Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1([CH3:20])[C:8](=[O:9])[NH:7][C:6]([C:10]2[N+:18]([O-])=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])=[N:5]1)([CH3:3])[CH3:2].C(OC(=O)C)(=[O:23])C.N1C=CC=CC=1.O>C1(C)C=CC=CC=1>[OH:23][C:17]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[C:10]([C:6]2[NH:7][C:8](=[O:9])[C:4]([CH:1]([CH3:3])[CH3:2])([CH3:20])[N:5]=2)[N:18]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)C1(C)N=C(c2c(C(=O)O)ccc[n+]2[O-])NC1=O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: CC(C)C1(C)N=C(c2nc(O)ccc2C(=O)O)NC1=O
Temperature: 10 °C

Procedure:
A mixture of 3 g of 2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)nicotinic acid -1-oxide, 2.24 g of acetic anhydride, and 0.4 g of pyridine in 80 mL of toluene is stirred and heated at reflux for 3 hours. The reaction mixture is cooled to 10° C. and 75 mL of cold water is added with vigorous stirring. The resulting yellow solid is filtered, washed with toluene, and air dried. Recrystallization of this solid from methanol affords the desired product as a white solid, mp 201°-203° C.
Reaction SMILES: [CH2:1]([C:3](O)([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[C:4]#[CH:5])[CH3:2].C[O:14][C:15]([CH3:17])=[CH2:16]>>[CH2:1]([C:3]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])=[CH:4][CH:5]=[CH:16][C:15](=[O:14])[CH3:17])[CH3:2]
Reactant: C=C(C)OC
Reactant: C#CC(O)(CC)CCC=C(C)C
Product: CCC(=CC=CC(C)=O)CCC=C(C)C

Procedure:
The acid catalysed reaction of 3-ethyl-7-methyl-oct-1-yn-6-en-3-ol with isopropenyl methyl ether and subsequent base-catalysed isomerisation of the resulting β-ketoallene (G. Saucy, R. Marbet, Helv. 50, 1158, 1967) gave a good yield of 6-ethyl-10-methyl-undeca-3,5,9-trien-2-one which was cyclised with 85% phosphoric acid in a known manner [H. Rouve, M. Stoll, Helv. 30, 2216 (1947)]. The resulting product contained 90% 11-methyl-α-ionone and 11-methyl-γ-ionone (two isomers) in the ratio of 7:3. In a manner analogous to the epoxidation of α-irone (Example 4), from 13.4 g (0.065 mol) of 11-methyl-α-ionone there were obtained 13.9 g of crude 11-methyl-α-ionone epoxide of which 13.4 g (~0.06 mol) were dissolved together with 6.1 g (0.03 mol) of aluminium isopropylate in 30 ml of isopropanol. By following the procedure described in Example 1 there were obtained 13.7 g of a crude product. From this crude product there were obtained by distillation over a 5 cm Widmer column 2.10 g (17%) of olfactorily good product of boiling point 73°-75° C./0.05 mmHg and which contained above 85% 17 and the corresponding 7-oxa-bicyclooctane 17a. A sample purified by means of preparative GC showed the following spectral data:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH2:15][CH2:16][C@H:17]([CH2:27][CH2:28][S:29][CH3:30])[C@@H:18]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])[C@@H:19]([OH:21])[CH3:20])[C:10]([O:12]C)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH2:15][CH2:16][C@H:17]([CH2:27][CH2:28][S:29][CH3:30])[C@@H:18]([O:22][CH2:23][CH:24]([CH3:25])[CH3:26])[C@@H:19]([OH:21])[CH3:20])[C:10]([OH:12])=[O:11])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)[C@H](CCC[C@H](CCSC)[C@@H](OCC(C)C)[C@H](C)O)NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: CSCC[C@@H](CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)[C@@H](OCC(C)C)[C@H](C)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.2 %

