Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-:1]I(=O)(=O)=O.[Na+].[CH3:7][S:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12]([Br:18])=[CH:11][C:10]=1[CH:19]([CH3:21])[CH3:20]>O.CO.CC(C)=O>[CH3:7][S:8]([C:9]1[CH:14]=[C:13]([CH:15]([CH3:16])[CH3:17])[C:12]([Br:18])=[CH:11][C:10]=1[CH:19]([CH3:21])[CH3:20])=[O:1]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSc1cc(C(C)C)c(Br)cc1C(C)C
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CO
Product: CC(C)c1cc(S(C)=O)c(C(C)C)cc1Br
Reaction time: 16 h

Procedure:
4-Bromo-2,5-diisopropylphenyl methyl sulfoxide was prepared as follows: A solution of 25.7 g of sodium m-periodate in 200 ml of water was added portionwise over 0.5 hour to 31.9 g of 4-bromo-2,5-diisopropylphenyl methyl sulfide (prepared in Example 1C) in 200 ml of methanol and 350 ml of acetone at ambient temperature. After stirring for 16 hours, the reaction mixture was filtered and the solid portion was extracted with chloroform. The filtrate was diluted with 1 liter of water and the solid residue that formed was collected on a filter. The second residue was extracted with chloroform. The two chloroform extracts were combined, washed with half-saturated sodium chloride solution, and dried over sodium sulfate. Removal of the chloroform gave a pale-yellow product containing some sulfide which was removed by recrystallization from n-hexane to give pure 4-bromo-2,5-diisopropylphenyl methyl sulfoxide which softened at 110°C and melted at 114°-117°C [Ʊ(S=O) 9.6μ].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:25][C:26]1[CH:27]=[CH:28][C:29]2[C:33]([CH3:35])([CH3:34])[O:32][B:31]([OH:36])[C:30]=2[CH:37]=1.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>C(Cl)Cl>[OH:36][B:31]1[C:30]2[CH:37]=[C:26]([NH:25][C:10](=[O:12])[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][CH:16]=3)[CH:27]=[CH:28][C:29]=2[C:33]([CH3:35])([CH3:34])[O:32]1
Reactant: CC(C)(C)OC(=O)N[C@H](CCc1ccc(C(F)(F)F)cc1)C(=O)O
Reactant: CC1(C)OB(O)c2cc(N)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H](CCc1ccc(C(F)(F)F)cc1)C(=O)Nc1ccc2c(c1)B(O)OC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
To a suspension of (R)-2-(tert-butoxycarbonylamino)-4-(4-(trifluoromethyl)phenyl)butanoic acid (LXXI) (1 g, 2.88 mmol) and 6-amino-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol (XCVIII) (0.615 g, 2.88 mmol) in dry DCM (10 mL) was added DIPEA (1.47 mL, 8.64 mmol). To this solution was added HATU (1.09 g, 2.88 mmol) and the mixture was stirred at room temperature overnight. The mixture was washed with 2 N aqueous HCl, 1 M aqueous K2CO3, brine, dried over MgSO4 and evaporated under vacuum to give (R)-tert-butyl 1-(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-ylamino)-1-oxo-4-(4-(trifluoromethyl)phenyl)butan-2-ylcarbamate (1.44 g, 2.84 mmol, 99% yield). ESIMS found for C25H30BF3N2O5 m/z 507.5 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=[O:7])=[C:4](OC)[CH:3]=1.[OH-].[Na+].[CH3:15]O>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:15])[CH:3]=1
Reactant: CO
Reactant: COc1cc(F)ccc1C(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(F)ccc1C(=O)O
Temperature: 25 °C
Yield: 85 %

