Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:22]3[CH:23]=[CH:24][CH:25]=[C:26]4[CH2:27][CH2:28][N:20]([C:21]=34)[C:19]3[CH:29]=[CH:30][C:31]([CH3:33])=[CH:32][C:18]=3[N:17]=2)[CH2:12][CH2:11]1.ClCCl>CN(C)C=O>[Br:1][C:30]1[C:31]([CH3:33])=[CH:32][C:18]2[N:17]=[C:16]([N:13]3[CH2:12][CH2:11][N:10]([CH3:9])[CH2:15][CH2:14]3)[C:22]3[CH:23]=[CH:24][CH:25]=[C:26]4[CH2:27][CH2:28][N:20]([C:21]=34)[C:19]=2[CH:29]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2c(c1)N=C(N1CCN(C)CC1)c1cccc3c1N2CC3
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc2c(cc1Br)N1CCc3cccc(c31)C(N1CCN(C)CC1)=N2
Reaction time: 0.5 h
Yield: 11.6 %

Procedure:
A solution of N-bromosuccinimide (0.91 g, 5.1 mmoles) in dimethylformamide (3 ml) was added dropwise to a solution of 6-(4-methyl-1-piperazinyl)-9-methyl-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine (1.6 g, 4.8 mmoles) in dimethylformamide (30 ml) at 0°-3° C. The reaction mixture was stirred for 30 minutes. The solution was poured into dichloromethane (250 ml), and was washed with brine (4 times, 150 ml), and dried over anhydrous magnesium sulfate. The solvent was removed at reduced pressure and the residue was dried. Purification was accomplished by flash chromatography on an aluminium oxide column (grade III, 60 g), eluted with dichloromethane (500 ml) and 2% methanol in dichloromethane (250 ml). The fractions containing the product were pooled and concentrated. Recrystallization from 2-propanol:water (1:1, 20 ml) yielded 230 mg (11.6%) of product, mp 177°-177° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:28]([NH2:30])=[O:29])[CH:19]=[C:20]([C:23]4[CH:27]=[CH:26][S:25][CH:24]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].[O-:31][CH2:32][CH3:33].[Na+]>C(O)C.CS(C)=O>[CH2:32]([O:31][CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:28]([NH2:30])=[O:29])[CH:19]=[C:20]([C:23]4[CH:27]=[CH:26][S:25][CH:24]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6])[CH3:33]
Reactant: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Reactant: CC[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCO
Product: CCOCCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccsc4)cc23)CC1

Procedure:
3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-(3-thienyl)-1H-indole-7-carboxamide (60 mg, 0.129 mmol) was reacted with sodium ethoxide (0.5 M in ethanol, 0.5 mL, 0.25 mmol) in a mixture of ethanol (5 ml) and DMSO (0.2 mL) at reflux for 16 h to form the desired product which was purified by reverse phase HPLC eluting with 10% B to 70% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) to give the title compound (10 mg, 17%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:16][C:10]=2[O:11][CH2:12][CH2:13][C:14]#[N:15])[C:5]([Cl:26])=[CH:4][N:3]=1.[NH2:27][C:28]1[CH:29]=[CH:30][C:31]2[C:37]([CH3:39])([CH3:38])[CH2:36][CH2:35][C:34](=[O:40])[NH:33][C:32]=2[CH:41]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(=O)(O)[O-].[Na+]>C(O)(C)C.O>[Cl:26][C:5]1[C:6]([NH:8][C:9]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:16][C:10]=2[O:11][CH2:12][CH2:13][C:14]#[N:15])=[N:7][C:2]([NH:27][C:28]2[CH:29]=[CH:30][C:31]3[C:37]([CH3:38])([CH3:39])[CH2:36][CH2:35][C:34](=[O:40])[NH:33][C:32]=3[CH:41]=2)=[N:3][CH:4]=1
Reactant: CC1(C)CCC(=O)Nc2cc(N)ccc21
Reactant: N#CCCOc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CC1(C)CCC(=O)Nc2cc(Nc3ncc(Cl)c(Nc4ccc(N5CCOCC5)cc4OCCC#N)n3)ccc21
Yield: 76 %

