Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18](B4OC(C)(C)C(C)(C)O4)=[CH:17][C:16]=3[O:30][CH3:31])=[O:13])=[N:8][NH:9]2)=[CH:5][CH:4]=1.Br[C:33]1[N:34]=[C:35]([C@H:43]2[CH2:48][CH2:47][C@H:46]([N:49]3[CH2:54][CH2:53][N:52]([CH3:55])[CH2:51][CH2:50]3)[CH2:45][CH2:44]2)[N:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[C:37]=12>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:33]4[N:34]=[C:35]([C@H:43]5[CH2:44][CH2:45][C@H:46]([N:49]6[CH2:50][CH2:51][N:52]([CH3:55])[CH2:53][CH2:54]6)[CH2:47][CH2:48]5)[N:36]5[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[C:37]=45)=[CH:17][C:16]=3[O:30][CH3:31])=[O:13])=[N:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(C(=O)Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3OC)n[nH]c2c1
Reactant: Cc1nccn2c1c(Br)nc2[C@H]1CC[C@H](N2CCN(C)CC2)CC1
Product: COc1ccc2c(C(=O)Nc3ccc(-c4nc([C@H]5CC[C@H](N6CCN(C)CC6)CC5)n5ccnc(C)c45)cc3OC)n[nH]c2c1

Procedure:
6-Methoxy-N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-indazole-3-carboxamide (28 mg) and 1-bromo-8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazine (26 mg) were reacted according to the procedure described in example 4 step 4c and purified by prep-HPLC (column Luna C18(2); gradient acetonitrile/water with constant 0.003M trifluoroacetic acid). Proper fractions were collected and made basic with aqueous sodium hydrogencarbonate, extracted with dichloromethane, organic layer dried (Na2SO4) and concentrated in vacuo to give 6-methoxy-N-(2-methoxy-4-(8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1H-indazole-3-carboxamide (7.5 mg).
Reaction SMILES: Cl[C:2]1[CH:12]=[C:11]([NH:13][CH3:14])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.Cl.[CH3:16][O:17][NH:18][CH3:19].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[CH3:16][O:17][N:18]([CH3:19])[C:2]1[CH:12]=[C:11]([NH:13][CH3:14])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1
Reactant: CNOC
Reactant: CCOC(=O)c1cnc(Cl)cc1NC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc(N(C)OC)cc1NC
Temperature: 180 °C
Yield: 73.8 %

Procedure:
A mixture of ethyl 6-chloro-4-(methylamino)nicotinate (8 g, 37.4 mmol) and O,N-dimethylhydroxylamine hydrochloride (91 g, 0.94 mol) in dioxane (10 mL) was heated to 180° C. for 6 h. The reaction mixture was cooled to RT, and saturated aq Na2CO3 solution was added until pH 7. The aqueous solution was extracted with EtOAc (3×100 mL). The combined organics were washed with brine, dried (MgSO4) and concentrated in vacuo to give ethyl 6-(methoxy(methyl)amino)-4-(methylamino)nicotinate (6.6 g, 74% yield), which was used in the next step without further purification. 1HNMR (400 MHz, DMSO-d6): δ 8.44 (s, 1 H), 7.82 (m, 1H), 6.05 (s, 1 H), 4.20 (q, J=7.2 Hz, 2 H), 3.67 (s, 3 H), 3.17 (s, 3 H), 2.82 (d, J=5.2 Hz, 3 H), 1.25 (t, J=7.2 Hz, 3 H), MS (ESI) m/z: 240.1 (M+H+)
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[NH2:7][C:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[NH:10][N:9]=1.O>N1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][N:2]([CH3:6])[C:3]([N:9]1[C:8]([NH2:7])=[C:16]2[C:11]([CH:12]=[C:13]([Cl:17])[CH:14]=[CH:15]2)=[N:10]1)=[O:4]
Reactant: CN(C)C(=O)Cl
Reactant: Nc1n[nH]c2cc(Cl)ccc12
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CN(C)C(=O)n1nc2cc(Cl)ccc2c1N
Yield: 58 %

