Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[C:12]([OH:23])=[CH:11][C:10]=2[C:24]([CH3:27])([CH3:26])O)=[CH:5][CH:4]=1.COC1C=C(C2C3C(=CC(C(F)(F)F)=CC=3)C(O)=CC=2C(C)(C)O)C=CC=1OC.C(C1C=CC=CC=1S(O)(=O)=O)CCCCCCCCCCC>C1(C)C=CC=CC=1>[CH3:20][O:19][C:16]1[C:15]([O:21][CH3:22])=[CH:14][C:13]2[C:12]([OH:23])=[CH:11][C:10]3[C:24]([CH3:27])([CH3:26])[C:5]4[CH:4]=[C:3]([C:2]([F:1])([F:29])[F:28])[CH:8]=[CH:7][C:6]=4[C:9]=3[C:18]=2[CH:17]=1
Reactant: COc1cc2c(O)cc(C(C)(C)O)c(-c3ccc(C(F)(F)F)cc3)c2cc1OC
Agent: CCCCCCCCCCCCc1ccccc1S(=O)(=O)O
Agent: COc1ccc(-c2c(C(C)(C)O)cc(O)c3cc(C(F)(F)F)ccc23)cc1OC
Solvent: Cc1ccccc1
Product: COc1cc2c(O)cc3c(c2cc1OC)-c1ccc(C(F)(F)F)cc1C3(C)C
Temperature: 25 °C

Procedure:
The products from Step 4 (1-(4-trifluoromethylphenyl)-2-(dimethylhydroxymethyl)-4-hydroxy-6,7-dimethoxynaphthalene and 1-(3,4-dimethoxyphenyl-2-(dimethylhydroxymethyl)-4-hydroxy-6-trifluoromethylnaphthalene, 51.7 grams) were placed in a reaction flask equipped with a Dean-Stark trap and 775 mL of toluene was added. The reaction mixture was stirred under a nitrogen atmosphere and dodecylbenzene sulfonic acid (8.3 grams) was added. The reaction mixture was heated to reflux for 5 hours. Upon cooling to room temperature the reaction mixture was concentrated by rotary evaporation. The resulting brown solid was slurried in 300 mL of 15% ethyl acetate/85% hexanes. The solid was collected by vacuum filtration yielding 35.1 grams of 2,3-dimethoxy-7,7-dimethyl-9-trifluoromethyl-7H-benzo[C]fluoren-5-ol. This material was not purified further but was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([NH:9][CH:10]([CH3:12])[CH3:11])=[CH:4][N:3]=1.Cl.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH:15]1[C:20](O)=[O:21].CCN(C(C)C)C(C)C.CS(C)=O>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:9]([CH:10]([CH3:12])[CH3:11])[C:20](=[O:21])[CH:15]3[CH2:16][O:17][CH2:18][CH2:19][N:14]3[C:6]=2[N:7]=1
Reactant: CC(C)Nc1cnc(Cl)nc1Cl
Reactant: O=C(O)C1COCCN1
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1C(=O)C2COCCN2c2nc(Cl)ncc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
A round-bottom flask was charged with 2,4-dichloro-N-isopropylpyrimidin-5-amine (940 mg, 4.56 mmol), morpholine-3-carboxylic acid hydrochloride (994 mg, 5.93 mmol), DIPEA (3.19 mL, 18.25 mmol) and DMSO (8 mL). The flask was heated overnight at 100° C. The solution was diluted with water and refrigerated for 2 hours. The aqueous solution was extracted twice with EtOAc. The organic layers were combined, dried over magnesium sulfate, filtered, and evaporated in vacuo to give 2-chloro-5-isopropyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one as a brown solid (1.2 g). MS [M+H] Found 283.
Reaction SMILES: [H-].[Na+].CS(C)=O.[CH2:7]([OH:9])[CH3:8].Cl.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH2:21][CH2:22][NH:23][CH:24]([CH3:26])[CH3:25])(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[ClH:11].[CH2:7]([O:9][C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH2:21][CH2:22][NH:23][CH:24]([CH3:26])[CH3:25])(=[O:19])=[O:20])=[CH:14][CH:13]=1)[CH3:8]
Reactant: CC(C)NCCS(=O)(=O)c1ccc(Cl)cc1
Reactant: CCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOc1ccc(S(=O)(=O)CCNC(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 6.6 g of a 60% dispersion of sodium hydride in oil (0.165 mole) in 300 mole of dimethyl sulfoxide was added 7.5 g (0.163 mole) of absolute ethanol. The mixture was stirred at room temperature for 0.5 hr, and 20.8 g (0.080 mole) of N-[2-(4-chlorophenylsulfonyl)ethyl]-2-propanamine hydrochloride was added as a solid. The mixture was heated at 120°-140° C. for 1 hr, and the solvent was removed in vacuo. The residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was dissolved in methanol, an excess of ethereal hydrogen chloride was added, and ether was added. A white solid precipitated in amount of 14.92 g (69.2%), m.p. 168°-170° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.F[C:10]1[CH:33]=[CH:32][C:13]([C:14]([C:16]2[CH:31]=[CH:30][C:19]([O:20][C:21]3[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=3)[C:24]([OH:26])=[O:25])=[CH:18][CH:17]=2)=[O:15])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.O>[NH2:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:32]1[CH:33]=[CH:10][CH:11]=[CH:12][C:13]=1[C:14]([C:16]1[CH:31]=[CH:30][C:19]([O:20][C:21]2[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=2)[C:24]([OH:26])=[O:25])=[CH:18][CH:17]=1)=[O:15]
Reactant: O=C(O)c1cccc(Oc2ccc(C(=O)c3ccc(F)cc3)cc2)c1
Reactant: Nc1cccc(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1cccc(Oc2ccccc2C(=O)c2ccc(Oc3cccc(C(=O)O)c3)cc2)c1
Reaction time: 8 h
Yield: 14 %

