Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]([C:6]1[CH:7]=[C:8]([C:17]([NH2:19])=[O:18])[C:9]2[O:15][CH2:14][CH2:13][CH2:12][S:11][C:10]=2[CH:16]=1)[CH3:5])=[N+]=[N-].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[NH2:1][CH:4]([C:6]1[CH:7]=[C:8]([C:17]([NH2:19])=[O:18])[C:9]2[O:15][CH2:14][CH2:13][CH2:12][S:11][C:10]=2[CH:16]=1)[CH3:5]
Reactant: CC(N=[N+]=[N-])c1cc2c(c(C(N)=O)c1)OCCCS2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(N)c1cc2c(c(C(N)=O)c1)OCCCS2
Temperature: 50 °C
Yield: 54.3 %

Procedure:
To 2-(1-azido-ethyl)-7,8-dihydro-6H-5-oxa-9-thia-benzocycloheptene-4-carboxylic acid amide (0.20 g, 0.73 mmol) in THF (5 mL) was added water (0.10 mL) and triphenylphosphine (0.19 g, 0.73 mmol). The mixture was heated to 50° C. for 20 h, evaporated, and chomatographed over silica gel (10% MeOH/CHCl3) to give a colorless oil (0.10 g, 55%).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([O:30]CC)=O)[C:24]=2[CH:33]=1)([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.Cl.[CH3:44][NH:45][CH2:46][CH3:47]>>[Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:36][C@H:37]([CH3:42])[O:38][C@H:39]([CH3:41])[CH2:40]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([N:45]([CH2:46][CH3:47])[CH3:44])=[O:30])[C:24]=2[CH:33]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Reactant: CCNC
Agent: Cl
Product: CCN(C)C(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12

Procedure:
Starting materials: Ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and N-methylethanamine hydrochloride
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][NH:11][C:12]1[N:13]=[C:14]([C:21]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[C:15]2[S:20][CH:19]=[CH:18][C:16]=2[N:17]=1)=O)CCC.[ClH:28]>CO.O1CCOCC1>[ClH:28].[ClH:28].[NH2:8][CH2:9][CH2:10][NH:11][C:12]1[N:13]=[C:14]([C:21]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[C:15]2[S:20][CH:19]=[CH:18][C:16]=2[N:17]=1
Reactant: CCCCOC(=O)NCCNc1nc(C(=O)c2cccs2)c2sccc2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NCCNc1nc(C(=O)c2cccs2)c2sccc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
A solution of 2-(2-butoxycarbonylaminoethylamino)thieno[3,2-d]pyrimidin-4-yl 2-thienylmethanone (58 mg, 0.14 mmol) in MeOH (5 mL) was treated with 4-M HCl in dioxane (0.5 mL), stirred at room temperature for 16 h and the resulting solid filtered and washed with ether to give the title compound (41 mg, 77%) as a white crystalline solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7](Br)=[CH:8][N:9]=1)(=[O:3])[CH3:2].[NH2:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([SH:18])[N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][C:7]([S:18][C:14]2[N:13]=[C:12]([NH2:11])[CH:17]=[CH:16][N:15]=2)=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: Nc1ccnc(S)n1
Reactant: CC(=O)Nc1ncc(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ncc(Sc2nccc(N)n2)s1
Temperature: 90 °C
Yield: 48.9 %

Procedure:
A mixture of 2-acetylamino-5-bromothiazole (2.2 g), 4-amino-2-mercaptopyrimidine (1.3 g) and potassium carbonate (2.0 g) in N,N-dimethylformamide (50 ml) was heated at 90° C. for 2 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was triturated with water. The precipitation was collected by filtration, washed with water and dried in vacuo to give solid. The solid was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 200 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the objective compound were combined and concentrated under reduced pressure no give 2-acetylamino-5-(4-aminopyrimidin-2-ylthio)thiazole (1.3 g, yield: 48.7%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=S)[CH2:6][CH2:5]2.[C:13]([NH:16][NH2:17])(=O)[CH3:14].C1(O)CCCCC1>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:13]([CH3:14])=[N:16][N:17]=[C:7]1[CH2:6][CH2:5]2
Reactant: S=C1CCc2cc(Br)ccc2N1
Reactant: CC(=O)NN
Solvent: O
Solvent: OC1CCCCC1
Product: Cc1nnc2n1-c1ccc(Br)cc1CC2

