Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[O:24])=[CH:19][CH:18]=1>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]([C:20]2[CH:21]=[CH:22][C:17]([O:16][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][CH:3]=3)=[CH:18][CH:19]=2)=[O:24])=[CH:26][CH:27]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=C(c1ccc(O)cc1)c1ccc(F)cc1
Product: COc1cc2nccc(Oc3ccc(C(=O)c4ccc(F)cc4)cc3)c2cc1OC
Temperature: 170 °C
Reaction time: 0.33 h
Yield: 56.4 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (112 mg) and commercially available 4-fluorophenyl 4-hydroxyphenyl ketone (324 mg) were mixed and stirred at 170° C. for 20 minutes. The reaction mixture was then purified in the same manner as described in Example 41 to obtain 114 mg of the title compound (yield: 57%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H+].[B-:7]([F:11])([F:10])([F:9])[F:8]>ClCCl.C(OCC)C>[F:8][B-:7]([F:11])([F:10])[F:9].[NH+:1]1[CH:5]=[CH:4][NH:3][CH:2]=1
Reactant: c1c[nH]cn1
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: ClCCl
Solvent: CCOCC
Product: c1c[nH+]c[nH]1

Procedure:
To a solution of imidazole (20 mmol) in dichloromethane (30 mL) at 0° C. HBF4 (20 mmol, 3.8 g of a diethyl etherate) in dichloromethane is added dropwise. The reaction mixture is diluted with diethyl ether (100 mL) to precipitate the title compound. It is then filtered, washed with ether and recrystallized from ether.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=O)=O.Cl.[CH2:35]([O:42][CH:43]1[CH2:49][CH:48]2[NH:50][CH:44]1[CH2:45][O:46][CH2:47]2)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)([O-])[O-].[K+].[K+].CC#N>CCOC(C)=O>[CH2:35]([O:42][CH:43]1[CH2:49][CH:48]2[N:50]([CH2:6][C@H:7]3[CH2:12][N:11]([S:13]([C:16]4[S:17][CH:18]=[CH:19][CH:20]=4)(=[O:14])=[O:15])[CH2:10][CH2:9][N:8]3[C:21]3[CH:22]=[CH:23][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:25][CH:26]=3)[CH:44]1[CH2:45][O:46][CH2:47]2)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Reactant: c1ccc(COC2CC3COCC2N3)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2C3COCC2C(OCc2ccccc2)C3)cc1)C(F)(F)F
Temperature: 150 °C

Procedure:
A 10 mL vial was charged with ((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (0.207 g, 0.391 mmol, Intermediate B), 6-(benzyloxy)-3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (endo) (0.100 g, 0.391 mmol, J. Org. Chem. 2010, 75, 1643), potassium carbonate (0.162 g, 1.173 mmol), and 3 mL of MeCN. The tube was sealed and heated in a microwave reactor (Emrys Optimizer Automated Microwave Synthesizer, Uppsala, Sweden) at 150° C. for 1 h. The mixture was diluted with EtOAc, filtered and the filtrate was concentrated and purified via column chromatography on silica gel (0 to 50% EA/Hex) to 2-(4-((2S)-2-((6-(benzyloxy)-3-oxa-8-azabicyclo[3.2.1]oct-8-yl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol as a mixture of four endo isomers (0.130 g).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH:21]([C:30](=O)[C:31]#[C:32][CH:33]1[CH2:36][CH:35]([CH2:37][CH:38]([CH3:40])[CH3:39])[CH2:34]1)[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.S([O-])([O-])(=O)=O.[Na+].[Na+].[Cl-].[CH3:52][O:53][NH3+:54]>N1C=CC=CC=1>[Si:1]([O:18][CH2:19][CH2:20][CH:21]([C:30](=[N:54][O:53][CH3:52])[C:31]#[C:32][CH:33]1[CH2:36][CH:35]([CH2:37][CH:38]([CH3:39])[CH3:40])[CH2:34]1)[CH2:22][C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])([C:14]([CH3:17])([CH3:15])[CH3:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CO[NH3+]
Reactant: CC(C)CC1CC(C#CC(=O)C(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC(=O)OC(C)(C)C)C1
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccncc1
Product: CON=C(C#CC1CC(CC(C)C)C1)C(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
tert-Butyl 3-[2-(tert-butyldiphenylsilanyloxy)ethyl]-6-(3-isobutylcyclobutyl)-4-oxo-5-hexynoate (58.1 g) and methanol (300 mL) were mixed. To the mixture were added sodium sulfate (21.55 g), pyridine (30 mL) and O-methylhydroxylammonium chloride (12.67 g) at ice temperature. The mixture was stirred at RT overnight and the resultant precipitate was removed by filtration. After concentration of the filtrate in vacuo, toluene (350 mL) was poured into the residue. The mixture was washed with 1 N hydrochloric acid (300 mL), water (300 mL) and brine (150 mL), then dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated in vacuo. After an addition of silica gel (80 g) and ethyl acetate/hexane=1/20 (600 mL) to the residue, the mixture was stirred at RT for 1 hr. The silica gel was filtered off and the filtrate was concentrated in vacuo to give the title compound (55.54 g) as a crude product.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]([O:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.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.O>[Br:8][C:5]1[CH:4]=[N:3][C:2]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([O:16][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:18]=2)=[N:7][CH:6]=1
Reactant: OB(O)c1cccc(OCc2ccccc2)c1
Reactant: Brc1cnc(Br)nc1
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: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Brc1cnc(-c2cccc(OCc3ccccc3)c2)nc1
Yield: 70.3 %

