Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC)(C)(C)C.C(Br)(Br)(Br)[Br:41]>CCCCCC>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][Br:41])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCCCOCc1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: COC(C)(C)C
Product: BrCCCCCOCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 59.4 %

Procedure:
7.0 g of 5-hydroxypentyl benzyl ether and 10.6 g of triphenylphosphine were added to 50 ml of methyl tert-butyl ether and then cooled to 0° C. Further, 13.2 g of carbon tetrabromide was added and the mixture was stirred at room temperature for 3 hours. Thereafter, 100 ml of hexane was added and the mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 5.5 g of 5-bromopentyl benzyl ether.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O>[C:10]1([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=2)[CH:7]=[O:8])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1cncc(Br)c1
Reactant: OB(O)c1ccccc1
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: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1cncc(-c2ccccc2)c1
Temperature: 25 °C

Procedure:
A mixture of commercially available 5-bromonicotinaldehyde (5.070 g; 26.43 mmol), phenylboronic acid (4.934 g; 39.65 mmol), and Pd(PPh3)4 (1.527 g; 1.32 mmol) in toluene (65 ml) and aq. 2 M Na2CO3 (59 ml) was heated to reflux, under nitrogen, for 2.5 h. After cooling to rt, water and AcOEt were added. The separated aq. layer was further extracted with AcOEt. The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (heptane/AcOEt=1/1) afforded 5-phenylnicotinaldehyde as a yellow oil. LC-MS (conditions A): tR=0.61 min.; [M+H]+: 184.48 g/mol.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]3[C:15]([C:16]4[N:17]=[N:18][N:19]([CH:21]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH3:22])[CH:20]=4)=[CH:14][N:13](C(OC(C)(C)C)=O)[C:10]3=[N:11][CH:12]=2)[CH:4]=[N:3]1.C(=O)([O-])[O-].[K+].[K+].O>CO>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]3[C:15]([C:16]4[N:17]=[N:18][N:19]([CH:21]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH3:22])[CH:20]=4)=[CH:14][NH:13][C:10]3=[N:11][CH:12]=2)[CH:4]=[N:3]1
Reactant: CC(c1ccccc1)n1cc(-c2cn(C(=O)OC(C)(C)C)c3ncc(-c4cnn(C)c4)cc23)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(c1ccccc1)n1cc(-c2c[nH]c3ncc(-c4cnn(C)c4)cc23)nn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 5-(1-methyl-1H-pyrazol-4-yl)-3-[1-(1-phenylethyl)-1H-1,2,3-triazol-4-yl]pyrrolo[2,3-b]pyridine-1-carboxylate (90 mg, 0.176 mmol) is dissolved in MeOH (5 ml), potassium carbonate (85 mg, 0.615 mmol) is added, and the mixture is stirred at RT for 1 h. Water is added, and the mixture is extracted three times with ethyl acetate. The organic phase is washed with saturated NaCl solution, dried over Na2SO4 and evaporated to dryness. The residue is triturated with ether and filtered off with suction, washed with ether and dried in a high vacuum, giving 5-(1-methyl-1H-pyrazol-4-yl)-3-[1-(1-phenylethyl)-1H-1,2,3-triazol-4-yl]-1H-pyrrolo[2,3-b]pyridine as colourless solid; HPLC/MS: Rt=1.874 min, [M+H]+ 370;
Reaction SMILES: C1COCC1.[CH2:6]([NH:13][C@H:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][C@H:15]1[O:27][CH3:28])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)(O)[O-].[Na+].Cl[C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36]>O>[CH2:6]([N:13]([C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])[C@H:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:16][C@H:15]1[O:27][CH3:28])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N(Cc1ccccc1)C(=O)OCc1ccccc1
Yield: 46.8 %

