Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7](Br)[N:6]=1)=[O:4].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:18][CH:19]([SH:21])[CH3:20]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:21][CH:19]([CH3:20])[CH3:18])[N:6]=1)=[O:4]
Reactant: CC(C)S
Reactant: COC(=O)c1cccc(Br)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(SC(C)C)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.2 %

Procedure:
6-Bromo-pyridine-2-carboxylic acid methyl ester (0.15 g, 0.69 mmol) was added with DMF (2.3 mL), Cs2CO3(0.45 g, 1.38 mmol) and 2-propanethiol (0.064 mL, 0.69 mmol) in turn, and the mixture was stirred at room temperature for 18 hours. After the termination of the reaction, the reactant was filtered and concentrated under reduced pressure to obtain the title compound (0.13 g, 88%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:8][C:9](=O)OC(C)(C)C.N1(OC2[N:31]=[C:30]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([C:39]4[N:40]=[CH:41][S:42][CH:43]=4)=[C:35]([F:44])[CH:34]=3)[C:29]([C:45]([NH2:47])=[O:46])=[CH:28][N:27]=2)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.C(O)(C(F)(F)F)=O>CN1C(=O)CCC1>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:31]=[C:30]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[N:40]=[CH:41][S:42][CH:43]=3)=[C:35]([F:44])[CH:34]=2)[C:29]([C:45]([NH2:47])=[O:46])=[CH:28][N:27]=1
Reactant: NC(=O)c1cnc(On2nnc3ccccc32)nc1Nc1ccc(-c2cscn2)c(F)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2cscn2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.3 %

Procedure:
A solution of tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (0.30 M in NMP, 1.00 mL, 0.300 mmol) in NMP (1 mL) was added to 2-(1H-benzo[d][1,2,3]triazol-1-yloxy)-4-(3-fluoro-4-(thiazol-4-yl)phenylamino)pyrimidine-5-carboxamide (12 mg, 0.027 mmol). DIEA (0.050 mL, 0.29 mmol) was also added. The mixture was stirred at 90 C for 1 h. After being cooled to room temperature, TFA (1 mL) was added. The solution was stirred at room temperature for 60 min. The mixture was purified by HPLC to give the titled compound (5 mg). MS 428.4 (M+H). UV λ=229.8, 313.8 nm.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][C:12]1[C:13](=[O:21])[CH2:14][C@@H:15]([O:17]C(=O)C)[CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C1C=CC=CC=1.C(OC(CC1C(=O)C[C@@H](OC(=O)C)C=1)=O)C>C(O)C>[CH2:1]([O:8][C:9]([CH2:11][C:12]1[C:13](=[O:21])[CH2:14][C@@H:15]([OH:17])[CH:16]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O[C@H]1C=C(CC(=O)OCc2ccccc2)C(=O)C1
Agent: CCOC(=O)CC1=C[C@H](OC(C)=O)CC1=O
Solvent: CCO
Solvent: OCc1ccccc1
Product: O=C(CC1=C[C@H](O)CC1=O)OCc1ccccc1

Procedure:
Example 34: Example 34 was conducted according the procedure of Example 32 except that the starting material was (R)-2-benzoxycarbonylmethyl-4-acetyloxy-2-cyclopenten-1-one (4 g, 97% e.e.) and benzyl alcohol were used instead of (R)-2-ethoxycarbonylmethyl-4-acetoxy-2-cyclopenten-1-one and ethanol. The titled compound was obtained with high optical purity (3.4 g, 99% e.e.).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][C:6](=[O:12])[CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH3:3].[BH4-].[Na+]>CO>[CH3:3][CH:2]([CH2:4][CH2:5][CH:6]([OH:12])[CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH3:1]
Reactant: CC(C)CCC(=O)CCC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CCC(O)CCC(C)C
Reaction time: 1 h
Yield: 40.4 %

