Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[N:13]=[CH:12][C:11]4[N:17]=[CH:18][N:19]([C:20]5[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=5[C:22]#[N:23])[C:10]=4[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:29][OH:30].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O>[OH:30][NH:29][C:22](=[NH:23])[C:21]1[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=1[N:19]1[C:10]2[C:9]3[CH:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:17]=[CH:18]1
Reactant: NO
Reactant: N#Cc1ccccc1-n1cnc2cnc3ccc(-c4ccccc4)cc3c21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N=C(NO)c1ccccc1-n1cnc2cnc3ccc(-c4ccccc4)cc3c21
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To 300 mg (0.832 mmol) of 2-(8-phenyl-imidazo[4,5-c]quinolin-1-yl)-benzonitrile (Example 63) and 360 mg (5.19 mmol) hydroxylamine hydrochloride in 7 ml DMF, a solution of 490 mg (4.61 mmol) sodium carbonate in 2.6 ml water is added using a syringe within 3 min. After a few minutes, a precipitate starts to appear. Stirring is continued for 4 h at 70° C. (tlc-control). The reaction mixture is cooled to 0° C. and is poured into 100 ml ice-water. The compound is filtered off, washed with water and hexane, and dried at 65° C. for 16 h (high-vacuum). mp: 249-251° C. MS: 380 (M+1); HPLC: tret=6.91 min (Grad 1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[C:4](Cl)[N:3]=1.Cl.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH:14]1[CH2:19][OH:20].C(N(CC)CC)C>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH:14]2[CH2:19][OH:20])[C:5]([O:9][CH3:10])=[C:6]([Cl:8])[N:7]=1
Reactant: COc1c(Cl)nc(Cl)nc1Cl
Reactant: OCC1COCCN1
Agent: Cl
Solvent: CCN(CC)CC
Product: COc1c(Cl)nc(Cl)nc1N1CCOCC1CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.6 %

Procedure:
A mixture of 2,4,6-trichloro-5-methoxy-pyrimidine (1 g, 4.68 mmol), morpholin-3-yl-methanol hydrochloride (0.86 g, 5.6 mmol) and triethylamine (0.9 mL, 6.5 mmol) in IMS (30 mL) was stirred at RT for 3 h, then concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, 0 to 50% ethyl acetate in cyclohexane) affording [4-(2,6-Dichloro-5-methoxy-pyrimidin-4-yl)-morpholin-3-yl]-methanol (614 mg, 45%). LCMS (method A): RT=2.63 min, [M+H]+=294/296.
Reaction SMILES: Br[C:2]1([C:8]([OH:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][NH:3]1.C([O-])([O-])=O.[Na+].[Na+].[F:17][C:18]1[CH:23]=[CH:22][C:21](B2OCC(C)(C)CO2)=[CH:20][CH:19]=1.CCO>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:4]2[N:3]=[C:2]([C:8]([OH:10])=[O:9])[CH:7]=[CH:6][CH:5]=2)=[CH:20][CH:19]=1
Reactant: O=C(O)C1(Br)C=CC=CN1
Reactant: CC1(C)COB(c2ccc(F)cc2)OC1
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: COCCOC
Solvent: CCO
Product: O=C(O)c1cccc(-c2ccc(F)cc2)n1
Temperature: 100 °C
Yield: 46 %

