Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:5][C:4](=[O:22])[CH:3]=1.C(Cl)(=O)[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C.C1COCC1>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[OH:1][C:2]1[CH2:7][C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:5][C:4](=[O:22])[C:3]=1[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C1C=C(O)CC(CCc2ccccc2)(c2ccccc2)O1
Reactant: O=C(Cl)CCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C1OC(CCc2ccccc2)(c2ccccc2)CC(O)=C1CCc1ccccc1

Procedure:
The title compound was prepared as described in General Method 5 using 3.0 mmol of 5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one, 3.2 mmol of hydrocinnamoyl chloride, 3.2 mmol of triethylamine, and 30 mL of THF, followed by 30 mL of toluene and catalytic DMAP. Chromatography of the residue afforded 1.5 mmol of the intermediate 3-acyl compound. Reduction of this acyl derivative was accomplished with 3 mmol of sodium cyanoborohydride. The product was triturated from ether:hexane (1:5) to give the title compound (m.p. 68°-70° C.). 1H NMR (DMSO-d6) δ2.20 (m, 2H), 2.35 (m, 2H), 2.42-2.59 (m, 4H plus DMSO), 3.06 (q, 2H), 7.00 (dd, 2H), 7.07-7.43 (m, 13H).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[S:13]1[C:17]2=[CH:18][N:19]=[CH:20][CH:21]=[C:16]2[CH:15]=[CH:14]1.[Br:22][C:23]1[CH:24]=[N:25][C:26]([Cl:29])=[N:27][CH:28]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1COCC1>[Br:22][C:23]1[C:24]([C:14]2[S:13][C:17]3=[CH:18][N:19]=[CH:20][CH:21]=[C:16]3[CH:15]=2)=[N:25][C:26]([Cl:29])=[N:27][CH:28]=1
Reactant: Clc1ncc(Br)cn1
Reactant: c1cc2ccsc2cn1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Clc1ncc(Br)c(-c2cc3ccncc3s2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Diisopropylamine (1.02 mL, 7.27 mmol) was added to a flask containing anhydrous THF (10 mL) and the mixture, while kept under an atmosphere of nitrogen, was cooled to −78° C. n-BuLi (2.5 M in hexanes, 2.9 mL, 7.27 mmol) was added dropwise to the mixture, which was stirred for 30 min. Thieno[2,3-c]pyridine (0.82 g, 6.06 mmol) dissolved in anhydrous THF (10 mL) was added to the reaction mixture dropwise. The reaction was stirred at −78° C. for 10 min and then at −40° C. for 20 min. 5-Bromo-2-chloropyrimidine, dissolved in anhydrous THF (5 mL) was added to the reaction slowly. The mixture was allowed to stir at −40° C. for 2 h and then was quenched with a 1:1 mixture of acetic acid/methanol (5 mL). The mixture was stirred for 15 min and a solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.72 g, 6.66 mmol) in 10 mL of THF was added. The reaction was stirred for an additional 15 min and then the cooling bath was removed. The mixture was stirred for 1 h and then cooled to 0° C. with an ice bath. 5 N sodium hydroxide (50 mL) was added to the reaction mixture, which was stirred for an additional 5 min. The reaction was then diluted with ethyl acetate (30 mL) and water (30 mL). The organic layer was washed with saturated aqueous sodium bicarbonate, water and brine. The organic layer was then dried with sodium sulfate, concentrated and purified by column chromatography using a gradient of 5 to 40% ethyl acetate in hexanes to obtain a light brown solid. Yield=0.5 g. MS (M+H)+ 326/328.
Reaction SMILES: [Br:1][CH:2]([CH2:17][CH2:18]Br)[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)=[O:4].[H-].[Na+]>O1CCCC1.O>[Br:1][CH:2]1[CH2:17][CH2:18][N:5]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[C:3]1=[O:4]
Reactant: O=C(NCc1ccc(C(F)(F)F)cc1)C(Br)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1C(Br)CCN1Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.4 %