Procedure:
A solution of 5.63 g (33 mmol) of 2,8-dimethylnonan-5-one in 150 ml of methanol was cooled to 0° C. and treated with 0.8 g (21 mmol) of sodium borohydride. After 1 h, the solution was quenched with 1N HCl; diluted with 1:1 hexane/ether; washed sequentially with 1N NaOH, water, and saturated brine; dried over MgSO4 ; and concentrated in vacuo. Flash chromatography using 10% ethyl acetate in hexane gave 2.30 g (40%) of the desired compound (Rf 0.36, 20% ethyl acetate in hexane) as a colorless oil. 1H NMR (CDCl3) 0.88 (d, J=7 Hz, 6H), 0.89 (d, J=7 Hz, 6H), 1.1-1.6 (m, 10H), 3.56 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:26]=[CH:25][C:12]([O:13][CH2:14][C:15]3[CH:24]=[CH:23][C:22]4[C:17](=CC=C[CH:21]=4)[N:16]=3)=[CH:11][CH:10]=2)[O:3]1.ClCC1C=CC(C)=CN=1>N1C=CC=CC=1>[CH3:21][C:22]1[CH:23]=[CH:24][C:15]([CH2:14][O:13][C:12]2[CH:11]=[CH:10][C:9]([B:4]3[O:5][C:6]([CH3:8])([CH3:7])[C:2]([CH3:27])([CH3:1])[O:3]3)=[CH:26][CH:25]=2)=[N:16][CH:17]=1
Reactant: CC1(C)OB(c2ccc(OCc3ccc4ccccc4n3)cc2)OC1(C)C
Agent: Cc1ccc(CCl)nc1
Solvent: c1ccncc1
Product: Cc1ccc(COc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)nc1

Procedure:
5-Methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)pyridine may be prepared in a manner analogous to 2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)quinoline using 2-(chloromethyl)-5-methylpyridine instead of 2-(chloromethyl)quinoline.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:14][CH2:13][C@@H:12]([N:15]([CH3:23])[C:16]3[CH:21]=[CH:20][N:19]=[C:18](Cl)[N:17]=3)[CH2:11]2)=[N:3][CH:2]=1.[CH3:24][NH2:25]>>[N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:14][CH2:13][C@@H:12]([N:15]([CH3:23])[C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:25][CH3:24])[N:17]=3)[CH2:11]2)=[N:3][CH:2]=1
Reactant: CN(c1ccnc(Cl)n1)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Reactant: CN
Product: CNc1nccc(N(C)[C@@H]2CCN(c3ncnc4[nH]ccc34)C2)n1
Temperature: 110 °C
Reaction time: 0.75 h

Procedure:
A mixture of (R)—N-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-2-chloro-N-methylpyrimidin-4-amine (26.0 mg, 0.08 mmol) and methylamine (in THF, 2.0 M, 5.0 mL, 10.0 mmol) was stirred at 110° C. for 45 min in an Initator™ Biotage microwave reactor. The volatiles were removed under reduced pressure and the residue was purified by chromatography on silica gel to give the title compound. MS (m/z): 325 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:8](OCC)=[O:9])[CH2:4][CH2:3]1.[H-].C([Al+]CC(C)C)C(C)C.CO.CCOCC>C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH:8]=[O:9])[CH2:4][CH2:3]1
Reactant: CCOC(=O)C1(c2ccccc2)CCN(C)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CN1CCC(C=O)(c2ccccc2)CC1

Procedure:
Ethyl 1-methyl-4-phenylpiperidine-4-carboxylate (2.7 g, 10 mmol) was dissolved in dry toluene (30 ml). The stirred solution was cooled to -63° C. under an atmosphere of N2, whereafter a solution of diisobutylaluminiumhydrid (DIBAH, 1 M, 20 ml) was added dropwise. Stirring was continued at -70° C. for 11/2 h, whereafter methanol (5 ml) was added, in order to destroy excess of DIBAH. At ambient temperature water (50 ml) was added, and the mixture was filtered through a pad of filter aid. The organic phase was dried over Na2SO4 and evaporated to leave an oily residue. Treatment with ether afforded precipitation of the side product 4-hydroxymethyl-1-methyl-4-phenylpiperidine as pale crystals. Filtration followed by evaporation of the filtrate left the title compound as an oil, which was processed without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12]C)[CH:10]=2)[CH2:5][NH:4][CH2:3]1.Br>>[CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[CH2:5][NH:4][CH2:3]1
Reactant: COc1ccc2c(c1)C(C)(C)CNC2
Agent: Br
Product: CC1(C)CNCc2ccc(O)cc21

