Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:20])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[N:5]1.[H-].[Na+].[CH3:23][O:24][CH2:25][CH2:26][N:27]1[C:31]2=[N:32][CH:33]=[CH:34][CH:35]=[C:30]2[N:29]=[C:28]1S(C)(=O)=O.O>CN(C=O)C>[F:20][CH:2]([F:1])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:28]3[N:27]([CH2:26][CH2:25][O:24][CH3:23])[C:31]4=[N:32][CH:33]=[CH:34][CH:35]=[C:30]4[N:29]=3)=[CH:15][CH:14]=2)=[N:5]1
Reactant: Oc1ccc(-c2nn(CC(F)F)c3cccnc23)cc1
Reactant: COCCn1c(S(C)(=O)=O)nc2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCn1c(Oc2ccc(-c3nn(CC(F)F)c4cccnc34)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.3 %

Procedure:
To a stirred solution of 4-(1-(2,2-difluoroethyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)phenol (50 mg) in DMF (4 mL) was added NaH (60% in oil, 4.80 mg) at room temperature. The mixture was stirred at room temperature for 30 min and then 3-(2-methoxyethyl)-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (52 mg) was added. The mixture was exposed to microwave irradiation at 180° C. for 30 min, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (AcOEt/hexane). The product was crystallized from AcOEt/hexane to give the title compound (24.0 mg).
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([NH:21][C:22](=O)OC)=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.CCOCC.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([NH:21][CH3:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Nc1ccc2c(c1)nc(C(C)(C)C)n2CC1CCOCC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CNc1ccc2c(c1)nc(C(C)(C)C)n2CC1CCOCC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Methyl [2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]carbamate (1.80 g, 5.21 mmol) was dissolved in 75 mL of THF at 0° C. 1M HCl/ether (7.3 mL, 7.29 mmol) was added dropwise and the solution was stirred at 0° C. for 15 min. LiAlH4 (988 mg, 26.1 mmol) was added slowly and the solution was stirred at rt overnight. The reaction was quenched at 0° C. by the addition of MeOH (5 mL) followed by water (10 mL) and the solution was left to stir at rt for 30 min. Anhydrous Na2SO4 (10 g) was added and the solution was stirred at rt for another 30 min. The solution was filtered and the solvent was evaporated. The residue was dissolved in EtOAc and washed with aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The solvent was evaporated. Yield: 1.54 g (98%). 1H NMR (400 MHz, CHLOROFORM-D): δ 1.49-1.53 (m, 4H), 1.53-1.57 (m, 9H), 2.22-2.32 (m, 1H), 2.87 (s, 3H), 3.26-3.35 (m, 2H), 3.95 (t, J=3.03 Hz, 1H), 3.97-4.00 (m, 1H), 4.13 (d, J=7.42 Hz, 2H), 6.61 (dd, J=8.59, 2.15 Hz, 1H), 6.99 (d, J=1.95 Hz, 1H), 7.11 (d, J=8.59 Hz, 1H).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.S(=O)(=O)(O)O.[CH3:19]O>>[CH3:19][O:11][C:10](=[O:12])[C@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[NH2:1]
Reactant: CO
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)[C@@H](N)Cc1ccccc1

Procedure:
279.0 g of wet crystals of L-Phe 1/2 sulfate hemihydrate (20% of adsorbed water based on the total weight, 1.00 mole as L-Phe) was suspended in 250 ml of MeOH and, after adding 60 ml of 98% sulfuric acid, reacted at 85° C. for 4 hours. The reaction was carried out while distilling off the water and MeOH and replenishing the MeOH.
Reaction SMILES: [C:1]([OH:5])(=O)[C:2]#[CH:3].[Cl:6][C:7]1[N:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13]([N:17]3[CH:21]([O:22][C:23]([N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[O:24])[C:20]4[S:31][CH2:32][CH2:33][O:34][C:19]=4[C:18]3=[O:35])=[N:14]2)=[CH:9][CH:8]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CO>[Cl:6][C:7]1[N:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13]([N:17]3[CH:21]([O:22][C:23]([N:25]4[CH2:26][CH2:27][N:28]([C:1](=[O:5])[C:2]#[CH:3])[CH2:29][CH2:30]4)=[O:24])[C:20]4[S:31][CH2:32][CH2:33][O:34][C:19]=4[C:18]3=[O:35])=[N:14]2)=[CH:9][CH:8]=1
Reactant: O=C(OC1C2=C(OCCS2)C(=O)N1c1ccc2ccc(Cl)nc2n1)N1CCNCC1
Reactant: C#CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CO
Product: C#CC(=O)N1CCN(C(=O)OC2C3=C(OCCS3)C(=O)N2c2ccc3ccc(Cl)nc3n2)CC1
Temperature: 25 °C
Yield: 23.9 %