Procedure:
0.15 mol of dimethylcarbamic acid chloride is added dropwise, while stirring, to 0.1 mol of 3-amino-6-chloroindazole in 50 ml of pyridine, in the course of which the temperature rises to 45° C. After 11/2 hours, 250 ml of water are allowed to run in and the reaction product is isolated by filtration. After dissolving the product in chloroform, filtering off a by-product of melting point 237°-238° C and evaporating the solution, 3-amino-6-chloroindazole-2-carboxylic acid dimethylamide (melting point: 178°-180° C; 58% of theory) is obtained.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH:6]1([CH3:16])[CH2:11][CH2:10][CH:9]([CH:12]([CH3:14])[CH3:13])[CH:8]([OH:15])[CH2:7]1.N1C=CC=CC=1>C(OCC)C>[Cl:1][CH2:2][C:3]([O:15][CH:8]1[CH:9]([CH:12]([CH3:13])[CH3:14])[CH2:10][CH2:11][CH:6]([CH3:16])[CH2:7]1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: CC1CCC(C(C)C)C(O)C1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC1CCC(C(C)C)C(OC(=O)CCl)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
A solution of chloroacetyl chloride (6.4 mL, 80 mmol) in 40 mL anhydrous diethyl ether was added dropwise within 2 h to a solution of (−)-menthol (3a) (12.5 g, 80 mmol) and pyridine (6.5 mL, 80 mmol) in anhydrous diethyl ether (160 mL) at 0° C. After warming to RT, the white suspension was stirred for 2 h and the resulting mixture was then filtered. The filtrate was washed with HCl (60 mL, 2 N), saturated. NaHCO3 (60 mL), brine and dried with Na2SO4. Removal of the solvent and drying under vacuum afford (−)-menthyl chloroacetate (4a) (17.64 g, 94%), which was used without further purification. U.S. Pat. No. 4,456,611; Helv. Chim. Acta 1988, 71, 1553.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2([C:12]#[N:13])[CH2:11][CH2:10][CH2:9]2)[CH:3]=1.[C:14]([O:18][C:19](=[O:27])[NH:20][C:21]1[S:22][CH:23]=[C:24]([CH3:26])[N:25]=1)([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19](=[O:27])[NH:20][C:21]1[S:22][C:23]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]3([C:12]#[N:13])[CH2:11][CH2:10][CH2:9]3)[CH:3]=2)=[C:24]([CH3:26])[N:25]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: N#CC1(c2cc(Br)ccn2)CCC1
Reactant: Cc1csc(NC(=O)OC(C)(C)C)n1
Product: Cc1nc(NC(=O)OC(C)(C)C)sc1-c1ccnc(C2(C#N)CCC2)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
The title compound is prepared in analogy to the procedure described in Step 1.3, but using 1-(4-bromo-pyridin-2-yl)-cyclobutanecarbonitrile (Step 19.3) and (4-methyl-thiazol-2-yl)-carbamic acid tert-butyl ester (Step 18.4). The reaction mixture is stirred for 3 h at 100° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=1[CH2:7][Cl:8].[C:11]1([P:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1C=CC=CC=1>[Cl-:8].[CH3:1][C:2]1[S:3][C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=1[CH2:7][P+:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1sc(C)c(CCl)c1C
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: Cc1sc(C)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1C
Product: [Cl-]
Temperature: 25 °C