Procedure:
A mixture of 4,4-dimethyl-6-methoxy-1,2,3,4-tetrahydroisoquinoline (23.9 g, 0.125 mol) and 48% aqueous hydrobromic acid (158 ml) were heated at vigorous reflux for 4 hours. The reaction mixture was cooled and evaporated in vacuo. The residue was triturated with diethyl ether (20 ml), 1:1 diethyl ether:thf (20 ml) and diethyl ether (3×20 ml) and dried in vacuo to afford the title compound as the hydrobromide salt (17.5 g, 53%).
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4].S(=O)(=O)(O)O.[CH2:15]=[C:16]([CH3:18])[CH3:17]>ClCCl>[Br:1][CH:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([O:5][C:16]([CH3:18])([CH3:17])[CH3:15])=[O:4]
Reactant: C=C(C)C
Reactant: CC(C)CC(Br)C(=O)O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(C)CC(Br)C(=O)OC(C)(C)C
Temperature: -40 °C
Yield: 98 %

Procedure:
The product from Step 1 above (63.3 g, 0.32 mol) was dissolved in dichloromethane (250 mL), concentrated sulfuric acid (2 mL) was added, and cooled to −40° C. in a pressure bottle. Isobutene was condensed into the solution to roughly double the volume, and the mixture was then allowed to warm to room temperature overnight. Following evaporation to half of the volume under reduced pressure, the solution was washed with 10% aqueous sodium bicarbonate, dried over Na2SO4, and thoroughly evaporated under reduced pressure at room temperature to leave the title compound as a yellow oil (79.9 g, 0.314 mol; 98%).
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[Na].[CH2:12](Br)[CH:13]([CH3:15])[CH3:14]>C(O)C>[CH2:12]([O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([NH2:10])=[O:9])[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)CBr
Reactant: NC(=O)c1ccccc1O
Agent: [Na]
Solvent: CCO
Product: CC(C)COc1ccccc1C(N)=O

Procedure:
Salicylamide (68.5 g.; prepared as described by R. Bogoczek, Farm. Polska, 1960, 16, 26) was added to a solution of sodium (11.5 g.) in anhydrous ethanol (400 ml.). Isobutyl bromide (60 ml.) was then added, and the mixture was stirred and heated to reflux overnight. The ethanol was evaporated, and sufficient water was added to the residue to dissolve the sodium bromide. The oil which did not dissolve was extracted with chloroform, the extract was washed twice with 2N sodium hydroxide solution and once with water, dried over magnesium sulphate, filtered and evaporated. The residue was triturated with light petroleum (b.p. 40°-60° C.) to give 2-isobutoxybenzamide, which was pure enough for use in the next stage of the synthesis. A pure sample, m.p. 125°-128° C., was obtained by recrystallisation of an aliquot from cyclohexane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:24])[CH2:9][N:10]([CH3:23])[S:11]([C:14]2[CH:18]=[C:17]([C:19](=[O:21])[CH3:20])[S:16][C:15]=2[NH2:22])(=[O:13])=[O:12])=[CH:4][CH:3]=1.[OH-].[Na+].FC1C=CC(CCl)=CC=1.[F:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=1>C(OCC)(=O)C.O1CCCC1>[C:19]([C:17]1[S:16][C:15]([NH:22][C:41](=[O:42])[C:40]2[CH:44]=[CH:45][C:37]([F:36])=[CH:38][CH:39]=2)=[C:14]([S:11](=[O:13])(=[O:12])[N:10]([CH2:9][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[OH:24])[CH3:23])[CH:18]=1)(=[O:21])[CH3:20]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CC(=O)c1cc(S(=O)(=O)N(C)CC(O)c2ccc(F)cc2)c(N)s1
Agent: Fc1ccc(CCl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)c1cc(S(=O)(=O)N(C)CC(O)c2ccc(F)cc2)c(NC(=O)c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-acetyl-2-amino-thiophene-3-sulfonic acid [2-(4-fluorophenyl)-2-hydroxy-ethyl]-methyl-amide (the compound of Preparation Example 99) (120 mg) in ethyl acetate-tetrahydrofuran (4:1) (30 mL) was added an aqueous solution (10 mL) of 2N sodium hydroxide. After stirring vigorously at room temperature, 4-fluorobenzyl-chloride (51 mg) was added. After 30 minutes, an aqueous solution (10 mL) of 2N sodium hydroxide, then 4-fluorobenzoyl-chloride (100 mg) were added, and the solution was stirred for 30 minutes. In addition, an aqueous solution (10 mL) of 2N sodium hydroxide, then 4-fluorobenzoyl-chloride (100 mg) were added. After stirring for 30 minutes, extraction was carried out by adding ethyl acetate, and the organic layer was dried with anhydrous magnesium sulfate. Purification was carried out by purification with silica gel column chromatography (hexane/ethyl acetate), and the title compound (59 mg) was obtained as yellow solids.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([OH:16])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>C1C=CC=CC=1>[C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([O:16][C:32](=[O:33])[C:31]3[CH:35]=[CH:36][C:28]([O:27][CH3:26])=[CH:29][CH:30]=3)[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CN1CCC(O)N(c2nnc(C(C)(C)C)s2)C1=O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1ccc(C(=O)OC2CCN(C)C(=O)N2c2nnc(C(C)(C)C)s2)cc1