Procedure:
A solution of 2-bromo-picolinic acid (Aldrich, 2.02 g, 10 mmol) in DME containing 4 mL of 10% aq Na2CO3 was purged with Ar gas. To this mixture was added Pd(PPh3)4 followed by 2-(4-fluorophenyl)-5,5-dimethyl-1,3,2-dioxaborinane (Aldrich, 2.40 g, 11.5 mmol) and EtOH (20 mL), and the mixture was purged with Ar gas. The reaction mixture was heated at 100° C. for 2.5 h in a sealed tube. Additional 2-bromo-picolinic acid (900 mg) and Pd(PPh3)4 was added, and after purging with Ar gas it was heated at 100° C. for 4.5 h. Trifluoroacetic acid (20 mL) was added to the reaction and the mixture was concentrated in vacuo. MeOH (150 mL) was added to the residue and the insoluble material was filtered, and the filtrate solution was concentrated in vacuo. Purification of the resulting residue by flash column chromatography on silica gel eluting with EtOAc/MeOH/900:100 followed by EtOAc/MeOH/HOAc/700:1500:50 provided the desired product (1.0 g, 40% based on borinane starting material) as a white solid. 1H NMR (CD3OD) δ 8.01 (d, 1H, J=7.7 Hz), 7.94-7.87 (m, 3H), 7.73 (d, 1H, J=7.7 Hz), 7.13 (t, 2H, J=8.8 Hz); MS (ESI+) m/z 234 (M+H)+.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH2:7])(=[O:3])[CH3:2].O=[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH:10]1[CH2:19][CH:20]=O>C(OCC)C>[N:7]1([CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:12][CH2:11][C:10]=2[CH:19]=[CH:20]1
Reactant: O=CCC1CCc2ccccc2C1=O
Reactant: CC(=O)NCCN
Solvent: CCOCC
Product: CC(=O)NCCn1ccc2c1-c1ccccc1CC2
Yield: 63.3 %

Procedure:
Molecular sieve 4 Å and 14.9 g of N-acetylethylenediamine (200 g) was added in succession under argon to a solution of 27.5 g of 1,2,3,4-tetrahydro-1-oxo-2-naphthaleneacetaldehyde in 275 ml of diethyl ether. The reaction mixture was stirred at boiling temperature for 5 hours and subsequently cooled. The molecular sieve was filtered off, the filtrate was freed from solvent and the crude product was chromatographed on 600 g of silica gel with ethyl acetate as the eluent. There were obtained 23.5 g (79%) of N-[2-(4,5-dihydro-1H-benzo[g]indol-1-yl)ethyl]-acetamide with a melting point of 95°-96° C. (ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])[CH3:9])=[O:7])=[CH:4][C:3]=1[C:19]1[CH:20]=[N:21][C:22]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:24]=1[C:25]#[N:26].Br[CH2:32][C:33]([CH3:37])([CH3:36])[CH2:34][OH:35].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:32][C:33]([CH3:37])([CH3:36])[CH2:34][OH:35])[CH3:9])=[O:7])=[CH:4][C:3]=1[C:19]1[CH:20]=[N:21][C:22]([C:27]([F:30])([F:28])[F:29])=[CH:23][C:24]=1[C:25]#[N:26]
Reactant: CN(C(=O)c1ccc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)c1)c1ccccc1O
Reactant: CC(C)(CO)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C(=O)c1ccc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)c1)c1ccccc1OCC(C)(C)CO
Temperature: 65 °C
Reaction time: 24 h

Procedure:
4-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-(2-hydroxy-phenyl)-N-methyl-benzamide (200 mg, 0.46 mmol) was dissolved in DMF (2 mL) and 3-bromo-2,2-dimethyl-propan-1-ol (72 μL, 0.94 mmol) and K2CO3 (192 μL, 1.08 mmol) were added. The mixture was stirred at 65° C. for 24 hrs, cooled to rt, diluted with EtOAc, washed with water and brine, dried (Na2SO4), filtered and concentrated. Silica gel column chromatography (1% MeOH in DCM with gradient up to 5% MeOH in DCM) followed by prep HPLC afforded 4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-[2-(3-hydroxy-2,2-dimethyl-propoxy)-phenyl]-N-methyl-benzamide. MS: 518.3 (M+H)+, tR=6.16 min (method 3).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20](Cl)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[CH:46]=[CH:45][C:39](/[CH:40]=[CH:41]/B(O)O)=[CH:38][CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20](/[CH:41]=[CH:40]/[C:39]2[CH:45]=[CH:46][C:36]([F:35])=[CH:37][CH:38]=2)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Reactant: OB(O)/C=C/c1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(/C=C/c2ccc(F)cc2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Temperature: 85 °C