Procedure:
A mixture of m-aminophenol (0.64 g, 5.87 mmol), 3-[4-(4-fluorobenzoyl)phenoxy]benzoic acid (2.0 g, 5.95 mmol), and anhydrous potassium carbonate (4.0 g) was stirred in dry dimethylsulfoxide (20 ml) at 120° C. under nitrogen for 48 hours. The cooled reaction mixture was poured into water and carefully neutralized with conc. hydrochloric acid to precipitate 2.58 g of a white solid. The crude product was digested in hot toluene, and the toluene solution (after decanting from a large quantity of gum) was allowed to stand overnight at 0° C. The crystals thus obtained were recrystallized to give 0.35 g of product, m.p. 144°-150° C. dec. (14%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][NH:13][CH2:12][CH:11]([NH:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10]1.[N:24]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C(N(CC)CC)C.O>ClCCl>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][N:13]([C:30]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:31])[CH2:12][CH:11]([NH:15][C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:23])[CH2:10]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: Cc1cccc(C2CNCC(NC(=O)c3ccccc3)C2)c1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cccc(C2CC(NC(=O)c3ccccc3)CN(C(=O)N3CCOCC3)C2)c1C
Temperature: 25 °C

Procedure:
At 0° C., 80 mg (0.26 mmol) of N-[5-(2,3-dimethylphenyl)piperidin-3-yl]benzamide were initially charged in 1.5 ml of dichloromethane, and 78 mg (0.52 mmol) of morpholine-4-carbonyl chloride and 55 μl (0.39 mmol) of triethylamine were added. The mixture was slowly warmed to RT overnight. Water was added, and the reaction mixture was extracted. The organic phase was dried over magnesium sulphate and concentrated under reduced pressure. The residue was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 75 mg (69% of theory)
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:31]([CH3:32])=[CH:30][C:15]2[N:16]=[C:17]([C:19]3[CH:20]=[C:21]4[CH:27]=[C:26]([CH3:28])[N:25]([CH3:29])[C:22]4=[N:23][CH:24]=3)[S:18][C:14]=2[C:13]=1[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:12]1[C:31]([CH3:32])=[CH:30][C:15]2[N:16]=[C:17]([C:19]3[CH:20]=[C:21]4[CH:27]=[C:26]([CH3:28])[N:25]([CH3:29])[C:22]4=[N:23][CH:24]=3)[S:18][C:14]=2[C:13]=1[C:33]1[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cnc4c(c3)cc(C)n4C)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2nc(-c3cnc4c(c3)cc(C)n4C)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 50 °C