Procedure:
To a mixture of (2S,6R,7R,8S)-methyl 2-((tert-butoxycarbonyl)amino)-8-hydroxy-7-isobutoxy-6-(2-(methylthio)ethyl)nonanoate (326 mg, 0.725 mmol) in THF (2.4 ml) and H2O (1.2 ml) was added LiO.H2O (91 mg, 2.2 mmol). The resulting mixture was stirred at room temperature for 3 h, quenched with 2N HCl (3 mL), diluted with H2O (20 mL), and extracted with EtOAc (3×20 mL). The organic extracts were combined, dried over Na2SO4, filtered, and concentrated to provide the title compound as a sticky colorless oil (307 mg, 97%): 1H NMR (400 MHz, CDCl3) δ 5.05 (d, J=7.3 Hz, 1H), 4.31 (s, 1H), 3.88 (p, J=6.3 Hz, 1H), 3.36 (dd, J=8.5, 6.3 Hz, 1H), 3.23 (dd, J=8.6, 6.6 Hz, 1H), 3.07 (dd, J=5.7, 3.9 Hz, 1H), 2.59 (ddd, J=13.9, 8.6, 5.3 Hz, 1H), 2.48 (dt, J=12.8, 7.5 Hz, 1H), 2.10 (s, 3H), 1.84 (tt, J=13.2, 7.1 Hz, 3H), 1.78-1.62 (m, 2H), 1.55 (dd, J=13.6, 5.8 Hz, 1H), 1.46 (s, 12H), 1.22 (d, J=6.3 Hz, 3H), 0.91 (dd, J=6.7, 2.0 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 155.81, 99.99, 84.81, 79.35, 68.26, 38.01, 32.80, 30.94, 29.22, 28.80, 28.32, 22.88, 19.51, 19.46, 19.13, 15.44; ESIMS m/z 436.3 ([M+H]+), 458.3 ([M+Na]+).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]=1.FC1C([Li])=CC(C)=CN=1.[I:30]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1.O>[F:13][C:14]1[C:19]([I:30])=[CH:18][C:17]([CH3:20])=[CH:16][N:15]=1
Reactant: II
Reactant: Cc1ccc(F)nc1
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Agent: [Li]c1cc(C)cnc1F
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: Cc1cnc(F)c(I)c1
Reaction time: 0.5 h
Yield: 33.4 %

Procedure:
26.5 ml of n-butyllithium (1.57 mol/l hexane solution) was dropwise added at −78° C. to a solution having 4.02 g (39.8 mmol) of diisopropylamine dissolved in 70 ml of tetrahydrofuran, followed by stirring for 30 minutes. To this solution, a solution having 4.42 g (39.8 mmol) of 2-fluoro-5-methylpyridine dissolved in 18 ml of tetrahydrofuran was added, followed by stirring for 4 hours to prepare 2-fluoro-5-methyl-3-pyridyllithium. Then, to this solution, a solution having 10.1 g (39.8 mmol) of iodine dissolved in 27 ml of tetrahydrofuran was added, followed by stirring for 2 hours. 16 ml of water and 120 ml of a sodium thiosulfate aqueous solution were charged, followed by extraction with ethyl ether. The organic layer was dried over magnesium sulfate and subjected to filtration, the solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel chromatography to obtain 3.15 g (yield: 33%) of 2-fluoro-3-iodo-5-methylpyridine.
Reaction SMILES: [NH2:1][C:2]1[C:17]([O:18][CH3:19])=[CH:16][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([CH3:15])([OH:14])[CH3:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([N:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])[C:24]([Cl:40])=[CH:23][N:22]=1>>[Cl:40][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([N:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])=[N:26][C:21]([NH:1][C:2]2[C:17]([O:18][CH3:19])=[CH:16][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12]([OH:14])([CH3:15])[CH3:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:22][CH:23]=1
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCN(CC(C)(C)O)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N(C)C)n1)CCN(CC(C)(C)O)CC2
Yield: 53 %