Procedure:
To a solution of 4-fluoro-2-methoxybenzoate (10.0 g, 58.8 mmol) in methanol (50 mL) was slowly added 6 M NaOH solution (30 mL). White solid immediately precipitated and the mixture was stirred for another hour at room temperature before it was re-dissolved in H2O and acidified with 6 M HCl solution until precipitation occurred. The white solid was collected by vacuum filtration and dried on vacuum oven overnight to afford 4-fluoro-2-methyl benzoic acid (44, 9.2 g, 85%) 1H NMR (300 MHz, CDCl3) δ 8.21 (dd, J=9.0 Hz, 6.9 Hz, 1H), 6.82-6.88 (m, 1H), 6.79 (dd, J=7.8 Hz, 2.1 Hz, 1H), 4.07 (s, 1H).
Reaction SMILES: [OH:1][CH:2]([CH2:33][OH:34])[CH2:3][O:4][CH2:5][CH2:6][O:7][C@H:8]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:10]([CH2:11][CH2:12][C@@H:13]3[C@@H:22]2[CH2:21][CH2:20][C@@:18]2([CH3:19])[C@:14]3([OH:32])[CH2:15][CH2:16][C@@H:17]2[C:27]2[CH:31]=[CH:30][O:29][CH:28]=2)[CH2:9]1.[S:35](Cl)([C:38]1[CH:44]=[CH:43][C:41]([CH3:42])=[CH:40][CH:39]=1)(=[O:37])=[O:36].O.C(OCC)(=O)C>N1C=CC=CC=1>[S:35]([O:34][CH2:33][CH:2]([OH:1])[CH2:3][O:4][CH2:5][CH2:6][O:7][C@H:8]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:10]([CH2:11][CH2:12][C@@H:13]3[C@@H:22]2[CH2:21][CH2:20][C@@:18]2([CH3:19])[C@:14]3([OH:32])[CH2:15][CH2:16][C@@H:17]2[C:27]2[CH:31]=[CH:30][O:29][CH:28]=2)[CH2:9]1)([C:38]1[CH:44]=[CH:43][C:41]([CH3:42])=[CH:40][CH:39]=1)(=[O:37])=[O:36]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@]12CC[C@H](OCCOCC(O)CO)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccoc3)CC[C@]12O
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(O)COCCO[C@H]2CC[C@@]3(C)[C@H](CC[C@@H]4[C@@H]3CC[C@]3(C)[C@@H](c5ccoc5)CC[C@]43O)C2)cc1
Yield: 88.9 %

Procedure:
To a solution of 1.7 g of 3β-(2-(2,3-dihydroxypropoxy)ethoxy)-17β-(3-furyl)-5β-androstan-14β-ol, prepared from 3γ-(2-hydroxyethoxy)-17β-(3-furyl)-5β-andostran-14β-ol, prepared as an intermediate in Ex.1, according to the sequence described in Ex. 2 and Ex. 15, in 13 ml of dry pyridine, 0.80 g of tosyl chloride were added at a temperature of 0° C. After 5 hrs 60 ml of water and 250 ml of ethyl acetate were added, the organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The crude product was purified by flash-chromatography (SiO2)using n-hexane/ethyl acetate 70/30 as eluant to give 2 g of 3β-(2- (3-tosyloxy-2-hydroxypropoxy)ethoxy)-17β-(3-furyl)-5β-androstan-14β-ol as a white solid.
Reaction SMILES: [N:1]1([S:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])[CH2:16]3)(=[O:12])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[N:23]1([CH2:28][CH2:29][O:30][C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[NH:36][C:35]([CH:40]=O)=[CH:34]3)[CH2:27][CH2:26][CH2:25][CH2:24]1>>[N:1]1([S:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])[C:16]3=[CH:40][C:35]2[NH:36][C:37]3[C:33]([CH:34]=2)=[CH:32][C:31]([O:30][CH2:29][CH2:28][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:39][CH:38]=3)(=[O:12])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Reactant: O=C1Cc2cc(S(=O)(=O)N3CCc4ccccc43)ccc2N1
Product: O=C1Nc2ccc(S(=O)(=O)N3CCc4ccccc43)cc2C1=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1