Procedure:
In a 30 mL sealed cap glass vial, tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (150 mg, 0.301 mmol), (E)-4-fluorostyrylboronic acid (49.9 mg, 0.301 mmol) and PdCl2(PPh3)2 (42.2 mg, 0.060 mmol) were dissolved in dioxane (5 mL). To the reaction mixture was added 2N aqueous sodium carbonate solution (2 mL). The cap was sealed and the reaction mixture was heated at 85° C. for 2 hours. The reaction mixture was subsequently diluted with water (5 mL) and was extracted into EtOAc (2×30 mL). The combined organic phase was dried over sodium sulfate and evaporated to give the intermediate, tert-butyl 6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-7-fluoro-4-((E)-4-fluorostyryl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate, which was treated with TFA (4 mL) for 1.5 hours to remove the protecting groups. TFA was subsequently evaporated from the reaction mixture. The residual material was dissolved in DMSO (8 mL) and purified by preparative HPLC, eluting with a gradient of 10-30% ACN (0.035% TFA) and water (0.05% TFA). The pure product fractions were combined, evaporated to a minimal volume, and lyophilized to give a TFA salt of the title compound as a tan solid (58 mg, 50%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.42-1.92 (m, 8H), 3.74 (br s, 1H), 4.40 (d, J=2.53 Hz, 2H), 4.51 (br s, 1H), 6.86 (d, J=6.57 Hz, 1H), 7.27 (t, J=8.84 Hz, 1H), 7.56-7.73 (m, 3H), 7.82 (br s, 3H), 8.14 (d, J=15.92 Hz, 1H), 8.49 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C21H22F2N4O, 385. found, 385.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[S:5][CH:4]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.O>C(N(CC)CC)C>[C:15]1([CH:4]2[CH:3]([CH2:2][O:1][S:27]([C:24]3[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=3)(=[O:29])=[O:28])[C:9](=[O:10])[NH:8][C:7]3[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=3[S:5]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1Nc2ccccc2SC(c2ccccc2)C1CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2C(=O)Nc3ccccc3SC2c2ccccc2)cc1
Yield: 91.3 %

Procedure:
5.7 g of 2,3-dihydro-3-hydroxymethyl-2-phenyl-1,5-benzothiazepin-4(5H)-one prepared as described in Reference Example 1 was dissolved in 20 ml of triethylamine. 3.8 g of p-toluenesulfonyl chloride was added to the solution while stirring and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture and the precipitated crystals were separated by filtration and recrystallized from a mixture of dichloromethane-n-hexane to obtain 8 g of 2,3-dihydro-2-phenyl-3-[(p-toluenesulfonyloxy)methyl]-1,5-benzothiazepin-4(5H)-one as colorless prisms having a melting point of 215° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[C:20](C(C(C)C)C)=[N:19][C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:26]([O:28]C)=[O:27])[CH:17]=4)[N:12]=3)[CH:9]=2)[NH:4][N:3]=1.[OH-].[Na+].Cl>CO.O>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[C:20]([N:12]([CH:11]([CH3:20])[CH3:8])[CH3:13])=[N:19][C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:26]([OH:28])=[O:27])[CH:17]=4)[N:12]=3)[CH:9]=2)[NH:4][N:3]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc4[nH]nc(C)c4c3)c(C(C)C(C)C)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1n[nH]c2ccc(-c3nc4ccc(C(=O)O)cc4nc3N(C)C(C)C)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 121.3 %

Procedure:
To a solution of methyl 2-(3-methyl-1H-indazol-5-yl)-3-(3-methylbutan-2-yl)quinoxaline-6-carboxylate (85 mg, 0.22 mmol) in methanol (20 mL) and water (1 mL) was added sodium hydroxide (18 mg, 0.45 mmol). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (20 mL), adjusted the pH value to 6 with 3N HCl and filtered to give 2-(3-methyl-1H-indazol-5-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid as a light yellow solid (50.1 mg, 61%).
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH2:10]([OH:24])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].CC(C)([O-])C.[K+].CC(N(C)C)=O>C(O)(C)(C)C>[CH2:10]([O:24][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: O=C(O)c1ccc(Br)o1
Reactant: CCCCCCCCCCCCCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CC(C)(C)O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)O)o1
Yield: 38.8 %

