Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][CH2:3][C:4]([O:6][CH3:7])=O.[CH2:8]([O:15][C:16]1[CH:17]=[C:18]([Mg]Br)[CH:19]=[CH:20][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1COCC1>CCOCC>[CH2:8]([O:15][C:16]1[CH:21]=[C:20]([C:3](=[O:2])[CH2:4][O:6][CH3:7])[CH:19]=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Br[Mg]c1cccc(OCc2ccccc2)c1
Reactant: COCC(=O)OC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COCC(=O)c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Yield: 14 %

Procedure:
To a solution of methyl methoxyacetate (available from Aldrich) (0.48 mL, 4.8 mmol) in ether (20.0 mL) was added a 1.0 M solution of (3-(benzyloxy)phenyl)magnesium bromide in THF (available from Aldrich) (5.0 mL, 5.0 mmol) dropwise at −78° C. The mixture was warmed to room temperature overnight, quenched with 1 N HCl, and diluted with EtOAc. The organics were washed with water and brine, dried (MgSO4), and concentrated. The crude product was purified by silica gel flash chromatography (0-20% EtOAc/hexane) to afford 1-(3-(benzyloxy)phenyl)-2-methoxyethanone (0.17 g, 14%) as a pale yellow oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:9][C:8]2[CH2:10][CH2:11][CH2:12][CH2:13][C:7]=2[C:6]=1[C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:3])[CH3:2].[H-].[Na+].[CH3:24]I.O>CN(C)C=O>[CH3:24][CH2:2][C:1]([NH:4][C:5]1[S:9][C:8]2[CH2:10][CH2:11][CH2:12][CH2:13][C:7]=2[C:6]=1[C:14](=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:3]
Reactant: CI
Reactant: CC(=O)Nc1sc2c(c1C(=O)c1ccccc1)CCCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(=O)Nc1sc2c(c1C(=O)c1ccccc1)CCCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5.0 g of 2-acetylamino-3-benzoyl-4,5,6,7-tetrahydrobenzo[b ]thiophene in 60 ml of dimethylformamide is added 0.9 g of 63% sodium hydride. The mixture is stirred at room temperature for 30 minutes. Then 71.3 g of methyl iodide in 20 ml of dimethylformamide is added thereto. The mixture is stirred at room temperature for 3 hours, then poured into water, and extracted with benzene. The benzene extracts are washed with water, dried over sodium sulfate, and the solvent is removed under reduced pressure to give 2-(N-methylacetylamino)-3-benzoyl-4,5,6,7-tetrahydrobenzo[b] thiophene as an oil. This layer chromatography (Kiesel gel) shows the Rf value of 0.44 using a mixture of ethyl acetate and chloroform (1 : 1 V/V).
Reaction SMILES: C1(S[CH2:8][N:9]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([O:25][CH3:26])=[CH:16][C:17]=3[CH:21]([CH2:23][CH3:24])[CH3:22])[S:10]2(=[O:12])=[O:11])C=CC=CC=1.S(Cl)([Cl:30])(=O)=O>C(Cl)Cl>[Cl:30][CH2:8][N:9]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][C:15]([O:25][CH3:26])=[CH:16][C:17]=2[CH:21]([CH2:23][CH3:24])[CH3:22])[S:10]1(=[O:12])=[O:11]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCC(C)c1cc(OC)cc2c1C(=O)N(CSc1ccccc1)S2(=O)=O
Solvent: ClCCl
Product: CCC(C)c1cc(OC)cc2c1C(=O)N(CCl)S2(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-phenylthiomethyl-4-sec-butyl-6-methoxysaccharin (2.6 g) in CH2Cl2 (20 mL) was added sulfuryl chloride (0.7 mL). The mixture was stirred at ambient temperature overnight, and the solvent was removed in vacuo. The residue was treated with hexane and the mixture was sonicated for 6 hours. A precipitate formed with a collected by filtration to afford 1.33 g of 2-chloromethyl-4-sec-butyl-6-methoxysaccharin.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([CH3:14])([CH3:13])[CH2:11][CH2:10][CH:9]1[CH:15](C(OC)=O)[C:16]([O:18]C)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>C1COCC1.CO>[C:1]([O:5][C:6]([N:8]1[C:12]([CH3:13])([CH3:14])[CH2:11][CH2:10][CH:9]1[CH2:15][C:16]([OH:18])=[O:17])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(C(=O)OC)C1CCC(C)(C)N1C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C(CC(=O)O)CCC1(C)C
Temperature: 65 °C
Reaction time: 20 h
Yield: 72.2 %