Procedure:
33.2 G. of 2,4,5-trimethyl-3-chloromethyl-thiophene and 55.0 g. of triphenyl phosphine were dissolved in 200 ml. of benzene. The resulting mixture was refluxed overnight under argon and then cooled to room temperature. The precipitated white phosphonium salt which formed was collected by filtration, washed several times with cold benzene and dried at 80° C. under high vacuum to yield (2,4,5-trimethyl-3-thenyl)triphenyl phosphonium chloride, m.p. 236°-237° C.
Reaction SMILES: C(Cl)CCl.[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH2:15][C@H:14]([O:18][C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=2[NH:29][C:30]2[C:31]3[C:38]([CH3:39])=[C:37]([C:40]([OH:42])=O)[S:36][C:32]=3[N:33]=[CH:34][N:35]=2)[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].O[N:44]1C(=O)CCC1=O>CN(C=O)C.CCOC(C)=O>[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH2:15][C@H:14]([O:18][C:19]2[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[CH:21][C:20]=2[NH:29][C:30]2[C:31]3[C:38]([CH3:39])=[C:37]([C:40]([NH2:44])=[O:42])[S:36][C:32]=3[N:33]=[CH:34][N:35]=2)[CH2:13]1)=[O:11])([CH3:6])([CH3:7])[CH3:8]
Reactant: O=C1CCC(=O)N1O
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(C(F)(F)F)cc3O[C@H]3CCCN(C(=O)OC(C)(C)C)C3)c12
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(C(F)(F)F)cc3O[C@H]3CCCN(C(=O)OC(C)(C)C)C3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
EDC (74 mg) added to a mixture of the 4-[2-((S)-1-tert-butoxycarbonyl-piperidin-3-yloxy)-4-trifluoromethyl-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (177 mg) and N-hydroxysuccinimide (55 mg) in DMF (4 ml). The reaction mixture was stirred at room temperature overnight. The reaction was diluted with EtOAc and washed with water and brine. The organics were passed through a hydrophobic frit and the solvent was evaporated. The residue was dissolved in DMF (2 ml) and ammonia in methanol (2 ml) was added. The reaction was stirred for 1 h. Further ammonia in methanol (2 ml) was added and the reaction was stirred again. After 30 min the reaction was diluted with EtOAc and washed with water and brine.
Reaction SMILES: Cl[C:2]1C=C(Cl)C=C[C:3]=1C1N=C(CC)C(N[C@H]2C3C(=CC=CC=3)C[C@@H]2OC)=NC=1CC.[Cl:31][C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=1[C:39]1[N:40]=[C:41]([CH:58]=[CH2:59])[C:42]([NH:47][C@@H:48]2[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[CH2:50][C@@H:49]2[OH:57])=[N:43][C:44]=1[O:45][CH3:46]>>[Cl:31][C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=1[C:39]1[N:40]=[C:41]([CH:58]=[CH2:59])[C:42]([NH:47][C@@H:48]2[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[CH2:50][C@@H:49]2[O:57][CH2:2][CH3:3])=[N:43][C:44]=1[O:45][CH3:46]
Reactant: C=Cc1nc(-c2ccc(Cl)cc2Cl)c(OC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@H]1c2ccccc2C[C@@H]1OC
Product: C=Cc1nc(-c2ccc(Cl)cc2Cl)c(OC)nc1N[C@@H]1c2ccccc2C[C@@H]1OCC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine but substituting (1R,2S)-1-{[5-(2,4-dichlorophenyl)-6-methoxy-3-vinylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 1.11–1.14, 3.04–3.08, 3.37–3.44, 3.60–3.68, 3.84, 4.28–4.30, 5.34–5.37, 5.68–5.71, 5.90–5.99, 6.66–6.73, 7.14–7.26, 7.32–7.40; MS (ESI+) for C24H23Cl2N3O2 m/z 456 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]([NH:12][CH:13]([CH3:15])[CH3:14])[CH2:7][C:6]=2[C:5]([O:16][CH3:17])=[CH:4][CH:3]=1.[CH:18](=O)[CH2:19][CH3:20].C([BH3-])#N.[Na+].C(Cl)(Cl)Cl>CO>[Br:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]([N:12]([CH:13]([CH3:14])[CH3:15])[CH2:18][CH2:19][CH3:20])[CH2:7][C:6]=2[C:5]([O:16][CH3:17])=[CH:4][CH:3]=1
Reactant: CCC=O
Reactant: COc1ccc(Br)c2c1C[C@@H](NC(C)C)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCN(C(C)C)[C@H]1COc2c(Br)ccc(OC)c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
(R)-8-Bromo-3-(N-isopropylamino)-5-methoxy-3,4-dihydro-2H-1-benzopyran (3.8 g, 11.3 mmol) was dissolved in anhydrous methanol (80 mL) and to this was propanal (8.1 mL, 0.113 mol) added. The reaction was cooled (ice-bath) then sodium cyanoborohydride (1.3 g, 20.3 mmol) was added, the pH was adjusted to 5, and the reaction was allowed to stir at room temperature overnight. The solvent was removed in vacuo, the remains were twice with diethyl ether. The combined ether portions were treated with brine, dried (Na2SO4) filtered, and taken into a 1M solution of Na2CO3 and then extracted the solvent removed in vacuo to give the crude residue. Chromatography on silica (eluent: 7% ethyl acetate/hexane) gave 3.75 g (97% yield) of the title compound as a clear oil [α]21D =-82.5° (C=0.1 CHCl3). GC-MS (70 eV) M=343 (29%). The hydrochloride salt was made by dissolving the base in diethyl ether and dropping an excess of an ethereal HCl solution. The salt was recrystallized from ethanol/diethyl ether to give a white solid. Mp: 177°-9° C.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(CCN(C)C)C.[Li]C(CC)C.CN([CH:30]=[O:31])C>CCOCC>[C:1]([N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[CH:30]=[O:31])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCCCC1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCCCC1C=O
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 60.8 %