Procedure:
A flask containing the title compound from Example 22 Step A (100 mg, 0.413 mmol), acetic hydrazide (40.8 mg, 0.496 mmol) and cyclohexanol (2.00 ml, 0.413 mmol) was heated at reflux for 2 days. The reaction was then poured into water and extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel (0-15% methanol in ethyl acetate) provided the title compound: LCMS m/z 265.99 [M+2+H]+; 1H NMR (500 MHz, CDCl3) δ 7.53 (br s, 1H), 7.50 (d, J=8.57 Hz, 1H), 7.35 (d, J=8.57 Hz, 1H), 3.13-3.11 (m, 2H), 3.00-2.98 (m, 2H), 2.74 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[N:7]=[CH:8][NH:9][C:10](=O)[C:5]=2[CH:4]=[N:3]1.P(Cl)(Cl)([Cl:14])=O>>[CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[N:9][C:10]([Cl:14])=[C:5]2[CH:4]=[N:3]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1ncc2c(=O)[nH]cnc21
Product: Cn1ncc2c(Cl)ncnc21
Reaction time: 12 h
Yield: 60.5 %

Procedure:
80 g. of 1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]- pyrimidin-4-one are added to 300 ml. of phosphorus oxychloride and the mixture is refluxed. After distilling off the excess phosphorus oxychloride, the semi-solid residue is extracted with 3 × 100 ml. of boiling benzene. The benzene extracts are combined and concentrated to half-volume, then added to petroleum ether. After standing 12 hours in the refrigerator, the precipitated 1-methyl-4-chloropyrazolo[3,4-d]- pyrimidine is filtered under suction and recrystallized from cyclohexane to obtain 54 g. of white crystals, m.p. 93°-96° (yield 60.5%).
Reaction SMILES: [NH3:1].[NH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]=[CH:5][CH:4]=[N:3]1.CCOCC>C(Cl)Cl.CCO.CC(O)=O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:2][N:3]=1
Reactant: N
Reactant: C1=Cc2ccccc2NN=C1
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCO
Product: NC1=NNc2ccccc2C=C1
Temperature: -78 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
Ammonia (500 mL) was condensed with a dry ice condenser and maintained at −78° C. To this was added a solution of 6 (35 g, 91 mmol) in CH2Cl2 (600 mL). After 8 h, the dry ice condenser was removed and the reaction was warmed to room temperature allowing the ammonia to evaporate. The remaining solution was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to yield a white solid. This solid was dissolved in EtOH (500 mL) and AcOH (15 mL), and the resulting solution was refluxed for 24 h, and concentrated to yield a yellow-red oil. Addition of Et2O (300 mL) to this oil resulted in the precipitation of 8 (13 g, 47%) as a white powder: 1H NMR (300 MHz, CDCl3) δ 9.32 (s, 1H), 7.83-7.05 (m, 8H), 4.39 (s, 2H); ESI MS m/z=305 [C15H11F3N2O+H]+.
Reaction SMILES: C(O)(=O)C.[CH2:5]([O:7][C:8]1[N:13]=[C:12]([CH:14]=O)[CH:11]=[CH:10][CH:9]=1)[CH3:6].[CH2:16]([O:18][C:19]([C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[NH2:26])=[O:20])[CH3:17].[BH3-]C#N.[Na+]>C(O)C>[CH2:16]([O:18][C:19]([C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[NH:26][CH2:14][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([O:7][CH2:5][CH3:6])[N:13]=1)=[O:20])[CH3:17]
Reactant: CCOc1cccc(C=O)n1
Reactant: CCOC(=O)c1[nH]ccc1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1[nH]ccc1NCc1cccc(OCC)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 45.5 %