Procedure:
In an analogous manner to Example 1534, the product was prepared from 1-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-2-methyl-propan-2-ol and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide. Product was isolated as a white solid (61 mg, 53%). mp: 188-189° C., MS (ESI+): 575 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.35 (s, 1H), 8.54 (d, J=8 Hz, 1H), 8.16 (s, 1H), 8.01 (s, 1H), 7.90 (d, J=8 Hz, 1H), 7.57 (t, 1H), 7.52 (s, 1H), 7.26 (m, 1H), 6.66 (s, 1H), 3.89 (s, 3H), 3.34 (s, 1H), 2.88-2.76 (m, 15H), 2.49 (s, 2H), 1.56 (s, 6H), 1.23 (s, 6H).
Reaction SMILES: [ClH:1].Cl.[CH2:3]([C:7]1[N:12]=[N:11][C:10]([O:13][CH2:14][CH:15]2[O:20][CH2:19][CH2:18][NH:17][CH2:16]2)=[CH:9][C:8]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:23][CH:22]=1)[CH2:4][CH2:5][CH3:6].Cl.[CH2:35](OCC)C>C(Cl)Cl>[ClH:1].[ClH:1].[CH2:3]([C:7]1[N:12]=[N:11][C:10]([O:13][CH2:14][CH:15]2[O:20][CH2:19][CH2:18][N:17]([CH3:35])[CH2:16]2)=[CH:9][C:8]=1[C:21]1[CH:22]=[CH:23][C:24]([O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:25][CH:26]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCOCC
Reactant: CCCCc1nnc(OCC2CNCCO2)cc1-c1ccc(OC2CCCCC2)cc1
Agent: Cl
Solvent: ClCCl
Product: CCCCc1nnc(OCC2CN(C)CCO2)cc1-c1ccc(OC2CCCCC2)cc1

Procedure:
To a solution of 2-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-morpholine dihydrochloride (0.067 mmol, 0.031 g) and aqueous formaldehyde (37%, 0.304 mmol, 0.025 mL) in dry DCM (2 mL) was added macroporous resin-bound triacetoxyborohydride (loading 2.36 mmol/gram, 0.364 mmol, 0.154 g). The mixture was shaken for 12 hours. The reaction was filtered and the resin was washed with DCM (5 mL). The solvent was removed under reduced pressure. The crude product was purified on a 4 g SiO2 cartridge with 4-6% (2N NH3 in MeOH) in DCM to give 2-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-4-methyl-morpholine. The neutral amine was treated with 2N HCl in diethyl ether (1 mL) and DCM (1 mL). The volatiles were removed under reduced pressure and the salt was triturated with diethyl ether and filtered to provide the title compound (0.022 g). LCMS: m/z 441 [M+1]. 1H NMR (400 MHz, CD3OD) δ 7.35-7.46 (3H, m), 7.09 (2H, d), 4.56-4.68 (2H, m), 4.38-4.47 (1H, m), 4.13-4.29 (2H, m), 3.91 (1H, t), 3.68 (1H, d), 3.49 (1H, d), 3.12-3.26 (2H, m), 3.00-3.09 (2H, m), 2.97 (3H, s), 1.99-2.02 (2H, m), 1.80-1.82 (2H, m), 1.19-1.66 (10H, m), 0.81 (3H, t).
Reaction SMILES: C([O:8][C@@H:9]([C@@H:12]1[O:20][C@H:19]2[C@H:15]([N:16]=[C:17]([N:21]([CH3:23])[CH3:22])[S:18]2)[C@@H:14]([O:24]CC2C=CC=CC=2)[C@@H:13]1[O:32]CC1C=CC=CC=1)[CH:10]=[O:11])C1C=CC=CC=1.B(Cl)(Cl)Cl.CO.[NH4+].[OH-]>ClCCl>[OH:8][C@@H:9]([C@H:12]1[O:20][C@H:19]2[C@H:15]([N:16]=[C:17]([N:21]([CH3:23])[CH3:22])[S:18]2)[C@@H:14]([OH:24])[C@@H:13]1[OH:32])[CH2:10][OH:11]
Reactant: CN(C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]([C@@H](C=O)OCc3ccccc3)O[C@@H]2S1
Agent: ClB(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CN(C)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H]([C@H](O)CO)O[C@@H]2S1
Reaction time: 0.13 h
Yield: 9.2 %