Procedure:
THF (16 mL) and water (4 mL) were added to tert-butyl cis(±)-4-benzylamino-3-methoxypiperidine-1-carboxylate obtained in Example (259a) (1.00 g, 3.1 mmol). While the mixture was stirred, saturated aqueous sodium bicarbonate solution (4 mL) and benzyl chloroformate (0.96 g, 5.6 mmol) were added at room temperature, followed by stirring overnight. The reaction solution was diluted with water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/9, 1/1) to obtain 0.66 g of the title compound as a colorless oily substance (58%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:45]=[CH:44][C:12]([C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][C:24]([C:26]([OH:28])=O)=[CH:25][C:19]=3[N:18]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH:37]4[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]4)=[CH:32][CH:31]=3)[C:17](=[O:43])[CH2:16]2)=[O:14])=[CH:11][CH:10]=1.Cl.[CH3:47][NH:48][CH3:49].C(N(CC)CC)C>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:47][N:48]([CH3:49])[C:26]([C:24]1[CH:23]=[CH:22][C:20]2[CH2:21][N:15]([C:13](=[O:14])[C:12]3[CH:44]=[CH:45][C:9]([Cl:8])=[CH:10][CH:11]=3)[CH2:16][C:17](=[O:43])[N:18]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH:37]4[CH2:38][CH2:39][NH:40][CH2:41][CH2:42]4)=[CH:32][CH:31]=3)[C:19]=2[CH:25]=1)=[O:28]
Reactant: CNC
Reactant: O=C(O)c1ccc2c(c1)N(Cc1ccc(OC3CCNCC3)cc1)C(=O)CN(C(=O)c1ccc(Cl)cc1)C2
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1ccc2c(c1)N(Cc1ccc(OC3CCNCC3)cc1)C(=O)CN(C(=O)c1ccc(Cl)cc1)C2
Reaction time: 8 h

Procedure:
5 mg (0.008 mmol) of 4-(4-chlorobenzoyl)-2-oxo-1-[4-(4-piperidyloxy)benzyl]-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-8-carboxylic acid trifluoroacetate was dissolved in 5 ml of dichloromethane. 2 mg (0.018 mmol) of dimethylamine hydrochloride, 3 mg (0.018 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 0.005 ml (0.036 mmol) of triethylamine were added to the obtained solution, and they were stirred overnight. The solvent was evaporated, and the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[C:13]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=4)=[N:14][CH:15]=[CH:16][CH:17]=3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:26][NH2:27]>C1COCC1.CC(O)C>[Cl:25][C:20]1[CH:19]=[C:18]([C:13]2[C:12]([C:9]3[CH:10]=[C:11]4[C:6](=[CH:7][CH:8]=3)[N:5]=[CH:4][N:3]=[C:2]4[NH:27][CH3:26])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:23]=[CH:22][C:21]=1[F:24]
Reactant: CN
Reactant: Fc1ccc(-c2ncccc2-c2ccc3ncnc(Cl)c3c2)cc1Cl
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CNc1ncnc2ccc(-c3cccnc3-c3ccc(F)c(Cl)c3)cc12