Procedure:
To a suspension of 2,4-dibromo-N-(4-(trifluoromethyl)benzyl)butanamide (6.8 g, 16.9 mmol) in tetrahydrofuran (200 mL) was added NaH (1.35 g, 34 mmol) and the reaction was stirred at rt for 4 h. The reaction mixture was then diluted with water and twice extracted with 30 mL of ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by silica gel chromatography eluting with 0-40% ethyl acetate/hexanes to afford 2.8 g of 3-bromo-1-(4-(trifluoromethyl)benzyl)pyrrolidin-2-one (48%). LCMS (method Q) RT 0.90 min, m/z 322.1 (M+H+; 1H NMR (400 MHz, chloroform-d) δ 12.39 (d, J=8.0 Hz, 2H), 12.16 (d, J=8.0 Hz, 2H), 9.46-9.38 (m, 1H), 9.25 (d, J=1.8 Hz, 2H), 8.27-8.17 (m, 1H), 7.99 (s, 1H), 7.43-7.31 (m, 1H), 7.14-7.05 (m, 1H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:19]3[C:14](=[C:15]([O:20][CH3:21])[CH:16]=[CH:17][CH:18]=3)[C:13]([NH:22][S:23]([C:26]3[S:27][C:28]([Cl:31])=[CH:29][CH:30]=3)(=[O:25])=[O:24])=[N:12]2)[CH:7]=[CH:8][CH:9]=1.C(N(CC)CC)C.[C:39](OC(=O)C)(=[O:41])[CH3:40].C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[Cl:31][C:28]1[S:27][C:26]([S:23]([NH:22][C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])[N:11]([CH2:10][C:6]3[CH:5]=[C:4]([CH2:3][NH:2][C:39](=[O:41])[CH3:40])[CH:9]=[CH:8][CH:7]=3)[N:12]=2)(=[O:25])=[O:24])=[CH:30][CH:29]=1
Reactant: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CNC(C)=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To N-[1-{[3-(aminomethyl)phenyl]methyl}-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide hydrochloride (for a preparation see Intermediate 4) (700 mg, 1.40 mmol) was added triethylamine (0.583 mL, 4.20 mmol) and DCM (3 mL) to give a suspension. Acetic anhydride (0.146 mL, 1.54 mmol) was added dropwise at room temperature and the resulting mixture was stirred at ambient temperature for 2 h. LCMS showed completion of the reaction. The reaction mixture was diluted with DCM (20 mL) and a saturated solution of NaHCO3 in water (20 mL). The organic solution was separated and the aqueous layer was further extracted with DCM (20 mL). Organic solutions were combined, washed with brine (20 mL), dried through an hydrophobic frit and concentrated under reduced pressure. The residue was loaded in 1:1 MeOH-DMSO and purified on reverse phase (C18) silica (330 g) using a gradient of 5% to 80% MeCN (+0.1% of NEt3) in water (pH=10 with ammonium bicarbonate) over 14 column lengths. The appropriate fractions were combined and evaporated in vacuo to give the title compound (570 mg, 81%) as a white solid. LCMS (System A) RT=1.01 min, ES+ve m/z 505/507 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[OH:8].C(O)C.[OH-].[K+].[CH2:27](Br)[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>C1(C)C=CC=CC=1.O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCBr
Reactant: CCCCCCCc1ccc(-c2ccc(O)c(F)c2)nc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCCCCc1ccc(-c2ccc(OCCCCCC)c(F)c2)nc1
Reaction time: 4 h
Yield: 65.4 %

