Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:23][C@H:24]1[CH2:29][C:28]2[C:30]([N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)=[CH:31][CH:32]=[CH:33][C:27]=2[O:26][CH2:25]1>CN(C)C=O>[CH3:40][N:37]1[CH2:38][CH2:39][N:34]([C:30]2[C:28]3[CH2:29][C@H:24]([NH:23][C:7]([C:6]4[CH:5]=[N:4][CH:3]=[C:2]([CH3:1])[CH:10]=4)=[O:9])[CH2:25][O:26][C:27]=3[CH:33]=[CH:32][CH:31]=2)[CH2:35][CH2:36]1
Reactant: Cc1cncc(C(=O)O)c1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CO3)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1cncc(C(=O)N[C@@H]2COc3cccc(N4CCN(C)CC4)c3C2)c1
Temperature: 25 °C
Reaction time: 28 h
Yield: 34.5 %

Procedure:
A solution of 5-methylnicotinic acid (141 mg, 1.03 mmol) and 1,1′-carbonyldiimidazole (183 mg, 1.13 mmol) in anhydrous N,N-dimethylformamide (5 mL) was stirred at 75° C. for 55 min. The mixture was allowed to cool, and a solution of (S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran (232 mg, 0.94 mmol) in N,N-dimethylformamide (5 mL) was added. The reaction mixture was stirred at room temperature for 28 h. The solvent was removed in vacuo, and the residue was purified by column chromatography on silica (eluent: chloroform/ethanol; 87:13+0.5% NH3). The product was contaminated with a large amount of imidazole which could be removed by the following procedure: The mixture was dissolved in diethyl ether (100 mL), washed with water (2×20 mL) and treated with brine (10 mL). The ethereal layer was dried (MgSO4), and the solvent was removed in vacuo to give 119 mg (35% yield) of the title compound as a white solid: mp sinters>68° C.; [α]21D−82° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 366 (21, M30 ).
Reaction SMILES: [OH:1][C:2]1[N:3](C(OC(C)(C)C)=O)[C:4]([C:7]([O:9][CH3:10])=[O:8])=[N:5][N:6]=1.[CH3:18][O:19][CH2:20][CH2:21]O.CCOC(/N=N/C(OCC)=O)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[CH3:18][O:19][CH2:20][CH2:21][O:1][C:2]1[NH:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[N:5][N:6]=1
Reactant: COCCO
Reactant: COC(=O)c1nnc(O)n1C(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCOc1nnc(C(=O)OC)[nH]1
Reaction time: 15 h
Yield: 54.9 %

Procedure:
To a solution of 4-tert-butyl 3-methyl 5-hydroxy-4H-1,2,4-triazole-3,4-dicarboxylate (0.170 g, 0.453 mmol) in THF (4 mL) was added 2-methoxyethanol (0.053 mL, 0.672 mmol), DEAD (0.107 mL, 0.682 mmol), PPh3 (0.142 g, 0.542 mmol) and stirred at it for 15 h. Reaction concentrated and ISCO purification (0-5% MeOH in DCM) to get methyl 5-(2-methoxyethoxy)-4H-1,2,4-triazole-3-carboxylate (0.050 g) as a colorless oil.
Reaction SMILES: [CH2:1]([OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].N1C=CN=C1.[C:20]([Si:24](Cl)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C>[Si:24]([O:14][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])([C:20]([CH3:23])([CH3:22])[CH3:21])([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCCCCCCCCCCCCO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCCCCCCCCCCCCO)(c1ccccc1)c1ccccc1
Temperature: 45 °C
Reaction time: 48 h
Yield: 46 %

