ml of glacial acetic acid, the mixture is stirred at room temperature for 24 hours, the solution is evaporated and the crude product is chromatographed on 60 g of silica gel (particle size 0.063-0.200 mm) while eluting with methylene chloride/methanol (3:1 v/v). After recrystallizing the resulting material from ethanol/ether there is obtained 2-ethyl-1-[[p-(dimethylamino)benzyl]-amino]-3-[[p-(dimethylamino)benzylidene]amino]imidazolium chloride of melting point 201°-202°.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[Br:6][C:7]([CH2:9]Br)=[CH2:8]>>[CH2:1]([N:3]([CH2:4][CH3:5])[CH:8]=[C:7]([Br:6])[CH3:9])[CH3:2]
Reactant: C=C(Br)CBr
Reactant: CCNCC
Product: CCN(C=C(C)Br)CC

Procedure:
Compound 6b is preferably synthesized by reacting diethylamine with 2,3-dibromopropene to produce 1-diethylamino-2-bromo-propene. Copper iodide is then added with THF and the mixture is cooled to below about -78° C. The solution is stirred and allowed to gradually rise to room temperature. The mixture may then be opened to air and poured into a solution of saturated ammonium chloride. Compound 6a may then be extracted with, e.g., ether, and dried.
Reaction SMILES: [F-:1].[K+].Cl[C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1>>[F:1][C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1
Reactant: [F-]
Reactant: O=C1OC(=O)c2cc(Cl)ccc21
Agent: [K+]
Product: O=C1OC(=O)c2cc(F)ccc21
Temperature: 220 °C

Procedure:
A mixture of 20 parts of anhydrous potassium fluoride, 20 parts of 4-chlorophthalic anhydride and 2 parts of Carbowax® m-peg 2000 catalyst was charged to a reaction vessel and heated at 220° C. for about 18 hours. The product was removed by distillation, then recrystallized from a chloroform-hexane solution to yield 8.13 parts of 4-fluorophthalic anhydride having a melting point of 76°-78° C. Following the procedure of Example 3B, the fluorophthalic anhydride is reacted with ammonia to yield the ammonium salts of a mixed 4- and 5-fluorophthalamic acid.
Reaction SMILES: [CH:1]1([C:7]2[CH:13]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH:21]([CH3:23])[CH3:22])[C:8]=2[NH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:24](Cl)(Cl)=[S:25].O.C(=O)([O-])[O-].[Ca+2]>ClCCl>[CH:1]1([C:7]2[CH:13]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH:21]([CH3:23])[CH3:22])[C:8]=2[N:9]=[C:24]=[S:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: S=C(Cl)Cl
Reactant: CC(C)c1cc(Oc2ccccc2)cc(C2CCCCC2)c1N
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCl
Solvent: O
Product: CC(C)c1cc(Oc2ccccc2)cc(C2CCCCC2)c1N=C=S
Reaction time: 5 h

Procedure:
A solution of 7.0 g of 2-cyclohexyl-4-phenoxy-6-isopropylaniline in 20 ml of dichloromethane is added dropwise, with efficient stirring, to 3.1 g of thiophosgene, 40 ml of dichloromethane, 20 ml of water and 5.0 g of ground calcium carbonate. The reaction mixture is stirred for 5 hours under reflux, then cooled and filtered over kieselguhr. The organic phase is separated, washed with water, dried over sodium sulfate and the solvent is removed under vacuum. The title compound of formula ##STR10## is obtained in the form of yellow crystals which melt at 58°-60° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[S:15]([CH3:18])(=[O:17])=[O:16]>S(=O)(=O)(O)O>[Cl:5][C:6]1[C:14]([N+:1]([O-:4])=[O:2])=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[S:15]([CH3:18])(=[O:16])=[O:17]
Reactant: CS(=O)(=O)c1cc(C(=O)O)ccc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To the mixture of conc. sulfuric acid (53.3 ml) and conc. nitric acid (36.0 ml) was added dropwise a solution of 4-chloro-3-methylsulfonylbenzoic acid (22.5 g) in conc. sulfuric acid (135.0 ml) for 10 minutes at 20°-30° C., and the mixture was stirred for 5 hours at 75°-80° C. After ice-cooling, the mixture was poured into ice-water and isolated precipitate was collected by filtration to give 4-chloro-3-methylsulfonyl-5-nitrobenzoic acid (24.85 g).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C([Li])CCC.Cl[Si:15]([CH3:18])([CH3:17])[CH3:16]>O1CCCC1>[CH3:16][Si:15]([CH3:18])([CH3:17])[N:6]([Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: C[Si](C)(C)Cl
Reactant: Nc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)N(c1ccc(Br)cc1)[Si](C)(C)C
Temperature: 0 °C