Procedure:
A solution of propiolic acid (0.52 g.) in anhydrous methylene chloride (10 cc.) is added to a suspension of 6-(7-chloro-1,8-naphthyridin-2-yl)-7-oxo-5-(piperazin-1-yl)carbonyloxy-2,3,6,7-tetrahydro-5H-1,4-oxathiino[2,3-c]pyrrole (3 g.) and N,N'-dicyclohexylcarbodiimide (1.52 g.) in anhydrous methylene chloride (70 cc.). The mixture is stirred for one and a half hours at a temperature of about 25° C. and then the insoluble product (dicyclohexylurea) is filtered off and washed with methylene chloride (3×5 cc.). The filtrate is concentrated to dryness under reduced pressure and the residue is treated with boiling ethanol (100 cc.). After cooling, the insoluble product is filtered off and washed with ethanol (20 cc.). This product is then dissolved in methylene chloride (200 cc.) and the solution is washed by decantation successively with 0.1 N methanesulphonic acid (50 cc.) and with water (2×50 cc.). After drying, the organic solution is filtered through silica gel (45 g.) contained in a column of diameter 2.2 cm. Elution is carried out using pure methylene chloride (1,000 cc.). The eluate is discarded. Elution is then carried out using a mixture of methylene chloride and methanol (99.5-0.5 by volume; 350 cc.) and the corresponding eluate is concentrated to dryness under reduced pressure (20 mm. Hg). The residue obtained is dissolved in a mixture of methylene chloride and methanol (90-10 by volume; 300 cc.) and the solution obtained is filtered and then concentrated to dryness under reduced pressure. 6-(7-Chloro-1,8-naphthyridin-2-yl)-7-oxo-5-(4-propioloylpiperazin-1-yl)carbonyloxy-2,3,6,7-tetrahydro-5H-1,4-oxathiino[2,3-c]pyrrole (0.8 g.), which melts at 302° C. with decomposition, is thus obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:3]=1.C([Li])CCC.[C:26](=[O:28])=[O:27].Cl>C(OCC)C.C(OCC)(=O)C.O>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:3]=[C:2]([C:26]([OH:28])=[O:27])[CH:7]=1
Reactant: O=C=O
Reactant: COc1cc(Br)nc(Oc2cccc(C(F)(F)F)c2)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)O)c1
Reaction time: 0.17 h

Procedure:
2-bromo-4-methoxy-6-[3-(trifluoromethyl)phenoxy] pyridine (3.00 g, 0.0086 mol) was suspended in about 30 ml of diethyl ether. While cooling in a dry ice-acetone bath in an argon atmosphere, the obtained suspension was mixed with n-butyl lithium [5.9 ml (ca. 1.69M hexane solution), 0.0086×1.1 mol], and the obtained suspension was stirred for about 10 minutes. After replacing an interior of the reactor with a carbon dioxide gas, the solution was removed from the bath and stirred at room temperature for about one hour. The obtained reaction solution was mixed with about 10 ml of a 1N aqueous hydrochloric acid solution, distributed in ethyl acetate-water, and then washed with saturated brine. The organic phase separated from the solution was dried with anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][N:9]([CH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1)[S:10]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([N+]([O-])=O)[CH:14]=1)(=[O:12])=[O:11].[CH:31]1[C:36]([N+:37]([O-:39])=[O:38])=[CH:35][CH:34]=[C:33]([OH:40])[CH:32]=1.[H-].[Na+]>CN(C)C=O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][N:9]([CH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1)[S:10]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([O:40][C:33]2[CH:32]=[CH:31][C:36]([N+:37]([O-:39])=[O:38])=[CH:35][CH:34]=2)[CH:14]=1)(=[O:12])=[O:11]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)N(CCC2CCCCO2)CCC2CCCCO2)ccc1Cl
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2cc(S(=O)(=O)N(CCC3CCCCO3)CCC3CCCCO3)ccc2Cl)cc1
Reaction time: 19 h

