Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[CH2:17][CH2:16][O:15][C:14]4[CH:18]=[C:19]([C:22]([O:24]C)=[O:23])[CH:20]=[N:21][C:13]=4[N:12]3[CH:26]=2)=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[Li+].[OH-].Cl>CO.O1CCCC1>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[CH2:17][CH2:16][O:15][C:14]4[CH:18]=[C:19]([C:22]([OH:24])=[O:23])[CH:20]=[N:21][C:13]=4[N:12]3[CH:26]=2)=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1cnc2c(c1)OCCc1nc(-c3ccnn3C(C)C)cn1-2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)n1nccc1-c1cn2c(n1)CCOc1cc(C(=O)O)cnc1-2
Reaction time: 6 h

Procedure:
A mixture of 21 mg (0.06 mmol) of methyl 9-(1-isopropyl-1H-pyrazol-5-yl)-6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepine-3-carboxylate and 1.0 ml of 1 N aq LiOH in 4 ml of methanol and 4 ml of tetrahydrofuran was stirred for 6 hours. The mixture was acidified to pH 3 by addition of 1 N HCl and concentrated in vacuum. The residue was partitioned between ethyl acetate and water, the organic layer was washed with brine, dried over Na2SO4 and concentrated. Yield 17 mg. MS(ESI+): 340.1
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[N:26]=[C:27](Br)[S:28][C:29]=2[NH:30]C(=O)OC(C)(C)C)=[O:24])[CH2:12][CH2:11]1)=O)CCC.[CH:39]1(/[CH:45]=[CH:46]/B(O)O)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>>[NH2:30][C:29]1[S:28][C:27](/[CH:46]=[CH:45]/[CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)=[N:26][C:25]=1[C:23]([NH:22][C:17]1[CH:18]=[N:19][N:20]([CH3:21])[C:16]=1[N:13]1[CH2:12][CH2:11][CH:10]([CH2:9][NH2:8])[CH2:15][CH2:14]1)=[O:24]
Reactant: OB(O)/C=C/C1CCCCC1
Reactant: CCCCOC(=O)NCC1CCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC1
Product: Cn1ncc(NC(=O)c2nc(/C=C/C3CCCCC3)sc2N)c1N1CCC(CN)CC1
Yield: 20 %

Procedure:
Following Example 278, Suzuki coupling of tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate and trans-(2-cyclohexylvinyl)boronic acid gave 257 as an off-white solid (17 mg, 20% over two steps). 1H NMR (400 MHz, d6-DMSO) δ 8.70 (s, 1H), 7.36 (s, 2H), 7.31 (s, 1H), 6.40 (dd, J=16.0, 1.3 Hz, 1H), 6.20 (dd, J=16.0, 6.7 Hz, 1H), 3.63 (s, 3H), 3.10-2.96 (m, 6H), 2.47 (d, J=5.9 Hz, 2H), 2.21-2.10 (m, 1H), 1.83-1.71 (m, 7H), 1.35-1.13 (m, 8H). LCMS (ES+) m/z 444 (M+1)
Reaction SMILES: CCCC1C=CC(OC2C=CC=CC=2)=C(O)C=1.[CH3:18][O:19][C:20]1[CH:50]=[CH:49][C:48]([N+:51]([O-])=O)=[CH:47][C:21]=1[CH2:22][N:23]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]([OH:38])=[O:37])[CH2:31][CH2:30][N:29]([CH2:39][C:40]([OH:42])=[O:41])[CH2:28][CH2:27][N:26]([CH2:43][C:44]([OH:46])=[O:45])[CH2:25][CH2:24]1>>[CH3:18][O:19][C:20]1[CH:50]=[CH:49][C:48]([NH2:51])=[CH:47][C:21]=1[CH2:22][N:23]1[CH2:24][CH2:25][N:26]([CH2:43][C:44]([OH:46])=[O:45])[CH2:27][CH2:28][N:29]([CH2:39][C:40]([OH:42])=[O:41])[CH2:30][CH2:31][N:32]([CH2:35][C:36]([OH:38])=[O:37])[CH2:33][CH2:34]1
Reactant: COc1ccc([N+](=O)[O-])cc1CN1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Agent: CCCc1ccc(Oc2ccccc2)c(O)c1
Product: COc1ccc(N)cc1CN1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Reaction time: 1 h
Yield: 95 %