Procedure:
The general procedure described by J. R. Pratt et al, in the publication entitled "Organosilicon Compounds. XX. Synthesis of Aromatic Diamines via Trimethylsilyl-Protecting Aniline Intermediates," J. Org. Chem, Vol. 40, No. 8, 1975, pages 1090 to 1094, was followed with some modifications as described herein To a tetrahydrofuran (500 ml) solution of p-bromoaniline (106.0g, 0.62 mol) cooled to 0° C. there was added over a period of one hour n-butyllithium (825 ml, 1.3 mol). The reaction mixture turned brown but remained homogeneous The reaction mixture was refluxed for 2 hours to complete the metallation, cooled to ice temperature, and then chlorotrimethylsilane (180 ml, 1 4 mol) was added so as to not let the reaction temperature exceed 15° C.. The reaction mixture was allowed to warm to room temperature and was refluxed overnight Filtration was accomplished by the Schlenk technique, and a gas chromatogram (GC) was taken. The solvent was evaporated and the residue was distilled to give three fractions Fraction 1 - b.p. 25°-89° C./0.5 torr, 22.0g (this forerun was discarded); Fraction 2 - b.p. 90°-108° C./0 5 torr, 32g, 95% pure by
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=2)[CH2:2]1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH3:28])[CH2:23][NH:22][CH2:21][CH2:20]2>C(O)(C)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH3:28])[CH2:23][N:22]([CH2:2][CH:3]([OH:1])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[CH2:21][CH2:20]2
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: O=[N+]([O-])c1ccc(OCC2CO2)cc1
Solvent: CC(C)O
Product: COc1cc2c(cc1OC)CN(CC(O)COc1ccc([N+](=O)[O-])cc1)CC2
Yield: 95.5 %

Procedure:
A mixture of 1,2-epoxy-3-(4-nitrophenoxy)propane (4 g) and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (5.4 g) in isopropanol (100 ml) was heated under reflux for 3 h and evaporated. The residue was purified by column chromatography to give the title compound (7.6 g) as a yellow oil which solidified on standing.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][C@@H:7]([OH:9])[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>N1C=CC=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3]([CH:4]1[CH2:8][CH:7]([O:9][S:25]([C:22]2[CH:23]=[CH:24][C:19]([CH3:18])=[CH:20][CH:21]=2)(=[O:27])=[O:26])[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])=[O:17]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C1CC(OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)OC(C)(C)C
Yield: 100.1 %