Procedure:
4-Chloro-6-(2-(3-chloro-4-fluorophenyl)pyridin-3-yl)quinazoline (75 mg), 2M MeNH2 in THF (2 mL) and i-PrOH (3 mL) were heated and stirred in a screw capped vial for 12 h at 65° C. The heterogeneous reaction mixture was cooled and filtered. The solid on the funnel was washed with water and dried to obtain 6-(2-(3-chloro-4-fluorophenyl)pyridin-3-yl)-N-methylquinazolin-4-amine (53 mg) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 8.72 (dd, J=4.7, 1.7 Hz, 1H), 8.47 (s, 1H), 8.31 (q, J=4.7 Hz, 1H), 8.25 (d, J=1.9 Hz, 1H), 7.95 (dd, J=7.8, 1.7 Hz, 1H), 7.61-7.50 (m, 3H), 7.36 (dd, J=8.6, 1.9 Hz, 1H), 7.24 (t, J=8.9 Hz, 1H), 7.13 (ddd, J=8.6, 4.8, 2.2 Hz, 1H), 2.98 (d, J=4.4 Hz, 3H). 19F NMR (282 MHz, DMSO-d6): δ −117.17 (td, J=8.6, 5.1 Hz). LCMS: rt 4.68 min (A), purity 99%, MS (m/e) 365 MH+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=3)[C:10]([C:18]([N:20]([CH3:22])[CH3:21])=[O:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1.N1CCCCC1.[S:29]1[CH:33]=[CH:32][N:31]=[C:30]1[C:34]([OH:38])([C:36]#[CH:37])[CH3:35]>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.[Cu]I.C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:37]#[C:36][C:34]([OH:38])([C:30]4[S:29][CH:33]=[CH:32][N:31]=4)[CH3:35])[CH:15]=3)[C:10]([C:18]([N:20]([CH3:22])[CH3:21])=[O:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: CN(C)C(=O)c1nn(-c2ccnc(N)n2)c2cc(Br)ccc12
Reactant: C#CC(C)(O)c1nccs1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CN(C)C(=O)c1nn(-c2ccnc(N)n2)c2cc(C#CC(C)(O)c3nccs3)ccc12
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
To a sealed tube was added 1-(2-aminopyrimidin-4-yl)-6-bromo-N,N-dimethylindazole-3-carboxamide (55%, 113 mg, 0.172 mmol), followed by piperidine (2 mL), tetrakis(triphenylphosphine)palladium (40 mg, 0.034 mmol), copper(I) iodide (7 mg, 0.034 mmol) and 2-(1,3-thiazol-2-yl)but-3-yn-2-ol (105 mg, 0.688 mmol). The reaction mixture was purged with nitrogen gas, capped and stirred at 60° C. for 1.5 hr. Reaction mixture was concentrated in vacuo. EtOAc (5 mL) added. Concentration in vacuo was repeated. The residue was purified using column chromatography (Biotage, 100% DCM to 10% MeOH/DCM) to give a brown solid. Trituration of the solid with DCM gave the title compound: 1H NMR (500 MHz, DMSO) delta 1.95 (3H, s), 3.12 (3H, s), 3.33 (3H, s), 7.12 (2H, s), 7.13-7.19 (2H, m), 7.42 (1H, dd, J=8.35, 1.42 Hz), 7.71 (1H, d, J=3.31 Hz), 7.80 (1H, d, J=3.15 Hz), 7.97-8.07 (1H, m), 8.35 (1 H, d, J=5.52 Hz), 8.94 (1H, s); LC-MS: m/z=+434.45 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([CH3:24])[CH:15]=3)[CH:11]=[C:10]([C:25]([F:28])([F:27])[F:26])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:29][C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][N:31]=1>>[CH3:24][C:16]1[CH:15]=[C:14]([C:12]2[CH:11]=[C:10]([C:25]([F:28])([F:27])[F:26])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:33]4[CH:34]=[CH:35][C:30]([NH2:29])=[N:31][CH:32]=4)[CH:7]=[CH:6][CH:5]=3)[N:13]=2)[CH:19]=[CH:18][C:17]=1[C:20]([F:23])([F:22])[F:21]
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)ccc1C(F)(F)F
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-c3cccc(-c4ccc(N)nc4)c3)n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-(3-methyl-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine (example E.49) (0.23 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.174 g, 73%). MS (ISP) 475.1 [(M+H)+]; mp 207° C.
Reaction SMILES: N[C:2]([CH3:6])=[CH:3][C:4]#[N:5].[C:7]([NH:11][NH2:12])([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C>C(O)C>[C:7]([N:11]1[C:4]([NH2:5])=[CH:3][C:2]([CH3:6])=[N:12]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)NN
Reactant: CC(N)=CC#N
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(N)n(C(C)(C)C)n1

Procedure:
To a mixture of 3-aminobut-2-enenitrile (60 g, 731 mmol) and tert-butylhydrazine (96 g, 731.1 mmol) in ethanol (35 ml), triethylamine (220 ml, 2195 mmol) was added. The mixture was refluxed for 12-16 h. The reaction mixture was then concentrated under reduced pressure. The concentrate was extracted with water (100 ml) and ethylacetate (700 ml). The organic layer was washed with brine and dried over Na2SO4 and concentrated under reduced pressure to obtain the title product.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=[C:4]([OH:18])[CH:3]=1.[C:19]([Cu])#[N:20]>CN(C=O)C.C(OCC)(=O)C>[OH:18][C:4]1[CH:3]=[C:2]([C:19]#[N:20])[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=1
Reactant: N#C[Cu]
Reactant: Oc1ccc(-c2nc3cc(O)cc(Br)c3o2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cc(O)cc2nc(-c3ccc(O)cc3)oc12
Temperature: 150 °C
Yield: 25.3 %