Procedure:
15.00 g (63.10 mmol) of 2,5-dibromopyrimidine (for preparation see: D. W. Arantz and D. J. Brown in Journal of the Chemical Society C, 1971, p. 1889), 14.40 g (63.10 mmol) of 3-benzyloxybenzeneboronic acid, 13.40 g (126.2 mmol) of sodium carbonate and 0.73 g (0.63 mmol) of tetrakis(triphenylphosphine)palladium(0) are heated at 80° C. for 4 hours in 150 ml of toluene, 75 ml of ethanol and 50 ml of water. The reaction mixture is subsequently partitioned between ether and water, the organic phase is washed twice with sodium chloride solution, dried over sodium sulfate and evaporated, and the residue is purified by chromatography (silica gel/dichloromethane), giving 15.14 g of 5-bromo-2-(3-benzyloxyphenyl)pyrimidine. ##STR14##
Reaction SMILES: C([C:5]1[C:13]([CH2:14][N:15]([C:17](=[O:30])[CH:18]([OH:29])[CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)[CH3:16])=[C:12]([NH2:31])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(C)(C)C.[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>C(Cl)Cl>[F:35][C:34]([F:37])([F:36])[C:32]([OH:38])=[O:33].[NH2:31][C:12]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:13]=1[CH2:14][N:15]([C:17](=[O:30])[CH:18]([OH:29])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[CH3:16]
Reactant: CN(Cc1c(N)ccc(C(=O)O)c1C(C)(C)C)C(=O)C(O)Cc1c[nH]c2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(Cc1cc(C(=O)O)ccc1N)C(=O)C(O)Cc1c[nH]c2ccccc12
Reaction time: 12 h

Procedure:
To a stirred solution of t-butyl-4-amino-3-[(2-hydroxy-3-indol-3-yl-N-methylpropanoylamino)methyl]benzoic acid (0.99 g, 2.34 mmole) in CH2Cl2 (20 mL) at RT was added TFA (20 mL). After 12 hr, the reaction contents were evaporated, washed with Et2O and dried under high vacuum overnight affording the title compound (0.86 g, 2.34 mmol) as a pink solid. This product was used without further purification: MS (ES) m/e 369 (M+H-TFA)+.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([O:22][CH:23]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[S:21])=[C:15]([CH3:19])[CH2:16][S:17](=O)[C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC=C(C)C.C(Br)(=O)C.O>C(Cl)Cl>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([O:22][CH:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[S:21])=[C:15]([CH3:19])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1=C(C(=S)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S(=O)C1
Agent: CC(=O)Br
Agent: CC=C(C)C
Solvent: ClCCl
Solvent: O
Product: CC1=C(C(=S)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1
Yield: 85.7 %