Procedure:
To a solution of trans-N-Boc-4-hydroxy-L-proline methyl ester (45 g, 0.183 mol) in pyridine (140 ml) and dry DCM (140 ml) at 0° C. was added dropwise 4-methyl-benzenesulfonyl chloride (41.9 g, 0.22 mol). After adding, the mixture was refluxed overnight. The solvent was evaporated and then the residue was dissolved in CH2Cl2 (140 ml). The organic phase was washed with water (150 ml), brine (140 mL), and dried over sodium sulphate. After removal of solvent, the crude 4-(toluene-4-sulfonyloxy)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester 73.2 g (92%) was obtained as yellow oil, which was used in the following reaction without further purification.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[O:19][CH3:20])=[CH:9][C:8](=[O:21])[NH:7][C:6]1=[S:22].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:47]([O:51][C:52]([NH:54][CH2:55][C:56](O)=[O:57])=[O:53])([CH3:50])([CH3:49])[CH3:48].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:20][O:19][C:12]1[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:11]=1[C:10]1[N:5]([CH2:4][CH2:3][NH:2][C:56](=[O:57])[CH2:55][NH:54][C:52](=[O:53])[O:51][C:47]([CH3:48])([CH3:49])[CH3:50])[C:6](=[S:22])[NH:7][C:8](=[O:21])[CH:9]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: COc1ccc(-c2cc(=O)[nH]c(=S)n2CCN)c(OC)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(-c2cc(=O)[nH]c(=S)n2CCNC(=O)CNC(=O)OC(C)(C)C)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
To a solution of 1-(2-aminoethyl)-6-(2,4-dimethoxyphenyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one hydrochloride (123 mg, 0.4 mmol)(the product of Example 6) in dry methylene chloride (4 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (182 mg, 0.48 mmol) and tert-butoxycarbonylamino-acetic acid (70 mg, 0.4 mmol) and diisoproplyethylamine (336 mg, 1.6 mmol). After stirring overnight at RT the reaction mixture was concentrated under reduced pressure and the residue purified by preparative thin layer chromatography (1:1 petroleum ether:ethyl acetate) to provide tert-butyl 2-(2-(6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)ethylamino)-2-oxoethylcarbamate (120 mg, 65%).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([OH:26])([C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1[O:17][CH3:18])([CH3:9])[CH3:8])C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[F:16][C:12]1[C:11]([O:17][CH3:18])=[C:10]([C:7]([CH3:8])([CH3:9])[CH2:6][C:5]([C:19]([F:24])([F:25])[C:20]([F:23])([F:22])[F:21])([OH:26])[CH2:4][OH:3])[CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)C(O)(CC(C)(C)c1cccc(F)c1OC)C(F)(F)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: COc1c(F)cccc1C(C)(C)CC(O)(CO)C(F)(F)C(F)(F)F
Temperature: 25 °C

Procedure:
1.0 g (3.54 mmol) of ethyl-4-(3-fluoro-2-methoxyphenyl)-2-oxo-4-methyl-valerate and 0.98 g (5.1 mmol) of (pentafluoroethyl)-trimethylsilane in 7 ml of THF are mixed with 65 mg (0.7 mmol) of tetramethylammonum fluoride at −40° C. The reaction mixture is heated to −25° C. and stirred at this temperature. After 4.5 hours, 1 ml of 2N hydrochloric acid is added, and the reaction mixture is added to water. It is extracted several times with ethyl acetate, washed with saturated sodium chloride solution, dried on sodium sulfate, and concentrated by evaporation in a vacuum. 1.65 g of ethyl-4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(pentafluoroethyl)valerate is obtained as a crude product. The ester is mixed in 80 ml of diethyl ether at 0° C. with 300 mg (8 mmol) of lithium aluminum hydride and stirred for 3.5 more hours at room temperature. A little water is carefully added to the batch at 0° C., and it is stirred vigorously for 15 more minutes. It is filtered by Cellite, and the precipitate is rewashed thoroughly with ethyl acetate. The filtrate is dried with sodium sulfate and concentrated by evaporation in a vacuum. After chromatographic purification on silica gel (hexane/ethyl acetate 10%-15%), 800 mg of 4-(3-fluoro-2-methoxyphenyl)-4-methyl-2-(pentafluoroethyl)pentane-1,2-diol is obtained. 1.8 ml (13 mmol) of triethylamine and, in portions over 10 minutes, 1.6 g (10 mmol) of pyridine SO3 complex are added to 800 mg (2.2 mmol) of diol in 25 ml of dichloromethane and 8.9 ml of DMSO. It is stirred for 2.5 hours, and saturated ammonium chloride solution is added. The mixture is stirred for another 15 minutes, the phases are separated, and it is extracted with dichloromethane. It is washed with water and dried on sodium sulfate. The solvent is removed in a vacuum, and the desired aldehyde is obtained quantitatively.
Reaction SMILES: [NH:1]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C@H:2]([C:18]([NH:20][C@H:21]([C:27]([NH:29][C@H:30]([C:35](OC)=[O:36])[CH2:31][CH2:32][CH2:33][CH3:34])=[O:28])[CH2:22][CH2:23][C:24](=[O:26])[NH2:25])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[NH2:46][NH2:47]>CN(C=O)C>[NH:1]([C:39]([O:41][C:42]([CH3:45])([CH3:43])[CH3:44])=[O:40])[C@H:2]([C:18]([NH:20][C@H:21]([C:27]([NH:29][C@H:30]([C:35]([NH:46][NH2:47])=[O:36])[CH2:31][CH2:32][CH2:33][CH3:34])=[O:28])[CH2:22][CH2:23][C:24](=[O:26])[NH2:25])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9]
Reactant: NN
Reactant: CCCC[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)OC
Solvent: CN(C)C=O
Product: CCCC[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)NN
Reaction time: 8 h
Yield: 88.5 %