Procedure:
In a Schlenk flask, 1,12-Dodecandiol (7.96 g, 39.4 mmol, 1 eq) was dissolved in 40 mL of dry DMF under nitrogen. Imidazole (2.63 g, 38.6 mmol, 1 eq) and tert-butylchlorodiphenylsilane (TBDPS) (10.84 g, 39.4 mmol, 1 eq) were added and the reaction mixture was heated to 45° C. After stirring for 48 h, the reaction was quenched with 300 mL of distilled water. The aqueous phase was extracted four times with diethyl ether, the organic phases were collected and washed twice with 2N HCl (2×100 mL), once with saturated NaHCO3 (200 mL), once with saturated NaCl (200 mL) and dried over Na2SO4. Column-chromatography over silica gel using 10/1 hexane/ethyl acetate as eluent yielded 7.98 g (46%) of the desired product as a slightly yellowish oil. 1H NMR (300.13 MHz): δ (ppm)=1.05 (s, 9H, tert-butyl), 1.26 (br, 16H, —O—CH2—CH2—CH2—CH2—CH2—), 1.58 (m, 4H, —O—CH2—CH2—), 3.65 (m, 4H, —O—CH2—), 7.40 (m, 6H, phenyl), 7.69 (m, 4H, phenyl). 13C NMR (75.48 MHz): δ (ppm)=19.2, 25.7, 25.8, 25.9, 29.3, 29.4, 29.58, 29.6, 32.6, 32.8, 63.1, 64.0, 127.5, 129.4, 134.1, 135.6.
Reaction SMILES: [Na].[C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[N:12])=[N:9][CH:10]=1)([OH:4])=[O:3].[CH2:13]([CH2:15]N)[OH:14].Cl>CO>[C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[O:14][CH2:13][CH2:15][N:12]=2)=[N:9][CH:10]=1)([OH:4])=[O:3]
Reactant: N#Cc1ccc(C(=O)O)cn1
Reactant: NCCO
Agent: Cl
Agent: [Na]
Solvent: CO
Product: O=C(O)c1ccc(C2=NCCO2)nc1

Procedure:
Under a nitrogen atmosphere, sodium (12 mmol) is added to a flask containing 10 ml of anhydrous methanol. After the sodium has dissolved, a solution of 5-carboxy-2-cyano-pyridine (5 mmol) in 5 ml of methanol is added dropwise. The mixture is heated at 50° for 1.5 h. The mixture is allowed to cool and a solution of ethanolamine (10 mmol) in a mixture of 5 ml methanol and 1.5 of concentrated HCl is added dropwise. After addition is complete, the reaction mixture is refluxed for 2 h. The solvent is evaporated, the residue dissolved in 45 ml of hot ethanol, the salts are filtered off and the filtrate on cooling gives crystals of the title compound, m.p. 286°-287°.
Reaction SMILES: C([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]([CH3:22])[CH2:17][C:18](=[O:21])[NH:19][N:20]=2)=[CH:11][C:10]=1[N+:23]([O-])=O)C1C=CC=CC=1.CO.Cl>[Pd].O>[NH2:23][C:10]1[CH:11]=[C:12]([C:15]2[CH:16]([CH3:22])[CH2:17][C:18](=[O:21])[NH:19][N:20]=2)[CH:13]=[CH:14][C:9]=1[NH2:8]
Reactant: CC1CC(=O)NN=C1c1ccc(NCc2ccccc2)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: CC1CC(=O)NN=C1c1ccc(N)c(N)c1

Procedure:
6-(4-Benzylamino-3-nitrophenyl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one was mixed with methanol and a separately prepared mixture of Pd/C catalyst, water and hydrochloric acid. After hydrogenation, the reaction mixture was filtered and the filtrate was alkalined with a sodium hydroxide solution. The precipitate was filtered, rinsed with water and methanol, filtered and dried, to obtain 6-(3,4-diaminophenyl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9](=[O:12])[C:8]2[CH:7]=[C:6]([C:13]([O:15]C)=[O:14])[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].Cl>C(O)C.C1COCC1>[CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9](=[O:12])[C:8]2[CH:7]=[C:6]([C:13]([OH:15])=[O:14])[CH:5]=[CH:4][C:3]1=2
Reactant: COC(=O)c1ccc2c(c1)C(=O)CCC2(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CCC(=O)c2cc(C(=O)O)ccc21
Reaction time: 16 h