Procedure:
5-(2,3-Dihydro-indole-1-sulfonyl)-1,3-dihydro-indol-2-one was condensed with 5-(2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carbaldehyde to give the title compound.
Reaction SMILES: [C:1]([C:4]1([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20]([C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=4)=[O:21])[CH:17]=3)[NH:12][N:11]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH2:5]1)(=[O:3])[CH3:2]>[Pd].C(OCC)(=O)C>[C:1]([C:4]1([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20]([C:22]4[CH:23]=[CH:24][C:25]([NH2:28])=[CH:26][CH:27]=4)=[O:21])[CH:17]=3)[NH:12][N:11]=2)[CH:5]=[CH:6][CH:7]=[CH:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)C1(c2n[nH]c3ccc(NC(=O)c4ccc([N+](=O)[O-])cc4)cc23)C=CC=CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)C1(c2n[nH]c3ccc(NC(=O)c4ccc(N)cc4)cc23)C=CC=CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
A suspension of N-(1-acetyl-3-phenyl(1H-indazol-5-yl))(4-nitrophenyl)carboxamide (246 mg, 0.710 mmol) and palladium on activated carbon (10%, 57 mg) in ethyl acetate (30 mL) was stirred under hydrogen atmosphere at room temperature for 18 hours. The reaction mixture was filtered through celite and combined with ethyl acetate washings. The filtrate was concentrated to give the title compound (246 mg, 94% yield). 1H NMR (DMSO-d6) δ 10.04 (s, 1H), 8.61 (s, 1H) 8.31 (d, 1H), 7.99 (m, 2H), 7.64 (m, 4H), 6.58 (d, 2H), 5.78 (s, 2H), 2.76 (s, 3H); ES-MS (m/z) 371 [M+1]+.
Reaction SMILES: [C:1]1([C:7]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](B(O)O)=[C:13]3[C:8]=2[CH:9]=[CH:10][CH:11]=[CH:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:24][C:25]1[CH:30]=[CH:29][C:28](Br)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[C:1]1([C:7]2[C:20]3[C:15]([C:14]([C:28]4[CH:29]=[CH:30][C:25]([Br:24])=[CH:26][CH:27]=4)=[C:13]4[C:8]=2[CH:9]=[CH:10][CH:11]=[CH:12]4)=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Brc1ccc(Br)cc1
Reactant: OB(O)c1c2ccccc2c(-c2ccccc2)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2c3ccccc3c(-c3ccccc3)c3ccccc23)cc1
Yield: 43.8 %

Procedure:
An amount of 2.46 g (8.26 mmol) of 10-phenylanthracene-9-boronic acid synthesized in the same manner as in Exemplary Synthesis 2, 9.75 g (41.3 mmol) of p-dibromobenzene, and 250 mg of tetrakis triphenylphosphine palladium as catalysis were dissolved in a mixed solvent of 60 ml of toluene and 15 ml of ethanol. Then, 30 ml of 2M sodium carbonate solution was added and allowed to react at 90° C. for 12 hours. After the reaction was completed, the organic layer was separated and purified by column chromatography to obtain 1.48 g (3.62 mmol) of 9-phenyl-10-(4-bromophenyl)anthracene. The yield was 43.8%.
Reaction SMILES: Cl[C:2]1[C:3]([N:7]2[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=[O:14])[CH2:9][CH2:8]2)=[N:4][S:5][N:6]=1.[N:16]1[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[CH:18][CH:17]=1.C(C(CCC)[O-])(C)(C)C.[K+].C(O)(C)(C)C>O>[N:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:23][C:2]2[C:3]([N:7]3[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=[O:14])[CH2:9][CH2:8]3)=[N:4][S:5][N:6]=2)=[CH:18][CH:17]=1
Reactant: OCc1ccncc1
Reactant: O=C(O)C1CCN(c2nsnc2Cl)CC1
Agent: CCCC([O-])C(C)(C)C
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(O)C1CCN(c2nsnc2OCc2ccncc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
1-(4-Chloro-[1,2,5]thiadiazol-3-yl)-piperidine-4-carboxylic acid (7.99 g, 32 mmol), pyridin-4-yl-methanol (7.39 g, 68 mmol) and a solution of 1M potassium tert-butyl butoxide in tert-butyl alcohol (100 mL, 100 mmol) were combined and stirred at room temperature overnight. The reaction mixture is diluted with H2O (500 mL) and washed with EtOAc (3×). The aqueous phase is concentrated to ˜250 mL and acidified to pH 5-6 with conc'd HCl. The resulting solids are filtered, washed with H2O and dried under high vacuum to give 6.04 g (59%) of 1-[4-(pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperidine-4-carboxylic acid. 1H NMR (DMSO-d6) 8.57 (d, 2H), 7.41 (d, 2H), 5.51 (s, 2H), 4.03 (m, 2H), 3.00 (m, 2H), 2.46 (m, 1H), 1.91 (m, 2H), 1.63 (m, 2H) ppm. LC-MS (M−)=319.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([NH:16][C:17]2[NH:43][C:20]3=[N:21][C:22]([O:38][CH2:39][CH:40]([F:42])[F:41])=[C:23]([C:25](=[O:37])[NH:26][C@H:27]4[CH2:32][CH2:31][C@H:30]([C:33]([F:36])([F:35])[F:34])[CH2:29][CH2:28]4)[CH:24]=[C:19]3[N:18]=2)[C:10]=1[Cl:44])(C)(C)C.Cl>O1CCOCC1.CO>[Cl:44][C:10]1[C:11]([NH:16][C:17]2[NH:43][C:20]3=[N:21][C:22]([O:38][CH2:39][CH:40]([F:41])[F:42])=[C:23]([C:25](=[O:37])[NH:26][C@H:27]4[CH2:32][CH2:31][C@H:30]([C:33]([F:36])([F:34])[F:35])[CH2:29][CH2:28]4)[CH:24]=[C:19]3[N:18]=2)=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]=1[CH2:8][NH2:7]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)c(Nc2nc3cc(C(=O)N[C@H]4CC[C@H](C(F)(F)F)CC4)c(OCC(F)F)nc3[nH]2)c1Cl
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NCc1ccc(Cl)c(Nc2nc3cc(C(=O)N[C@H]4CC[C@H](C(F)(F)F)CC4)c(OCC(F)F)nc3[nH]2)c1Cl
Reaction time: 0.25 h