Procedure:
Acetic acid (0.3 mL) was added to 6-ethoxy-pyridine-2-carbaldehyde (0.59 g, 3.9 mmol) and 3-amino-1H-pyrrole-2-carboxylic acid ethyl ester (0.30 g, 1.9 mmol) in ethanol (10 mL). After 1.5 h, NaCNBH3 (0.24 g, 3.9 mmol) was added, and the resulting mixture was stirred at ambient temperature for 19 h. The solvent was removed in vacuo, ethyl acetate was added to the residue, and insoluble material was removed by filtration. The filtrate was concentrated and the crude product was purified by flash column chromatography (heptane/ethyl acetate gradient; 0 to 35% ethyl acetate), obtaining 0.25 g (45%) of the title product as a solid.
Reaction SMILES: [S].[BH4-].[Na+].[CH2:4]([O:7][C:8]1[CH:9]=[C:10]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH:11]=[C:12]([F:17])[C:13]=1[N+:14]([O-])=O)[CH:5]=[CH2:6]>O1CCCC1>[CH2:4]([O:7][C:8]1[CH:9]=[C:10]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH:11]=[C:12]([F:17])[C:13]=1[NH2:14])[CH:5]=[CH2:6]
Reactant: C=CCOc1cc(N2CCOCC2)cc(F)c1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Agent: [S]
Solvent: C1CCOC1
Product: C=CCOc1cc(N2CCOCC2)cc(F)c1N
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 64.3 %

Procedure:
Sulfur (0.320 g, 9.98 mmol) was added to Sodium tetrahydroborate (0.126 g, 3.33 mmol) in Tetrahydrofuran (8 mL). After 5 min, a solution of 4-(3-Allyloxy-5-fluoro-4-nitro-phenyl)-morpholine (0.188 g, 0.666 mmol) in Tetrahydrofuran (6 mL) was added and the mixture was heated at 60° C. overnight. The mixture was cooled and diluted with 25 mL satd. sodium bicarbonate, then extracted 2×25 mL EtOAc. The organic extract was washed with water (10 mL) and brine (25 mL), then dried over sodium sulfate, and was concentrated in vacuo. The residue was partitioned between EtOAc (20 mL) and 1N HCl (20 mL); the resulting precipitate was filtered off. The filtrate was separated, the aq. washed 2×25 mL EtOAc, then neutralized with satd. sodium bicarbonate solution before being extracted with DCM (2×20 mL). The organic extract was dried over sodium sulfate and conc. in vacuo to afford 2-Allyloxy-6-fluoro-4-morpholin-4-yl-phenylamine (108 mg, 64%). LCMS: 253 (M+H); 1H-NMR (CDCl3): 6.30 (m, 2H), 6.06 (m, 1H), 5.42 (d, 1H, J=17 Hz), 5.29 (d, 1H, J=10.5 Hz), 4.55 (m, 2H), 3.80 (m, 4H), 3.49 (s, 2H), 3.00 (m, 4H); 19F-NMR (CDCl3): −133.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:12]1([NH2:17])[CH2:16][CH2:15][CH2:14][CH2:13]1>C(O)(C)(C)C>[NH2:17][C:12]1([C:2]2[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Reactant: NC1CCCC1
Solvent: CC(C)(C)O
Product: NC1(c2nc(Cl)ccc2C(=O)O)CCCC1
Temperature: 100 °C
Yield: 29.5 %