Procedure:
To a solution of methyl-5,5-dimethyl-5,6-dihydro-naphthalen-8(7H)-one-2-carboxylate (Compound E2, 1.05 g, 4.5 mmol) in 10 mL of ethanol and THF (10 mL) was added sodiumhydroxide 9 mL (1M solution). The solution was stirred for 16 h and thereafter acidified with 10% HCl. The mixture was extracted with ethyl acetate, the combined organic layer was washed with water and brine, and dried over MgSO4. The solvent was distilled off under reduced pressure to afford the title compound as a white solid.
Reaction SMILES: [CH:1]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:19])[CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[OH:20].[O:21](S(C(F)(F)F)(=O)=O)[S:22]([C:25]([F:28])([F:27])[F:26])(=O)=[O:23].Cl>C(Cl)Cl.N1C=CC=CC=1>[F:26][C:25]([F:28])([F:27])[S:22]([O:20][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11](=[CH:10][C:9]([O:19][S:22]([C:25]([F:26])([F:27])[F:28])(=[O:21])=[O:23])=[CH:8][CH:7]=3)[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[CH:1]=1)(=[O:23])=[O:21]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Oc1ccc2c3ccc(O)cc3c3ccccc3c2c1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Oc1ccc2c3ccc(OS(=O)(=O)C(F)(F)F)cc3c3ccccc3c2c1)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Triphenylene-2,7-diol (314 mg, 1.2 mmol) was dissolved in DCM (13 mL) and pyridine (1 mL). The solution was cooled to 0° C. and Tf2O (0.48 mL, 2.65 mmol) was added dropwise. After stirring for 2 h, the reaction mixture was poured into HCl (1N) and extracted with DCM. The organic layer was washed with brine, dried over MgSO4, and concentrated. Taken on crude.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[CH:2]=1.CN1CCOCC1.[Si](I)(C)(C)C>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(c2cccnc2)c2cccnc2)CC1
Agent: C[Si](C)(C)I
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: c1cncc(C(c2cccnc2)N2CCNCC2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 65.4 %

Procedure:
A round bottom flask was charged with tert-butyl 4-(di(pyridin-3-yl)methyl)piperazine-1-carboxylate (220 mg, 0.621 mmol), CH2Cl2 (20 mL), and NMM (136 μL, 1.23 mmol). The reaction was cooled to 0° C. and TMSI (106 μL, 0.745 mmol) was added dropwise. After 10 min at 0° C., additional TMSI (100 μL, 0.700 mmol) was added. After stirring 10 min at 0° C. the reaction was allowed to warm to room temperature. After 15 min at room temperature the reaction was diluted in CH2Cl2 and washed (1×) sat Na2CO3. The organics were dried (Na2SO4), filtered, and concentrated and yielded 103 mg crude product (0.406 mmol, 65%) as a yellow oil, which was used without further purification in the next step. 1H NMR 400 MHz (CDCl3) δ 8.64 (d, J=2.4 Hz, 2H), 8.47 (dd, J=4.8, 1.6 Hz, 2H), 7.70 (dt, J=8.0, 2.0 Hz, 2H), 7.23 (dd, J=7.9, 4.8 Hz, 2H), 4.36 (s, 1H), 2.91 (t, J=4.9 Hz, 4H), 2.38 (t, J=5.0 Hz, 5H). LCMS (ESI, m/z): 255 [M+H]+.
Reaction SMILES: [Li]CCCC.CC1(C)CCCC(C)(C)N1.C(=O)=O.[F:19][C:20]1[CH:25]=[N:24][CH:23]=[CH:22][N:21]=1.[O:26]1[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]1>C1COCC1.CCCCCC>[F:19][C:20]1[C:25]([C:29]2([OH:32])[CH2:30][CH2:31][O:26][CH2:27][CH2:28]2)=[N:24][CH:23]=[CH:22][N:21]=1
Reactant: O=C1CCOCC1
Reactant: Fc1cnccn1
Agent: CC1(C)CCCC(C)(C)N1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC1(c2nccnc2F)CCOCC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A 2.5M solution of nBuLi (4.49 mL, 11.22 mmol)/hexane in THF (3 mL) was first cooled to −78° C. To the cooled solution was added dropwise, 2,2,6,6-tetramethylpiperidine (2.065 mL, 12.24 mmol). The dry ice bath was then switched to a 0° C. bath. The reaction mixture was stirred for 10 min at 0° C. and then the dry ice bath was switched back to recool the reaction mixture to −78° C. To the cooled solution was added 2-fluoropyrazine (1 g, 10.20 mmol), dropwise. After 5 min of stirring at −78° C., a solution of dihydro-2H-pyran-4(3H)-one (0.937 mL, 10.20 mmol) in 0.6 mL of THF was added dropwise. The resulting mixture was allowed to gradually warm to room temperature overnight. Reaction was quenched with saturated NH4Cl and extracted with EtOAc. Purification by Biotage (0-100% EtOAc/hexane) produced product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([CH2:23][NH:24]C(=O)OC(C)(C)C)=[N:21][N:22]=3)[N:19]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13].C(O)(C(F)(F)F)=O.C(Cl)Cl>>[NH2:24][CH2:23][C:20]1[N:18]2[N:19]=[C:14]([C:4]3[CH:5]=[CH:6][C:7]([N:8]4[CH2:12][CH2:11][CH2:10][C:9]4=[O:13])=[C:2]([F:1])[CH:3]=3)[CH:15]=[CH:16][C:17]2=[N:22][N:21]=1
Reactant: CC(C)(C)OC(=O)NCc1nnc2ccc(-c3ccc(N4CCCC4=O)c(F)c3)nn12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1nnc2ccc(-c3ccc(N4CCCC4=O)c(F)c3)nn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 50 mL recovery flask was charged with tert-butyl (6-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (0.117 g, 0.274 mmol), TFA (0.0211 ml, 0.274 mmol), and DCM (0.0177 ml, 0.274 mmol), then stirred open to air at room temperature for 2 hours. The mixture was concentrated, then taken up in MeOH. K2CO3 was added, and this was stirred for 1 hour. The mixture was concentrated, then the residue was taken up in MeOH/CHCl3 then filtered. The filtrate was evaporated, taken up in water, then passed through a reverse phase C18 column, eluting with MeOH/DCM, then concentrated.
Reaction SMILES: [CH2:1]1[CH:13]2[CH:5]([C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:12]2=O)[CH2:4][CH2:3][CH2:2]1.[CH3:15][Mg]Br.Cl>O1CCCC1>[CH3:15][C:12]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]2[C:13]=1[CH2:1][CH2:2][CH2:3][CH2:4]2
Reactant: C[Mg]Br
Reactant: O=C1C2=C(CCCC2)C2CCCCC12
Agent: Cl
Solvent: C1CCOC1
Product: CC1=C2CCCCC2C2=C1CCCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.8 %