Procedure:
3-[2-(2,5-Dichloro-pyrimidin-4-ylamino)-5-morpholin-4-yl-phenoxy]-propionitrile (88 mg, 0.22 mmol), 8-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (46 mg, 0.22 mmol), and 10-Camphorsulfonic acid (7.8 mg, 0.033 mmol) in Isopropyl alcohol (2 mL) was irradiated in a CEM microwave (140° C., 30 min). The mixture was diluted with 2 mL water and 0.25 mL satd. sodium bicarbonate, stirred for 10 min, then cooled for 1 h. The resultant solids were collected, washing with water, drying in vacuo to afford 3-{2-[5-Chloro-2-(5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-ylamino)-pyrimidin-4-ylamino]-5-morpholin-4-yl-phenoxy}-propionitrile as dark yellow solids (94 mg, 75%). MP: 150-156° C., LCMS 562 (M+H), 1H-NMR (CDCl3): 8.00 (d, 1H, J=8.9 Hz), 7.98 (s, 1H), 7.55 (s, 1H), 7.30 (d, 1H, J=8.4 Hz), 7.04 (s, 1H), 6.96 (d, 1H, J=8.4 Hz), 6.61 (d, 1H, J=8.8 Hz), 6.52 (s, 1H), 4.27 (t, 2H, J=6.2 Hz), 3.90 (t, 4H, J=4.7 Hz), 3.23 (t, 4H, J=4.7 Hz), 2.87 (t, 2H, J=6.2 Hz), 2.38 (t, 2H, J=7.0 Hz), 2.09 (t, 2H, J=7.0 Hz).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[C:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)(=[O:27])[CH3:26]>>[C:25]([C:28]1[CH:33]=[C:32]([C:5]2[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]3[S:11][CH:12]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=4)[N:14]=3)=[CH:7][CH:6]=2)[CH:31]=[CH:30][CH:29]=1)(=[O:27])[CH3:26]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: CC(=O)c1cccc(B(O)O)c1
Product: CC(=O)c1cccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)c1
Yield: 22.4 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with 3-acetylphenylboronic acid (available from Combi-Blocks Inc.; 66 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 3′-acetyl-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2-carboxylic acid (21 mg, 23%). 1H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.40 (d, J=1.8 Hz, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.25 (dd, J=8.0, 2.0 Hz, 1H), 8.10 (dd, J=8.5, 2.0 Hz, 1H), 8.00 (d, J=7.8 Hz, 1H), 7.96 (s, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.55-7.71 (m, 3H), 2.63 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9](C)[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[NH:25]1[CH2:30][CH2:29][CH:28]([C:31]([OH:33])=[O:32])[CH2:27][CH2:26]1>O1CCOCC1.CS(C)=O.CO>[OH:23][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([N:25]3[CH2:30][CH2:29][CH:28]([C:31]([OH:33])=[O:32])[CH2:27][CH2:26]3)[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:15][CH:16]=1)([CH3:22])[CH3:21]
Reactant: O=C(O)C1CCNCC1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Solvent: C1COCCO1
Solvent: CO
Solvent: CS(C)=O
Product: CC(C)(O)c1ccc(C(=O)Nc2cc(N3CCC(C(=O)O)CC3)n3nccc3n2)cc1
Temperature: 25 °C
Yield: 9.2 %