Procedure:
15 g of 2,6-dichloronicotinic acid (70.31 mmol, Aldrich) and 34.7 ml of cyclopentylamine (351.56 mmol) are placed in a sealed tube containing 40 ml of tert-butanol. The mixture is heated at 100° C. overnight and evaporated to dryness. The residue is taken up in water and the product is acidified by pouring in an aqueous solution of acetic acid at 10%, and the mixture is then extracted with choloroform. The organic phases are combined, dried over sodium sulphate, filtered, and concentrated under vacuum. The solid residue is triturated in an ether/pentane mixture so as to give 5 g of expected product in the form of an off-white solid (yield=29.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[C:20]3[C:11](=[C:12]4[C:17](=[CH:18][CH:19]=3)[NH:16][C:15]([CH3:22])([CH3:21])[CH:14]=[C:13]4[CH3:23])[CH:10]([OH:24])[O:9][C:5]=2[CH:6]=[CH:7][CH:8]=1.[CH2:25]([Si](C)(C)C)[CH:26]=[CH2:27]>C(Cl)Cl>[CH2:27]([O:24][CH:10]1[C:11]2=[C:12]3[C:17](=[CH:18][CH:19]=[C:20]2[C:4]2[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=2[O:9]1)[NH:16][C:15]([CH3:21])([CH3:22])[CH:14]=[C:13]3[CH3:23])[CH:26]=[CH2:25]
Reactant: COc1cccc2c1-c1ccc3c(c1C(O)O2)C(C)=CC(C)(C)N3
Reactant: C=CC[Si](C)(C)C
Solvent: ClCCl
Product: C=CCOC1Oc2cccc(OC)c2-c2ccc3c(c21)C(C)=CC(C)(C)N3
Temperature: 0 °C
Yield: 90.9 %

Procedure:
A three-necked round bottom flask was charged with the product from Example 6 (59.0 g, 0.182 mol) followed by CH2Cl2 (1.18 L). The resulting suspension was stirred briefly before adding allyltrimethylsilane (58 ml, 0.364 mol) all at once at room temperature. The suspension was cooled to 0° C. under nitrogen and was treated with BF3OEt2 (46.3 ml, 0.364 mol) dropwise keeping the reaction temperature below 2° C. After complete addition, the mixture was stirred at 0° C. for ˜1 hour. The completion of the reaction was monitored with HPLC until the starting material was consumed. The reaction mixture was poured into saturated NaHCO3 solution and stirred for 30 minutes. The organic layer was separated, washed with brine, dried over Na2SO4, treated with charcoal, filtered and concentrated to an oil. EtOH (200 ml) was added and the solution was concentrated to give a crystalline solid which was suspended with heptane at 0° C. for 2 hours before filtration to give a solid which was dried under reduced pressure at 45° C. to provide the title compound as a light yellow crystalline solid (60.1 g, 95.1%). Anal. Calcd for C23H25NO2: C, 79.51; H, 7.25; N, 4.03; Found: C, 79.26; H, 7.12; N, 3.80, 1H NMR [(CD3)2SO] δ 1.16 (3H, s) 1.17 (3H, s), 2.18 (3H, s), 2.22 (1H, m), 2.46 (1H, m), 3.85 (3H, s), 5.01 (2H, m), 5.44 (1H, br s), 5.77 (1H, dd), 5.82 (1H, m), 6.10 (1H, br s), 6.52 (1H, d), 6.60 (1H, d), 6.70 (1H, d), 7.06 (1H, d), 7.06 (1H, t), 7.96 (1H, d); 13CNMR [(CD3)2SO] δ 23.8, 28.8, 28.9, 36.5, 49.7, 55.6, 73.4, 105.6, 110.5, 113.4, 113.4, 116.1, 116.4, 127.3, 117.3, 127.3, 127.7, 132.2, 133.8, 134.5, 145.8, 151.1, 156.4. MS (APCI) m/z: 348 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C@H:5]([C:13]([O:15]C)=[O:14])[CH2:4][CH2:3]1.[OH-].[Na+].Cl>CO>[O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C@H:5]([C:13]([OH:15])=[O:14])[CH2:4][CH2:3]1
Reactant: COC(=O)[C@@H]1CCC(=O)N1c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)[C@@H]1CCC(=O)N1c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
To a stirred solution of methyl 5-oxo-1-phenylprolinate (3.50 g, 15.96 mmol) in methanol (200 mL) was added 1 M NaOH solution (40 mL). After being stirred at room temperature for 2 h, the reaction mixture was acidified with 1 M HCl solution and the mixture was concentrated under reduced pressure. The resulting residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting light yellow solid was triturated with hexane to give the title compound (2.47 g, 75%) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:17]3[CH:21]=[CH:20][N:19]=[C:18]3[CH3:22])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][OH:16])=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:17]3[CH:21]=[CH:20][N:19]=[C:18]3[CH3:22])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][O:16][C:27]2[CH:28]=[CH:29][C:24]([CH3:23])=[CH:25][CH:26]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(O)cc1
Reactant: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCO)o1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1ccc(OCCCc2oc(-n3ccnc3C)nc2-c2ccc(Cl)cc2)cc1
Reaction time: 1 h