Procedure:
To a solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(1,2-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-methylbenzo[d]thiazol-6-yl)acetate: (49 mg, 0.09 mmol) in THF/CH3OH (1.0 mL/1.0 mL) was added 2N NaOH (0.44 mL, 0.9 mmol). The reaction mixture was heated at 50° C. for 2 h and the crude was purified by reverse phase HPLC, eluting by 0-100% acetonitrile in H2O with 0.1% TFA to give the product. LCMS-ESI+: calc'd for C29H28ClN3O3S: 534.2 (M+H+); Found: 534.2 (M+H+); 1H NMR (400 MHz, CD3OD) δ 8.82 (d, J=1.6 Hz, 1H), 8.41 (d, J=2 Hz, 1H), 7.82 (s, 1H), 7.70-7.58 (m, 5H), 5.25 (s, 1H), 3.80 (s, 3H), 2.61 (s, 3H), 2.49 (s, 3H), 0.97 (s, 9H).
Reaction SMILES: C(OC(=O)[N:7]([CH2:31][C:32]1[CH:41]=[CH:40][C:35]2[O:36][CH2:37][CH2:38][O:39][C:34]=2[CH:33]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([C:26]([O:28][CH3:29])=[O:27])=[CH:18][C:17]2=[O:30])[CH2:10][CH2:9]1)(C)(C)C.[ClH:43].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:43].[O:36]1[C:35]2[CH:40]=[CH:41][C:32]([CH2:31][NH:7][CH:8]3[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]4[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[C:19]([C:26]([O:28][CH3:29])=[O:27])=[CH:18][C:17]4=[O:30])[CH2:10][CH2:9]3)=[CH:33][C:34]=2[O:39][CH2:38][CH2:37]1
Reactant: COC(=O)c1cc(=O)n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2ccccc12
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(=O)n(CCN2CCC(NCc3ccc4c(c3)OCCO4)CC2)c2ccccc12
Temperature: 25 °C
Reaction time: 42 h

Procedure:
To 1 mL of an ethyl acetate solution containing 30 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(4-methoxycarbonyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 1 mL of 4 mol/L hydrogen chloride/ethyl acetate was added, and stirred at room temperature for 42 hours. The resulting solid was filtered to give 18 mg of methyl 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-1,2-dihydro-2-oxoquinoline-4-carboxylate hydrochloride as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1.[NH2:25][C:26]1[C:27]([C:32](O)=[O:33])=[N:28][CH:29]=[CH:30][CH:31]=1>>[NH2:25][C:26]1[C:27]([C:32]([NH:1][CH2:2][C@H:3]2[C@H:9]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=3)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]2)=[O:33])=[N:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CN)C1
Reactant: Nc1cccnc1C(=O)O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CNC(=O)c2ncccc2N)C1

Procedure:
Using tert-butyl (6R,7R)-6-(aminomethyl)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-carboxylate and 3-aminopyridine-2-carboxylic acid, and by a method similar to that of Example 39, step A, the title compound was obtained.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]([OH:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[CH3:14][C:15]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])[CH3:16].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[Br:1][C:2]1[S:6][C:5]([CH:7]([O:13][Si:18]([C:15]([CH3:17])([CH3:16])[CH3:14])([CH3:20])[CH3:19])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)C(O)c1ccc(Br)s1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(O[Si](C)(C)C(C)(C)C)c1ccc(Br)s1
Reaction time: 8 h
Yield: 69.9 %