Procedure:
A mixture of 125.0 g (0.652 mole) of 5-bromo-2-furoic acid, 210.0 g (0.978 mole) of 1-tetradecanol, 183.0 g (1.630 mole) of potassium tert-butoxide and 2500 ml of dimethylacetamide is heated with stirring. The tert-butanol formed in the reaction is allowed to distill off, then the mixture is heated to reflux with stirring for 48 hours. To the cooled mixture is added 6 liters of ice water, and the mixture is acidified with malonic acid. The resulting precipitate is collected, dried and recrystallized twice from methanol to give 82.0 g (29%) of 5-tetradecyloxy-2-furoic acid, M.P. 112°-115° C. (dec.).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[C:9]([CH:13]=[O:14])[NH:10]2)=[CH:6][CH:5]=1.[CH3:15]I>CN(C=O)C>[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[C:9]([CH:13]=[O:14])[N:10]2[CH3:15])=[CH:6][CH:5]=1
Reactant: CI
Reactant: O=Cc1cc2ccc(Br)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(C=O)cc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 106.8 %

Procedure:
Sodium hydride (60% weight dispersion in mineral oil, 80.0 mg, 1.98 mmol) was added to a solution of 6-bromo-1H-indole-2-carbaldehyde (371 mg, 1.66 mmol) in DMF (10.0 mL) at 0° C. under N2. Methyl iodide (0.124 mL, 1.98 mmol) was added, and the reaction mixture was allowed to warm slowly to room temperature. After stirring for 4 h, the mixture was quenched with H2O at 0° C., upon which a solid precipitated out of solution. The slurry was extracted with ethyl ether (3×). The combined organic layers was dried over Na2SO4, filtered and concentrated to give the title compound (422 mg, 99%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.89 (s, 1H), 7.59 (d, J=9.0 Hz, 2H), 7.28 (dd, J=8.5, 2.0 Hz, 1H), 7.22 (s, 1H), 4.07 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:19])[NH:7][N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:10]=1)=[O:4].[C:20]1([CH2:26][CH2:27][CH2:28]Br)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:19])[N:7]([CH2:28][CH2:27][CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:10]=1)=[O:4]
Reactant: COC(=O)c1cc(-c2ccc(OC)cc2)n[nH]c1=O
Reactant: BrCCCc1ccccc1
Product: COC(=O)c1cc(-c2ccc(OC)cc2)nn(CCCc2ccccc2)c1=O
Yield: 94 %

Procedure:
Using 4-methoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and 3-phenylpropyl bromide as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 94.0%.
Reaction SMILES: [C:1]([N:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@H:9]([C:16]([OH:18])=[O:17])[CH2:10][C:11]1[N:15]=[CH:14][NH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>C(Cl)(Cl)Cl>[C:4]([O:17][C:16](=[O:18])[C@H:9]([CH2:10][C:11]1[N:15]=[CH:14][NH:13][CH:12]=1)[N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H](Cc1c[nH]cn1)C(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)[C@H](Cc1c[nH]cn1)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C

Procedure:
Nα,Nτ -bis-BOC-Histidine tert-Butyl Ester (23) was synthesized from Nα,Nτ -bis-BOC-histidine (13) according to the general procedure: yield, 77%; mp 98° C.; [α]25D +17.8° (c 1.3, CHCl3); IR 3880, 1750, 1710 cm-1 ; 1H NMR δ 7.98 (d, 1H, J=0.8), 7.13 (s, 1H), 5.59 (br d, 1H, J=8.4), 4.43 (dd, 1H, J=2.9, 5.1), 3.00 (d, 2H, J=5.2). Anal. Calcd for C20H34N3O6 : C, 58.2; H, 8.3,; N, 10.1. Found: C, 58.6; H, 8.2; N, 10.1.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[CH3:2].[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[S:25](Cl)(=[O:27])=[O:26].C(N(C(C)C)CC)(C)C>ClCCl>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([S:25]([C:16]2[CH:17]=[CH:18][C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:15]=2)(=[O:27])=[O:26])[CH2:13][CH2:14]1)[CH3:2]
Reactant: CCc1ccccc1N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1ccccc1N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Yield: 99 %