Procedure:
To 7-bromo-2-(4-hydroxy-phenyl)-benzooxazol-5-ol (96 mg) in DMF (3 mL) was added CuCN (84 mg). The mixture was placed in an oil bath and heated to 150° C. for 3 h. The mixture was cooled to room temperature and diluted with ethyl acetate and washed with 1N HCl, saturated aqueous EDTA, brine (3×), dried (Na2SO4), and concentrated. Flash chromatography on silica gel eluting with 20% ethyl acetate-hexane afforded 20 mg (25%) of the title compound as a solid. MS: 253 (MH+), HPLC tR: 2.06 min.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:6](=[O:16])[N:7]2[C:12]=1[C:11]1[S:13][CH:14]=[CH:15][C:10]=1[CH2:9][CH2:8]2.Cl[C:24](OC1C=CC=CC=1)=[O:25].N1C=CC=CC=1.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>O1CCOCC1.C(Cl)(Cl)Cl>[N:39]1([C:24]([O:1][CH2:2][C:3]2[CH:4]=[C:5]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6](=[O:16])[N:7]3[C:12]=2[C:11]2[S:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8]3)=[O:25])[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1
Reactant: C1COCCN1
Reactant: O=c1c(-c2ccccc2)cc(CO)c2n1CCc1ccsc1-2
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1COCCO1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C(OCc1cc(-c2ccccc2)c(=O)n2c1-c1sccc1CC2)N1CCOCC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A suspension of 0.59 g of 4,5-dihydro-10-(hydroxy-methyl)-8-phenyl-7H-thieno[2,3-a]quinolizine-7-one in 15 ml of dioxane was treated with 0.38 ml of phenyl chloroformate and 0.27 ml of pyridine and stirred at room temperature for 2.5 hours. Then. 3 ml of morpholine were added and the mixture was stirred further until the reaction was completed. The mixture was diluted with chloroform, washed with 1N hydrochloric acid, 10 percent potassium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. By crystallization from ethanol, there was obtained pure (4,5-dihydro-7-oxo-8-phenyl-7H-thieno[2,3-a]quinolizin-10-yl)methyl 4-morpholine carboxylate of m.p. 163°-164°.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[CH2:8][CH2:7]2)[N:5]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:4][NH:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].O1CCCC1.Br[CH2:44][C:45]1[CH:46]=[C:47]([CH:55]=[CH:56][CH:57]=1)[C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49]>CN(C)C=O.C(OCC)(=O)C>[C:51]([O:50][C:48]([C:47]1[CH:46]=[C:45]([CH:57]=[CH:56][CH:55]=1)[CH2:44][N:3]1[C:2](=[O:1])[C:6]2([CH2:7][CH2:8][N:9]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:13])[CH2:10][CH2:11]2)[N:5]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:4]1)=[O:49])([CH3:54])([CH3:52])[CH3:53]
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Reactant: CC(C)(C)OC(=O)c1cccc(CBr)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(C(=O)OCc4ccccc4)CC3)C2=O)c1
Yield: 100 %