Procedure:
A solution of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 500 mg, 1.51 mmol) and piperidine-4-carboxylic acid (390 mg, 3.02 mmol) in Dioxane (15 mL) was stirred at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 30-40% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (59 mg, 50%). 1H NMR (DMSO-d6) δ: 10.89 (s, 1H), 8.09 (d, J=2.3 Hz, 1H), 8.00 (d, 2H), 7.60 (d, 2H), 7.42 (s, 1H), 6.35 (d, J=2.3 Hz, 1H), 4.30-4.39 (m, 2H), 3.20 (td, J=11.7, 1.6 Hz, 2H), 2.57-2.69 (m, 1H), 1.97-2.07 (m, 2H), 1.70-1.83 (m, 2H), 1.45 (s, 6H). ESI-MS: m/z 424.0 (M+H)+.
Reaction SMILES: [C:1]1([O:11][CH3:12])[C:2](=[CH:4][CH:5]=[C:6]([CH:10]=1)[CH2:7][CH:8]=[CH2:9])[OH:3]>[Os](Cl)(Cl)Cl>[C:1]1([O:11][CH3:12])[C:2](=[CH:4][CH:5]=[C:6]([CH:10]=1)/[CH:7]=[CH:8]\[CH3:9])[OH:3].[C:1]1([O:11][CH3:12])[C:2](=[CH:4][CH:5]=[C:6]([CH:10]=1)/[CH:7]=[CH:8]/[CH3:9])[OH:3]
Reactant: C=CCc1ccc(O)c(OC)c1
Agent: Cl[Os](Cl)Cl
Product: C/C=C/c1ccc(O)c(OC)c1
Product: C/C=C\c1ccc(O)c(OC)c1
Yield: 5.5 %
Yield: 94.5 %

Procedure:
A mixture of 20 g. of crude clove oil containing about 80% of eugenol and 50 mg. of osmium trichloride is heated for 41/4 hours to 135° C. After distillation, a fraction weighing 13.3 g. and containing, (as determined by gas-liquid chromatography) 5.5% of cis-isoeugenol and 94.5% of trans-isoeugenol is obtained. The yield is 83%, based on the eugenol originally present in the clove oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:4](=[N:13][N:14]([CH2:24][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[C:32]([Cl:35])[CH:33]=4)[N:28]=[CH:27][CH:26]=3)[C:15]=2[C:16]2[N:20]([CH3:21])[CH:19]=[C:18]([C:22]#[N:23])[CH:17]=2)[N:5]([CH2:9][CH:10]2[CH2:12][CH2:11]2)[C:6](=[O:8])[N:7]=1.[CH2:36]1[CH2:46]CN2C(=NCCC2)C[CH2:37]1.ClCC(=O)C.O>CN(C=O)C.C(OCC)(=O)C>[Cl:35][C:32]1[CH:33]=[C:34]2[C:29](=[CH:30][CH:31]=1)[N:28]=[CH:27][CH:26]=[C:25]2[CH2:24][N:14]1[C:15]([C:16]2[N:20]([CH3:21])[CH:19]=[C:18]([C:22]#[N:23])[CH:17]=2)=[C:3]2[C:2]3[N:7]([C:36]([CH3:46])=[CH:37][N:1]=3)[C:6](=[O:8])[N:5]([CH2:9][CH:10]3[CH2:12][CH2:11]3)[C:4]2=[N:13]1
Reactant: Cn1cc(C#N)cc1-c1c2c(N)nc(=O)n(CC3CC3)c2nn1Cc1ccnc2ccc(Cl)cc12
Reactant: C1CCC2=NCCCN2CC1
Agent: CC(=O)CCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cnc2c3c(-c4cc(C#N)cn4C)n(Cc4ccnc5ccc(Cl)cc45)nc3n(CC3CC3)c(=O)n12
Temperature: 125 °C
Yield: 25.5 %