Procedure:
To a mixture of 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropanol (635 mg), 4-methylphenol (432 mg), tributylphosphine (607 mg) and tetrahydrofuran (5 ml) was added 1,1′-(azodicarbonyl)dipiperidine (757 mg) at room temperature, and the resulting mixture was stirred for 1 hour. After the reaction mixture was concentrated, the residue was subjected to silica gel column chromatography, and 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(4-methylphenoxy)propyl]oxazole was obtained as an oil (475 mg, 58%) from an ethyl acetate-hexane (1:1, v/v)-eluted fraction.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CO.CS(O[C@H:14]1[CH2:19][CH2:18][C@H:17]([CH3:20])[CH2:16][CH2:15]1)(=O)=O>O>[CH3:20][C@@H:17]1[CH2:18][CH2:19][C@H:14]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH2:15][CH2:16]1
Reactant: C1CNCCN1
Reactant: CS(=O)(=O)O[C@H]1CC[C@H](C)CC1
Solvent: O
Solvent: CO
Product: C[C@H]1CC[C@@H](N2CCNCC2)CC1
Reaction time: 0.25 h
Yield: 56.8 %

Procedure:
Piperazine (54.9 g) and methanol (5 ml) was stirred at 120° C. to melt for 15 minutes. To the solution was dropwise added trans-4-methylcyclohexyl methanesulfonate (33.0 g) and the mixture was stirred at the same temperature for 2 hours. After cooling, to the reaction mixture was added water (150 ml) and extracted three times with a mixture of ethyl acetate (100 ml) and THF (100 ml). The extracts were collected, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (600 ml) eluting with a mixture of dichloromethane, methanol and conc. ammonium hydroxide (4:1:0.1 v/v). The fractions containing the desired compound were collected and evaporated under reduced pressure to give cis-1-(4-methylcyclohexyl)piperazine (17.76 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>CC#N>[C:14]([O:13][C:11]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:20][CH2:19]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 140 °C
Yield: 94.8 %