Procedure:
A mixture of N-{2,4-dichloro-3-[6-(trans-4-trifluoromethyl-cyclohexylcarbamoyl)-5-(2,2-difluoro-ethoxy)-3H-imidazo[4,5-b]pyridin-2-ylamino]benzyl}-carbamic acid tert-butyl ester (6.3 g, 9.3 mmol), 4 M HCl in dioxane (60 ml) and MeOH (5 ml) is stirred for 15 min. The mixture is concentrated, diluted with water and basified with conc. NH3. The precipitate is collected by filtration, washed with water, dried and purified via prep HPLC. The product fractions are concentrated, basified with conc. NH3, extracted with EtOAc. The organic phases are dried with Na2SO4 and concentrated to give the crude sub-title compound (4.8 g).
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH:5]=[CH2:6].[Br:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Br)=[CH:10][CH:9]=1.Cl>O1CCCC1>[CH2:12]([C:11]1[CH:14]=[CH:15][C:8]([Br:7])=[CH:9][CH:10]=1)[CH2:6][CH2:5][CH:4]=[CH2:3]
Reactant: BrCc1ccc(Br)cc1
Reactant: C=CCCBr
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CCCCc1ccc(Br)cc1
Yield: 12.7 %

Procedure:
To a suspension of 970 mg of magnesium in 20 ml of tetrahydrofuran was added dropwise a solution of 5.4 g of 4-bromo-1-butene in 20 ml of tetrahydrofuran while keeping at 50° C. Then, a solution of 10.0 g of 4-bromobenzyl bromide in 20 ml of tetrahydrofuran was added dropwise slowly, and the mixture was refluxed for an hour, made acidic with dilute hydrochloric acid and extracted with n-hexane. The organic layer was washed with water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was chromatographed on silica gel column with n-hexane to give 1.14 g of 4-(4-pentenyl)bromobenzene.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[C:4]([CH3:12])[CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.[OH-].[Na+]>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][OH:7])=[C:4]([CH3:12])[CH:3]=1
Reactant: COC(=O)c1ccc(Br)cc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(Br)ccc1CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 4-bromo-2-methylbenzoate (2 g, 8.7 mmol) in THF (20 mL) was added LAH (663 mg, 17.5 mmol) at 0° C. The mixture was stirred at RT for 1 h, then diluted with NaOH (1.0M, 10 mL) and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by normal phase silica gel column provided (4-bromo-2-methylphenyl)methanol as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.O>S(Cl)(Cl)=O.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[O:9])=[CH:5][C:4]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCOc1cc(C(=O)O)ccc1OC
Reactant: C1COCCN1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: O
Product: CCCCCOc1cc(C(=O)N2CCOCC2)ccc1OC
Temperature: 70 °C
Reaction time: 5 h
Yield: 67.9 %