Procedure:
A solution of 102 (500 mg, 0.9 mmol) in dichloromethane (20 mL) was treated with BCl3 (9 ml, 9 mmol, 1 M in dichloromethane) at −60° C. under nitrogen for 30 min. The reaction was then quenched with methanol (20 mL). Volatiles were distilled out to give a residue, which was dissolved into methanol (5 mL) and neutralized with Con. NH4OH (2 ml, 26% aqueous solution). After concentration, the crude product was purified by a silica gel column, eluted with 10° A) methanol in dichloromethane to give a mixture of the two epimers; the two epimers were separated by Prep-HPLC with the following conditions: Agilent Prep 1200 Detecl): Column, SunFire Prep C18; mobile phase, Water with 0.05% ammonia and CH3CN; 5% CH3CN up to 60% in 8 min; Detector, 220 nm) to afford (3aR,5R,6S,7R,7aR)-5-((R)-1,2-dihydroxyethyl)-2-(dimethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol as a white solid (23.1 mg, 9%), Faster eluting isomer; (ES, m/z): [M+H]+ 279.0; 1H NMR (300 MHz, D2O) δ 6.17 (d, J=6.3 Hz, 1H), 4.13 (t, J=6.0 Hz, 1H), 3.95 (t, J=4.5 Hz, 1H), 3.78-3.83 (m, 1H), 3.61-3.71 (m, 2H), 3.50-3.54 (m, 2H), 2.88 (s, 6H); and (3aR,5R,6S,7R,7aR)-5-((S)-1,2-dihydroxyethyl)-2-(dimethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol as a white solid (37.5 mg, 13%), Slower eluting isomer; (ES, m/z): [M+H]+ 279.0; 1H NMR (300 MHz, D2O) δ 6.18 (d, J=6.3 Hz, 1H), 4.05 (t, J=6.0 Hz, 1H), 3.90 (t, J=5.1 Hz, 1H), 3.75-3.81 (m, 1H), 3.65-3.69 (m, 1H), 3.44-3.53 (m, 3H), 2.87 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5](Cl)=[N:6][CH:7]=1.[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[S:18](Cl)(=[O:20])=[O:19].Cl>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][S:18]([C:12]2[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]=2[F:10])(=[O:20])=[O:19])[CH:5]=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1Cl
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Agent: Cl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cncc(Br)c1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 69.4 %

Procedure:
To a solution of 5-bromo-2-chloropyridin-3-amine (0.500 g, 2.89 mmol) in pyridine (1.45 ml) was dropwise added 2,4-difluorobenzene-1-sulfonyl chloride (0.614 ml, 2.89 mmol) at 0° C. The mixture was stirred for 40 min at room temperature and acidified with 1 N HCl. The residue was extracted with EtOAc and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give N-(5-bromopyridin-3-yl)-2,4-difluorobenzenesulfonamide (0.70 g, 70% yield) as a white solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 6.92-7.04 (2H, m), 7.76-7.84 (1H, m), 7.86-7.95 (1H, m), 8.27 (1H, d, J=2.4 Hz), 8.44 (1H, d, J=2.4 Hz); NH peak was not observed.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:21])[C:7]4[C:22](=[O:26])[NH:23][C:24](=[O:25])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1.[C:27](O)(=[O:29])[CH3:28]>>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:8]1[C:7]2[C:22](=[O:26])[NH:23][C:24](=[O:25])[C:6]=2[C:5]2[C:4]3[CH:3]=[C:2]([NH:1][C:27](=[O:29])[CH3:28])[CH:14]=[CH:13][C:12]=3[NH:11][C:10]=2[CH:9]=1
Reactant: CC(=O)O
Reactant: Nc1ccc2[nH]c3cc(-c4ccccc4Cl)c4c(c3c2c1)C(=O)NC4=O
Product: CC(=O)Nc1ccc2[nH]c3cc(-c4ccccc4Cl)c4c(c3c2c1)C(=O)NC4=O
Yield: 43 %