Procedure:
The tripeptide methyl ester (XIII) (1 g, 1.6 mmol) was suspended in DMF (5 ml), hydrazine (0.8 g, 0.78 ml, 16 mmol) was added and the mixture was stirred overnight. The solvent was removed in vacuo and the residue solidified using MeOH/EtOAc to give (XIV) (0.9 g, 90%). T.l.c. RfA3 =0.70 This was used immediately in the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].[NH2:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([OH:26])[CH:24]=2)[CH:19]=[CH:18][CH:17]=1.C(O)(=O)C>O>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([N:15]([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([OH:26])[CH:24]=4)[CH:19]=[CH:18][CH:17]=3)[C:10](=[O:11])[C:5]=12)=[O:9])([O-:3])=[O:2]
Reactant: Nc1cccc2ccc(O)cc12
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2cccc([N+](=O)[O-])c2C(=O)N1c1cccc2ccc(O)cc12
Yield: 71.8 %

Procedure:
The starting material used in the above example can be prepared as follows: A mixture of 1.93 g (0.01 mol) of 3-nitrophthalic anhydride, 1.59 g (0.01 mol) of 1-amino-7-naphthol and 30 ml of acetic acid is refluxed for 17 hours. The resulting suspension is stirred with 300 ml of water, then filtered and the filter residue is then washed with water and dried. 2.9 g of crude product are obtained and are extracted with chloroform. The chloroform extract is stirred with 4 g of silica gel, filtered with suction whilst hot, and evaporated to dryness. 2.4 g (72% of theory) of 1-(3-nitrophthalimidyl)-7-hydroxynaphthalene are obtained; melting point 136°-7° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.CN(C)[CH:24]=[O:25]>O1CCCC1>[O:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[O:10][CH2:9][CH2:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[CH:24]=[O:25]
Reactant: CN(C)C=O
Reactant: Brc1cccc(CCOC2CCCCO2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cccc(CCOC2CCCCO2)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-[2-(3-bromo-phenyl)-ethoxy]-tetrahydro-pyran (20 g) in anhydrous tetrahydrofuran (300 mL) at −78° C. was added n-butyl lithium (2.5M in hexanes, 33.6 ml) dropwise over 5 minutes. The dark solution was kept at −78° C. for 30 minutes then N,N-dimethylformamide (16.35 ml) was added. The mixture was stirred −78° C. for half hour then quenched with aqueous ammonium acetate, and allowed to warm to room temperature. The resulting mixture was extracted with ethyl acetate, and the organics washed with brine, dried over sodium sulfate and concentrated in vacuo to give a yellow/orange oil (16.0 g). The material was used in the next step without further purification.
Reaction SMILES: Cl.[C:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][NH:5]1)#[CH:3].[OH-].[Na+].[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([N:22]2[N:26]=[CH:25][CH:24]=[N:23]2)=[C:17]([CH:21]=1)[C:18](Cl)=[O:19]>C1(C)C=CC=CC=1.CCOC(C)=O>[C:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:18]([C:17]1[CH:21]=[C:13]([CH3:12])[CH:14]=[CH:15][C:16]=1[N:22]1[N:26]=[CH:25][CH:24]=[N:23]1)=[O:19])#[CH:3]
Reactant: Cc1ccc(-n2nccn2)c(C(=O)Cl)c1