Procedure:
5-Nitro-2-chloropyridine (21) (350 mg, 2.21 mmol) and 1-Boc-piperazine (430 mg, 2.31 mmol) were dissolved in MeCN (3.6 mL). TEA (400 μL, 2.87 mmol) was added and the mixture heated at 140° C. in the microwave (250 W, stirring) for 30 minutes. The solvent was evaporated in vacuo and the residue dissolved in DCM (75 mL). The solution was washed with 0.5N HCl (2×20 mL) and the organic phase washed with saturated brine solution (40 mL), then dried (MgSO4), filtered and the solvent evaporated in vacuo to afford the title compound as a yellow solid (646 mg, 95%); LCMS, Rt=2.97 min (MeOH-FA method), m/z 309 (MH+).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][C:8]1[C:9](=[O:15])[NH:10][N:11]=[C:12]([CH3:14])[CH:13]=1.[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([CH:25](Br)[C:26]([NH:28][S:29]([C:32]3[CH:37]=[CH:36][C:35]([CH:38]([CH3:40])[CH3:39])=[CH:34][CH:33]=3)(=[O:31])=[O:30])=[O:27])=[CH:24][C:19]=2[O:18][CH2:17]1>CN(C=O)C>[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([CH:25]([N:10]3[C:9](=[O:15])[C:8]([CH3:7])=[CH:13][C:12]([CH3:14])=[N:11]3)[C:26]([NH:28][S:29]([C:32]3[CH:37]=[CH:36][C:35]([CH:38]([CH3:40])[CH3:39])=[CH:34][CH:33]=3)(=[O:30])=[O:31])=[O:27])=[CH:24][C:19]=2[O:18][CH2:17]1
Reactant: CC(C)c1ccc(S(=O)(=O)NC(=O)C(Br)c2ccc3c(c2)OCO3)cc1
Reactant: Cc1cc(C)c(=O)[nH]n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c(=O)n(C(C(=O)NS(=O)(=O)c2ccc(C(C)C)cc2)c2ccc3c(c2)OCO3)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.3 g of caesium carbonate are added to a solution of 1.55 g of 2,3-dihydro-4,6-dimethylpyridazin-3-one (prepared according to F. H. McMillan et al., J. Am.Chem. Soc. 78, 407 (1956)) and 4.52 g of 2-(1,3-benzodioxol-5-yl)-2-bromo-N-(4-isopropylphenylsulfonyl)acetamide in 100 ml of DMF. The mixture is stirred at room temperature for 2 hours and worked up in the customary manner and 2-(1,3-benzodioxol-5-yl)-2-(2,3-dihydro-4,6-dimethylpyridazin-3-on-2-yl)N-(4-isopropylphenylsulfonyl)acetamide is obtained, m.p. 105°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8](Br)[C:7]([NH2:11])=[C:6]([F:12])[C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21].[C:23](N)(C)([CH3:25])[CH3:24]>C(O)(C)C.O.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([C:23]([CH3:25])=[CH2:24])[C:7]([NH2:11])=[C:6]([F:12])[C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21]
Reactant: COC(=O)c1cc(Br)c(N)c(F)c1Nc1ccc(Cl)cc1Cl
Reactant: CC(C)(C)N
Solvent: CC(C)O
Solvent: O
Solvent: CCOC(C)=O
Product: C=C(C)c1cc(C(=O)OC)c(Nc2ccc(Cl)cc2Cl)c(F)c1N
Yield: 49.5 %

Procedure:
A mixture of 4-amino-5-bromo-2-(2,4-dichlorophenylamino)-3-fluorobenzoic acid methyl ester (502 mg, 1.23 mmol), potassium isopropenyl trifluoroborate (218 mg, 1.47 mmol, Org. Lett. 2002, 4, 107), PdCl2(dppf)CH2Cl2 (101 mg, 0.122 mmol), and t-BuNH2 (0.39 mL, 3.67 mmol) in i-PrOH-H2O (2:1, 12 mL) was refluxed for 16 hours. The reaction mixture was diluted with EtOAc, washed with water, dried over MgSO4, filtered, and concentrated in vacuo to give the crude material which was purified by silica gel flash column chromatography (20% CH2Cl2 in hexanes) to give the desired product (225 mg, 49%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7](=[O:24])[CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3[CH:18]=[CH:19][N:20]=[C:21]([CH:22]=O)[C:10]2=3)[CH2:3][CH2:2]1.[N:25]1[C:34]2[C@@H:33]([NH2:35])[CH2:32][CH2:31][CH2:30][C:29]=2[CH:28]=[CH:27][CH:26]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[O:1]1[CH2:6][CH2:5][N:4]([C:7](=[O:24])[CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3[CH:18]=[CH:19][N:20]=[C:21]([CH2:22][NH:35][C@@H:33]4[C:34]5[N:25]=[CH:26][CH:27]=[CH:28][C:29]=5[CH2:30][CH2:31][CH2:32]4)[C:10]2=3)[CH2:3][CH2:2]1
Reactant: O=Cc1nccc2c3ccccc3n(CC(=O)N3CCOCC3)c12
Reactant: N[C@H]1CCCc2cccnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(Cn1c2ccccc2c2ccnc(CN[C@H]3CCCc4cccnc43)c21)N1CCOCC1
Yield: 85 %