Procedure:
5-[4-amino-2-[(6-chloroquinolin-4-yl)methyl]-7-(cyclopropylmethyl)-6-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]-1-methyl-1H-pyrrole-3-carbonitrile (75 mg, 0.15 mmol) was dissolved in 1.5 mL anhydrous DMF with 30 mg DBU. Chloroacetone (28 mg, 0.3 mmol, 2.0 eq.) was added and the resulting solution heated in the microwave for 90 minutes at 125° C. Two addition eq. chloroacetone were added, and the reaction returned to the microwave and heated an additional 90 minutes at 125° C. The reaction mixture was diluted with 50 mL. water and 50 mL ethyl acetate. The aqueous layer was washed 3×50 mL with ethyl acetate. The combined organic fractions were washed with 50 mL brine and dried over sodium sulfate. The crude product was purified by chromatography on silica (gradient: dichloromethane to 10% methanol in dichloromethane), followed by reverse phase HPLC using 40% aqueous acetonitrile, yielding 20 mg product. 1H NMR (300 MHz, CHLOROFORM-D) d ppm 0.55 (m, 4H) 1.48 (m, 1H) 2.27 (d, J=0.94 Hz, 3H) 3.42 (s, 3 H) 4.13 (m, 2H) 5.82 (m, 2H) 6.62 (dd, J=4.52, 1.88 Hz, 1H) 6.76 (d, J=4.33 Hz, 1H) 7.36 (d, J=1.51 Hz, 1H) 7.44 (d, J=1.13 Hz, 1H) 7.70 (dd, J=9.04, 2.26 Hz, 1H) 7.90 (d, J=2.26 Hz, 1H) 8.10 (m, 1H) 8.81 (d, J=4.52 Hz, 1H); ES M+H+=524.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.[CH3:10]C(C[AlH]CC(C)C)C.Br[C:20]1([CH3:26])[CH:25]=[CH:24][CH:23]=C[NH:21]1>O1CCCC1>[CH3:10][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:23]=[CH:24][CH:25]=[C:20]([CH3:26])[N:21]=2)=[CH:5][CH:4]=1
Reactant: CC1(Br)C=CC=CN1
Reactant: Cc1ccc(Br)cc1
Reactant: CC(C)C[AlH]CC(C)C
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccc(-c2cccc(C)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Magnesium (1.6 g) and p-bromotoluene (10.2 g) in 100 ml of tetrahydrofuran were stirred and warmed until the reaction commenced. When the exothermic reaction had finished, the mixture was refluxed for 1 hour. In a separate flask, a solution of palladium(II)bis(triphenylphosphine)dichloride (1.4 g) in 60 ml of tetrahydrofuran was prepared, and 4 ml of DIBAL (1M in toluene) added, followed by 2-bromopicoline (6.9 g). To this mixture, the magnesium reagent prepared above was added dropwise, causing an exothermic reaction. The reaction mixture was stirred overnight at room temperature, and then quenched by addition of ether/water. The mixture was washed with dilute hydrochloric acid, water, and then saturated brine. The organic layer was separated, dried over sodium sulfate, the solvent evaporated under reduced pressure, and the residue chromatographed on silica gel, eluting with 30-50% methylene chloride in heptane, to yield 4.5 g of 2-(4-methylphenyl)-6-methylpyridine, a compound of Formula (31), as an oil.
Reaction SMILES: B(Br)(Br)[Br:2].CO[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:18])[O:16][CH3:17].C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[Br:2][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:18])[O:16][CH3:17]
Reactant: BrB(Br)Br
Reactant: COCc1ccccc1NC(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)Nc1ccccc1CBr
Reaction time: 2 h

Procedure:
38.6 g (150 mmol) of boron tribromide are added dropwise to 10 g (51 mmol) of methyl N-(2-methoxymethylphenyl)-carbamate (Example 2b) in 100 ml of methylene chloride. Stirring is carried out for 2 hours, after which the vigorously stirred reaction mixture is added dropwise to a solution of 11.8 g (0.17 mol) of NaHCO3 in water. The organic phase is separated off and the aqueous phase is extracted once with methylene chloride and once with ethyl acetate. The combined organic phases are dried over MgSO4 and evaporated down. 9.5 g (39 mmol=76%) of the title compound are obtained as a colorless solid.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([C:9]#[N:10])[CH:6]=[N:7][CH:8]=1.Cl.S(Cl)([Cl:14])=O>C(Cl)Cl.O1CCOCC1.C1(C)C=CC=CC=1>[Cl:14][CH2:2][C:3]1[CH:4]=[C:5]([C:9]#[N:10])[CH:6]=[N:7][CH:8]=1
Reactant: N#Cc1cncc(CO)c1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: N#Cc1cncc(CCl)c1
Temperature: 60 °C
Yield: 70.8 %