Procedure:
4-Methoxy-3-pentyloxybenzoic acid (250 mg, 1.05 mmol, 1 eq) was dissolved in thionyl chloride (1.05 ml) in a stream of nitrogen, and the solution was stirred at 70° C. for 5 hours. The mixture was cooled to room temperature, and excess thionyl chloride was evaporated under reduced pressure. The residue was added to a solution of morpholine (274 mg, 3.15 mol, 3.0 eq) in DMF (3 ml) under ice-cooling. The mixture was stirred under ice-cooling for 30 minutes, and then further at room temperature for 1.5 hours. Water (30 ml) was added to this reaction mixture and the mixture was extracted twice with ethyl acetate (50 ml). The organic layers were combined, washed with saturated brine (50 ml) and dried over anhydrous sodium sulfate. The drying agent was fltered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=2/1) to give (4-methoxy-3-pentyloxyphenyl)morpholin-4-yl-methanone (219 mg, 67.9%) as an oil
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([CH3:22])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([CH3:22])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: Cc1cc(OC2CN(C(=O)OC(C)(C)C)C2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(OC2CN(C(=O)OC(C)(C)C)C2)ccc1N
Yield: 90.7 %

Procedure:
The 3-(3-Methyl-4-nitro-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (12.0 g, 43 mmol) was dissolved in 50 mL methanol and 50 mL ethyl acetate. An amount of 1.0 g of 10% wet Pd—C (50% w/w) was added. The reaction mixture was subjected to hydrogenation under 40 PSI of hydrogen for 3 hours. The solution was then filtered through Celite to remove catalyst. The filtrate was concentrated under reduced pressure to give the desired product (10.8 g, 39 mmol). 1H-NMR (400 MHz, CDCl3): δ=6.60 (m, 1H), 6.02 (m, 1H), 5.95 (m, 1H), 4.78 (m, 1H), 4.24 (m, 2H), 3.95 (m, 2H), 3.45 (br, 1H), 2.15 (s, 3H), 1.45 (s, 9H). MS: 301 (M++23).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[CH3:8].[OH-].[NH4+].ClC1N=[N:17]C(N)=CC=1C>>[Cl:9][C:5]1[N:4]=[N:3][C:2]([NH2:17])=[C:7]([CH3:8])[CH:6]=1
Reactant: Cc1cc(Cl)nnc1Cl
Reactant: Cc1cc(N)nnc1Cl
Agent: [NH4+]
Agent: [OH-]
Product: Cc1cc(Cl)nnc1N
Temperature: 100 °C
Yield: 85 %

Procedure:
A 20 mL microwave vial was charged with, a stir bar, 3,6-dichloro-4-methylpyridazine (4.0 g, 24.54 mmol) and 14 mL of a new, freshly opened bottle of ammonium hydroxide. The vial was quickly sealed. The solution was heated in a microwave (Personal Chemistry, Emrys Optimizer) to 100° C. for 3 h. The vial was cooled, opened, and a stream of nitrogen was used to remove excess ammonium hydroxide. Water was added, the solid was collected by filtration, washed with water and dried to provide a mixture of 6-chloro-5-methylpyridazin-3-amine and 6-chloro-4-methylpyridazin-3-amine (3 g, 20.90 mmol, 85% yield). The mixture was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:28]2[C:19](=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]([CH3:29])[CH2:23][CH2:22][CH2:21]3)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH:15]([CH3:14])[C:28]4[C:19](=[C:20]5[C:25](=[CH:26][CH:27]=4)[N:24]([CH3:29])[CH2:23][CH2:22][CH2:21]5)[CH2:18][CH2:17]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2c1ccc1c2CCCN1C
Product: CC1c2ccc3c(c2CCN1C(=O)c1cc2ncc(Br)cn2n1)CCCN3C

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 4,7-Dimethyl-1,2,3,4,7,8,9,10-octahydro-[3,7]phenanthroline to provide the title compound in moderate yield.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5](Cl)=[N:6][CH:7]=1.Cl.[CH3:12][C:13]1([OH:17])[CH2:16][NH:15][CH2:14]1.CCN(CC)CC>C1COCC1>[Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5]([N:15]2[CH2:16][C:13]([CH3:12])([OH:17])[CH2:14]2)=[N:6][CH:7]=1
Reactant: CC1(O)CNC1
Reactant: COc1nc(Cl)ncc1Br
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1nc(N2CC(C)(O)C2)ncc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.1 %