Procedure:
2-(m-Fluoro-p-hydroxyphenyl)-5-heptylpyridine (2 g, 0.007 mol), ethanol (20 ml), potassium hydroxide (0.48 g, 0.008 mol) and n-hexylbromide (1.4 g, 0.008 mol) were heated under reflux with stirring for 4 hours, followed by cooling the resulting reaction fluid, adding water and toluene, transferring the mixture into a separating funnel, washing the resulting organic layer with 2N-NaOH aqueous solution, then washing it with water, distilling off the solvent under reduced pressure, recrystallizing the residue from ethanol, filtering off it in a refrigerator and drying it to obtain the objective final product 2-(m-fluoro-p-hexyloxyphenyl)-5-heptylpyridine (1.7 g).
Reaction SMILES: [C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])([CH3:3])=[CH2:2].[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[CH:15]=[CH2:16].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.CO>CN(C=O)C.C(OCC)(=O)C>[CH2:19]([O:18][C:14](=[O:17])[CH2:15][CH2:16][N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:4]([C:1]([CH3:3])=[CH2:2])[C:5]1=[O:13])[CH3:20]
Reactant: C=CC(=O)OCC
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CO
Product: C=C(C)n1c(=O)n(CCC(=O)OCC)c2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.9 %

Procedure:
To a solution of 1-Isopropenyl-2-benzimidazolidinone (2.5 g, 14.4 mmol) in DMF (10 mL) were added ethyl acrylate (1.7 mL, 15.8 mmol) and benzyltrimethyl ammonium hydroxide in MeOH (1.4 g, 8.6 mmol). The resulting mixture was stirred at room temperature for 1.5 h. When the reaction was complete, the reaction mixture was diluted with ethyl acetate and washed with water (×4). The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 1:1 Hexanes:Ethyl acetate as an eluent to afford 3.0 g (76%) of the desired product along with methyl ester. Since the methyl ester was the major product, this product was used for the next reaction.
Reaction SMILES: C([N:8]([C@@H:16]1[CH2:21][C:20]2[C:22]([O:27][CH3:28])=[CH:23][CH:24]=[C:25]([F:26])[C:19]=2[O:18][CH2:17]1)CC1C=CC=CC=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.C1COCC1.[Pd]>[NH2:8][C@@H:16]1[CH2:21][C:20]2[C:22]([O:27][CH3:28])=[CH:23][CH:24]=[C:25]([F:26])[C:19]=2[O:18][CH2:17]1
Reactant: COc1ccc(F)c2c1C[C@@H](N(Cc1ccccc1)Cc1ccccc1)CO2
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(F)c2c1C[C@@H](N)CO2
Temperature: 50 °C
Yield: 91.4 %

Procedure:
(R)-3-(N,N-Dibenzylamino)-8-fluoro-5-methoxy-3,4-dihydro-2H-1-benzopyran (13.0 g, 34.4 mmol) was dissolved in 265 mL methanol and 115 mL THF. To this was 10% Pd/C (4 g) and ammonium formate (51.5 g, 0.817 mol) added. The reaction was heated to 50° C. for 2.5 h. The reaction was filtered and the solvent was removed in vacuo, the remains were taken into a 2 M solution of NaOH and then extracted twice with ether. The combined ether portions were treated with brine, dried (Na2SO4), filtered, and the solvent removed in vacuo to give 6.2 g (91% yield) of the title compound as a clear oil. [α]21D =-15.3° (C=1 CHCl3) GC-MS (70 eV) M=197 (51%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[C:11]1[C:22](=[O:23])[N:21]([CH3:24])[C:14]2[N:15]=[C:16]([S:19][CH3:20])[N:17]=[CH:18][C:13]=2[CH:12]=1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH:25]1([NH:28][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([C:11]3[C:22](=[O:23])[N:21]([CH3:24])[C:14]4[N:15]=[C:16]([S:19][CH3:20])[N:17]=[CH:18][C:13]=4[CH:12]=3)[CH:4]=2)[CH2:27][CH2:26]1
Reactant: CSc1ncc2cc(-c3cc(C(=O)O)ccc3C)c(=O)n(C)c2n1
Reactant: NC1CC1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: CSc1ncc2cc(-c3cc(C(=O)NC4CC4)ccc3C)c(=O)n(C)c2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 14.9 %