Procedure:
To a solution of 1,2,3,4,4a,5,6,7,8,9a-decahydrofluoren-9-one (90.7 mg, 0.477 mmol) in tetrahydrofuran (5 ml), 0.35 ml (1.05 mmol) of methylmagnesium bromide (3.0 M in Et2O) was added dropwise under nitrogen at −78° C. The resulting cloudy mixture was kept at −78° C. for 3 hours and then allowed to warm to room temperature and stirred for 14 hours. The reaction mixture was acidified with 15% aqueous HCl (5 ml), followed by extraction in Et2O (4×20 ml). All organic layers were combined, washed with water, brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give 82.5 mg (92%) of 2,3,4,4a,5,6,7,8-octahydro-9-methyl-1H-fluorene and 1,3,4,5,6,7,8,9a-octahydro-9-methyl-2H-fluorene in the ratio of 3 to 1. 1H-NMR (CDCl3): δ 2.6–0.9 (m), 13C NMR: 155.77, 136.49, 133.51, 111.70, 61.12, 50.29, 42.14, 29.74, 27.41, 25.46, 25.11, 23.38, 22.81.
Reaction SMILES: [N:1]1([C:7]2[CH2:8][CH2:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1>C(O)(=O)C.C(Cl)Cl>[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH2:8][CH2:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:23][CH:22]=1
Reactant: FC(F)(F)c1nnc2n1N=C(N1CCNCC1)CC2
Reactant: O=Cc1ccc(F)cc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: Fc1ccc(CN2CCN(C3=Nn4c(nnc4C(F)(F)F)CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.9 %