Procedure:
To a solution of ethyl 2-(5-bromothiophen-2-yl)-2-hydroxyacetate (2.5 g, 9.43 mmol, 1.0 eq), DMAP (115 mg, 0.94 mmol, 0.1 eq) in dichloromethane (30 mL) was added TBDMSCl (2.85 g, 18.91 mmol, 2.0 eq) and triethylamine (5.0 mL, 35.97 mmol, 3.8 eq) at 0° C. After addition, the ice-water bath is removed and the mixture is allowed to reach room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed (brine), dried (Na2SO4), filtered and concentrated to give a residue, which was purified by silica gel column chromatography (PE:EA=50:1) to produce ethyl 2-(5-bromothiophen-2-yl)-2-(tert-butyldimethylsilyloxy)acetate (2.5 g, 69.9%). 1H NMR (400 MHz, DMSO-d6): δ 0.03 (s, 3H), 0.07 (s, 3H), 0.85 (s, 9H), 1.16 (t, J=7.0 Hz, 3H), 4.09-4.15 (m, 2H), 5.56 (d, J=0.8 Hz, 1H), 6.91-6.92 (m, 1H), 7.08 (d, J=4.0 Hz, 1H).
Reaction SMILES: [C:1]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25]N)=[CH:21][CH:20]=1.Cl.[CH2:28](O)[CH3:29]>>[ClH:18].[Cl:18][C:19]1[CH:24]=[C:23]2[C:22](=[CH:21][CH:20]=1)[NH:25][C:1]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:28][CH3:29])=[O:16]
Reactant: NNc1ccc(Cl)cc1
Reactant: O=C(O)CCCCCCC(=O)c1cccnc1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)CCCCCc1c(-c2cccnc2)[nH]c2ccc(Cl)cc12
Reaction time: 20 h

Procedure:
A mixture of 9.60 g of 7-nicotinoylheptanoic acid and 7.34 g of 4-chlorophenylhydrazine in 100 ml of ethanol is stirred and refluxed under nitrogen overnight. The reaction mixture is concentrated in vacuo to give a gum, which is suspended in 100 ml of ethanol, treated with 40 ml of 6N ethanolic hydrogen chloride, and refluxed under nitrogen for 22 hours. The suspension is cooled and an additional 50 ml of 6N ethanolic hydrogen chloride is added. Refluxing is resumed and continued for about 20 hours. The suspension is cooled in an ice-water bath and filtered. The filtrate is concentrated in vacuo to give a partially solid residue, which is triturated with ether-ethanol (10:1) and the yellow solid formed is collected to give 5-chloro-3-[5-(ethoxycarbonyl)pentyl]-2-(3-pyridyl)indole hydrochloride, m.p. 141°-145°.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>ClCCl>[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[NH:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=2)[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccccn3)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C(=C1CCNCC1)c1cccc(Oc2ccccn2)c1
Reaction time: 3 h

Procedure:
A solution of tert-butyl-4-(3-(pyridin-2-yloxy)benzylidene)piperidine-1-carboxylate (0.483 g) in dichloromethane (2.5 mL, 0.53 M) was treated with trifluoroacetic acid (2.5 mL). The reaction was allowed to stir for 3 hours, then concentrated to give an oil. The oil was used without purification. 0.652 g, quantitative yield.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[C:6]([I:8])[N:7]=1)[CH3:2].[F:12][C:13]1[CH:14]=[C:15]([CH2:23][CH2:24][CH:25]=O)[CH:16]=[CH:17][C:18]=1[C:19]([F:22])([F:21])[F:20]>>[CH2:1]([C:3]1[N:4]2[CH2:9][CH2:10][NH:11][CH:25]([CH2:24][CH2:23][C:15]3[CH:16]=[CH:17][C:18]([C:19]([F:20])([F:21])[F:22])=[C:13]([F:12])[CH:14]=3)[C:5]2=[C:6]([I:8])[N:7]=1)[CH3:2]
Reactant: CCc1nc(I)cn1CCN
Reactant: O=CCCc1ccc(C(F)(F)F)c(F)c1
Product: CCc1nc(I)c2n1CCNC2CCc1ccc(C(F)(F)F)c(F)c1

Procedure:
According to the general procedure (GP10), the microwave-assisted Pictet-Spengler reaction (60 W; 100° C.; 8 bars; 10 min.) between 2-(2-ethyl-4-iodo-imidazol-1-yl)-ethylamine (312.8 mg; 1.180 mmol) and 3-(3-fluoro-4-trifluoromethyl-phenyl)-propionaldehyde (260.4 mg; 1.180 mmol) afforded 3-ethyl-8-[2-(3-fluoro-4-trifluoromethyl-phenyl)-ethyl]-1-iodo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine which was Boc-protected and finally purified by HPLC.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17](O)[CH3:18].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:17][CH2:18][O:11][C:10]([C@@H:9]1[CH2:13][C@@H:14]([OH:16])[CH2:15][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:12]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: CCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 173.5 %