Procedure:
To 0.2 g (1.49 mmol) of 5-(hydroxymethyl)pyridine-3-carbonitrile in 2 mL of DCM is added 1 mL (4 mmol) of HCl 4N in dioxane. The mixture is concentrated under reduced pressure and then added to 0.65 mL (8.95 mmol) of thionyl chloride followed by heating for 3 hours at 60° C. After cooling to room temperature, the medium is taken up in 20 mL of toluene, and the precipitate formed is filtered off and then treated with 30 mL of DCM and 30 mL of saturated NaHCO3 solution. The organic phase is separated out and dried over Na2SO4 and then concentrated under reduced pressure. 161 mg of 5-(chloromethyl)pyridine-3-carbonitrile are obtained in the form of an oil.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:8]O>O>[C:1]1([C:6](=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:8])[OH:7].[C:1]1([CH:6]=[CH:5][C:4]([OH:8])=[CH:3][CH:2]=1)[OH:7]
Reactant: OO
Reactant: Oc1ccccc1
Solvent: O
Product: Oc1ccc(O)cc1
Product: Oc1ccccc1O
Yield: 70.3 %

Procedure:
It is known that phenol can be hydroxylated in the nucleus with aqueous hydrogen peroxide in the presence of catalytic quantities of a strong acid (DAS No. 2,064,497). The initial concentration of water in the reaction mixture, which is not regarded as critical, is less than 20% and preferably less than 10%. According to DAS No. 2,064,497, yields of around 70.3% pyrocatechol and hydroquinone, based on the hydrogen peroxide used, are obtained by using a 20-fold molar excess of the phenol, based on the quantity of peroxide, and working with hydrogen peroxide having a water content of about 5% (Example 1 of DAS No. 2,064,497). In cases where hydrogen peroxide with a water content of 56% is used (Example 4), the yield of pyrocatechol and hydroquinone is reduced to 63% under the same reaction conditions, whilst the reaction time is increased from 30 minutes to 3 hours. According to DAS No. 2,064,497, a reduction in the excess of phenol from 20 mols to 10 mols, based on 1 mol of hydrogen peroxide, reduces the yield to 60% under otherwise the same reaction conditions (Example 7 of DAS No. 2,064,497).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][CH3:3].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(N(CC)CC)C.[C:25]([N:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]1C(O)=O)(=O)[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1>ClCCl.C(OCC)(=O)C>[N:28]1[CH:29]=[CH:30][CH:31]=[C:26]([C:25]2[N:33]3[C:34]([CH2:35][CH2:36][CH2:37][CH2:38]3)=[C:2]([C:1]([O:5][CH3:6])=[O:4])[CH:3]=2)[CH:27]=1
Reactant: O=C(O)C1CCCCN1C(=O)c1cccnc1
Reactant: CCC(=O)OC
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-c2cccnc2)n2c1CCCC2