Procedure:
4-Methyl-3-(8-methyl-2-methylsulfanyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl)-benzoic acid (150 mg, 0.44 mmol) was taken up in 2 mL DMF, and cyclopropylamine (50 mg, 0.88 mmol) was added, followed by EDCI (1.2 g, 0.527 mmol, 1.2 eq.). The reaction mixture was stirred at room temperature for 90 minutes, then partitioned between water and EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (EtOAc/hexanes 1:1) to give 25 mg of N-cyclopropyl-4-methyl-3-(8-methyl-2-methylsulfanyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl)-benzamide MS (M+H)=381.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:9]([O:16][C:17]1[CH:32]=[CH:31][C:20]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])=[CH:19][C:18]=1[OH:33])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1C=CN=C1.O>ClCCl>[Si:1]([O:33][C:18]1[CH:19]=[C:20]([CH:31]=[CH:32][C:17]=1[O:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C(OCc1ccccc1)c1ccc(OCc2ccccc2)c(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cc(C(=O)OCc2ccccc2)ccc1OCc1ccccc1
Yield: 108.7 %

Procedure:
A solution of tert-butyldimethylsilyl chloride (579 mg, 3.84 mmol) in dichloromethane (10 cm3) was added to a stirred solution of benzyl 4-benzyloxy-3-hydroxy-benzoate (642.3 mg, 1.92 mmol) and imidazole (327 mg, 4.80 mmol) in dichloromethane (15 cm3). A thick precipitate formed immediately. After 1 h the mixture was poured into water (50 cm3). The layers were shaken and separated and then the aqueous phase was further extracted with dichloromethane (2×50 cm3). The combined extracts were washed with brine (50 cm3) then dried (Na2SO4) and evaporated to a pale yellow oil. This was taken up in 20% ethyl acetate in petroleum ether and filtered through a plug of silica. Evaporation of the filtrate gave the title compound as a pale yellow oil (936 mg) which was used immediately for the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][C:6]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7]1.[F:19][C:20]([F:46])([F:45])[CH:21]([CH3:44])[CH:22]([C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]2[CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][C:39]=3[F:42])[C:34]2=[O:43])=[CH:28][CH:27]=1)[C:23](O)=[O:24].O.ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:46][C:20]([F:19])([F:45])[CH:21]([CH3:44])[CH:22]([C:26]1[CH:27]=[CH:28][C:29]([CH2:32][N:33]2[CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][C:39]=3[F:42])[C:34]2=[O:43])=[CH:30][CH:31]=1)[C:23]([NH:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][C:6]1([C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])[CH2:8][CH2:7]1)=[O:24]
Reactant: CC(C(C(=O)O)c1ccc(CN2Cc3c(F)cccc3C2=O)cc1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)C1(Cc2cccc(N)c2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C(C(=O)Nc1cccc(CC2(C(=O)OC(C)(C)C)CC2)c1)c1ccc(CN2Cc3c(F)cccc3C2=O)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
110.8 mg (0.41 mmol) of tert-butyl 1-(3-aminobenzyl)cyclopropanecarboxylate were added to a solution of 129.0 mg (0.33 mmol) of 4,4,4-trifluoro-2-{4-[(4-fluoro-1-oxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-3-methylbutanoic acid and 52.9 mg (0.39 mmol) of 1-hydroxy-1H-benzotriazole hydrate in 1 ml of DMF. At 0° C., 142 μl (0.82 mmol) of DIEA and then, a little at a time, 136.5 mg (0.36 mmol) of HATU were added to the resulting mixture. The reaction mixture was then slowly warmed to RT and stirred at RT for 2.5 h. The mixture was added to water and extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by preparative RP-HPLC (mobile phase: acetonitrile/water gradient). This gave 97.4 mg (47.6% of theory) of the title compound.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[N:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.[NH2:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][C:30]=1[Cl:31])[CH2:27][C:26]1([C:35](=[O:36])[NH:34][C:33](=[O:37])[N:32]1[CH3:38])[CH2:25]2.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:31][C:30]1[CH:29]=[C:28]2[C:24]([CH2:25][C:26]3([C:35](=[O:36])[NH:34][C:33](=[O:37])[N:32]3[CH3:38])[CH2:27]2)=[CH:23][C:22]=1[NH:21][C:8](=[O:10])[CH2:7][N:6]1[C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[N:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[C:2]1=[O:1]
Reactant: CN1C(=O)NC(=O)C12Cc1cc(N)c(Cl)cc1C2
Reactant: O=C(O)Cn1c(=O)n(-c2ccccn2)c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1C(=O)NC(=O)C12Cc1cc(Cl)c(NC(=O)Cn3c(=O)n(-c4ccccn4)c4ccccc43)cc1C2