Procedure:
To a solution of benzhydryl 7-phenylacetamido-3-methylthio-3-cephem-4-carboxylate-1-oxide (6.5 g) and amylene (2.53 ml) in methylenechloride (100 ml) was dropwise added acetyl bromide (2.4 ml) under ice-cooling with stirring. The mixture was stirred at ambient temperature for 30 minutes. The resultant solution was added to water. The separated organic layer was washed with a saturated aqueous solution of sodium chloride twice and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give benzhydryl 7-phenylacetamido-3-methylthio-3-cephem-4-carboxylate (5.4 g).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[NH:21][N:20]=[C:19]([NH2:22])[CH:18]=2)=[CH:13][CH:12]=1.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[NH:21][N:20]=[C:19]([NH:22][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][Br:1])[CH:18]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(-c2cc(N)n[nH]2)cc1
Reactant: O=C(Cl)CCCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COc1ccc(-c2cc(NC(=O)CCCCBr)n[nH]2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 5-bromovaleryl chloride (2.1 mL, 15.7 mmol) in dry dimethylacetamide (DMA) (35 mL) was cooled to −10° C. (ice water bath) under N2; a solution of 5-(4-methoxy-phenyl)-1H-pyrazol-3-ylamine (3.0 g, 15.7 mmol) and diisopropylethylamine (2.74 mL, 15.7 mmol) in dry DMA (15 mL) was added over 30 min. After two hours at −10° C., LCMS shows completion of the reaction (acylation on the pyrazole ring was also detected). The reaction was quenched by addition of H2O (ca. 50 mL), and the thick white precipitate formed upon addition of water is recovered by filtration. When the reaction was allowed to reach room temperature before quenching, a putative exchange of Br with Cl caused reactivity problems in subsequent steps. Washing with Et2O (3×10 mL) efficiently removed the byproduct (acylation on pyrazole ring). 4.68 g of the title compound was obtained as a white powder (13.3 mmol, 85% yield). Mp=149.5-151.5° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][O:5][CH2:6]Cl.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:26])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1>C(Cl)Cl.C(Cl)(Cl)Cl>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([O:26][CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:9])([CH3:8])[CH3:1])([C:18]([F:19])([F:20])[F:21])[C:22]([F:24])([F:25])[F:23])=[CH:15][CH:16]=1
Reactant: OC(c1ccc(Br)cc1)(C(F)(F)F)C(F)(F)F
Reactant: C[Si](C)(C)CCOCCl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: C[Si](C)(C)CCOCOC(c1ccc(Br)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.9 %

Procedure:
A solution of 2-(trimethylsilyl)ethoxymethyl chloride (25.9 g, 0.155 mol) in CH2Cl2 (50 mL) was added dropwise to a solution of 2-(4-bromophenyl)-1,1,1,3,3,3-hexafluoro-2-propanol from Step 1 (38.6 g, 0.120 mol) in the same solvent (500 mL) at 0° C. After completion of the addition, the mixture was allowed to warm to room temperature, and stirred for 3 h before it was diluted with CHCl3 (500 mL). The resulting solution was washed successively with 1N HCl (2×), saturated aqueous NaHCO3, water and brine, dried (Na2SO4) and concentrated. The residue was distilled under reduced pressure (bp 128° C./0.9 mmHg) to afford the title compound as a colorless liquid (50.0 g, 92%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH:10]1[CH2:19][CH2:18][C:13]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:12][CH:11]1[C:20]([O-:22])=[O:21].[CH3:23][O-].[Na+]>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C@@H:10]1[CH2:19][CH2:18][C:13]2([O:14][CH2:15][CH2:16][O:17]2)[CH2:12][C@H:11]1[C:20]([O:22][CH3:23])=[O:21]
Reactant: C[O-]
Reactant: O=C([O-])C1CC2(CCC1c1cc(F)c(F)cc1F)OCCO2
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@@H]1CC2(CC[C@H]1c1cc(F)c(F)cc1F)OCCO2
Temperature: 25 °C

Procedure:
To a stirred solution of 8-(2,4,5-trifluorophenyl)-1,4-dioxaspiro[4.5]decane-7-carboxylate (1.95 g, 5.9 mmol) in methanol (50 mL) was added sodium methoxide (0.5M in methanol, 14.2 ml, 7.1 mmol), and the resulting solution was refluxed overnight under a nitrogen atmosphere, cooled to room temperature and evaporated to yield the crude product which was purified by chromatography on a Biotage® system (silica gel, ethyl acetate in hexanes gradient 25-54%) to yield the title compound containing some cis isomer.
Reaction SMILES: [C@:1]12([CH2:11][S:12]([OH:15])(=O)=[O:13])[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6][CH2:7]1)[CH2:4][C:2]2=O.S(Cl)(Cl)=O.[NH3:20]>C1(C)C=CC=CC=1.CN(C)C=O>[CH3:9][C:8]1([CH3:10])[CH:5]2[CH2:6][CH2:7][C:1]31[C:2]([CH2:4]2)=[N:20][S:12](=[O:15])(=[O:13])[CH2:11]3
Reactant: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Reactant: N
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC1(C)C2CCC13CS(=O)(=O)N=C3C2
Temperature: 80 °C
Reaction time: 2 h
Yield: 101.5 %