Procedure:
To a nitrogen purged aqueous (50 ml) solution containing 50 mg of Pt02 was added 50 mg of 1-(2-methoxy-5-nitrobenzyl)-1,4,7,10-tetraazacyclododecane-4,7,10-triacetic acid (prepared by the procedure of Example 23). After hydrogenating in a Parr bomb for one hour, the solution was filtered and the aqueous filtrate freeze-dried to give the aniline derivative as a tan solid (95 percent yield), MP>240° C. dec, and further characterized by:
Reaction SMILES: [C:1]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH-:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1.[Na+]>C1COCC1>[CH2:2]([C:1]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[C:20]1[CH:19]=[CH:18][CH:17]=[CH:21]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: c1cc[cH-]c1
Reactant: CCCCCCCCC(=O)c1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCC(=C1C=CC=C1)c1ccccc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 72.5 %

Procedure:
Under a nitrogen atmosphere, 2.0 g (9.2 mmol) of n-nonanophenone and 30 mL of dry THF were put into a 100-mL Schlenk flask to produce a solution. To this solution, 5.6 mL (11.2 mmol) of a solution of 2.0-M sodium cyclopentadienide in THF was added under cooling with ice, and the product was stirred at room temperature for 19 hours. Then, the obtained deep red solution was quenched with dilute aqueous hydrochloric acid under cooling with ice. Then, 30 mL of diethyl ether was added thereto, and the soluble part in diethyl ether was extracted, and the organic layer was neutralized and washed with an aqueous solution of saturated sodium hydrogen carbonate, water, and a saturated salt solution and then dehydrated with anhydrous magnesium sulfate. The solvent was distilled off, and then the residue was purified by silica gel column chromatography to obtain an objective that was a red liquid (amount: 1.77 g and yield: 72.5%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4](C=C[C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.ClC1[S:20]C(CCl)=CC=1>>[Cl:17][C:16]1[S:20][C:4]([CH2:5][N:6]2[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]2)=[CH:3][CH:2]=1
Reactant: ClCc1ccc(Cl)s1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: NCC1CN(Cc2ccc(Cl)s2)CCO1

Procedure:
Intermediate 13 was prepared in an analogous manner to Intermediate 1 (Alternative procedure) from Intermediate 19 and 2-chloro-5-(chloromethyl)thiophene, followed by a deprotection reaction yielding the title compound.
Reaction SMILES: C1C2C(CO[C:16]([N:18]3[CH2:23][C:22]4([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[O:21][CH2:20][CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:16][N:18]1[CH2:23][C:22]2([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[O:21][CH2:20][CH2:19]1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)N1CCOC2(CCNCC2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCOC2(CCNCC2)C1
Temperature: 25 °C
Yield: 154.3 %

Procedure:
To a mixture of compound 404 (586.4 mg, 1.545 mmol) in tetrahydrofuran (20 mL) was added lithium aluminum hydride (240.5 mg, 6.34 mmol). After 1.5 hours at reflux the reaction was cooled to room temperature and quenched with water (240.5 μl), followed by 1N NaOH (240.5 μL), and then water (2×240.5 μL). The remaining solids were filtered off, and the filtrate was concentrated to give compound 405 (406 mg), as a sticky white solid. LCMS-ESI (POS), M/Z, M+1: Found 171.1, Calculated 171.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[NH:11][C:12]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[S:13]>[OH-].[Na+].[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+]>[CH:14]1([C:12]2[S:13][C:5]3[C:6]([O:9][CH3:10])=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=3[N:11]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COc1ccc(OC)c(NC(=S)C2CCCCC2)c1
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: [K+]
Agent: [Na+]
Product: COc1ccc(OC)c2sc(C3CCCCC3)nc12
Temperature: 0 °C
Reaction time: 24 h
Yield: 88.1 %