Procedure:
A mixture of 5-bromo-2-chloro-4-methoxypyrimidine (3.5 g, 15.7 mmol), 3-methylazetidin-3-ol hydrochloride (2.90 g, 23.5 mmol), and Et3N (4.4 mL, 31.3 mmol) in THF (50 mL) was stirred for 18 h at rt. 3-Methylazetidin-3-ol hydrochloride (1 g) was added. The reaction mixture was stirred for 72 h at rt and concentrated. The residue was purified by flash chromatography (hexane/EtOAc 1:1) to afford 2.5 g of the title compound. tR: 0.81 min (LC-MS 2); ESI-MS: 274.2 [M+H]+ (LC-MS 2); Rf: 0.25 (hexane/EtOAc 1:1).
Reaction SMILES: [Li]CCCC.[CH3:6][C:7]1[S:11][CH:10]=[N:9][CH:8]=1.F[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24]>CCCCCCC.C1COCC1>[CH3:6][C:7]1[S:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:14]=2[N+:23]([O-:25])=[O:24])=[N:9][CH:8]=1
Reactant: Cc1cncs1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: Cc1cnc(-c2ccc(C(F)(F)F)cc2[N+](=O)[O-])s1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 28.7 %

Procedure:
A solution of n-BuLi (2.5 mmol) in heptane (c=2.5 M) under nitrogen atmosphere was cooled to −78° C. To the solution was added drop-wise 5-methyl-thiazole (750 mg, 7.5 mmol) dissolved in anhydrous THF (10 ml). The reaction was stirred for 20 min at −78° C. followed by the addition of 1-fluoro-2-nitro-4-trifluoromethyl-benzene (1.56 g, 7.5 mmol) dissolved in anhydrous THF (10 ml). The reaction was stirred for 10 min at −78° C. and then allowed to reach ambient temperature. The reaction was quenched with aqueous sodium bicarbonate and the phases separated. The ether phase was washed with brine, dried with MgSO4 and filtered. The solvent was removed in vacuo and the residue purified by flash chromatography (Silica, Hexane/ethyl acetate) to afford the title compound (620 mg, 29%). LC/MS (Method I): tR=1.44 min, >90%, m/z (ESI+)=289 (MH+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([OH:18])=O.[NH2:19][C@H:20]1[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:22]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:21]1>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([NH:19][C@H:20]1[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[C@H:22]([CH2:32][O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:21]1)=[O:18]
Reactant: CC(C)(C)OC(=O)N1C[C@H](N)C[C@H]1COCc1ccccc1
Reactant: O=C(O)[C@@H]1CCCCN1c1nc2ccccc2o1
Product: CC(C)(C)OC(=O)N1C[C@H](NC(=O)[C@@H]2CCCCN2c2nc3ccccc3o2)C[C@H]1COCc1ccccc1

Procedure:
The title compound was prepared by a similar method to Example 1 from (2S)-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxylic acid [see Preparation 3] and tert-butyl (2S,4R)-4-amino-2-[(benzyloxy)methyl]pyrrolidine-1-carboxylate [see Preparation 34]. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 70:30 changing to 50:50, by volume, hexane:ethyl acetate to afford tert-butyl (2S,4R)-4-([(2S)-1-(1,3-benzoxazol-2-yl)-2-piperidinyl]carbonylamino)-2-[(benzyloxy)methyl]pyrrolidine-1-carboxylate as a foam.
Reaction SMILES: Cl.[CH3:2][S:3]([N:6]1[CH2:11][CH2:10][NH:9][C@@H:8]([C:12]([OH:14])=[O:13])[CH2:7]1)(=[O:5])=[O:4].C([O-])(O)=O.[Na+].[CH2:20]([O:27][C:28](Cl)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O.O1CCOCC1.CCOCC>[CH2:20]([O:27][C:28]([N:9]1[CH2:10][CH2:11][N:6]([S:3]([CH3:2])(=[O:4])=[O:5])[CH2:7][C@@H:8]1[C:12]([OH:14])=[O:13])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CS(=O)(=O)N1CCN[C@@H](C(=O)O)C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOCC
Product: CS(=O)(=O)N1CCN(C(=O)OCc2ccccc2)[C@@H](C(=O)O)C1
Reaction time: 2 h
Yield: 102.1 %

Procedure:
To a solution of (2R)-4-methanesulfonylpiperazine-2-carboxylic acid hydrochloride (2.10 g) in H2O (20 ml) and dioxane (20 ml) were added NaHCO3 (2.38 g) and a solution of benzyloxycarbonyl chloride (1.76 g) in Et2O (10 ml) at room temperature. After stirring for 2 hours, Et2O and dioxane were evaporated in vacuo. The solution was acidified with 1N HCl and extracted with AcOEt (80 ml). The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo to give 3.0 g of (2R)-1-benzyloxycarbonyl-4-methanesulfonylpiperazine-2-carboxylic acid as an amorphous powder.