Procedure:
To a solution of (4R)-(tert-Butoxycarbonyl)-4-hydroxy-L-proline (26) (0.92 g, 4.0 mmol) in dry CH2Cl2 (30 ml) was added ethanol (1 ml, 21 mmol). To the reaction was added DCC (1.64 g, 8.0 mmol) and DMAP (cat) and the reaction mixture was, stirred under nitrogen at room temperature overnight. The reaction was then concentrated under reduced pressure. The residue was dissolved in ethyl acetate: water (10:1) (100 ml). The organic was washed with water (30 ml, 2×) and 10% NaOH (10 ml), dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using CH2Cl2:CH3OH (10:1)to give 1.8 g oil as desired product.
Reaction SMILES: C[O:2][C:3]1[C:4]([N+:12]([O-])=O)=[C:5]([CH:7]=[C:8]([O:10]C)[CH:9]=1)[NH2:6].N1C=CC=CC=1.[C:21](Cl)(=O)[CH:22]([CH3:24])[CH3:23].C(O)C>Cl.[Pd]>[OH:2][C:3]1[C:4]2[NH:12][C:21]([CH:22]([CH3:24])[CH3:23])=[N:6][C:5]=2[CH:7]=[C:8]([OH:10])[CH:9]=1
Reactant: CC(C)C(=O)Cl
Reactant: COc1cc(N)c([N+](=O)[O-])c(OC)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC(C)c1nc2cc(O)cc(O)c2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3,5-dimethoxy-2-nitroaniline (55.0 g, 321 mmol) and pyridine (400 mL) was added isobutyryl chloride (41.0 mL, 391 mmol). After stirring for 16 hours, the reaction mixture was concentrated in vacuo. The resulting oil was partitioned between H2O (200 mL) and ethyl acetate (200 mL). The aqueous layer was extracted with more ethyl acetate (2×200 mL). The organic layers were washed with brine (50 mL), dried (MgSO4) and concentrated. The solid was recrystallized from hexane/ethyl acetate at 5° C. to afford yellow crystals. To a slurry of the yellow crystals, 4N HCl (200 mL) and ethanol (250 mL) was added 10% Pd/C (1.30 g). The slurry was placed under 50 psi of H2 (g) and shaken for 4 hours. The mixture was then filtered and concentration of the filtrate afforded a white solid. The white solid was dissolved in 2N HCl (200 mL) and refluxed for 4 hours. The reaction mixture was concentrated. The resulting solid was dissolved in 48% HBr (100 mL) and H2O (100 mL) and refluxed for 15 hours. The reaction was then cooled to ambient temperature and concentrated. The solids were dissolved in H2O (200 mL) and neutralized (KHCO3). The aqueous layer was then extracted with n-butanol (3×500 mL). The organic layer was washed with brine (50 mL), treated with activated charcoal and concentrated to afford 4,6-dihydroxy-2-isopropylbenzimidazole, a compound of formula (11).
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[C:7]([CH2:9][OH:10])[N:6]=[CH:5]1)([CH3:3])[CH3:2].[CH3:11][C:12]([Si:15](Cl)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:14])[CH3:13].O>ClC(Cl)C.CN(C1C=CN=CC=1)C>[Si:15]([O:10][CH2:9][C:7]1[N:6]=[CH:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH:8]=1)([C:12]([CH3:14])([CH3:13])[CH3:11])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)n1cnc(CO)c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CC(Cl)Cl
Product: CC(C)n1cnc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Reaction time: 17 h

Procedure:
This (1-isopropyl-1H-imidazol-4-yl)methanol was dissolved in dichloroethane (200 mL), and at room temperature TEA (10.9 mL), TBDPSCl (10.2 mL) and DMAP (0.320 g) were added, followed by stirring for 17 hours. The reaction solution was poured into water, and extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and subsequently the solvent was distilled off under reduced pressure. The resulting residue was purified by flash chromatography (ethyl acetate/hexane=20%→100%) using silica gel column (product name: Hi-Flash Column 3 L, manufactured by Yamazen Corporation) to afford the title compound (9.11 g).
Reaction SMILES: Br[C:2]1[C:3]2[O:23][CH:22]=[CH:21][C:4]=2[C:5](=[O:20])[N:6]([CH2:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH:7]=1.[N:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>>[N:24]1[CH:29]=[CH:28][C:27]([C:2]2[C:3]3[O:23][CH:22]=[CH:21][C:4]=3[C:5](=[O:20])[N:6]([CH2:8][CH2:9][C:10]3[CH:19]=[CH:18][C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:11]=3)[CH:7]=2)=[CH:26][CH:25]=1
Reactant: O=c1c2ccoc2c(Br)cn1CCc1ccc2ccccc2n1
Reactant: OB(O)c1ccncc1
Product: O=c1c2ccoc2c(-c2ccncc2)cn1CCc1ccc2ccccc2n1