Reactant: C#CC1CCCCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C#CC1CCCCN1C(=O)c1cc(C)ccc1-n1nccn1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a rapidly-stirred mixture of 2-ethynylpiperidine hydrochloride (329 mg, 2.26 mmol), toluene (5 mL), and 1N NaOH (4.7 mL), cooled at 0° C., was added a solution of 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl chloride (500 mg, 2.26 mmol) in toluene (8 mL) dropwise over 20 mins. The mixture was stirred at 0° C. for 20 mins, then allowed to warm to ambient temperature. After 1 h, the solution was diluted with EtOAc and the layers separated. Brine was added to the aqueous layer and it was extracted with EtOAc. The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel flash chromatography eluting with 0-60% EtOAc in hexanes to provide (2-ethynylpiperidin-1-yl)[5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone as a collapsing white foam. The compound gave a high resolution mass spectrum (ES+) m/z of 259.1553, calculated for M+H+ [C17H18N4O: 295.1553]. 1H NMR δ (ppm) (CDCl3): 7.75-7.86 (3H, m), 7.30-7.34 (1 H, m), 7.18-7.20 (1H, m), 5.76 (1H, d, J=33.6 Hz), 4.50-4.67 (1H, m), 3.20-3.31 (1H, m), 2.91-3.08 (1H, m), 2.43 (3H, s), 2.04-2.36 (1H, m), 1.64-1.91 (2H, m), 1.42-1.61 (1H, m), 1.30-1.37 (1H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:21]4=[C:22]([CH2:25]OC(=O)C)[CH:23]=[CH:24][N:20]4[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.C(OC(=O)[NH:39][C:40]([CH3:44])([CH3:43])[CH2:41][OH:42])(C)(C)C.CCN(C(C)C)C(C)C>C(#N)C>[NH2:39][C:40]([CH3:43])([CH3:44])[CH2:41][O:42][CH2:25][C:22]1[CH:23]=[CH:24][N:20]2[C:21]=1[C:16]([NH:15][C:11]1[CH:10]=[C:9]3[C:14](=[CH:13][CH:12]=1)[N:6]([CH2:5][C:4]1[CH:30]=[CH:31][CH:32]=[C:2]([F:1])[CH:3]=1)[N:7]=[CH:8]3)=[N:17][CH:18]=[N:19]2
Reactant: CC(=O)OCc1ccn2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12
Reactant: CC(C)(CO)NC(=O)OC(C)(C)C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(N)COCc1ccn2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12
Temperature: 0 °C
Yield: 11.8 %

Procedure:
A mixture of acetic acid 4-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethylester (100 mg, 0.24 mmol), (2-hydroxy-1,1-dimethyl-ethyl)-carbamic acid tert-butyl ester 156 mg, 3 equiv) and DIPEA (62 μL, 1.5 equiv) in dry acetonitrile (0.2 mL) in a vial was placed in a microwave reactor (Personal Chemistry's Smith Creator) and irradiated for 10 min at 109° C. The solvent was removed and the residue was taken up in dry DCM (3 mL) and cooled to 0° C. TFA (3 mL) was added and after 1.5 hr, the solvents were removed. The residue was partitioned between DCM and saturated NaHCO3 solution. The organic phase was dried (Na2SO4) and the solvent was removed. Purification by radial chromatography (1 mm silica gel plate, gradient elution with 0 to 5% MeOH in DCM) gave the title compound (13 mg, 12% yield): MS: 460 (M+H)+; HPLC Ret Time: 1.34 min, YMC Xterra ODS S7 3.0×50 mm, 2 min gradient, 5 mL/min).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=2)=[CH:11][C:10]([C:20]([F:23])([F:22])[F:21])=[N:9]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:31][C:32]([O:34][CH3:35])=[O:33]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=2)[O:19][CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:11][C:10]([C:20]([F:23])([F:21])[F:22])=[N:9]1
Reactant: COC(=O)CBr
Reactant: Oc1cccc(-c2cc(C(F)(F)F)nn2-c2ccccc2Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)COc1cccc(-c2cc(C(F)(F)F)nn2-c2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.6 %