Procedure:
Amine (919) prepared as described in example 467 and acetic acid were reacted using the procedure described in example 468 with a reaction time of 4 h to give the acetamide (926) (43%) as a yellow powder, mp 240–245° C. 1H NMR δ [(CD3)2SO] 12.04 (br s, 1H), 11.07 (br s, 1H), 10.10 (s, 1H), 8.95 (d, J=2.1 Hz, 1H), 7.90 (dd, J=8.8, 2.1 Hz, 1H), 7.58 (m, 2H), 7.42–7.51 (m, 4H), 2.10 (s, 3H). FABMS found: [M+H]+=404.0787, 406.0776. C22H15ClN3O3 requires 404.0802, 406.0772.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]1[C:19]2[CH:18]=[CH:17][C:16](OS(C3C=CC(C)=CC=3)(=O)=O)=[C:15]3[C:31](=[O:38])[C:32]4[CH:33]=[CH:34][N:35]=[CH:36][C:37]=4[C:13]([C:14]=23)=[N:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:39][N:40]([CH3:44])[CH2:41][CH2:42][NH2:43]>N1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]1[C:19]2[CH:18]=[CH:17][C:16]([NH:43][CH2:42][CH2:41][N:40]([CH3:44])[CH3:39])=[C:15]3[C:31](=[O:38])[C:32]4[CH:33]=[CH:34][N:35]=[CH:36][C:37]=4[C:13]([C:14]=23)=[N:12]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc3c4c(nn3CCNC(=O)OC(C)(C)C)-c3cnccc3C(=O)c24)cc1
Reactant: CN(C)CCN
Solvent: c1ccncc1
Product: CN(C)CCNc1ccc2c3c(nn2CCNC(=O)OC(C)(C)C)-c2cnccc2C(=O)c13
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A suspension of 2-[2-(N-tert-butoxycarbonylamino)ethyl]-5-(p-toluenesulfonyloxy)isoquino[8,7,6-cd]indazole-6(2H)-one (0.056 g) and 2-(dimethylamino) ethylamine (0.080 mL) in dry pyridine (0.50 mL) is heated at 80° C. The dark solution obtained is held at this temperature for 1 hour, then it is left at room temperature overnight. The dark precipitate obtained is separated by suction and purified by column chromatography (SiO2 ; eluant ethyl acetate and then methylene chloride/methanol 9/0.5 v/v) to give 2-[2-(N-tert-butoxycarbonylamino)ethyl]-5-[[2-(dimethylamino)ethyl]amino]isoquino[8,7,6-cd]indazole-6(2H)-one (0.024 g) as a red-orange solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[C:6]([C:9]1[CH:10]=[CH:11][C:12](Br)=[N:13][CH:14]=1)(=[O:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CN(C)C=O.O>[C:6]([C:9]1[CH:10]=[CH:11][C:12]([N:2]2[N:3]=[CH:4][CH:5]=[N:1]2)=[N:13][CH:14]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)c1ccc(Br)nc1
Reactant: c1c[nH]nn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccc(-n2nccn2)nc1
Temperature: 100 °C
Yield: 17 %

Procedure:
207 mg (corresponding to 3.00 mmol) of 1H-1,2,3-triazole was dissolved in 5 mL of dimethylformamide. Then, 200 mg (corresponding to 1.00 mmol) of 5-acetyl-2-bromopyridine and 414 mg (corresponding to 3.00 mmol) of potassium carbonate were added thereto. The resulting solution was heated at 100° C. for 3 hours. After the completion of the reaction, the reaction solution was cooled down to room temperature, supplemented with a saturated ammonium chloride aqueous solution and water, and extracted 3 times with dichloromethane. The combined dichloromethane layer was washed with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (elution solvent: dichloromethane/ethyl acetate=4/1), to obtain 31.9 mg (corresponding to 0.170 mmol) of 5-acetyl-2-(2H-1,2,3-triazole-2-yl)pyridine (FIG. 2, step 1).
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]1.FC(F)(F)C(O)=O>ClCCl>[O:1]=[C:2]1[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCCC(CCN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1N(CCC2CCCNC2)c2ccccc2C12COc1cc3c(cc12)OCO3
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.2 %