Procedure:
A solution of N-Boc-Piperidine (6.0 g, 32.4 mmol) in ether (65 mL) was cooled to −60° C. and treated with TMEDA (4.9 mL, 32.4 mmol) followed by sec-BuLi (54.8 mL, 71.2 mmol) dropwise. The mixture was slowly warmed to −20° C. and stirred for 10 min and then cooled to −78° C. The mixture was treated with a solution of DMF (3.8 mL, 48.6 mmol) in 6 mL of ether via syringe, stirred for 10 min, and then quenched with 60 mL saturated ammonium chloride solution. The mixture was warmed to room temperature, and the organic layer was separated. The aqueous layer was extracted three times with ether, and the combined extracts were dried over K2CO3. The organic layer was concentrated to give a crude product as an orange oil. Purification by column chomatography on silica gel with hexanes:EtOAc (4: 1) afforded 4.2 g (67%) of the product as a clear oil which was homogeneous by TLC analysis. 1H NMR (300 MHz) δ9.58 (s, 1 H), 4.69-4.51 (br. m, 1 H), 4.12-3.85 (br. m, 1 H), 2.85 (br. s, 1 H), 2.19-2.13 (d, 1 H), 1.72-1.23 (m, 15 H); 13C NMR (75 MHz) 201.4 (s), 80.4 (s), 43.0 (br. s), 28.3 (s), 24.7 (s), 23.6 (s), 20.9 (s) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[C:10]([Cl:14])=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[CH3:15][O:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([NH2:24])[CH:19]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(OCC)(=O)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:15][O:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C:6](=[O:8])[CH2:5][O:4][C:3]2[CH:9]=[C:10]([Cl:14])[C:11]([Cl:13])=[CH:12][C:2]=2[Cl:1])[CH:19]=1
Reactant: COC(=O)c1ccnc(N)c1
Reactant: O=C(O)COc1cc(Cl)c(Cl)cc1Cl
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccnc(NC(=O)COc2cc(Cl)c(Cl)cc2Cl)c1
Yield: 24.4 %

Procedure:
To solution of (2,4,5-trichloro-phenoxy)-acetic acid (150 mg, 0.59 mmol), 2-amino isonicotinic acid methyl ester (179 mg, 1.18 mmol) and DMAP (144 mg, 1.18 mmol) in DMF 13 mL was added PyBOP (614 mg, 1.18 mmol) at room temperature. Reaction mixture was stared at room temperature. Resulting mixture poured onto ice cold water, was diluted by ethyl acetate. The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The residue was purified by flash silica gel column chromatography (EtoAC:Hexane=1:1) to give 2-[2-(2,4,5-trichloro-phenoxy)-acetylamino]-isonicotinic acid methyl ester as a colorless solid (0.056 g, 24.45% yield).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH2:9][C:10]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[N:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:4][CH2:3]1.C([N-]C(C)C)(C)C.[Li+].[CH:34](=[O:37])[CH2:35][CH3:36].O>O1CCCC1.C(Cl)(Cl)Cl>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]([CH:34]([OH:37])[CH2:35][CH3:36])[C:10]([N:19]3[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]3)=[N:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(C2=Nc3ccccc3N=C(N3CCN(C)CC3)C2)CC1
Reactant: CCC=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CCC(O)C1C(N2CCN(C)CC2)=Nc2ccccc2N=C1N1CCN(C)CC1
Temperature: -30 °C
Yield: 92 %