Procedure:
Dimethyl 2-(1-(tert-butoxycarbonyl)-5,5-dimethylpyrrolidin-2-yl)malonate (220 mg, 0.7 mmol) was placed in 1:1 THF:MeOH (3 mL). KOH (0.8 mL, 1.7 mmol) was then added, and the reaction heated to 65° C. for 6 hours. The reaction was then cooled to room temperature and concentrated to remove the THF and MeOH. The reaction was then acidified with 6M HCl and then heated to 85° C. overnight to achieve decarboxylation. The reaction was then cooled to room temperature and basicified with solid NaOH until a pH of 14. THF (10 mL) and Boc2O (5 equivalents) were then added. The reaction was stirred for 20 hours at 50° C. and then cooled to room temperature. The reaction was extracted with DCM, and the organic fraction was discarded. The aqueous fraction was then acidified to a pH of 2 with 10% aqueous citric acid and then extracted with DCM. The combined organic fractions were dried, filtered, and concentrated to give the product 2-(1-(tert-butoxycarbonyl)-5,5-dimethylpyrrolidin-2-yl)acetic acid (130 mg, 75% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])/[C:5](/O)=[CH:6]/[C:7](=O)[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)[CH3:2].O.[NH2:23][NH2:24]>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)[NH:24][N:23]=1)=[O:21])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)/C(O)=C/C(=O)c1ccc(OC(F)(F)F)cc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(-c2ccc(OC(F)(F)F)cc2)[nH]n1

Procedure:
In analogy to the procedure described for example 4 b], (Z)-2-hydroxy-4-oxo-4-(4-trifluoromethoxy-phenyl)-but-2-enoic acid ethyl ester was reacted with hydrazine monohydrate in ethanol under reflux conditions to give 5-(4-trifluoromethoxy-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester as yellow crystals.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH:5]=[CH:4][C:3]1=[O:8].[N+:9]([C:12]1[CH:18]=[CH:17][C:15](N)=[CH:14][CH:13]=1)([O-:11])=[O:10]>>[N+:9]([C:12]1[CH:18]=[CH:17][C:15]([C:4]2[C:3]([N:2]([CH3:1])[C:6](=[O:7])[CH:5]=2)=[O:8])=[CH:14][CH:13]=1)([O-:11])=[O:10]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: CN1C(=O)C=CC1=O
Product: CN1C(=O)C=C(c2ccc([N+](=O)[O-])cc2)C1=O

Procedure:
A 100 g portion of N-methylmaleimide was reacted with 126.2 g of p-nitroaniline as described in Example 6, giving 78 g of 2-(p-nitrophenyl)-N-methylmaleimide.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:9])[NH:5][CH:6]=[CH:7][CH:8]=1.[OH-].[K+].[CH3:12]I>CO>[CH3:12][N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]1=[O:9]
Reactant: COc1ccc[nH]c1=O
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cccn(C)c1=O

Procedure:
A mixture of 3-methoxy-2(1H)-pyridone (25 g., 0.2 moles), potassium hydroxide (16 g., 0.24 moles) and methyl iodide (45.4 g., 0.32 moles) in 400 ml. methanol is heated at reflux for 5 hours. The methanol is removed under reduced pressure leaving a solid redidue which is extracted with methylene chloride. The methylene chloride extracts are washed with water, a saturated salt solution, and dried over sodium sulfate. Evaporation of the dried extracts, under reduced pressure, affords 1-methyl-3-methoxy-2(1H)-pyridone as a colorless oil which solidifies on standing (26.2 g., 94%). The pyridone is very hygroscopic and rapidly liquifies on exposure to air.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]2=[C:8]3[C:13](=[C:14]([NH2:16])[N:15]=[C:6]2[CH:5]=1)[N:12]=[CH:11][CH:10]=[CH:9]3)([O-])=O>CCO.C(Cl)Cl.[Pd]>[CH:9]1[C:8]2[C:13](=[C:14]([NH2:16])[N:15]=[C:6]3[CH:5]=[C:4]([NH2:1])[CH:18]=[CH:17][C:7]3=2)[N:12]=[CH:11][CH:10]=1
Reactant: Nc1nc2cc([N+](=O)[O-])ccc2c2cccnc12
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: Nc1ccc2c(c1)nc(N)c1ncccc12