Procedure:
(Polystyrylmethyl)trimethylammonium cyanoborohydride (4.1 mmol/g, 125 mg, 0.510 mmol) was added to 6-(piperazin-1-yl)-3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazine (100 mg, 0.365 mmol) and 4-fluorobenzaldehyde (63 mg, 0.510 mmol) in 10% acetic acid in DCM (2.2 mL). The resulting mixture was stirred at ambient temperature for 16 hours, then the resin removed by filtration and the solvents evaporated. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to give 6-[4-(4-fluorobenzyl)piperazin-1-yl]-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine (85 mg, 61%) as a solid. 1H NMR (399.9 MHz, DMSO-d6) δ 2.44 (4H, m), 2.88 (2H, t), 3.13 (2H, t), 3.52 (6H, m), 7.16 (2H, m), 7.36 (2H, m); m/z=383 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[CH2:10][C:11](=[NH:13])[NH2:12].C[O-].[Na+].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28]([CH:29]3[CH2:31][CH2:30]3)[C:27](=[O:32])[N:26]([CH2:33][C:34]([NH:36]N)=O)[N:25]=2)=[CH:20][CH:19]=1>CO>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28]([CH:29]3[CH2:31][CH2:30]3)[C:27](=[O:32])[N:26]([CH2:33][C:34]3[NH:12][C:11]([CH2:10][C:4]4[C:3]([Cl:2])=[CH:8][CH:7]=[CH:6][C:5]=4[Cl:9])=[N:13][N:36]=3)[N:25]=2)=[CH:20][CH:19]=1
Reactant: NNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Reactant: N=C(N)Cc1c(Cl)cccc1Cl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=c1n(Cc2nnc(Cc3c(Cl)cccc3Cl)[nH]2)nc(-c2ccc(Cl)cc2)n1C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
58 mg (0.24 mmol) of 2-(2,6-dichlorophenyl)ethaneimidamide hydrochloride were initially charged in 1 ml of dry methanol, 66 μl (0.24 mmol) of a 25% strength methanolic sodium methoxide solution were added and the mixture was stirred at RT for 1 h. 50 mg (0.16 mmol) of the compound from Example 21A, dissolved in 0.6 ml of methanol, were then added. The reaction was stirred at room temperature overnight. The precipitated colorless solid was filtered off with suction, washed with a little methanol and dried under high vacuum. The solid was then suspended in xylene and stirred under reflux for 4 h. After cooling, the mixture was concentrated under reduced pressure and the residue was purified by chromatography [Method 19]. This gave 30 mg (39% of theory) of the target compound as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:17]2([O:23][CH3:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[S:5][C:6]=1[S:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=O)[CH3:15])=[CH:10][CH:9]=1.Cl.[NH2:26][OH:27]>>[Br:1][C:2]1[N:3]=[C:4]([C:17]2([O:23][CH3:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[S:5][C:6]=1[S:7][C:8]1[CH:13]=[CH:12][C:11](/[C:14](=[N:26]/[OH:27])/[CH3:15])=[CH:10][CH:9]=1
Reactant: COC1(c2nc(Br)c(Sc3ccc(C(C)=O)cc3)s2)CCOCC1
Reactant: NO
Agent: Cl
Product: COC1(c2nc(Br)c(Sc3ccc(/C(C)=N/O)cc3)s2)CCOCC1
Yield: 96 %

Procedure:
Using an analogous procedure to that described in Example 15, 4'-[4-bromo-2-(4-methoxytetrahydropyran-4-yl)thiazol-5-ylthio]acetophenone was reacted with hydroxylamine hydrochloride to give (E)-4'-[4-bromo-2-(4-methoxytetrahydropyran-4-yl)thiazol-5-ylthio]acetophenone oxime in 96% yield, m.p. 130° C.;
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:34]#[C:35][C:36]([CH3:45])([CH3:44])[CH2:37][CH2:38][O:39][Si](C)(C)C)=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:25][CH2:24][CH:23]([O:26][Si](C(C)(C)C)(C)C)[CH2:22][CH2:21]1)[C:11]([CH:13]1[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[O:46]1[CH2:51][CH2:50][C:49](=O)[CH2:48][CH2:47]1.C([SiH](CC)CC)C.C([O-])(O)=O.[Na+]>[N+](C)([O-])=O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:34]#[C:35][C:36]([CH3:45])([CH3:44])[CH2:37][CH2:38][O:39][CH:49]2[CH2:50][CH2:51][O:46][CH2:47][CH2:48]2)=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([CH:13]1[CH2:14][CH2:15][CH:16]([CH3:19])[CH2:17][CH2:18]1)=[O:12])=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)CCO[Si](C)(C)C)cc1N(C(=O)C1CCC(C)CC1)C1CCC(O[Si](C)(C)C(C)(C)C)CC1
Reactant: O=C1CCOCC1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C[N+](=O)[O-]
Product: COC(=O)c1sc(C#CC(C)(C)CCOC2CCOCC2)cc1N(C(=O)C1CCC(C)CC1)C1CCC(O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 4.8 %

Procedure:
3-[[4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexyl]-(4-methyl-cyclohexanecarbonyl)-amino]-5-(3,3-dimethyl-5-trimethylsilanyloxy-pent-1-ynyl)-thiophene-2-carboxylic acid methyl ester (230 mg, 0.34 mmol) was added to a solution of tetrahydro-pyran-4-one (29 mg, 0.29 mmol) and FeCl3 (2.8 mg, 0.017 mmol) in nitromethane (5.0 mL) at 0° C. Triethylsilane (0.054 mL, 0.34 mmol) was added and the reaction warmed to room temperature and stirred for 2 h. Sat. NaHCO3 was added and the reaction extracted with dichloromethane. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated to give the crude product. Purification by HPLC with CH3CN (0.1% TFA)/H2O (0.1% TFA) provided 5-[3,3-dimethyl-5-(tetrahydro-pyran-4-yloxy)-pent-1-ynyl]-3-[(4-hydroxy-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (8 mg, 4%) as solid.
Reaction SMILES: [C:1]1(C)C=CC=CC=1.Br[C:9]1[CH:10]=[CH:11][C:12]([NH2:17])=[C:13]([CH:16]=1)[CH2:14][NH2:15]>CCOC(C)=O>[NH:17]1[C:12]2[C:13](=[CH:16][CH:9]=[CH:10][CH:11]=2)[CH:14]=[N:15][CH2:1]1
Reactant: Cc1ccccc1
Reactant: NCc1cc(Br)ccc1N
Solvent: CCOC(C)=O
Product: C1=NCNc2ccccc21
Temperature: 25 °C