Procedure:
A mixture of benzyl 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (12.5 g, 34.21 mmol, 1 equiv), sodium bis(trimethylsilyl)amide, 1M in tetrahydrofuran (37.63 ml, 37.63 mmol, 1.1 equiv), and tert-butyl 3-(bromomethyl)benzoate (9.27 g, 34.21 mmol, 1 equiv) in N,N-dimethylformamide was stirred for 16 h at ambient temperature. Reaction was diluted with ethyl acetate and the organic layer was washed with water and brine. The combined organic layers were dried over MgSO4 and concentrated in vacuo. The crude residue was purified using the Biotage flash chromatography system (SNAP 100 g cartridge, Rf=0.6, 10%-50% ethyl acetate in hexanes) to afford benzyl 3-(3-(tert-butoxycarbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (19 g, quant) as a cream solid; 1H NMR (400 MHz, DMSO-d6): δ 1.53 (s, 9H); 1.71 (d, 2H, J=13.6 Hz); 2.37-2.42 (m, 2H); 3.6 (bs, 2H); 4.01-4.03 (m, 2H); 4.61 (s, 2H); 4.64 (s, 2H); 5.14 (d, 2H, J=7.2 Hz); 6.69 (d, 2H, J=8 Hz); 6.79 (t, 2H, J=7.2 Hz); 7.16-7.2 (m, 2H); 7.32-7.39 (m, 5H); 7.49-7.56 (m, 2H); 7.81-7.85 (m, 2H); MS for C33H37N3O5 m/z 556.28 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:29])[C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)=[N:18][CH:17]=1.[N+:30]([O-])([OH:32])=[O:31].C(OC(=O)C)(=O)C.C(=O)([O-])O.[Na+]>C(#N)C>[O:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:29])[C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]2)=[N:18][CH:17]=1)[N+:30]([O-:32])=[O:31]
Reactant: CN1CCN(c2ccc(C(=O)NCCCCCCCCCCCCO)cn2)CC1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC#N
Product: CN1CCN(c2ccc(C(=O)NCCCCCCCCCCCCO[N+](=O)[O-])cn2)CC1
Reaction time: 6 h
Yield: 69 %

Procedure:
2.00 g of N-(12-hydroxy-1-dodecanyl)-6-(4-methyl-1-piperazinyl)nicotinamide were suspended in 40 ml of acetonitrile and to the suspension was added dropwise under ice-cooling a mixed solution of 0.8 ml of fuming nitric acid and 1.9 ml of acetic anhydride and stirred for 6 hrs. This reaction mixture was poured into an aqueous sodium hydrogencarbonate solution, extracted with methylene chloride, washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated to give 1.54 g (69%) of the title compound. m.p. 74°-76° C.
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:12]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.N12CCCN=C1CCCCC2.[CH3:28][O:29][C:30]1[N:35]=[C:34]([CH3:36])[N:33]=[C:32]([N:37](C2C=CC=CC=2)[C:38](=O)[O-:39])[N:31]=1>O1CCOCC1>[CH:1]1([O:6][C:7]2[C:12]([S:13]([NH:16][C:38]([NH:37][C:32]3[N:31]=[C:30]([O:29][CH3:28])[N:35]=[C:34]([CH3:36])[N:33]=3)=[O:39])(=[O:15])=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1nc(C)nc(N(C(=O)[O-])c2ccccc2)n1
Reactant: NS(=O)(=O)c1cccnc1OC1CCCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2cccnc2OC2CCCC2)n1
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
To a mixture of 4.84 g of 2-cyclopentyloxypyridin-3-ylsulfonamide and 3.13 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene in 50 ml of absolute dioxan are added 5.46 g of N-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)phenylcarbamate at 20° to 25° C. The mixture is stirred for 1/2 hour, the precipitate is isolated and the filtrate is concentrated by evaporation. The residue is triturated with 10 ml of 2N hydrochloric acid and the crystals so obtained are isolated, washed with ether and water and dried, affording 7.79 g of N-(2-cyclopentyloxypyridin-3-ylsulfonyl)-N'-(4-methoxy-6methyl-1,3,5-triazin-2-yl)urea with a melting point of 170°-172° C.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]2[CH2:20][CH:19]3[CH:15]([CH2:16][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]3)[C:14]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([OH:28])[CH2:13]2)(=O)=O)=CC=1.[C-:36]#[N:37].[K+]>>[C:36]([CH2:11][CH:12]1[CH2:20][CH:19]2[CH:15]([CH2:16][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]2)[C:14]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([OH:28])[CH2:13]1)#[N:37]
Reactant: Cc1ccc(S(=O)(=O)OCC2CC3CN(C(=O)OC(C)(C)C)CC3C(O)(c3ccccc3)C2)cc1
Reactant: [C-]#N
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CC2CC(CC#N)CC(O)(c3ccccc3)C2C1
Yield: 134.3 %