Procedure:
A mixture of 8-nitrobenzo[f][1,7]naphthyridin-5-amine (from the previous step) (1.0 eq) and Pd/C (wet, 10% wt) in EtOH was stiffed under H2 balloon overnight. The reaction mixture was diluted with DCM. The insoluble solid was filtered off through celite, and the filtrate was concentrated en vacuo to obtain a crude residue. The crude material was washed with acetone to give benzo[f][1,7]naphthyridine-5,8-diamine as an off white solid: 1H NMR (methanol-d4): δ 8.73 (dd, 1H), 8.71 (dd, 1H), 8.11 (d, 1H), 7.69 (dd, 1H), 6.86 (d, 1H), 6.82 (dd, 1H). LRMS [M+H]=211.1.
Reaction SMILES: [OH:1][CH:2]1[C:7]([O:10][CH3:11])([O:8][CH3:9])[CH2:6][CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3]1.[H-].[Na+].C1(C)C=CC(S(O[CH2:31][CH2:32][F:33])(=O)=O)=CC=1>CN(C=O)C>[F:33][CH2:32][CH2:31][O:1][CH:2]1[C:7]([O:8][CH3:9])([O:10][CH3:11])[CH2:6][CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Reactant: COC1(OC)CCN(C(=O)OC(C)(C)C)CC1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(OC)CCN(C(=O)OC(C)(C)C)CC1OCCF
Yield: 97.7 %

Procedure:
The same operation as in Example (90a) was performed using tert-butyl 3-hydroxy-4,4-dimethoxypiperidine-1-carboxylate (6.2 g, 23.7 mmol), sodium hydride (55% content, 1.57 g, 36 mmol), 2-fluoroethyl p-toluenesulfonate (7.85 g, 46 mmol) and DMF (50 mL). The residue was purified by column chromatography (elution solvent: hexane/ethyl acetate=10/1, 4/1, 2/1) to obtain 7.12 g of the title compound as a colorless oily substance (98%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]([C:19]1[S:20][CH:21]=[CH:22][N:23]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13](F)=[CH:12][C:11]=1[F:18])(=[O:9])=[O:8].[CH3:30][N:31]1[C:35]([C@H:36]2[CH2:40][CH2:39][CH2:38][C@@H:37]2[OH:41])=[CH:34][CH:33]=[N:32]1.[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]([C:19]1[S:20][CH:21]=[CH:22][N:23]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:41][C@H:37]2[CH2:38][CH2:39][CH2:40][C@@H:36]2[C:35]2[N:31]([CH3:30])[N:32]=[CH:33][CH:34]=2)=[CH:12][C:11]=1[F:18])(=[O:9])=[O:8]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1
Reactant: Cn1nccc1[C@H]1CCC[C@@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2cc(F)c(O[C@H]3CCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Yield: 73.6 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1a by using the N-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(1,3-thiazol-2-yl)benzenesulfonamide (184 mg, 0.414 mmol) prepared in Example 15a, (1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol (68.7 mg, 0.414 mmol) prepared in Example 8a, sodium hydride (63%; 31.6 mg, 0.830 mol) and DMF (2.0 mL), to yield the title compound (180 mg, 73%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=S)[NH:10][NH2:11])[CH:5]=[CH:6][CH:7]=1.Cl[CH:14]([C:20]([CH3:22])=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16].Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:20]([CH3:22])[NH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: NNC(=S)Nc1cccc(Cl)c1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.3 %