Procedure:
A mixture of (2-oxo-3-pyridin-2-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetic acid (57 mg, 0.211 mmol, described in Intermediate 4), 5′-amino-6′-chloro-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione, enantiomer B (51 mg, 0.192 mmol, described in Intermediate 48), PyBOP (120 mg, 0.230 mmol), and N,N-diisopropylethylamine (0.033 mL, 0.192 mmol) was stirred in DMF (1 mL) at 50° C. for 18 h. The crude mixture was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound as a white solid. MS: m/z=517 (M+1). HRMS: m/z=517.1383; calculated m/z=517.1386 for C26H22ClN6O4.
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([CH3:12])[C:3]=1[C:13]([O:15]CC)=[O:14].[C:18](=O)([O-])[O-].[K+].[K+].CI.O>CC(C)=O>[CH3:18][O:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([CH3:12])[C:3]=1[C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)c1c(C)nc2cc(C)nn2c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CI
Product: COc1c(C(=O)O)c(C)nc2cc(C)nn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
The ethyl 7-hydroxy-2,5-dimethylpyrazolo[1,5-a]pyrimidine-6-carboxylate (235 mg) obtained above was suspended in acetone (5 ml), and potassium carbonate (138 mg) was added thereto and stirred for 30 minutes at room temperature. Methyl iodide (1.0 ml) was added to the mixture which was then refluxed for 2 hours. The reaction mixture was cooled to room temperature, then water was added to the reaction mixture which was extracted with chloroform, and the organic phase was washed with a saturated saline solution and dried over sodium sulfate anhydrous. The resulting product was concentrated under reduced pressure, and the resulting crystals were dissolved in ethanol (5 ml). 5 N Sodium hydroxide solution (1 ml) was added thereto and stirred for 1 hour at 50° C. The reaction mixture was cooled to room temperature, and water was added to the mixture which was then washed with ethyl acetate. 2 N Hydrochloric acid was added to the aqueous phase until it became acidic, and precipitated crystals were collected by filtration and washed with water and n-hexane. The crystals were dried under reduced pressure to give the title compound (162 mg, Y.:73%) as white crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[NH:16][CH:15]=[CH:14]4)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:38]2[CH:57]=[CH:56][C:41]([CH2:42][N:43]3[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][CH2:44]3)=[CH:40][CH:39]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[NH:16]1[C:17]2[C:18](=[CH:19][C:11]([C:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([C:38]5[CH:57]=[CH:56][C:41]([CH2:42][N:43]6[CH2:44][CH2:45][N:46]([C:49]([O:51][C:52]([CH3:53])([CH3:55])[CH3:54])=[O:50])[CH2:47][CH2:48]6)=[CH:40][CH:39]=5)[CH:3]=4)[NH:8][CH:9]=3)=[CH:12][CH:13]=2)[CH:14]=[CH:15]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc4[nH]ccc4c3)c3cc(Br)cnc32)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-c3cnc4[nH]cc(-c5ccc6[nH]ccc6c5)c4c3)cc2)CC1
Temperature: 150 °C
Yield: 35.1 %