Procedure:
1.26 g (4.50 mmol) of N-(2,5-dimethoxyphenyl)cyclohexanecarbothioamide is dissolved in 100 ml of a 1.5 M sodium hydroxide solution (100 ml) and the reaction medium is cooled down to 0° C. before adding 25 ml of a freshly prepared 20% aqueous solution of potassium ferricyanide (5.05 g of K3[Fe(CN)6]; 3.4 eq.). The reaction mixture is maintained under stirring at ambient temperature for 24 hours, then 1.1 g (yield=88%) of the expected benzothiazole derivative is obtained by filtration, washing with cold water and drying under reduced pressure in the presence of P2O5.
Reaction SMILES: [CH2:1]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:17]N=O)(C)(C)C.ON1C(=O)C2=CC=CC=C2C1=O.C1(=NO)CCCCCCCCCCC1.[N+](C1CCCCCCCCCCC1)([O-])=O>C(N(CC)CC)C.C(O)(=O)C>[C:1]1(=[O:17])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCCCCCCCCCC1
Reactant: CC(C)(C)ON=O
Agent: O=C1c2ccccc2C(=O)N1O
Agent: O=[N+]([O-])C1CCCCCCCCCCC1
Agent: ON=C1CCCCCCCCCCC1
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: O=C1CCCCCCCCCCC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Cyclododecane (1.66 g; 9.88 mmol), t-butylnitrite (2 mmol), N-hydroxyphthalimide (0.4 mmol), and acetic acid (2 ml) were placed in a flask and were stirred at 80° C. in an atmosphere of argon gas for 1 hour. The resulting mixture was further treated with triethylamine (300 mg) with stirring at 80° C. for 30 minutes. The resulting reaction mixture was analyzed to find that cyclododecanone oxime, nitrocyclododecane, and cyclododecanone were formed in yields of 39%, 7%, and 5%, respectively.
Reaction SMILES: Br[C:2]1[C:3]([CH2:9][N:10](C)[C:11](=O)OC(C)(C)C)=[N:4][S:5][C:6]=1[O:7][CH3:8].CC([O-])=O.[K+].Cl.O1CCOCC1>CO.CCOC(C)=O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:8][O:7][C:6]1[S:5][N:4]=[C:3]([CH2:9][NH:10][CH3:11])[CH:2]=1
Reactant: COc1snc(CN(C)C(=O)OC(C)(C)C)c1Br
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CO
Product: CNCc1cc(OC)sn1
Temperature: 25 °C
Yield: 122.7 %

Procedure:
In a sealed 20 ml microwave vial, a solution of compound 52 (340 mg, 1.01 mmol), KOAc (297 mg, 3.02 mmol) and Pd(PtBu3)2 (52.7 mg, 0.101 mmol) in MeOH (5 mL) was heated in the microwave for 45 min at 100° C. Diluted with EtOAc, washed with water and brine, dried (MgSO4), filtered and concentrated under vacuum. The residue was dissolved in DCM (2.50 mL) then 4 N HCl in dioxane (2.52 mL, 10.1 mmol) was added. The reaction was stirred at room temperature and concentrated under vacuum to give compound 178 (196 mg, quantitative) as a solid. 1H NMR (400 MHz, DMSO-d6) δ 9.46 (br. s., 2H), 6.92 (s, 1H), 4.15 (s, 2H), 4.00 (s, 3H), 2.58 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.CCN(CC)CC.[CH2:17]=[O:18].Cl>CC#N>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([OH:9])[C:3]=1[CH:17]=[O:18]
Reactant: C=O
Reactant: Oc1cc(F)cc(F)c1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=Cc1c(O)cc(F)cc1F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of commercially available 3,5-difluorophenol (3.000 g; 23.10 mmol), anh. magnesium chloride MgCl2 (6.587 g; 69.20 mmol), and NEt3 (8.04 ml; 57.70 mmol) in anh. MeCN (100 ml) was stirred at rt, under nitrogen, for 20 min. Paraformaldehyde (3.459 g; 115.00 mmol) was then added, and the resulting mixture was heated to 80° C., under nitrogen, for 1.5 h. After cooling to rt, aq. 1N HCl (80 ml) was added, and the aq. layer was extracted with AcOEt. The mixed organic layers were dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 2,4-difluoro-6-hydroxybenzaldehyde as a yellow oil. LC-MS (conditions A): tR=0.67 min.; no ionisation.
Reaction SMILES: C(OC([N:7]1[CH2:12][CH2:11][C:10]2[C:13]([C:27](=[O:29])[NH2:28])=[C:14]([NH:16][C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[O:18])[S:15][C:9]=2[CH2:8]1)=O)C=C.N1CCOCC1>C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([NH:19][C:17](=[O:18])[NH:16][C:14]2[S:15][C:9]3[CH2:8][NH:7][CH2:12][CH2:11][C:10]=3[C:13]=2[C:27]([NH2:28])=[O:29])=[CH:25][CH:24]=1
Reactant: C=CCOC(=O)N1CCc2c(sc(NC(=O)Nc3ccc(Cl)cc3)c2C(N)=O)C1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: ClCCl
Product: NC(=O)c1c(NC(=O)Nc2ccc(Cl)cc2)sc2c1CCNC2