Procedure:
A stirred slurry of 8 g (0.04 mole) of 4-(3-chlorophenyl)-3-thiosemicarbazide in 75 mL of absolute ethanol was treated with 6.8 g (0.04 mole) of ethyl 2-choroacetoacetate. The reactants quickly dissolved but a precipitate soon formed. After stirring at room temperature for 2 hr the reaction mixture was treated with 40 mL of 2N ethanolic hydrogen chloride and heated at reflux for 1 hr, then filtered while hot to remove the insoluble sulfur. The filtrate on cooling yielded 3.5 g of yellow solid and an additional 4.7 g was obtained when the filtrate was concentrated in vacuo. Recrystallization from benzene/ligroin gave 4.2 g of pale yellow brown product. Additional ligroin added to the filtrate gave, upon cooling at ~7-10° C. for ~16 hr, additional crystals but also some oil; this tri-phase mixture was filtered to yield 1.5 g of additional product. Both solids had identical mass spectra. They were combined and recrystallized twice from benzene/ligroin and finally from benzene by dissolving the solids and reducing the volume until crystallization began. Upon cooling, 3.93 g of beige plate-like crystals were collected, mp 159.5°-160° C.
Reaction SMILES: C([SnH](CCCC)CCCC)CCC.N(C(C)(C)C#N)=NC(C)(C)C#N.Br[CH2:27][CH2:28][C:29]([N:31]1[CH:36]=[CH:35][C:34](=[O:37])[CH2:33][CH:32]1[C:38]1[CH:43]=[CH:42][C:41]([F:44])=[C:40]([F:45])[CH:39]=1)=[O:30].O>C1C=CC=CC=1>[F:45][C:40]1[CH:39]=[C:38]([CH:32]2[CH2:33][C:34](=[O:37])[CH2:35][CH:36]3[N:31]2[C:29](=[O:30])[CH2:28][CH2:27]3)[CH:43]=[CH:42][C:41]=1[F:44]
Reactant: O=C1C=CN(C(=O)CCBr)C(c2ccc(F)c(F)c2)C1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: O
Solvent: c1ccccc1
Product: O=C1CC2CCC(=O)N2C(c2ccc(F)c(F)c2)C1
Reaction time: 3 h

Procedure:
To a solution of 4-methoxypyridine (2.7 g) in tetrahydrofuran (50 mL), 3,4-difluorophenylmagnesium bromide (0.5 M solution in tetrahydrofuran; 50 mL) was added dropwise at −40° C. to −20° C. over 10 minutes. To this solution, 3-bromopropionyl chloride (2.49 mL) was added dropwise at −40° C. to −20° C., and the reaction solution was stirred at −20° C. for 30 minutes. The reaction solution was poured into a 10% hydrochloric acid solution, and the mixture was stirred for 20 minutes, followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 3.4 g of 1-(3-bromopropionyl)-2-(3,4-difluorophenyl)-2,3-dihydro-1H-pyridin-4-one. A solution of tributyltin hydride (5.75 mL) and 2,2′-azobis(isobutyronitrile) (0.657 g) in benzene (50 mL) was added dropwise to a solution of 1-(3-bromopropionyl)-2-(3,4-difluorophenyl)-2,3-dihydro-1H-pyridin-4-one obtained above (3.4 g) in benzene (50 mL) at 90° C. over four hours. The reaction solution was stirred at the same temperature for three hours. The reaction solution was returned to room temperature and poured into water, followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 1.4 g of the title compound. The property value of the compound is as follows.
Reaction SMILES: [N+:1]([CH2:3][C:4](OC)=[O:5])#[C-:2].[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>>[N+:1]([CH2:3][C:4]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=[O:5])#[C-:2]
Reactant: C1COCCN1
Reactant: [C-]#[N+]CC(=O)OC
Product: [C-]#[N+]CC(=O)N1CCOCC1

Procedure:
To stirred and cooled (0° C.) methyl 2-isocyanoacetate (96% technical grade, 1.0 g, 10.09 mmol) was slowly added morpholine (1.05 g, 12.11 mmol). The mixture was stirred for 1 h with continuous stirring at room temperature and then concentrated. The resulting oil was co-evaporated twice from a mixture CH2Cl2:hexane to obtain crude 2-isocyano-1-morpholinoethanone, SLA 19178, as a yellow oil (1.65 g, 99% yield) and used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.Br[C:15]1[CH:16]=[C:17]2[C:21]3=[C:22]([CH2:24][S:25][CH2:26][CH2:27][N:20]3[C@H:19]3[CH2:28][CH2:29][N:30](C(OC(C)(C)C)=O)[CH2:31][C@@H:18]23)[CH:23]=1>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:15]1[CH:16]=[C:17]2[C:21]3=[C:22]([CH2:24][S:25][CH2:26][CH2:27][N:20]3[C@H:19]3[CH2:28][CH2:29][NH:30][CH2:31][C@@H:18]23)[CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CCSC3
Reactant: OB(O)c1ccccc1C(F)(F)F
Product: FC(F)(F)c1ccccc1-c1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCSC2