Procedure:
To a solution of the chloro derivative from Step 2 (6.5 g, 13.2 mmol) and p-nitrophenol (1.95 g, 14.0 mmol) in dimethylformamide (75 mL) was added 60% sodium hydride mineral oil suspension (0.56 g, 14.0 mmol). The resulting solution was stirred at 60° under nitrogen for 19 hours. After concentrating under reduced pressure at 60° , the residue was partitioned between ethyl acetate and brine. The organic extract was dried (Na2SO4) filtered and concentrated. The residue was flash chromatographed over silica gel and 6.8 g of pure product was eluted with 15% ethyl acetate - 85% n-butylchloride.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]1[CH:25]=O>>[CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:25][C:17]1[NH:16][C:24]2[C:19]([CH:18]=1)=[CH:20][CH:21]=[CH:22][CH:23]=2)(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1cc2ccccc2[nH]1
Product: CNS(=O)(=O)c1ccc2c(c1)C(=Cc1cc3ccccc3[nH]1)C(=O)N2

Procedure:
5-Methylaminosulfonyl-2-oxindole was condensed with indole-2-carbaldehyde to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9](I)[CH3:10].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:10]
Reactant: CCI
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccc(Cl)cc1

Procedure:
p-Chlorophenol (10 g., 0.077 mole), ethyl iodide (13.1 g., 0.084 mole) and anhydrous potassium carbonate (10.6 g., 0.077 mole) were combined in 130 ml. of acetone and the stirred mixture heated to reflux for 16 hours. The reaction mixture was filtered and the filtrate evaporated to dryness. The residue was taken up in 300 ml. of chloroform, washed in sequence with two 120 ml. portions of lN sodium hydroxide, 50 ml. of brine and 50 ml. of water, dried over anhydrous magnesium sulfate, filtered and evaporated to yield 4-ethoxyphenyl chloride as an oil [10.5 g.; pnmr/CDCl3 /delta 1.4 (t, 3H), 4.0 (q, 2H), 6.6-7.3 (m, 4H)].
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][C:4]2[O:8][C:9]([F:12])([F:11])[O:10][C:3]=2[CH:2]=1.Cl.[C:14](Cl)(Cl)=[S:15].ClCCl>O>[N:7]([C:6]1[CH:1]=[CH:2][C:3]2[O:10][C:9]([F:11])([F:12])[O:8][C:4]=2[CH:5]=1)=[C:14]=[S:15]
Reactant: Nc1ccc2c(c1)OC(F)(F)O2
Reactant: S=C(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: FC1(F)Oc2ccc(N=C=S)cc2O1
Reaction time: 0.5 h

Procedure:
34.6 g of 5-amino-2,2-difluorobenzodioxole were added dropwise to a solution of 90 ml of conc. hydrochloric acid in 350 ml of water. The mixture was stirred for a further 30 minutes and then 27 g of thiophosgene were metered in rapidly. The mixture was stirred at the given temperature for a further 3 hours, the almost colourless suspension was admixed with 150 ml of dichloromethane and the dichloromethane was removed. The crude product was distilled at 45 mbar. 28 g (=89% of theory) were obtained as a colourless to yellowish liquid.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH:6]([N:9]=[N:10][C:11]1([C:17]#[N:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([CH3:8])[CH3:7]>>[CH:6]([N:9]=[N:10][C:11]1([C:17](=[O:2])[NH2:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([CH3:8])[CH3:7]
Reactant: CC(C)N=NC1(C#N)CCCCC1
Reactant: O=S(=O)(O)O
Product: CC(C)N=NC1(C(N)=O)CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 100 ml of 96% sulfuric acid cooled to 0° C. in an ice bath was added 13.5 grams (0.0755 moles) of 1-isopropylazo-1-cyanocyclohexane (from Example 4-b-6) dropwise over 1/2 hour while holding the temperature at 0° C. After the addition was complete the temperature was allowed to rise to 10° C. over 1/2 hour and to 25° C. over another 1/2 hour and then stirred another 1/2 hour at 25° C. The reaction mixture was poured onto 1/2 liter of ice and stirred until all of the ice dissolved. A white solid that formed was filtered off and the aqueous acid filtrate was extracted with 200 ml of methylene chloride. The methylene chloride extract was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and the methylene chloride evaporated under reduced pressure on a rotating evaporator. The product was a light brown liquid and weighed 5.0 grams (33.7% crude yield). The infrared spectrum of the product was in agreement with the structure of 1-isopropylazo-1-carbamylcyclohexane (strong broad carbonyl band at 1675-1750 cm-1 and NH band at 3500 cm-1).
Reaction SMILES: [C:1]([CH2:8][N:9]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17][N:16]([CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([O:3]C(C)(C)C)=[O:2].CCOCC>C(C(O)=O)(F)(F)F.C(Cl)Cl>[C:1]([CH2:8][N:9]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17][N:16]([CH2:23][C:24]([OH:26])=[O:25])[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([OH:3])=[O:2]
Reactant: CC(C)(C)OC(=O)CN1CCCNCCN(CC(=O)OC(C)(C)C)CCCNCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: O=C(O)CN1CCCNCCN(CC(=O)O)CCCNCC1
Yield: 98 %