Procedure:
1.33 g of methyl propionate are added to a solution of 3.01 g of para-toluenesulphonyl chloride in 17 cm3 of dichloromethane. A solution of the triethylamine salt of N-nicotinoylpiperidine-2-carboxylic acid in 17 cm3 of dichloromethane, prepared from 3.38 g of N-nicotinoylpiperidine-2-carboxylic acid and 2 cm3 of triethylamine, is added slowly with stirring. 2.3 cm3 of triethylamine are then added slowly. The mixture is kept at 25° C. with stirring overnight at ambient temperature. The reaction mixture is concentrated at reduced pressure (2.7 kPa) at a temperature close to 40° C. A residue is thus obtained, which is taken up in 25 cm3 of ethyl acetate and filtered. The filtrate is concentrated at reduced pressure (2.7 kPa) at a temperature close to 40° C. This residue is taken up again in 25 cm3 of ethyl acetate and filtered and then the filtrate is concentrated to dryness. The residue is crystallized from 15 cm3 of ethyl ether. The solid is filtered off and dried in air. 1.1 g of methyl 3-(3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carboxylate are thus obtained in the form of a cream solid melting at 122° C., containing approximately 5% of methyl 3-(3-pyridyl)-5,6,7,8-tetrahydroindolizine-2-carboxylate.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[S:13][C:14]([CH3:28])=[C:15]([CH2:17][N:18]2[CH:22]=[C:21]([C:23]([O:25]CC)=[O:24])[CH:20]=[N:19]2)[N:16]=1.[OH-].[Na+].O>C(O)C.O1CCCC1>[F:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[S:13][C:14]([CH3:28])=[C:15]([CH2:17][N:18]2[CH:22]=[C:21]([C:23]([OH:25])=[O:24])[CH:20]=[N:19]2)[N:16]=1
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3cccc(C(F)(F)F)c3F)sc2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Cc1sc(-c2cccc(C(F)(F)F)c2F)nc1Cn1cc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
To a mixed solution of the compound (200 mg, 0.48 mmol) obtained in Example 80f in ethanol/tetrahydrofuran (v/v=1/1, 4 mL) was added 2N aqueous sodium hydroxide solution (0.97 mL, 1.9 mmol), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the aqueous layer was washed with diethyl ether, neutralized with 1N aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was recrystallized (ethyl acetate-hexane) to give the title compound (150 mg, 81%) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:15]([CH3:16])=[CH:14][C:13]([N:17]4[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][OH:25])[CH2:19][CH2:18]4)=[N:12][N:11]3[C:26]=2[C:27]2[CH:32]=[CH:31][N:30]=[C:29]3[N:33](S(C4C=CC=CC=4)(=O)=O)[CH:34]=[CH:35][C:28]=23)=[CH:4][CH:3]=1.O1CCCC1.CO.[OH-].[Na+]>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[C:15]([CH3:16])=[CH:14][C:13]([N:17]4[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][OH:25])[CH2:19][CH2:18]4)=[N:12][N:11]3[C:26]=2[C:27]2[CH:32]=[CH:31][N:30]=[C:29]3[NH:33][CH:34]=[CH:35][C:28]=23)=[CH:6][CH:7]=1
Reactant: Cc1cc(N2CCN(CCO)CC2)nn2c(-c3ccnc4c3ccn4S(=O)(=O)c3ccccc3)c(-c3ccc(F)cc3)nc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(N2CCN(CCO)CC2)nn2c(-c3ccnc4[nH]ccc34)c(-c3ccc(F)cc3)nc12
Temperature: 50 °C
Yield: 64.8 %

Procedure:
Added to a solution of 0.22 g (0.36 mmol) of 2-{4-[2-(4-fluorophenyl)-8-methyl-3-{1-[phenylsulphonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}imidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}ethanol in 5 ml of a mixture of tetrahydrofuran and methanol (1/1), is 0.12 ml (0.72 mmol) of a 6N aqueous solution of sodium hydroxide. The mixture is heated at 50° C. for 1 hour, then poured into 20 ml of water. The product is extracted with dichloromethane. The organic phase is separated, dried over sodium sulphate and the solvent is removed by evaporation under reduced pressure. The yellowish residue obtained is then purified by chromatography on a silica gel column (40 g) by eluting with a mixture of dichloromethane, methanol and aqueous ammonia (95/5/0.5) in order to give 0.110 g of 2-{4-[2-(4-fluorophenyl)-8-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}ethanol after crystallization in 10 ml of acetonitrile, filtration and drying.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:15][CH2:16][O:17][CH2:18][CH:19](Cl)Cl>CS(C)=O>[C:1]([N:4]1[N:5]([C:6](=[O:8])[CH3:7])[CH:19]=[CH:18][O:17][CH:16]=[CH:15]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NNC(C)=O
Reactant: CCOCC(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)n1ccoccn1C(C)=O
Temperature: 20 °C