Procedure:
Using 2-(trifluoromethyl)phenylboronic acid and following the procedures described in EXAMPLE 7, Parts B and C, tert-butyl (7bR,11aS)-6-bromo-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 7, Part A was converted into the title compound of EXAMPLE 147. 1H NMR (CDCl3) δ: 9.50 (broad s, 1H), 9.30 (broad s, 1H), 7.68 (d, 1H, J=8.1 Hz), 7.50 (t, 1H, J=7.3 Hz), 7.40 (t, 1H, J=7.3 Hz), 7.26 (d, 1H), 6.93 (s, 1H), 6.87 (s, 1H), 3.80 (ABq, 2H, JAB=15.8 Hz), 3.61-3.45 (m, 2H), 3.37-3.05 (m, 6H), 2.90-2.80 (m, 1H), 2.70-2.57 (m, 1H), 2.25-2.10 (m, 2H). LRMS (ES)+: 391.4 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]([NH2:12])[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.C([O:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]2[C:41]3[C:36](=[CH:37][C:38]([C:42](O)=[O:43])=[CH:39][CH:40]=3)[C:35]([CH3:45])=[C:34]2[CH3:46])=[CH:28][CH:27]=1)=[O:19])(C)(C)C>>[CH3:46][C:34]1[N:33]([CH2:32][C:29]2[CH:30]=[CH:31][C:26]([C:21]3[C:20]([C:18]([OH:19])=[O:17])=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:27][CH:28]=2)[C:41]2[C:36]([C:35]=1[CH3:45])=[CH:37][C:38]([C:42](=[O:43])[NH:12][C@H:2]([C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)[CH3:1])=[CH:39][CH:40]=2
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: C[C@H](N)c1ccc([N+](=O)[O-])cc1
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3ccc([N+](=O)[O-])cc3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using (S)-α-methyl-4-nitrobenzylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. LC-MS 548 (M+H).
Reaction SMILES: B([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([F:14])[C:12]=1[CH3:13])[C:7]([OH:9])=[O:8])(O)O.Br[C:16]1[C:21](=[O:22])[N:20]([CH3:23])[C:19]2[N:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])[N:25]=[CH:26][C:18]=2[CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].CCOCC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:33][C:32]1[CH:31]=[CH:30][CH:29]=[C:28]([F:34])[C:27]=1[N:24]1[C:19]2[N:20]([CH3:23])[C:21](=[O:22])[C:16]([C:4]3[CH:5]=[C:6]([CH:10]=[C:11]([F:14])[C:12]=3[CH3:13])[C:7]([OH:9])=[O:8])=[CH:17][C:18]=2[CH:26]=[N:25]1
Reactant: Cc1c(F)cc(C(=O)O)cc1B(O)O
Reactant: Cn1c(=O)c(Br)cc2cnn(-c3c(F)cccc3F)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1c(F)cc(C(=O)O)cc1-c1cc2cnn(-c3c(F)cccc3F)c2n(C)c1=O
Temperature: 130 °C
Yield: 78.1 %