Procedure:
Tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3 -methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 4-Methoxybenzoyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield the desired product tetrahydro-1-(5-t-butyl-1,3,4 -thiadiazol-2-yl)-3-methyl-6-(4-methoxybenzoyloxy)-2(1 H)-pyrimidinone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[N+:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1)([O-:12])=[O:11].O>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:17](=[O:18])[C:16]2[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:21][CH:20]=2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(N)cc1
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2)cc1
Yield: 73.6 %

Procedure:
12.3 g of p-anisidine were added in small fractions to a suspension of 18.6 g of 4-nitrobenzoic acid chloride in 100 ml of pyridine and the mixture was heated for 2 hours at reflux. After returning to ambient temperature, the solution was poured into 500 ml of iced water and the precipitate formed was separated and washed with water, then dried under reduced pressure at 80° C. to obtain 20 g of N-(4-methoxyphenyl)-4-nitrobenzamide melting at 200° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]([OH:12])=O.S(Cl)([Cl:15])=O>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]([Cl:15])=[O:12]
Reactant: O=C(O)Cc1c(F)cccc1F
Reactant: O=S(Cl)Cl
Product: O=C(Cl)Cc1c(F)cccc1F
Reaction time: 1 h

Procedure:
75.3 g (0.44 mol) of 2,6-difluorophenylacetic acid are dissolved in 96 ml (156.5 g; 1.32 mol) of thionyl chloride, stirred for 1 hour at 60° and then heated under reflux for 2 hours. The excess thionyl chloride is then distilled off and the residue is fractionated, yielding 79.5 g (95% of the theoretical yield) of 2,6-difluorophenylacetyl chloride.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH:12][CH2:13][C:14]([CH2:20][OH:21])([CH3:19])[C:15]([O:17][CH3:18])=[O:16].[CH3:22][O:23][CH:24](OC)[CH2:25][CH2:26]OC.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH3:22][O:23][CH2:24][CH2:25][CH:26]1[O:21][CH2:20][C:14]([CH3:19])([C:15]([O:17][CH3:18])=[O:16])[CH2:13][O:12]1
Reactant: COCCC(OC)OC
Reactant: COC(=O)C(C)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COCCC1OCC(C)(C(=O)OC)CO1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
51 mg of 4-toluenesulphonic acid are added to a solution of 400 mg of methyl 3-hydroxyl-2-(hydroxymethyl)-2-methylpropanoate and 362 mg of 1,1,3-trimethoxypropane in toluene, and the mixture is stirred at 80° C. for 4 hours. After addition of saturated sodium bicarbonate solution, the organic phase is separated off and dried over sodium sulphate, and the solvent is removed under reduced pressure. The residue is filtered through silica gel (mobile phase cyclohexane/ethyl acetate 4:1). This gives 478 mg of methyl 2-(2-methoxyethyl)-5-methyl-1,3-dioxane-5-carboxylate as a mixture of two isomeric forms in a purity of about 38% (LCMS).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[N+:33]([O-:35])=[O:34])[C:27]([OH:29])=O.[CH2:36]([NH:41][CH2:42][CH2:43][CH:44]([CH3:46])[CH3:45])[CH2:37][CH:38]([CH3:40])[CH3:39]>C1COCC1.C(Cl)(Cl)Cl>[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[N+:33]([O-:35])=[O:34])[C:27]([N:41]([CH2:42][CH2:43][CH:44]([CH3:46])[CH3:45])[CH2:36][CH2:37][CH:38]([CH3:39])[CH3:40])=[O:29]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: CC(C)CCNCCC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)CCN(CCC(C)C)C(=O)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 20 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
1-hydroxybenzotriazole (HOBt) (8 g, 1.1 eq) in solution in THF (60 ml) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (ED)C) (11.4 g, 1.1 eq) in solution in chloroform (60 ml) are added successively to 3-fluoro-4-nitrobenzoic acid (10 g, 1 eq) in solution in anhydrous THF (60 ml). The mixture is stirred for 2 hours at a temperature of approximately 20° C. then diisoamylamine (12.2 ml, 1.1 eq) is added. After stirring for 4 hours at a temperature of approximately 20° C., the reaction mixture is concentrated under reduced pressure at 40° C. The residue is taken up in dichloromethane (300 ml) and water (100 ml). After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. Purification by flash chromatography on silica gel (eluent: heptane 100% to heptanel ethyl acetate 70:30) produces the expected compound (12.36 g; 71% yield).
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][NH:17][CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=CC=1.C1(C)C=CC=CC=1.[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33]>>[CH:10]1[C:11]2[C:20]3[CH2:19][CH2:18][NH:17][CH2:16][C:15]=3[CH:14]=[N:13][C:12]=2[NH:8][N:9]=1.[C:32]([OH:34])([C:31]([F:36])([F:35])[F:30])=[O:33]
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CNCC4)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: c1nc2[nH]ncc2c2c1CNCC2