Procedure:
165.2 but using 7-bromo-5-(2-(quinolin-2-yl)ethyl)furo[3,2-c]pyridin-4(5H)-one (61.7 mg, 0.167 mmol) and pyridin-4-ylboronic acid (22.82 mg, 0.167 mmol mmol). The title compound was obtained as yellowish solid (yield: 22 mg, 35.8.9%).
Reaction SMILES: C[Al](C)C.[F:5][C:6]([F:10])([F:9])[CH2:7][NH2:8].C[O:12][C:13](=O)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[C:23]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[N:24][O:25][C:26]=2[CH3:27])=[N:16][CH:15]=1.O>O1CCOCC1>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([C:23]2[C:22]([CH2:21][O:20][C:17]3[CH:18]=[CH:19][C:14]([C:13]([NH:8][CH2:7][C:6]([F:10])([F:9])[F:5])=[O:12])=[CH:15][N:16]=3)=[C:26]([CH3:27])[O:25][N:24]=2)=[CH:33][CH:32]=1
Reactant: NCC(F)(F)F
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2C)nc1
Agent: C[Al](C)C
Solvent: O
Solvent: C1COCCO1
Product: Cc1onc(-c2ccc(Cl)cc2)c1COc1ccc(C(=O)NCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 401 μL, 0.8 mmol) was added dropwise (exothermic) to a solution of 2,2,2-trifluoroethylamine (79 mg, 63 μL, 0.8 mmol) in dioxane (5 mL) and the resulting mixture was stirred at room temperature for 1 h. Then a solution of 6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (72 mg, 0.2 mmol) in dioxane (2.5 mL) was added. The resulting mixture was then heated at 85-95° C. for 1 h and then cooled to room temperature and then poured into water and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (66 mg, 77%) which was obtained as a white solid. MS: m/e=426.0 [M+H]+.
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH3:34][O:35][P:36]([CH:39]([NH:43][C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[CH:40]([CH3:42])[CH3:41])(=O)[OH:37].[CH3:54][O:55][C:56](=[O:70])[CH:57]([OH:69])[CH2:58][CH2:59][CH2:60][NH:61][C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63].CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:54][O:55][C:56](=[O:70])[CH:57]([O:69][P:36]([CH:39]([NH:43][C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[CH:40]([CH3:42])[CH3:41])([O:35][CH3:34])=[O:37])[CH2:58][CH2:59][CH2:60][NH:61][C:62]([O:64][C:65]([CH3:67])([CH3:66])[CH3:68])=[O:63]
Reactant: COP(=O)(O)C(NC(=O)OCc1ccccc1)C(C)C
Reactant: COC(=O)C(O)CCCNC(=O)OC(C)(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C(CCCNC(=O)OC(C)(C)C)OP(=O)(OC)C(NC(=O)OCc1ccccc1)C(C)C
Yield: 68.7 %

Procedure:
A solution of PyBOP (2.1 g, 4.0 mmol) in DMF (3 mL) was added to a mixture of (1-benzyloxycarbonylamino-2-methyl-propyl)-phosphonic acid monomethyl ester (1.0 g, 3.32 mmol) and 5-tert-butoxycarbonylamino-2-hydroxy-pentanoic acid methyl ester (865 mg, 3.5 mmol) in DMF (4 mL) under argon. DIPEA (2.28 mL, 13.3 mmol) was added dropwise and the mixture was stirred over night. Ethyl acetate was added and the mixture was washed with 10% KHSO4, satd. NaHCO3 and brine and dried. Concentration under reduced pressure followed by chromathography (heptane/EtOAc, 1:1→1:6) gave 2-[(1-benzyloxycarbonylamino-2-methyl-propyl)-methoxy-phosphinoyloxy]-5-tert-butoxycarbonylamino-pentanoic acid methyl ester (1.21 g, 69%).