Procedure:
A suspension of 2,4-bis(4-methyl-1-piperazinyl)-3H-[1,5]benzodiazepine (17.024 g, 50 mmol) in tetrahydrofuran (200 ml) under constant flow of argon was cooled to −30° C. A solution of lithium diisopropylamide (LDA) (2 M, 37.5 ml, 75 mmol) was added dropwise. Thus obtained dark brown suspension was allowed to warm to −5° C., and then again cooled to −30° C. Propionaldehyde (5.50 ml, 75 mmol) was added during 5 min. The resulting pale brown suspension was allowed to warm to 10° C., while strongly agitated water (250 ml) was added. The solution was transferred to a separating funnel, chloroform (150 ml) was added and the phases were separated. The water phase was extracted with chloroform (2×50 ml). The combined organic phases were dried over anhydrous Na2SO4 and the solvent was evaporated at reduced pressure. The crude product was suspended in hexane (750 ml), filtered off and washed with hexane (75 ml) to give 18.34 g (92%) of the title compound as an off-white powder. For analytical purposes the product was recrystallised from ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N+:15]([O-:18])=[N:14][CH:13]=[C:12]([CH3:19])[C:11]=2[C:10](=O)[CH2:9]1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].Cl.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N+:15]([O-:18])=[N:14][CH:13]=[C:12]([CH3:19])[C:11]=2[C:10](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:9]1
Reactant: Cc1cn[n+]([O-])c2c1C(=O)CC(c1ccccc1Cl)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: Cc1cn[n+]([O-])c2c1C(=NNC(=N)N)CC(c1ccccc1Cl)C2
Temperature: 90 °C
Reaction time: 3.5 h
Yield: 170.7 %

Procedure:
To a mixture of 7-(2-chlorophenyl)-4-methyl-5,6,7,8-tetrahydrocinnolin-5-one-1-oxide (173 mg) and aminoguanidine hydrochloride (73 mg) were added ethanol (4 ml) and concentrated hydrochloric acid (0.07 ml), and the mixture was stirred at 90° C. (bath temperature) for 3.5 hours. The reaction solution was cooled to room temperature, and the resulting crystals were filtered and dried to give 7-(2-chlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydrocinnolin-1-oxide hydrochloride (Compound 159) (195 mg) as colorless crystals.
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([C:7]([NH:9][CH2:10][C:11]([OH:13])=O)=[O:8])=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH3:52][N:53]([CH:64]1[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[C:60]([F:63])([F:62])[F:61]>CN(C=O)C.O>[CH3:52][N:53]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[C:60]([F:63])([F:61])[F:62])[CH:64]1[CH2:69][CH2:68][N:67]([C:11](=[O:13])[CH2:10][NH:9][C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:66][CH2:65]1
Reactant: CN(c1ccccc1C(F)(F)F)C1CCNCC1
Reactant: O=C(O)CNC(=O)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN(c1ccccc1C(F)(F)F)C1CCN(C(=O)CNC(=O)c2ccc(-c3ccccc3)cc2)CC1
Reaction time: 8 h
Yield: 17.9 %