Procedure:
A solution of 3-(4-methoxy-benzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine (0.14 g, 0.47 mmol) in trifluoroacetic acid (2 mL) was heated at 65° C. for 16 hours. On completion of the reaction, toluene (5 mL) was added. The solvent was then removed under reduced pressure to give a dark brown solid. The solvent was removed under reduced pressure to give 6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine as a TFA salt. LCMS [M+H]: 175.
Reaction SMILES: ClC(OC(Cl)C)=O.C([N:15]1[CH2:20][C@H:19]([CH3:21])[O:18][C@@H:17]([CH3:22])[CH2:16]1)C1C=CC=CC=1.C(N(CC)C(C)C)(C)C.C([O-])([O-])=O.[K+].[K+].F[C:39]1[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][C:40]=1[CH:41]=[O:42]>C(Cl)Cl>[CH3:22][C@@H:17]1[O:18][C@@H:19]([CH3:21])[CH2:20][N:15]([C:39]2[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][C:40]=2[CH:41]=[O:42])[CH2:16]1
Reactant: C[C@H]1CN(Cc2ccccc2)C[C@H](C)O1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1F
Agent: CC(Cl)OC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H]1CN(c2ccc([N+](=O)[O-])cc2C=O)C[C@H](C)O1
Temperature: 25 °C