Procedure:
Sulfonylation of 1-(2-ethylphenyl)piperazine (293 mg, 1.54 mmol) with naphthalene-2-sulfonyl chloride (350 mg, 1.54 mmol) was carried out according to a similar procedure described for example 3A using anhydrous dichloromethane (5 mL) as solvent and diisopropylethylamine (0.670 mL, 3.85 mmol) as base. 1-(2-ethylphenyl)-4-(2-naphthylsulfonyl)piperazine was obtained in 99% yield (579 mg) as white solid.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH2:14])[CH3:13])[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:8]=2[C:21]=1[CH3:22].Cl[C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[N:26]=[CH:27][N:28]2C1CCCCO1.CCN(C(C)C)C(C)C>CC(O)C>[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH:14][C:24]3[N:32]=[CH:31][N:30]=[C:29]4[C:25]=3[N:26]=[CH:27][NH:28]4)[CH3:13])[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:8]=2[C:21]=1[CH3:22]
Reactant: Cc1c(F)ccc2nc([C@H](C)N)n(-c3ccccn3)c12
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1c(F)ccc2nc([C@H](C)Nc3ncnc4[nH]cnc34)n(-c3ccccn3)c12
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 51.5 %

Procedure:
To a solution of (S)-1-(6-fluoro-7-methyl-1-pyridin-2-yl-1H-benzoimidazol-2-yl)ethylamine dihydrochloride (300 mg, 0.87 mmol) in IPA (10 mL) was added 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (271 mg, 1.14 mmol) and DIPEA (448 μL, 2.62 mmol) and the reaction mixture heated at 90° C. for 16 h. The reaction mixture was concentrated in vacuo and the resultant residue subjected to flash chromatography (SiO2, eluting with 0-10% methanol in EtOAc). LCMS (Method C): RT=2.81 min, [M+H]+=473. The product was dissolved HCl in methanol (5 mL, 2.5M) and the reaction stirred at RT for 30 min. The reaction mixture was concentrated in vacuo and the resultant residue loaded onto an SCX 2 cartridge, washed with methanol then eluted with ammonia in methanol (2M). The eluent was concentrated in vacuo and the residue triturated with diethyl ether to give 288 as a white solid (174 mg, 51%) 1H NMR 400 MHz δ (DMSO-d6 80° C.): 8.55-8.49 (1H, m), 8.01 (1H, s), 7.89 (1H, td, J=7.7, 1.9 Hz), 7.65 (1H, d, J=7.6 Hz), 7.49 (1H, dd, J=8.7, 4.7 Hz), 7.46 (1H, ddd, J=7.6, 4.9, 0.9 Hz), 7.17 (1H, br s), 7.02 (1H, dd, J=10.6, 9.0 Hz), 5.57 (1H, br s), 1.66 (3H, s), 1.55 (3H, d, J=6.8 Hz). LCMS (Method K): RT=3.01 min, [M+H]+=389
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([CH:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[OH:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mn]([O-])(=O)(=O)=O.[K+]>O>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:17]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:14]([O:15][CH3:16])[CH:13]=2)=[O:18])[CH:20]=1
Reactant: COc1cc(C(O)c2cccnc2)ccc1OCc1ccccc1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: COc1cc(C(=O)c2cccnc2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
ba) 3.2 g of alpha-[4-(benzyloxy)-5-methoxyphenyl]-3-pyridinemethanol suspended in 50 ml of water are treated with 2.5 g of potassium permanganate, whereupon the mixture is stirred at 90° for 30 minutes After adding a further 1.0 g of potassium permanganate and stirring for a further 30 minutes at 90° the mixture is cooled to room temperature and extracted twice with 150 ml of ethyl acetate each time. The combined ethyl acetate phases are washed with sodium chloride solution, dried over sodium sulfate and evaporated. The thus-obtained residue is chromatographed on 50 g of silica gel with ethyl acetate. After recrystallization from methylene chloride/hexane there is obtained 4-(benzyloxy)-3-methoxyphenyl 3-pyridyl ketone of m.p. 76°.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.[CH2:7]([O:9][C:10](=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH2:19])[CH:13]=1)[CH3:8].C(N(CC)CC)C.Cl>C(Cl)Cl>[CH2:7]([O:9][C:10](=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH:19][S:2]([CH3:1])(=[O:4])=[O:3])[CH:13]=1)[CH3:8]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)Cc1cccc(CN)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1cccc(CNS(C)(=O)=O)c1
Reaction time: 1 h
Yield: 92.8 %