Procedure:
To a solution of tert-butyl 3-[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]piperidine-1-carboxylate (1.48 g, 3.0 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (4 mL) at 0° C. The mixture was stirred at ambient temperature for 2 h and concentrated in vacuo to dryness. The residue was diluted in dichloromethane (100 mL) and washed with saturated aqueous sodium bicarbonate solution (2×30 mL), water (30 mL), and dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to dryness to give 3-[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]piperidine (0.72 g, 60%): MS (ES+) m/z 393.4 (M+1).
Reaction SMILES: [N:1]1([C:6]2[N:11]=[CH:10][C:9]([O:12][CH2:13][C:14]3[CH:18]=[N:17][N:16]([CH:19]4[CH2:24][CH2:23][N:22]([C:25](=[O:40])[CH2:26][CH:27]5[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]5)[CH2:21][CH2:20]4)[N:15]=3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.[ClH:41]>ClCCl>[ClH:41].[N:1]1([C:6]2[N:11]=[CH:10][C:9]([O:12][CH2:13][C:14]3[CH:18]=[N:17][N:16]([CH:19]4[CH2:20][CH2:21][N:22]([C:25](=[O:40])[CH2:26][CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)[CH2:23][CH2:24]4)[N:15]=3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)N2CCC(n3ncc(COc4ccc(-n5cnnn5)nc4)n3)CC2)CC1
Agent: Cl
Solvent: ClCCl
Product: O=C(CC1CCNCC1)N1CCC(n2ncc(COc3ccc(-n4cnnn4)nc3)n2)CC1
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 4-(2-(4-(-((6-(1H-tetrazol-1-yl)pyridine-3-yloxy)methyl)-2H-1,2,3-triazol-2-yl)piperidin-1-yl)-2-oxoethyl)piperidine-1-carboxylate (110 mg, 0.20 mmol) in dichloromethane (5 mL) cooled to 0° C. was added hydrochloric acid (4M in 1,4-dioxane, 5 eq.) dropwise. After the reaction was stirred for 3 h the solvents were removed in vacuo to afford the desired HCl salt. 1H NMR (DMSO-d6): δ 10.06 (1H, s), 8.78 (1H, br), 8.40 (1H, d), 7.98 (1H, d), 7.94 (1H, s), 7.87 (1H, dd), 5.35 (2H, s), 4.79 (1H, m), 4.34 (1H, m), 3.92 (1H, m), 3.20 (3H, m), 2.83 (2H, m), 2.31 (2H, d), 2.10 (2H, m), 1.93 (2H, m), 1.77 (3H, m), 1.32 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[CH:22])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:23].Br[C:25]1[C:26]([F:36])=[CH:27][C:28]([F:35])=[C:29]([S:31]([NH2:34])(=[O:33])=[O:32])[CH:30]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:15])([F:17])[F:16])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[C:22][C:25]4[C:26]([F:36])=[CH:27][C:28]([F:35])=[C:29]([S:31]([NH2:34])(=[O:32])=[O:33])[CH:30]=4)=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:23]
Reactant: NS(=O)(=O)c1cc(Br)c(F)cc1F
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(C)c3)nc12
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C#Cc4cc(S(N)(=O)=O)c(F)cc4F)c3n2)ccc1Cl