Procedure:
Compound (5) (1.12 g, 2.61 mmol) was dissolved in a mixture of CF3CO2H (TFA) and CH2Cl2 (1:1 (v/v), 40 ml). The resultant mixture was stirred at an ambient temperature for 24 hours. The solvent was evaporated under reduced pressure to give an oily residue, which was then treated with Et2O to obtain an off-white solid of compound (6) (1.39 g, 98% yield, calculated as 2 equivalents of TFA for the basic weight). 1H NMR (500 MHz, D2O): δ 3.31 (brs, 2H), 3.22-2.95 (m, 8H), 2.94-2.72 (m, 8H), 2.64 (brs, 2H), 1.83 (brs, 4H); 13C NMR (125 MHz, D2O): δ 180.9, 57.5, 56.9, 55.4, 49.2, 46.2, 23.7; HRMS (FAB) calculated for C14H28N4O4: 317.2189 [(M+H)+], measured value: 317.2185 [(M+H)+].
Reaction SMILES: [CH2:1]([C:5]1[N:6]([N:18]=[C:19]([CH3:21])[CH3:20])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+]>CO>[CH2:1]([C:5]1[N:6]([NH:18][CH:19]([CH3:20])[CH3:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cnc3ccccc3c2n1N=C(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCc1nc2cnc3ccccc3c2n1NC(C)C
Reaction time: 48 h
Yield: 90.9 %

Procedure:
A solution of N-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)isopropylideneamine (406 mg, 1.45 mmol) in 15 mL of MeOH was treated with NaBH4 (500 mg, 13.2 mmol). After stirring for 2 days (d), the reaction was quenched with saturated NaHCO3 solution and extracted into ethyl acetate (EtOAc). The organic portion was washed with H2O and brine and dried over Na2SO4. Chromatography (SiO2, EtOAc) gave N-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)isopropylamine (372 mg) as a mauve solid.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[N:19][CH:18]=[C:17]([Cl:21])[C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=1)=[O:5].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:20]=[N:19][CH:18]=[C:17]([Cl:21])[C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH:15]=[O:16])=[CH:12][CH:13]=1)=[O:5]
Reactant: O=C(NCc1ccc(CCO)cc1)c1c(Cl)cncc1Cl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=CCc1ccc(CNC(=O)c2c(Cl)cncc2Cl)cc1