Procedure:
Methanesulfonyl chloride (2.6 mL, 34 mmol) was slowly added to a solution of (3-aminomethyl-phenyl)-acetic acid ethyl ester hydrochloride (7.31 g, 34 mmol) and triethylamine (9.8 mL, 70 mmol) in CH2Cl2 (100 mL) at 0° C. The mixture was stirred for 1 h and 1N aqueous HCl solution was added. The aqueous solution was extracted with CH2Cl2 (3×) and the combined organic extracts were washed with brine. The organic solution was dried over MgSO4, filtered, and concentrated. Purification by flash chromatography (1:1 hexanes:EtOAc) provided the title sulfonamide (8.56 g) as a clear and colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.34-7.21 (m, 4H), 4.70 (broad, 1H), 4.29 (d, 2H), 4.12 (q, 2H), 3.60 (s, 2H), 2.86 (s, 3H), 1.24 (t, 3H).
Reaction SMILES: [C:1]([C:4]1[C:5](=O)[CH2:6][C:7]([CH3:13])([CH3:12])[CH2:8][C:9]=1[O:10]C)(=[O:3])[CH3:2].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH2:23][CH2:24][C:25](=[O:28])[NH:26][N:27]=2)=[CH:18][CH:17]=1>C(O)C>[C:1]([C:4]1[C:9](=[O:10])[CH2:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH2:23][CH2:24][C:25](=[O:28])[NH:26][N:27]=2)=[CH:18][CH:17]=1)(=[O:3])[CH3:2]
Reactant: COC1=C(C(C)=O)C(=O)CC(C)(C)C1
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1
Solvent: CCO
Product: CC(=O)C1=C(Nc2ccc(C3=NNC(=O)CC3)cc2)CC(C)(C)CC1=O
Yield: 94.2 %

Procedure:
230 mg of 2-acetyl-5,5-dimethyl-3-methoxy-2-cyclohexene-1-one and 284 mg of 4,5-dihydro-6-(4-aminophenyl)-3(2H)-pyridazinone was suspended in 2 ml of ethanol, and the resulting mixture was heated to reflux for an hour. After cooled, crude crystal was collected by filtrating, and purified by silica gel column chromatography (eluting solvent: chloroform:methanol=30:1). 390 mg of the title compound was obtained. m.p. 212.0°-213.5° C.
Reaction SMILES: C(OC([N:8]1[C:13](=[O:14])[CH:12]2[CH:10]([CH:11]2[C:15]([O-:17])=[O:16])[CH:9]1[C:18]([O-:20])=[O:19])=O)(C)(C)C.Cl.[CH2:22]([O:29][NH2:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>C1COCC1.[C-]#N.[K+]>[C:15]([CH:11]1[CH:12]([C:13]([NH:30][O:29][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:14])[CH:10]1[CH:9]([C:18]([OH:20])=[O:19])[NH2:8])([OH:17])=[O:16]
Reactant: NOCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C(=O)C2C(C(=O)[O-])C2C1C(=O)[O-]
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NC(C(=O)O)C1C(C(=O)O)C1C(=O)NOCc1ccccc1
Reaction time: 8 h
Yield: 134.2 %

Procedure:
To a solution of ethyl (1SR, 2 SR, 5RS, 6RS) 3-tert -butoxycarbonyl-4-oxo-3-azabicyclo[3.1.0]hexane-2,6-dicarboxylate (150 mg, 0.44 mmol) in dry THF (3 mL) under argon was added O-benzylhydroxylamine hydrochloride (421.5 mg, 2.64 mmol), potassium cyanide (1.43 mg, 0.02 mmol) and triethylamine (0.36 mL, 2.64 mmol). After stirring overnight in an ultrasonic bath, the solvent was removed under reduced pressure. The residue was directly purified by flash chromatography (hexane/ethyl acetate 1.5/1) to give 182 mg of the desired compound (89% yield).