Procedure:
To toluene (200 mL), 5-bromo-2-amino-benzylamine (9.5 g, 47.2 mmol) and trimethylbenzoic orthoester (8.2 g, 47.2 mmol) were added, followed by p-toulensulfonic acid (1.35 g, 7.1 mmol). The resulting suspension was stirred at reflux for 50 hours. The reaction mixture was cooled at r.t., diluted with AcOEt (150 mL), washed with saturated sodium bicarbonate, then with water. The organic layer was dried and concentrated to provide the intermediate dihydroquinazoline as a light brown solid (8.5 g; 63%). This intermediate is dissolved in DCM (20 mL) at r.t., then MnO2 (5.1 g) was added. The resulting mixture was stirred at r.t. for 48 hrs, then filtered on celite. The filtrate was concentrated to provide the title product as white solid (8.1 g, 95%). C14H9BrN2; MW: 285.15; MS m/z: 286 (M+1). 1H-NMR (300 MHz, d6-DMSO) ppm: 7.58-7.61 (m, 3H), 8.02 (d, 1H), 8.17 (dd, 1H), 8.49-8.56 (m, 3H), 9.70 (s, 1H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[C:8]([CH3:10])[N:7]=[C:6]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:5]=1.Cl[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1.O>CN(C=O)C>[Cl:3][C:4]1[N:9]=[C:8]([CH3:10])[N:7]=[C:6]([N:11]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:5]=1
Reactant: COc1ccc(CNc2cc(Cl)nc(C)n2)cc1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(Cl)nc(C)n2)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 98.9 %

Procedure:
Sodium hydride (60 wt % in mineral oil) (0.340 g, 8.51 mmol) was added in one portion to a mixture of 6-chloro-N-(4-methoxybenzyl)-2-methylpyrimidin-4-amine (1.87 g, 7.09 mmol) and 1-(chloromethyl)-4-methoxybenzene (1.059 mL, 7.80 mmol) in DMF (50 mL) at 0° C. The resulting mixture was stirred at 0° C. for 5 min and then was warmed to 25° C. and stirred for 2 h. Water (200 mL) was then added, and the precipitated solid was collected by vacuum filtration, washed with water (150 mL), and dried in vacuo to furnish 6-chloro-N,N-bis(4-methoxybenzyl)-2-methylpyrimidin-4-amine (2.69 g, 7.01 mmol, 99% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.11 (d, J=7.24 Hz, 4H); 6.86 (d, J=7.24 Hz, 4H); 6.26 (s, 1H); 4.65 (br. s., 4H); 3.80 (s, 6H); 2.53 (s, 3H). m/z (ESI, +ve ion) 384.1 (M+H)+.
Reaction SMILES: [C:1]([N:20]1[CH2:25][CH2:24][CH:23]([C:26]([OH:28])=O)[CH2:22][CH2:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([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.[CH3:30][O:31][NH:32][CH3:33].C(N(CC)CC)C.CCN=C=NCCCN(C)C>ClCCl>[CH3:33][N:32]([O:31][CH3:30])[C:26]([CH:23]1[CH2:22][CH2:21][N:20]([C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:25][CH2:24]1)=[O:28]
Reactant: CNOC
Reactant: O=C(O)C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 1-tritylpiperidine-4-carboxylic acid (7.0 g), O,N-dimethylhydroxylamine hydrochloride (2.0 g) and triethylamine (2.9 ml) in dichloromethane (70 ml) was added WSC (3.97 g), and the mixture was stirred at room temperature for 1 hour and concentrated. To the residue was added ethyl acetate, and the mixture was washed with water, dried (MgSO4) and concentrated. The resulting crystals (6.3 g) were washed with isopropylether.