Procedure:
In a 25 mL sealed glass tube, a mixture of tetrakis(triphenylphosphine)palladium(0) (42 mg, 37 μmol), 3-borono-5-fluoro-4-methylbenzoic acid (218 mg, 1101 μmol), and 5-bromo-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (312 mg, 917 μmol) in 4.6 mL of dioxane and 1.0 M solution of sodium carbonate (2.3 mL, 2.3 mmol) was heated in a microwave at 130° C. for 30 min. The reaction mixture was treated with 15 mL of ether and washed with 5 mL of 2 N NaOH, The ether layer was discarded. The aqueous extracts were acidified to pH 4 with 5 N HCl and extracted with 3×25 mL EtOAc. The combined EtOAc layers were dried over MgSO4, filtered and concentrated in vacuo (rotovap) affording the title compound (296 mg) as a viscous oil which solidified to an off-white amorphous solid under vacuum overnight. MS (ESI, pos.ion) m/z: 414.0 (M+1).
Reaction SMILES: O=[C:2]([C:7]1[CH:19]=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][C:13]([C:20](=O)[CH2:21][CH2:22][CH2:23][CH3:24])=[CH:14][CH:15]=3)[CH2:10][C:9]=2[CH:8]=1)[CH2:3][CH2:4][CH2:5][CH3:6].O.NN.C(O)COCCO.[OH-].[K+]>O>[CH2:2]([C:7]1[CH:19]=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][C:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:14][CH:15]=3)[CH2:10][C:9]=2[CH:8]=1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC(=O)c1ccc2c(c1)Cc1cc(C(=O)CCCC)ccc1-2
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: CCCCCc1ccc2c(c1)Cc1cc(CCCCC)ccc1-2
Temperature: 130 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
A Dean-Stark trap with reflux condenser was fitted to a 1 liter conical flask, and 2,7-di(1-oxopentyl)fluorene (30.4129 g, 91.0566 mmol), hydrazine monohydrate (44.2 ml) and diethylene glycol (400 ml) were introduced and heated at 130° C. After 2 hours, KOH (20.5628 g) was added and heated at 200° C. After 3 hours, the reaction liquid was returned to room temperature, water was added, and the organic layer was extracted twice with ether. The organic layer was washed with 1N-HCl, saturated sodium bicarbonate solution, water (twice) and a saturated salt solution, and dried using MgSO4. The solution obtained was filtered, and concentrated under reduced pressure to obtain a crude product (27.6591 g, yellow solid). The crude product was purified by silica gel chromatography (hexane) to obtain 2,7-di-n-pentylfluorene (26.2137 g, yellow solid).
Reaction SMILES: C([O-])(O)=O.[Na+].[I:6]N1C(=O)CCC1=O.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:22](C(O)=O)=[C:23]3[CH2:28][CH2:27][CH:26]([CH3:29])[N:24]3[N:25]=2)=[CH:17][CH:16]=1.O>CN(C)C=O>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:22]([I:6])=[C:23]3[CH2:28][CH2:27][CH:26]([CH3:29])[N:24]3[N:25]=2)=[CH:17][CH:16]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CC1CCc2c(C(=O)O)c(-c3ccc(F)cc3)nn21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1CCc2c(I)c(-c3ccc(F)cc3)nn21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3.1 g (36.9 mmol) of NaHCO3 and 2.8 g (12.3 mmol) of N-iodosuccinimide are added to a solution of 3.2 g (12.3 mmol) of 2-(4-fluorophenyl)-6-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylic acid in 25 ml of dimethylformamide. The reaction mixture is stirred at room temperature for 16 h, water is added and the precipitated solid is filtered off and dried. This gives 3.30 g of the desired product in a purity of 77% which are reacted further without further purification: (log P(HCOOH): 3.82); 1H-NMR (ppm): δ (DMSO-d6)=1.42 (d, 3H), 2.11-2.18 (m, 1H), 2.72-2.82 (m, 3H), 4.49 (m, 1H), 7.28 (dd, 2H), 7.79 (dd, 2H); LC-MS: m/z=343 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:43]=[CH:42][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:41]=[CH:40][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])=[CH:18][C:17]=3[CH2:30][NH:31][C:32](=[O:39])[C:33]3[CH:38]=[CH:37][CH:36]=[N:35][CH:34]=3)=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][C:17]=3[CH2:30][NH:31][C:32](=[O:39])[C:33]3[CH:38]=[CH:37][CH:36]=[N:35][CH:34]=3)=[CH:40][CH:41]=2)=[O:10])=[CH:42][CH:43]=1
Reactant: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(CNC(=O)c2cccnc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(CNC(=O)c2cccnc2)c1
Temperature: 25 °C
Yield: 114.9 %

Procedure:
To a solution of tert-butyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-(nicotinamidomethyl)phenyl)acetate (0.005 g, 0.008 mmol) in dichloromethane (1.0 ml) was added TFA (1.0 ml) and the reaction was stirred at ambient temperature. After 1 hour the reaction was concentrated to give 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-(nicotinamidomethyl)phenyl)acetic acid (0.005 g). MS −449.1 [M—CO2H].
Reaction SMILES: [CH3:1][CH:2]([P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[CH2:3][CH:4](OCC)[O:5]CC.Cl>O.CC(C)=O>[CH3:1][CH:2]([P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[CH2:3][CH:4]=[O:5]
Reactant: CCOC(CC(C)P(=O)(OCC)OCC)OCC
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: CCOP(=O)(OCC)C(C)CC=O
Temperature: 62 °C

Procedure:
A solution of 400 grams (1.42 moles) of diethyl 1-methyl-3,3-diethoxypropylphosphonate in 1 liter of water and 4 liters of acetone containing 30 ml of concentrated hydrochloric acid was stirred and refluxed under nitrogen at 62° C. for 1.5 hours. Low boiling materials were removed at 80° C./16 mm to give the diethyl 1-methyl-3-oxopropylphosphonate in a 296 grams (quantitative) yield as a pale yellow liquid. The structure was confirmed by NMR.