Procedure:
N,N-Dimethylformamide (230 g) and (1S)-(+)-10-camphorsulfonic acid (190 kg, 818 mol) were added to toluene (190 L), and thionyl chloride (116.8 kg, 982 mol) was added in a thin stream at 70° C.-80° C. over 2 h, and the mixture was stirred at the same temperature for 2 h. The obtained solution of camphorsulfonyl chloride in toluene was added dropwise at −10° C. to 25° C. over 3 h to a mixture of 28 wt % aqueous ammonia (248.7 kg, 4.1 kmol) and toluene (277 L), which mixture had been separately prepared and cooled to −10° C. to −5° C. The container of acid chloride was washed with toluene (29 L) and the washing was added to the reaction mixture, which was followed by stirring at 10° C.-25° C. for 2 h. The reaction mixture was heated to 80° C. over 85 min and stirred at 80° C.-83.3° C. for 3 h. The amount of the ammonia gas generated was 39 m3. The reaction mixture was cooled to 60° C. over 20 min and aged at 54° C.-60° C. for 15 min. The reaction mixture was cooled to 20° C. over 1 h and stirred at 15° C.-20° C. for 40 min. The reaction mixture was filtered at 15° C. and washed successively with toluene (57 L) and water (380 kg) to give wet crystals (177.1 kg). The crystals were partially dried and analyzed. As a result, the crystals contained the title compound in an amount of 144.7 kg (yield 83%).
Reaction SMILES: [CH3:1][N:2]1[CH2:22][CH2:21][C:5]2[N:6]([CH2:14][CH2:15][C:16](OCC)=[O:17])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH:23]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH:23]1([NH:28][C:16](=[O:17])[CH2:15][CH2:14][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:22][CH2:21][C:5]2=3)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: NC1CCCC1
Reactant: CCOC(=O)CCn1c2c(c3cc(C)ccc31)CN(C)CC2
Product: Cc1ccc2c(c1)c1c(n2CCC(=O)NC2CCCC2)CCN(C)C1
Temperature: 110 °C
Yield: 15.2 %

Procedure:
A mixture of ethyl 3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanoate (100 mg, 0.33 mmol) and cyclopentylamine (1 ml, 10 mmol) was heated at 100-120° C. for 3-4 h to obtain 17 mg of N-cyclopentyl-3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanamide after purification on neutral alumina chromatography eluting with methanol-dichloromethane gradient.
Reaction SMILES: C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].[F:15][C:16]1[C:21]([C@@H:22]([N:24]2[CH2:29][C@H:28]([CH3:30])[O:27][C:26](=[O:31])[C:25]2=[O:32])[CH3:23])=[CH:20][CH:19]=[C:18]([F:33])[N:17]=1.[OH-].[Na+].OO.S([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C1COCC1.C1COCC1>[F:15][C:16]1[C:21]([C@@H:22]([N:24]2[CH2:29][CH:28]([CH3:30])[O:27][C@H:26]([OH:31])[C:25]2=[O:32])[CH3:23])=[CH:20][CH:19]=[C:18]([F:33])[N:17]=1
Reactant: C[C@H]1CN([C@@H](C)c2ccc(F)nc2F)C(=O)C(=O)O1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: O=S([O-])O
Agent: OO
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC1CN([C@@H](C)c2ccc(F)nc2F)C(=O)[C@@H](O)O1
Reaction time: 2 h
Yield: 99.7 %

Procedure:
A THF solution (20 mL) of 1 M lithium tri-s-butyl borohydride was dropwise added to a THF solution of (S)-4-[(S)-1-(2,6-difluoropyridin-3-yl)ethyl]-6-methylmorpholin-2,3-dione (4.5 g) at −50° C. or below. The resulting reaction solution was stirred for 2 hr. To the reaction solution, a 5 N sodium hydroxide aqueous solution (1.66 mL) and 30% hydrogen peroxide aqueous solution (6.78 mL) were added in this order at −10° C. or below. The resulting reaction solution was stirred for 1 hr, and then sodium hydrogensulfite (520 mg) was added thereto. The resulting reaction solution was stirred for 30 min, and then saturated saline and 50% toluene-THF were added thereto. The organic layer was separated, and the water layer was extracted with 50% toluene-THF. All the organic layers were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=1:1 to 0:1) to give 4.52 g of the title compound. The physical property values of this compound were as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[C:4](I)[CH:3]=1.[Br:18][C:19]1[C:20]([NH2:26])=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=1>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[Br:18][C:19]1[C:20]([NH:26][C:4]2[CH:3]=[C:2]([Cl:1])[CH:16]=[CH:15][C:5]=2[O:6][CH2:7][CH:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=1
Reactant: CN1CCC(COc2ccc(Cl)cc2I)CC1
Reactant: Cc1cnc(N)c(Br)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cnc(Nc2cc(Cl)ccc2OCC2CCN(C)CC2)c(Br)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 80 %