Procedure:
1-Chloroethyl chloroformate (292 μL, 2.68 mmol, Aldrich) is added to a solution of (2S,6S)-4-benzyl-2,6-dimethylmorpholine (in CH2Cl2 (6 mL) with stirring in an ice bath. The solution is allowed to warm to room temperature and stirred for 2.5 hours. The solvent is removed by rotary evaporation and the residue is dissolved in methanol (6 mL). This solution is heated to reflux for 2.5 hours and the methanol is removed by rotary evaporation. The residue is dissolved in CH3CN (5 mL) and treated with N,N-diisopropylethylamine (244 μL, 1.4 mmol, Aldrich). K2CO3 (190 mg, 1.37 mmol, Mallinkrodt) and 2-fluoro-5-nitrobenzaldehyde (230 mg, 1.36 mmol, Oakwood) are added and the mixture is heated at 60° C. for 21 hours. The mixture is filtered and the solvent is removed by rotary evaporation. The residue is dissolved in CH2Cl2 (100 mL) and washed sequentially with water (75 mL) and brine (75 mL). The organic layer is purified on a Biotage Flash 25M+ using a 40% EtOAc in heptane as eluent. The product containing fractions are pooled and the solvent is removed by rotary evaporation. The product is dried under vacuum yielding a yellow syrup.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:29]Br>C(#N)C.C(OCC)(=O)C>[C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]2)=[CH:9][C:10]=1[Br:29])(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: CC(=O)Oc1ccc(N2CCN(C)CC2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(=O)Oc1ccc(N2CCN(C)CC2)cc1Br
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of 4-(4-methylpiperazin-1-yl)phenyl acetate 247 mg (1.05 mmol) and p-toluenesulfonic acid 209 mg (1.1 mmol) in acetonitrile was cooled in an ice bath and bromine 0.056 ml (1.1 mmol) was added dropwise. The reaction was stirred at room temperature until complete (3-4 hours), was diluted with ethyl acetate and extracted with water and saturated NaHCO3. The organic phase, dried over Na2SO4 and evaporated, was purified by flash chromatography (DCM/MeOH 85/15) to give the product as a dark brown oil. HPLC (254 nm) method 2 Rt 4.05 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.25 (s, 3H) 2.36 (s, 3H) 2.39 (m, 4H) 3.44 (m, 4H) 6.50 (dd. J=2.1, 8.3 Hz, 1H) 7.03 (d, J=8.3 Hz, 1H) 7.21 (d, J=2.1 Hz, 1H). Mass. Calc. 313.0546 Mass. Found: 313.0538
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH:8](P(OCC)(OCC)=O)[F:9])=[O:7].[C:18]([C:21]1[O:25][C:24]2[C:26]([C:30]3[CH:35]=[C:34]([CH2:36][CH3:37])[CH:33]=[C:32]([C:38]([CH3:41])([CH3:40])[CH3:39])[C:31]=3[O:42][CH2:43][CH2:44][CH3:45])=[CH:27][CH:28]=[CH:29][C:23]=2[CH:22]=1)(=O)[CH3:19].O>CN(C=O)C>[CH2:4]([O:5][C:6](=[O:7])[C:8]([F:9])=[C:18]([C:21]1[O:25][C:24]2[C:26]([C:30]3[CH:35]=[C:34]([CH2:36][CH3:37])[CH:33]=[C:32]([C:38]([CH3:41])([CH3:40])[CH3:39])[C:31]=3[O:42][CH2:43][CH2:44][CH3:45])=[CH:27][CH:28]=[CH:29][C:23]=2[CH:22]=1)[CH3:19])[CH3:3]
Reactant: CCCOc1c(-c2cccc3cc(C(C)=O)oc23)cc(CC)cc1C(C)(C)C
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1c(-c2cccc3cc(C(C)=C(F)C(=O)OCC)oc23)cc(CC)cc1C(C)(C)C
Reaction time: 0.25 h

Procedure:
To a mixture of 43 mg (0.89 mmol) of NaH in 1 mL of dry DMF was added 216 mg (0.89 mmol, 0.15 mL) of triethyl 2-fluoro-2-phosphonoacetate diluted in 1 mL of dry DMP at 0° C. After the gas evolution ceased, the solution was stirred at this temperature for 15 minutes and 0.296 mmol of 2-acetyl-7-(2-propoxy-3-tert-butyl-5-ethylphenyl) benzo[b]furan diluted in 1 mL of dry DMF was added dropwise. The reddish solution was stirred to 0° C. until completion (TLC monitoring). After cooling, water was added and the mixture as extracted with ethyl acetate. The organic layer was washed with water and brine and dried over MgSO4. The solvents were evaporated under reduced pressure, and the residual oil was purified over silica gel (eluent: ethyl acetate/hexane: 5/95) to afford 2-fluoro-3-[7-(2-propoxy-3-tert-butyl-5-ethylphenyl)-benzo[b]furan-2-yl]-but-2-enoic acid ethyl ester as a clear yellow oil. 1H NMR (CDCl3), δ: 7.52 (d, J=7.8 Hz, 1H), 7.52 (d, J=7.2 Hz, 1H), 7.39 (d, J=3.4 Hz, 1H), 7.33 (t, J=7.6 Hz, 1H), 7.22 (d, J=2.1 Hz, 1H), 7.17 (d, J=2.2 Hz, 1H), 3.27 (t, J=6.2 Hz, 2H), 2.66 (dd, J=15.1, 7.5 Hz, 1H), 2.54 (d, J=3.4 Hz, 3H), 1.46 (s, 9H), 1.27 (t, J=7.7 Hz, 3H), 1.19 (m, 2H), 0.50 (t, J=7.4 Hz, 3H).