Procedure:
To a stirred solution of [(biphenyl-4-carbonyl)-amino]-acetic acid (0.075 g, 0.00029 mol) in DMF (3 mL), was added DIPEA (0.1519 g, 0.00117 mol), HOBt (0.03981 g, 0.00029 mol) and EDCI.HCl (0.06758 g, 0.00035 mol) at ambient temperature. After 2 minutes methyl-piperidin-4-yl-(2-trifluoromethyl-phenyl)-amine hydrochloride (0.06959 g, 0.00026 mol) was added and the resulting mixture was stirred at the same temperature overnight. The reaction mixture was diluted with cold water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed aqueous sodium bicarbonate solution followed by brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to afford 0.023 g (16%) of biphenyl-4-carboxylic acid (2-{4-[methyl-(2-trifluoromethyl-phenyl)-amino]-piperidin-1-yl}-2-oxo-ethyl)-amide. LCMS: 496.2 (M+1)+, 98.28%, 1H NMR (DMSO-d6): δ 8.6 (t, 1H), 7.56-7.3 (m, 4H), 7.8-7.6 (m, 7H), 7.98 (d, 2H), 4.4 (bs, 1H), 4.15 (d, 2H), 3.9 (bs, 1H), 3.2-2.9 (m, 2H), 1.7 (bs, 2H), 1.5-1.2 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:12][C:13]([O:16][C:17]([N:19]1[CH2:25][C:24]2[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:23]=2[O:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:27]2[CH:28]=[CH:29][C:23]3[O:22][CH2:21][CH2:20][N:19]([C:17]([O:16][C:13]([CH3:14])([CH3:12])[CH3:15])=[O:18])[CH2:25][C:24]=3[CH:26]=2)=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ncc(Br)cc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(B(O)O)cc2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOc2ccc(-c3cnc(N)c([N+](=O)[O-])c3)cc2C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
A suspension of 5-bromo-3-nitropyridin-2-amine (4.84 g, 22.2 mmol), (4-{[(1,1-dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)boronic acid (6.51 g, 22.2 mmol), dichloro[1,1-bis(diphenyl)phosphino]ferrocenepalladium (II) dichloromethane adduct (1.60 g, 10 mol %) in dioxane (75 mL) and water (15 mL) was degassed with nitrogen, and then cesium carbonate (14.46 g, 44.4 mmol) was added. The reaction mixture was stirred at 90° C. overnight. The mixture was cooled to room temperature, water (150 mL) was added and stirred for 30 min to give a precipitate. The product 1,1-dimethylethyl 7-(6-amino-5-nitropyridin-3-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (8.1 g, 94% yield) was collected by filtration, dried under vacuum. MS (EI) for C19H22N4O5: 387.1 (MH+).
Reaction SMILES: [C:1]([NH2:4])(=[NH:3])[CH3:2].[Cl:5][C:6]1[CH:7]=[C:8]([CH:15]=[CH:16][C:17]=1[Cl:18])[CH:9]=[CH:10][S:11](Cl)(=[O:13])=[O:12]>>[Cl:5][C:6]1[CH:7]=[C:8]([CH:15]=[CH:16][C:17]=1[Cl:18])[CH:9]=[CH:10][S:11]([NH:3][C:1](=[NH:4])[CH3:2])(=[O:13])=[O:12]
Reactant: CC(=N)N
Reactant: O=S(=O)(Cl)C=Cc1ccc(Cl)c(Cl)c1
Product: CC(=N)NS(=O)(=O)C=Cc1ccc(Cl)c(Cl)c1

Procedure:
Reaction of acetamidine with 3,4-dichlorostyrylsulfonyl chloride according to the above procedure affords N-[(3,4-DICHLOROSTYRYL)SULFONYL]ACETAMIDINE, m.p. 197.5°-198.5° C. (corr.), crystallized from acetone-isopropanol.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].C([O-])([O-])=O.[Na+].[Na+].[NH2:24][CH2:25][CH:26]([OH:28])[CH3:27]>O>[OH:28][CH:26]([CH3:27])[CH2:25][NH:24][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Reactant: CC(O)CN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(O)CNc1c([N+](=O)[O-])cc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 1 h

Procedure:
27 g of 4-chloro-5-trifluoromethyl-1,3-dinitrobenzene are initially introduced into 100 ml of water with 5.3 g of Na2CO3, and 13.5 g of 1-aminopropan-2-ol are added at 80° C. in the course of 30 minutes. The mixture is subsequently stirred at 80° C. for one hour and then cooled to room temperature, and the product which has precipitated is filtered off and dried in a vacuum drying cabinet.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[CH3:32][NH:33][CH2:34][CH2:35][CH2:36][CH3:37]>C(Cl)Cl>[C:2]([O:4][C@H:5]1[C:14]2[C@:15]3([CH3:30])[C:16](/[C:17](=[CH:18]\[N:33]([CH2:34][CH2:35][CH2:36][CH3:37])[CH3:32])/[C:23](=[O:24])[O:25][C@@H:26]3[CH2:27][O:28][CH3:29])=[C:20]([OH:19])[C:21](=[O:22])[C:13]=2[CH:8]2[C@@:7]([CH3:31])([C@@H:11]([OH:12])[CH2:10][CH2:9]2)[CH2:6]1)(=[O:3])[CH3:1]
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Reactant: CCCCNC
Solvent: ClCCl
Product: CCCCN(C)/C=C1/C(=O)O[C@H](COC)[C@@]2(C)C1=C(O)C(=O)C1=C2[C@H](OC(C)=O)C[C@@]2(C)C1CC[C@@H]2O
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
To a solution of 50 mg (0.12 mmol) 17-hydroxywortmannin in 0.5 mL CH2Cl2 is added 20.9 mg (0.24 mmol) N-methylbutylamine. The reaction mixture is stirred at room temperature overnight. CH2Cl2 is removed in vacuo. The residue is triturated with Et2O to give 38 mg (61.2%) product as an orange powder. MS (ESI) m/z 518.25 (M+1).