Procedure:
In a oven dried 50 mL round bottom flask were sequentially added Compound 173 (620 mg, 1.69 mmol), 3-bromo-5-methylpyridin-2-amine (381 mg, 2.03 mmol), Pd2(dba)3 (77 mg, 0.08 mmol), xantphos (59 mg, 0.10 mmol) and NatBuO (244 mg, 2.53 mmol) at room temperature. The solid materials were kept under vacuum for 5 min. and then refilled with nitrogen. This process was repeated thrice before adding dry, degassed dioxane (8 mL). The heterogeneous mixture was stirred at room temperature for 15 min. and then at 100° C. for 2 h. Finally upon completion of the reaction, it was diluted with EtOAc and filtered through a small pad of silica gel with several washings. All the washings and filtrate concentrated in vacuum and the crude residue was further purified by flash chromatography to provide pure Compound 174 (574 mg, 80%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([N:27]1[C@H:32]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:31](=[O:37])[NH:30][C@H:29]([CH:38]2[CH2:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH2:39]2)[C:28]1=[O:47])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19]CC1C=CC=CC=1)=[O:11]>C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([N:27]1[C@H:32]([CH2:33][CH:34]([CH3:35])[CH3:36])[C:31](=[O:37])[NH:30][C@H:29]([CH:38]2[CH2:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH2:39]2)[C:28]1=[O:47])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19])=[O:11]
Reactant: CC(C)C[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1C(C(=O)Nc1ccccc1OCc1ccccc1)c1ccc(F)cc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1C(C(=O)Nc1ccccc1O)c1ccc(F)cc1F
Yield: 91.3 %

Procedure:
(2RS)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-(2-benzyloxyphenyl)ethanamide (3.381 g) was dissolved in ethyl acetate (200 ml) and hydrogenated at atmospheric pressure over 10% palladium on carbon catalyst (0.980 g of 10% Pd/C:water 1:1 w/w) at room temperature for five hours. The reaction mixture was filtered through Celite and the solvent was removed under reduced pressure to give the (2RS)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-(2-hydroxyphenyl)ethanamide as a cream-coloured foam (2.650 g).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[CH2:7]([O:14][C:15]1[CH:25]=[C:18]2[C:19](=[O:24])[NH:20][CH2:21][CH2:22][CH2:23][N:17]2[N:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[CH2:27][CH:28]1[CH2:30][CH2:29]1>CN(C=O)C>[CH2:7]([O:14][C:15]1[CH:25]=[C:18]2[C:19](=[O:24])[N:20]([CH2:27][CH:28]3[CH2:30][CH2:29]3)[CH2:21][CH2:22][CH2:23][N:17]2[N:16]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: BrCC1CC1
Reactant: O=C1NCCCn2nc(OCc3ccccc3)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1c2cc(OCc3ccccc3)nn2CCCN1CC1CC1
Temperature: 150 °C
Reaction time: 18 h
Yield: 26.9 %

Procedure:
To a solution of Cs2CO3 (0.8 g, 2.43 mmol) in DMF (10 mL) were added 2-(benzyloxy)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one (0.3 g, 1.16 mmol) and (bromomethyl)cyclopropane (0.3 g, 2.34 mmol) at 0° C. The mixture was stirred at 150° C. for 18 hours. The mixture was diluted with ice-water and extracted with AcOEt. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in petroleum ether 0/10 to 1/10) to yield 2-(benzyloxy)-5-(cyclopropylmethyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one (97 mg, 27% yield). C18H21N3O2. 1H NMR (400 MHz, CDCl3) δ ppm 0.27-0.39 (m, 2H), 0.51-0.66 (m, 2H), 1.01-1.14 (m, 1H), 2.28 (quin, J=6.7 Hz, 2H), 3.43 (d, J=7.3 Hz, 2H), 3.48 (t, J=6.4 Hz, 2H), 4.28 (t, J=7.0 Hz, 2H), 5.18 (s, 2H), 6.18 (s, 1H), 7.28-7.40 (m, 3H), 7.41-7.47 (m, 2H).