Procedure:
A mixture of 35 g of diacetylhydrazine (0.3 mol), 124.4 g or 165.8 g of ground potassium carbonate (0.9 or 1.2 mol, respectively), 85.8 g of 2,2-dichlorodiethyl ether (0.6 mol) and 560 ml of solvent (see Table 2) is heated to 125° C. and maintained at 125-130° C. or 80-90° C. (in the case of DMSO) for 5 hours. The mixture is then cooled to 20° C. and filtered, and the filtration residue is washed with the solvent. The yield is given by the content of title compound in the combined filtrate.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=1)[C:2]#[C:3][CH3:4].[CH3:15][C:16]1[C:17]([NH2:31])=[N:18][C:19]2([C:29]3[C:24](=[CH:25][CH:26]=[C:27]([NH2:30])[CH:28]=3)[O:23][CH2:22][CH2:21]2)[N:20]=1>>[NH2:31][C:17]1[C:16]([CH3:15])=[N:20][C:19]2([C:29]3[C:24](=[CH:25][CH:26]=[C:27]([NH:30][C:12](=[O:14])[C:9]4[CH:8]=[CH:7][C:6]([O:5][CH2:1][C:2]#[C:3][CH3:4])=[CH:11][N:10]=4)[CH:28]=3)[O:23][CH2:22][CH2:21]2)[N:18]=1
Reactant: CC1=NC2(CCOc3ccc(N)cc32)N=C1N
Reactant: CC#CCOc1ccc(C(=O)O)nc1
Product: CC#CCOc1ccc(C(=O)Nc2ccc3c(c2)C2(CCO3)N=C(C)C(N)=N2)nc1
Yield: 15.5 %

Procedure:
The title compound (15 mg, 16% yield) was prepared as described for Example 13a starting from 5-(but-2-ynyloxy)picolinic acid (Intermediate 19, 45 mg, 0.24 mmol) and 5′-methylspiro[chroman-4,2′-imidazole]-4′,6-diamine (Intermediate 30, 54.7 mg, 0.24 mmol): 1H NMR (500 MHz, CDCl3) δ ppm 1.87 (t, 3 H), 2.03 (m, 1 H), 2.30 (m, 1 H), 2.39 (m, 3 H), 4.50 (m, 1 H), 4.62 (m, 1 H), 4.76 (m, 2 H), 6.92 (d, 1 H), 6.98 (m, 1 H), 7.41 (dd, 1 H), 7.49 (m, 1 H), 8.18 (d, 1 H), 8.28 (d, 1 H), 9.61 (s, 1 H); MS (ES+) m/z 404 [M+H]+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[CH:4]=[CH:3][CH:2]=1.[CH3:12][C:13](C)([O-:15])[CH3:14].[K+].Cl[CH2:19][C:20]([CH2:22]Cl)=[CH2:21].[I-].[K+]>O.CN(C)C=O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH2:19][C:20]([CH2:22][O:15][C:13]2[CH:14]=[CH:7][CH:6]=[C:5]3[C:12]=2[N:1]=[CH:2][CH:3]=[CH:4]3)=[CH2:21])[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1cccc2cccnc12
Reactant: C=C(CCl)CCl
Reactant: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(COc1cccc2cccnc12)COc1cccc2cccnc12
Temperature: 25 °C
Yield: 23.4 %

Procedure:
Into 50 ml of dimethylformamide were dissolved 7.0 g (0.048 mol) of 8-quinolinol, to which 5.0 g (0.045 mol) of potassium tert-butoxide were added. The resulting mixture was stirred until a gas ceased generating and the liquid became transparent and thereafter mixed with 2.5 g (0.020 mol) of 2-chloromethyl-3-chloro-1-propene and a small amount of potassium iodide. The mixture was reacted at 70° C. for 24 hours with stirring. The reaction mixture was then cooled to room temperature, mixed with 150 ml of water and extracted thrice with 50 ml of benzene. The benzene phase was washed thrice with 100 ml of water and dried over anhydrous magnesium sulfate. The benzene was removed in vacuo and the residue was subjected to silica gel chromatography using chloroform as an elution liquid, thereby to separate 1.6 g (yield: 47%) of 2-(8-quinolyloxy)methyl-3-(8-quinolyloxy)-1-propene as a colorless solid having a melting point of about 101°-102° C. The chemical structure of this intermediate product was elucidated by NMR, IR and MS. The mass spectrometric analysis gave a molecular weight of 342.1375 (calculated: 342.1367 as C22H18N2O2).