Procedure:
Starting material 9 (750 mg, 1.7 mmol) was dissolved under Nitrogen atmosphere in 10 ml DCM in a 2 necked flask and a solution of morpholine (3 ml, 34.5 mmol) in 34.5 ml DCM was added. The solution was stirred for 5 Min. then a solution of Tetrakis(triphenylphosphin)-palladium(0) (199 mg, 0.2 mmol) in 17.2 ml DCM was added. After about 8 Min a brown suspension was formed. The reaction was stirred at ambient temperature for another 40 Min. The solvent was then reduced and product 5 was thereby isolated in two fractions: very pure as white crystals (246 mg, 0.7 mmol, 41%) and with 56% content in a brown solid (250 mg, 56% Gehalt an 5, 0.4 mmol), which contained side products as well but could be purified by prep. HPLC (Method 2). The pure product fractions were merged, the solvent reduced and the product lyophilized.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[OH:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O>C1(C)C=CC=CC=1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=2)=[N:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: NC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(Oc2ccc(C(N)=O)cc2)nc1
Temperature: 120 °C
Yield: 94.4 %

Procedure:
Combine 6-chloro-nicotinonitrile (1.0 g, 7.22 mmol), 4-hydroxybenzamide (1.09 g, 7.94 mmol), and potassium carbonate (1.49 g, 10.83 mmol) in toluene (8 mL). Add DMA (24 mL) to the reaction mixture. Heat the reaction mixture for 1.5 hour at 120° C. Let the reaction mixture cool to room temperature. Pour the reaction mixture onto water and filter the precipitate washing with water. Dry the solid under vacuum to provide the title compound (1.63 g, 94%)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:23])[CH:3]=1.[CH3:24][C@@H:25]1[CH2:29][O:28][C:27](=[O:30])[NH:26]1>>[F:23][C:4]1[CH:3]=[C:2]([N:26]2[C@H:25]([CH3:24])[CH2:29][O:28][C:27]2=[O:30])[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=2)[CH2:12][CH2:11]1)=[O:9]
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)nc1
Reactant: C[C@@H]1COC(=O)N1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)cc3F)CC2)nc1
Yield: 94.7 %

Procedure:
By reaction and treatment in the same manner as in Example 110 and using (4-bromo-2-fluorophenyl)[4-(5-methylpyridin-2-yl)piperazin-1-yl]methanone (378 mg) described in Preparation Example 184 and (R)-4-methyloxazolidin-2-one (171 mg) described in Preparation Example 25, the title compound (377 mg) was obtained.
Reaction SMILES: [CH3:1][CH2:2][C:3]([NH:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:4].C(N(CC)CC)C.[Br:26][CH2:27][CH2:28][C:29](Cl)=[O:30]>C1(C)C=CC=CC=1>[Br:26][CH2:27][CH2:28][C:29]([NH:16][C:15]1[CH:14]=[CH:13][C:12]([N:9]2[CH2:10][CH2:11][CH:6]([NH:5][C:3](=[O:4])[CH2:2][CH3:1])[CH2:7][CH2:8]2)=[CH:18][CH:17]=1)=[O:30]
Reactant: O=C(Cl)CCBr
Reactant: CCC(=O)NC1CCN(c2ccc(N)cc2)CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCC(=O)NC1CCN(c2ccc(NC(=O)CCBr)cc2)CC1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
16 Grams of p-[4-(N-methylacetylamino)-1-piperidyl]aniline was dissolved in 150 ml of toluene. then to this solution was added 9.12 ml of triethylamine. Next, 11 g of β-bromopropionyl chloride in 30 ml of toluene solution was added dropwise thereto under stirring at 80° C. The reaction was continued further for 30 minutes, then the resinous materials formed in the reaction mixture were removed, then the remaining liquid was washed with water, dried and the solvent was removed by evaporation to yield 18 g of N-(β-bromopropionyl)-p-[4-(N-methylacetylamino)-1-piperidyl]-aniline as in the form of an oily substance.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])=[N:9][N:10]=2)[N:7]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[N:19]1([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C:11]4[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=4)[C:14]#[N:15])=[N:9][N:10]=3)[N:7]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: C1CCNCC1
Reactant: N#Cc1cccc(-c2nnc3ccc(Cl)nn23)c1
Product: N#Cc1cccc(-c2nnc3ccc(N4CCCCC4)nn23)c1