Procedure:
To a suspension of 3-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenol (229 mg, 0.68 mmol) and K2CO3 (179 mg, 1.3 mmol) in acetonitrile (3.0 mL) was added methyl bromoacetate (85 μL, 0.90 mmol). The suspension was stirred at ambient temperature for 16 hours at which time HPLC analysis showed conversion to a product with a slightly longer retention time. The reaction suspension was filtered through a plug of Celite that was then washed thoroughly with EtOAc. The filtrate was concentrated to afford a pale yellow oil. This material was further purified by flash column chromatography eluting with a gradient from 0% to 28% EtOAc/hexane to afford methyl 2-(3-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenoxy)acetate (158 mg, 57% yield) as an oil. MS(ES): 411 [M+H]+.
Reaction SMILES: [S:1]1[C:5]2=[CH:6][CH:7]=[CH:8][C:9]([NH2:10])=[C:4]2[N:3]=[N:2]1.C1C(=O)N([Br:18])C(=O)C1>C1COCC1>[Br:18][C:6]1[CH:7]=[CH:8][C:9]([NH2:10])=[C:4]2[C:5]=1[S:1][N:2]=[N:3]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cccc2snnc12
Solvent: C1CCOC1
Product: Nc1ccc(Br)c2snnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.3 %

Procedure:
A mixture of 1,2,3-benzothiadiazol-4-amine (200.0 mg, 1.323 mmol) and NBS (341.4 mg, 1.918 mmol) in THF (10 mL) was stirred at RT overnight. The solution was adsorbed onto silica gel and purified by ISCO chromatography (10 to 30% EtOAc:heptane) to afford 80 mg (30%) of the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 6.74 (d, J=8.3 Hz, 1 H), 6.97 (s, 2 H), 7.60 (d, J=8.3 Hz, 1 H).
Reaction SMILES: S(=O)(=O)(O)O.[O:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[CH:14]([C:16]([CH3:18])=[O:17])=[CH2:15]>C1C=CC=CC=1>[CH2:10]1[C:9]2([CH2:12][CH2:18][C:16](=[O:17])[CH:14]=[CH:15]2)[CH2:8][CH2:7][O:6][CH2:11]1
Reactant: O=CC1CCOCC1
Reactant: C=CC(C)=O
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: O=C1C=CC2(CCOCC2)CC1
Reaction time: 3 h

Procedure:
0.5 ml of sulphuric acid is added to 317 mmol of tetrahydro-2H-pyran-4-carboxaldehyde and 317 mmol of methyl vinyl ketone in 500 ml of benzene. The reaction mixture is then refluxed for 3 hours, water being removed using a Dean-Stark apparatus, and then a further 317 mmol of methyl vinyl ketone are added and reflux is continued for 3 hours. The mixture is subsequently washed, dried and then concentrated, and the residue obtained is distilled to yield the expected product.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+].[C:27](OC(=O)C)(=O)[CH3:28]>CN(C=O)C.O>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]2[CH:10]([OH:20])[C:3]3[C:2](=[C:7]([CH3:8])[C:6]([OH:9])=[CH:5][CH:4]=3)[O:1][C:27]=2[CH3:28])=[CH:13][CH:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(CC(=O)c2ccc(O)c(C)c2O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C2=C(C)Oc3c(ccc(O)c3C)C2O)cc1
Reaction time: 5 h

Procedure:
To a solution of 1-(2,4-dihydroxy-3-methyl-phenyl)-2-(4-methoxy-phenyl)-ethanone (1 eq) in anhydrous DMF was added K2CO3 (3 eq). Acetic anhydride (3 eq) was added dropwise to the solution, which was then refluxed, under nitrogen whilst stirring for 5 h. The solution was taken up in water and extracted using ethyl acetate, dried over MgSO4 and concentrated in vacuo to give 3-(4-methoxy-phenyl)-2,8-dimethyl-4H-chromene-4,7-diol as a yellow solid.