Procedure:
Intermediate B (131 mg) and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazine-1-carboxylate (136 mg) were suspended in 2 mL of acetonitrile and treated with 2 mL of 1 M sodium carbonate solution and dichloro-bis-(triphenylphosphine)-palladium(II) (10 mg). The resulting mixture was heated in a microwave reactor cell for 20 minutes at 150° C., resulting in de-tosylated material which was purified by MPLC chromatography (0-3% methanol) to provide an analytical sample of the title compound (50 mg, 508 M+H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]2[CH2:14][CH2:13][C@:12]3([CH2:18][CH2:17][NH:16][C:15]3=[O:19])[N:11]=2)[CH:5]=1.Cl[CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26].[CH2:29]1COCC1>>[Br:3][C:4]1[CH:9]=[C:8]([CH3:29])[N:7]=[C:6]([C:10]2[CH2:14][CH2:13][C@:12]3([CH2:18][CH2:17][N:16]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:15]3=[O:19])[N:11]=2)[CH:5]=1
Reactant: C1CCOC1
Reactant: O=C1NCC[C@]12CCC(c1cc(Br)ccn1)=N2
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(Br)cc(C2=N[C@]3(CC2)CCN(COCC[Si](C)(C)C)C3=O)n1
Reaction time: 0.75 h

Procedure:
Method B Sodium hydride (60% dispersion in oil, 26.03 mg, 0.6500 mmol) was added in two portions to a stirred solution of (5R)-2-(4-bromo-2-pyridyl)-1,7-diazaspiro[4.4]non-1-en-6-one (which may be prepared as described in Description 19) (174.mg, 0.5900 mmol) in dry THF (8 mL) at ambient temperature under nitrogen. After stirring for 45 mins, 2-(chloromethoxy)-ethyl-trimethyl-silane (0.12 mL, 0.6500 mmol) was added dropwise over 2 minutes. The reaction mixture was stirred over the weekend. The reaction mixture was quenched by the addition of saturated ammonium chloride solution (20 ml) and the product extracted with dichloromethane twice. The combined organic extracts were passed through a hydrophobic frit and the solvent evaporated at reduced pressure. The product was purified by silica gel chromatography eluting with 0-100% ethyl acetate in iso-hexane to give a colourless solid (199 mg) (5R)-2-(4-bromo-6-methyl-2-pyridyl)-7-(2-trimethylsilylethoxymethyl)-1,7-diazaspiro[4.4]non-1-en-6-one (D42R) (199 mg);
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH:6]1[CH2:9][NH:8][CH2:7]1.C(N(CC)CC)C.Cl[C:21]1[N:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:22]=1[C:23]([OH:25])=[O:24]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH:6]1[CH2:9][N:8]([C:21]2[N:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][C:22]=2[C:23]([OH:25])=[O:24])[CH2:7]1
Reactant: O=C(O)c1cc(C(F)(F)F)cnc1Cl
Reactant: Fc1cccc(OC2CNC2)c1
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(O)c1cc(C(F)(F)F)cnc1N1CC(Oc2cccc(F)c2)C1

Procedure:
To a mixture of 3-(3-fluorophenoxy)azetidine) (D50) (106.73 mg, 0.638 mmol) and triethylamine (0.11 ml, 0.798 mmol) in methanol (3 ml), 2-Chloro-5-(trifluoromethyl)nicotinic acid (120 mg, 0.532 mmol) was added and the mixture was heated 10 min (2 cycles of 5 min each) under microwave irradiation at 150° C. After solvent evaporation the residue was purified by SPE-Si cartridge (25 g) eluting with a mixture dichloromethane/methanol from 100/0 to 50/50. Collected fraction after solvent evaporation afforded the title compound (D121) (83 mg)