Procedure:
A mixture of 3-(6-chloro-1,2,4-triazolo[4,3-b]pyridazin-3-yl)benzonitrile (450 mg) and piperidine (5 ml) was stirred with heating under reflux for 2 hours. The reaction solution was concentrated under reduced pressure, and the resultant residue was extracted with chloroform. The extract was washed with saturated aqueous solution of ammonium chloride and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resultant crude crystals were recrystallized from ethanol to obtain 3-[6-(piperidin-1-yl)-1,2,4-triazolo[4,3-b]pyridazin-3-yl)benzonitrile (435 mg) as slightly yellowish crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1Cl.[CH2:15]([SH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[S:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: SCc1ccccc1
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc([N+](=O)[O-])c1SCc1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
45.4 g (0.21 mol) of 2-chloro-3-nitrobenzoic acid methyl ester and 24.8 ml (0.21 mol) of benzyl mercaptan are dissolved in 420 ml of dimethylformamide, and then 29.2 g (0.21 mol) of potassium carbonate are added and the batch is stirred for 8 hours at 80° C. It is then poured onto ice/water and extracted twice with ethyl acetate. The extracts are washed with water, dried over magnesium sulfate and concentrated by evaporation.
Reaction SMILES: COC(=O)N(C(C)C)C=CC(C)=C.C(#N)C=C.[CH:18]([N:21]([CH:26]1[CH:31]=[C:30]([CH3:32])[CH2:29][CH2:28][CH:27]1[C:33]#[N:34])[C:22]([O:24][CH3:25])=[O:23])([CH3:20])[CH3:19].[S]>>[CH:18]([N:21]([C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=1[C:33]#[N:34])[C:22]([O:24][CH3:25])=[O:23])([CH3:20])[CH3:19]
Reactant: COC(=O)N(C(C)C)C1C=C(C)CCC1C#N
Agent: C=C(C)C=CN(C(=O)OC)C(C)C
Agent: [S]
Solvent: C=CC#N
Product: COC(=O)N(c1cc(C)ccc1C#N)C(C)C
Reaction time: 1 h

Procedure:
915 g N-isopropyl-N-(3-methyl-1,3-butadienyl)-carbamic acid methyl ester are heated without a solvent to 120° C. and 345 g acrylonitrile added dropwise. After completion of the addition the mixture is stirred for 1 hour at 140°. The resulting 2-(N-isopropyl-N-carbomethoxyamino)-4-methyl-3-cyclohexene-nitrile is heated at 200° and treated over a period of 2 hours portionwise with 386 g powdered sulphur. The reaction mixture is then stirred for 2 hours at 205° C. The resulting mixture is distilled under high vacuum at 110°-120° (0,1 torr), recrystallisation of the residue from benzine fraction yields the title product m.p. 100°-101°.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH:8][C:9]2[C:10](=[CH:14][CH:15]=[CH:16][C:17]=2[O:18][CH3:19])[C:11](O)=O)=[CH:6][CH:5]=[N:4]1)[CH3:2].[NH4+].[OH-].O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:11]1[C:10]2[C:9](=[C:17]([O:18][CH3:19])[CH:16]=[CH:15][CH:14]=2)[N:8]=[C:7]2[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][C:6]=12
Reactant: CCn1nccc1Nc1c(OC)cccc1C(=O)O
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Product: CCn1ncc2c(Cl)c3cccc(OC)c3nc21