Procedure:
The title compound was prepared from 5-(4-chloro-3-methyl-phenyl)-3-ethynyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.11) (178 mg, 0.5 mmol) and commercially available 5-bromo-2,4-difluoro-benzenesulfonamide (136 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (125 mg, 47%). MS (ISN) 525.2 [(M−H)−]; mp 294° C.
Reaction SMILES: [N:1]#[C:2][NH2:3].[Pb].[CH3:5][NH:6][C:7]([NH:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[CH:18]=[CH:17][S:16][N:15]=1)=S.CN(C)C=O>C(#N)C>[C:2]([NH:3][C:7]([NH:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[CH:18]=[CH:17][S:16][N:15]=1)=[N:6][CH3:5])#[N:1]
Reactant: N#CN
Reactant: CNC(=S)NCCSCc1ccsn1
Agent: [Pb]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CN=C(NC#N)NCCSCc1ccsn1

Procedure:
Lead cyanamide (52.6 g.) was added to a solution of N-methyl-N'-[2-(3-isothiazolylmethylthio)ethyl]thiourea (17.7 g.) in acetonitrile (500 ml.) containing dimethylformamide (50 ml.). The mixture was stirred under reflux for 48 hours, then filtered and concentrated. The product was chromatographed on silica gel with ethyl acetate as eluant and recrystallised from isopropyl acetate-ether to give N-cyano-N'-[2-(3-isothiazolylmethylthio)ethyl]-N"-methylguanidine, in a crystalline form, m.p. 63°-64°. Further recrystallisation from isopropyl acetate afforded the cyanoguanidine in a crystalline form, m.p. 91°-92°. (Found: C, 42.6; H, 5.2; N, 27.4; S, 25.4. C9H13N5S2 requires: C, 42.3; H, 5.1; N, 27.4; S, 25.1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:17][C:18]12[CH2:25][CH2:24][CH:21]([CH2:22][CH2:23]1)[CH2:20][CH2:19]2)[C:13](OC)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].OS([O-])=O.[Na+]>CO>[C:18]12([CH2:17][CH:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:13][OH:14])[CH2:19][CH2:20][CH:21]([CH2:22][CH2:23]1)[CH2:24][CH2:25]2
Reactant: COC(=O)C(CC12CCC(CC1)CC2)NC(=O)OCc1ccccc1
Agent: O=S([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C(NC(CO)CC12CCC(CC1)CC2)OCc1ccccc1
Reaction time: 1.5 h

Procedure:
methyl 2-(benzyloxycarbonylamino)-3-(bicyclo[2.2.2]octan-1-yl)propanoate (720 mg, 2.087 mmol, 1 eq.) was dissolved in 15 mL of MeOH. NaBH4 (631 mg, 16.7 mmol, 8 eq.) was added in portions. The mixture was stirred for 1.5 h. Saturated aq; NaHSO3 (20 mL) was added and the pH of the mixture was adjusted to 7-8 with NaHSO3 (s). The mixture was evaporated and extracted with EtOAc (20 mL×5). The organic phase was combined and evaporated to give benzyl 1-(bicyclo[2.2.2]octan-1-yl)-3-hydroxypropan-2-ylcarbamate as oil, which was used in the next step without further purification. MS ESI +ve m/z 318 (M+H).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.Cl>C1(C)C=CC=CC=1.Cl[Ni](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:2]1([C:5]2[CH:4]=[CH:3][CH:2]=[CH:11][C:6]=2[CH3:7])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc2ccccc12
Agent: Cl[Ni](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1cccc2ccccc12
Yield: 184.8 %

Procedure:
The Grignard solution was subsequently added dropwise to a solution of 118 g (0.57 mol) of 1-bromonaphthalene and 3.5 g of bis(triphenylphosphine)nickel dichloride in 800 cm3 of toluene at such a rate that the internal temperature did not exceed 50° C. Subsequently, the mixture was heated under reflux for a further 3 hours, admixed with 500 ml of 10% strength aqueous HCl, the phases were separated and the organic phase was freed of solvent under reduced pressure. Filtration through silica gel (hexane) gave 115 g (92%) of 6 as a colorless oil.