Procedure:
The procedure is as described for Example 13 below, starting from 1.1 g of (3aRS,4RS,6RS,7aSR)-6-p-toluenesulphonyloxymethyl-4-phenyl-2-tert-butyloxycarbonylperhydroisoindol-4-ol and 0,214 g of potassium cyanide, and gives 1.05 g of (3aRS,4RS,6RS,7aSR)-6-cyanomethyl-4-phenyl-2-tert-butyloxycarbonylperhydroisoindol-4-ol in the form of a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[CH:9]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:11])[CH3:10].B(O)O.C(=O)([O-])[O-].[K+].[K+].CCO>C1(C)C=CC=CC=1.O>[NH2:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:19]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:13]([N:12]([CH:9]([CH3:10])[CH3:11])[CH:21]([CH3:22])[CH3:23])=[O:20]
Reactant: Nc1ccncc1Br
Reactant: CC(C)N(C(=O)c1ccccc1)C(C)C
Agent: O=C([O-])[O-]
Agent: OBO
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CC(C)N(C(=O)c1ccccc1-c1cnccc1N)C(C)C
Temperature: 80 °C

Procedure:
The bromopyridine 1 (1.4 g, 8.1 mmol), boronic acid 2 (2.0 g, 8.9 mmol) and potassium carbonate (2.2 g, 15.9 mmol) were dissolved in 80 mL toluene, 8 mL EtOH and 8 mL H2O. This mixture was evacuated and refilled with nitrogen several times. Then, tetrakistriphenylphosphine palladium (0) (350 mg, 0.30 mmol) was added to the mixture and the mixture was heated to 80° C. overnight. Water (100 mL) was then added to the reaction and the organic layer was partitioned. The aqueous layer was extracted with EtOAc (2×100 mL) and the combined organics were dried with Na2CO3 and concentrated. The crude reaction product was triturated with diethyl ether (25 mL) and filtered. The resulting solid (2.0 g, 83%) was collected and characterized as the biphenyl amine 3. 1H NMR (CDCl3): δ 8.17 (d, 1H), 8.03 (s, 1H), 7.45 (m, 2H), 7.25 (m, 2H), 6.55 (d, 1H), 4.50 (bs, 2H), 3.61 (m, 1H), 3.31 (m, 1H), 1.49 (d, 3H), 1.16 (d, 3H), 1.03 (d, 3H), 0.83 (d, 3H).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:14]([OH:16])=O)[C:10]([CH3:13])([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH3:40][C:41]1[N:45]2[C:46](=[O:55])[N:47]([CH:49]3[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]3)[CH2:48][C:44]2=[CH:43][N:42]=1.C1CCN2C(=NCCC2)CC1>C(#N)C.C(N(CC)CC)C>[CH3:13][C:10]([CH3:11])([CH3:12])[C@@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[C:14]([N:52]1[CH2:51][CH2:50][CH:49]([N:47]2[CH2:48][C:44]3=[CH:43][N:42]=[C:41]([CH3:40])[N:45]3[C:46]2=[O:55])[CH2:54][CH2:53]1)=[O:16]
Reactant: Cc1ncc2n1C(=O)N(C1CCNCC1)C2
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ncc2n1C(=O)N(C1CCN(C(=O)[C@H](NC(=O)OC(C)(C)C)C(C)(C)C)CC1)C2
Yield: 93.3 %

Procedure:
To a solution of Boc-D-tert-leucine (0.23 g) and HOBt (0.23 g) in acetonitrile (5 ml) was added WSC (0.29 g), and the reaction mixture was mixed at room temperature for 15 minutes. Then, a solution of 5-methyl-2-(4-piperidinyl)-1,2-dihydro-3H-imidazo[1,5-c]imidazol-3-one dihydrochloride (0.29 g), DBU (0.30 g) and triethylamine (0.30 g) in acetonitrile (5 ml) was added thereto. The reaction mixture was mixed at room temperature for 15 hours, the solvent was then distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with an aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with basic silica gel column (ethyl acetate to ethyl acetate/methanol=5/1) to obtain the title compound as colorless powder (0.40 g, 92%).