Procedure:
1.5 mmol of 9-(2-morpholino-2-oxoethyl)-9H-pyrido[3,4-b]indole-1-carbaldehyde, 1.5 mmol of (S)-5,6,7,8-tetrahydroquinolin-8-amine, and 3.00 mmol of sodium triacetoxyborohydride in 20 ml dichloromethane were stirred for 2 hours at room temperature, then reaction was quenched with saturated sodium bicarbonate solution. Organic layer was dried over magnesium sulfate, filtered off, and evaporated. Desired product was purified with column chromatography using dichloromethane:methanol:NH4OH (9:1:0.1) solvent system (85% yield). ESI+ MS: m/z (rel intensity) 456.2 (100, [M+H]+). 1H-NMR (400 MHz, CDCl3): δ 8.38 (d, 1H, J=4.8 Hz), 8.36 (d, 1H, J=1.6 Hz), 8.12 (d, 1H, J=7.6 Hz), 7.92 (d, 1H, J=5.6 Hz), 7.55 (dt, 1H, J=1.2, 8.0 Hz), 7.37 (d, 1H, J=7.6 Hz), 7.29 (q, 2H, J=4.8 Hz), 7.07 (q, 1H, 4.8 Hz), 6.11 (d, 1H, J=18.0 Hz), 5.74 (d, 1H, J=17.6 Hz), 4.46 (d, 1H, J=12.0 Hz), 4.33 (d, 1H, J=12.0 Hz), 4.00 (t, 1H, J=5.6 Hz), 3.82-3.76 (m, 1H), 3.73-3.60 (m, 6H), 3.55-3.50 (m, 1H), 2.78 (t, 2H, J=6.4 Hz), 2.18-2.08 (m, 1H), 1.96-1.66 (m, 4H).
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.[CH:14]([C@H:17]([CH2:22][CH:23]=[O:24])[C:18]([O:20]C)=O)([CH3:16])[CH3:15]>>[CH:14]([C@@H:17]1[CH2:22][CH:23]([CH2:4][N+:1]([O-:3])=[O:2])[O:24][C:18]1=[O:20])([CH3:15])[CH3:16]
Reactant: C[N+](=O)[O-]
Reactant: COC(=O)[C@@H](CC=O)C(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@@H]1CC(C[N+](=O)[O-])OC1=O
Reaction time: 3 h

Procedure:
363 mg (1.0 mmol, 1.03 eq) zinctriflate, 1 ml (18.5 mmol, 19 eq) nitromethane and 174 μl (1.0 mmol, 1.03 eq) diisopropylethylamine were placed in a dry schlenk vessel under Nitrogen. The yellow slurry was cooled in ice and 153.3 mg (0.97 mmol) (S)-methyl 2-isopropyl-4-oxobutanoate was added. The reaction mixture was stirred for 3 h, after which it was quenched with 2 ml 1 N ammonium chloride solution. After separation the water phase was extracted 3 times with 4 ml dichloromethane and the combined organic phases were washed with 4 ml brine and dried with Na2SO4, yielding 365 mg crude material after film evaporation, which contained still diisopropylethylamine according to NMR. The material was dissolved in 5 ml dichloromethane, washed 3 times with 1 ml 1 N HCl, dried with sodiumsulphate yielding 161 mg after removal of the solvent. Column separation (30/70 v/v ethylacetate/heptane) gave the pure target compound (3S)-3-isopropyl-5-(nitromethyl)dihydrofuran-2(3H)-one.