Procedure:
A mixture of N-(1-ethylpyrazol-5-yl)-3-methoxyanthranilic acid of example 9(d) and POCl3 (50 ml) is refluxed overnight. The reaction mixture is poured into ice waterl, neutralized with NH4OH and the mixture is extracted with CH2Cl2 (3×150 ml). The CH2Cl2 extracts are combined, dried over MgSO4, filtered and evaporated. The residue is purified by column chromatography on silica gel eluting with 35% EtOAc/hexane to afford 0.4 g of 4-chloro-1-ethyl-8-methoxy-1H-pyrazolo[3,4-b]quinoline, m.p. 168°-170° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12]CCOCCOCCOCCO.C(N(CC)CC)C>ClCCl>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:12])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: OCCOCCOCCOCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of p-toluenesulfonyl chloride (9.82 g, 51.5 mmol) in 2-{2-[2-(2-hydroxy-ethoxy)-ethoxy]-ethoxy}-ethanol, (20 g, 103 mmol) at 0° C. was added dropwise triethylamine (13 ml, 93 mmol). The suspension was stirred at 0° C. for 1 hour and then at room temperature for another 16 hours. The resulting mixture was dissolved in dichloromethane (350 ml). The clear and colourless solution that was obtained was extracted with 1 M hydrochloric acid (2×100 ml) and once with water (200 ml). The organic phase was dried (MgSO4), filtered and evaporated to afford a colourless oil. The crude product was purified by flash chromatography using ethyl acetate. Tetraethylene glycol ditosylate, eluted first followed by toluene-4Sulfonic acid 2-{2-[2-(2-hydroxy-ethoxy)ethoxy]-ethoxy}-ethyl ester, as a colourless oil; 8.89 g (49%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[CH2:12]([NH2:15])[CH2:13][NH2:14]>>[NH2:14][CH2:13][CH2:12][NH:15][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1
Reactant: NCCN
Reactant: FC(F)(F)c1ccc(Cl)nc1
Product: NCCNc1ccc(C(F)(F)F)cn1

Procedure:
2-Chloro-5-(trifluoromethyl)pyridine (5.0 g) was heated with ethylenediamine (20 ml) at 120° C. overnight. The excess ethylenediamine was removed by rotary evaporation and the residue was partitioned between dichloromethane and 2.5 M aqueous sodium hydroxide. The aqueous layer was extracted 5 times further with dichloromethane. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried, then concentrated in vacuo to give (2-aminoethyl)[5-(trifluoromethyl)(2-pyridyl)]amine as an orange oil.
Reaction SMILES: CN(C)CCN(C)C.[Li]CCCC.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1.CN([CH:25]=[O:26])C.Cl>C1CCCCC1>[CH3:14][C:15]1[CH:16]=[CH:17][C:18]([SH:21])=[C:19]([CH:20]=1)[CH:25]=[O:26]
Reactant: Cc1ccc(S)cc1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCCCC1
Product: Cc1ccc(S)c(C=O)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 80.5 %

Procedure:
Tetramethylethylenediamine (TMEDA)(12.6 mL, 83.5 mmol) was added via syringe to n-BuLi (33 mL of 1.6 M in hexanes, 82.5 mmol) and the solution was chilled to 0° C. A solution of p-thiocresol (4.53 g, 36.5 mmol) in cyclohexane (40 mL) was added with stirring over 5 minutes. The resulting tan slurry was stirred overnight at room temperature, chilled to 0° C., and DMF (4.0 mL, 3.77 g, 51.6 mmol) was added via syringe over 2 minutes. The resulting gummy slurry was stirred at room temperature for 1.3 hours. The reaction mixture was added to 3 N HCl (150 mL). This mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo yielding a brown oil. This oil was purified by flash chromatography over silica gel, eluting with 10% ethyl acetate-hexanes to afford 5-methyl-2-mercaptobenzaldehyde (4.47 g, 69%) as an intensely yellow solid suitable for use without further purification.