Procedure:
To a stirred solution of 3,5-Dichloro-N-[4-(2-hydroxy-ethyl)-benzyl]-isonicotinamide (105 mg, 0.32 mmol) in anhydrous CH2Cl2 (2.4 mL) was added Dess-Martin periodinane (206 mg, 0.48 mmol). The resultant solution was stirred at room temperature for 1 h. The mixture was diluted with 100 mL CH2Cl2, filtered through celite, and concentrated in vacuo. The crude product (74 mg, 71%) was used in the next step without further purification.
Reaction SMILES: C([O:3][C:4](=[O:44])[CH2:5][CH2:6][C:7]1[CH:42]=[CH:41][C:10]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][N:20]3[CH2:25][CH2:24][C:23]4([C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:26]4)[CH2:22][CH2:21]3)=[CH:15][CH:14]=2)=[CH:9][C:8]=1[F:43])C.[OH-].[K+]>C(O)C.O>[C:37]([O:36][C:34]([N:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:23]2([CH2:22][CH2:21][N:20]([CH2:19][C:16]3[CH:15]=[CH:14][C:13]([CH2:12][O:11][C:10]4[CH:41]=[CH:42][C:7]([CH2:6][CH2:5][C:4]([OH:44])=[O:3])=[C:8]([F:43])[CH:9]=4)=[CH:18][CH:17]=3)[CH2:25][CH2:24]2)[CH2:26]1)=[O:35])([CH3:40])([CH3:38])[CH3:39]
Reactant: CCOC(=O)CCc1ccc(OCc2ccc(CN3CCC4(CC3)CN(C(=O)OC(C)(C)C)c3ccccc34)cc2)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC2(CCN(Cc3ccc(COc4ccc(CCC(=O)O)c(F)c4)cc3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.2 %

Procedure:
A mixture of tert-butyl 1′-[[4-[[4-(3-ethoxy-3-oxo-propyl)-3-fluoro-phenoxy]methyl]phenyl]methyl]spiro[indoline-3,4′-piperidine]-1-carboxylate (0.32 g, 0.53 mmol) and KOH (0.148 g, 2.65 mmol) in ethanol:water (3:1, 4 mL) is stirred at room temperature for 16 hours. The reaction mixture is evaporated to dryness. The residue is re-dissolved in water (8 mL), cooled to 0° C., acidified with 1.5 N HCl to pH˜6, and extracted with EtOAc (3×15 mL). The combined organic layer is washed with water (15 mL) and saturated brine solution (15 mL), dried with a drying agent, filtered, and evaporated to dryness to give the title compound as an off-white solid (0.22 g, 72.1%). ESI/MS m/z 575.6 (M+H)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:35]#[N:36])=[C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][N:13]([CH:18]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:19]([O:21]CC3C=CC=CC=3)=[O:20])[C:12](=[O:34])[CH:11]=2)[CH:9]=1>C1COCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:35]#[N:36])=[C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][N:13]([CH:18]([CH2:29][C:30]([CH3:32])([CH3:33])[CH3:31])[C:19]([OH:21])=[O:20])[C:12](=[O:34])[CH:11]=2)[CH:9]=1
Reactant: COc1cn(C(CC(C)(C)C)C(=O)OCc2ccccc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cn(C(CC(C)(C)C)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Reaction time: 0.25 h

Procedure:
17.5 mg (438 μmol, 60% in mineral oil) of sodium hydride were added to a solution of 140 mg (292 μmol) of benzyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4,4-dimethylpentanoate (racemate) in 5 ml of THF (not dry), and the mixture was stirred for another 15 min. The reaction was terminated by addition of 5 ml of saturated aqueous ammonium chloride solution, 10 ml of dichloromethane and 0.5 ml of hydrochloric acid (1N). The phases were separated and the aqueous phase was extracted three times with 5 ml of dichloromethane. The combined organic phases were dried over sodium sulphate and filtered, and the solvent was removed under reduced pressure. The residue corresponded to the title compound and was used for the next step without further purification. Yield: 110 mg (83% of theory, purity 86%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9]O)=[C:5]([CH:11]=[CH2:12])[CH:4]=1.P(Br)(Br)[Br:14].O>C(OCC)C>[Br:14][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH:11]=[CH2:12]
Reactant: C=Cc1cc(OC)ccc1CO
Reactant: BrP(Br)Br
Solvent: O
Solvent: CCOCC
Product: C=Cc1cc(OC)ccc1CBr

Procedure:
To a solution of (4-methoxy-2-vinylphenyl)-methanol (7.90 g, 48.2 mmol) in diethyl ether (100 mL) at 0° C. is added PBr3 (5.0 mL, 53 mmol) over 1 min. Water is added carefully to destroy excess PBr3. The mixture is partitioned carefully between EtOAc and NaHCO3 (plus a small amount of KOH to adjust pH to 7˜8). The organic extract is dried with MgSO4 and concentrated to give the title compound and it is used directly in the next step: 1H NMR (CDCl3) δ 3.83 (s, 3H), 4.57 (s, 2H), 5.44 (dd, J=1, 11 Hz, 1H), 5.74 (dd, J=1, 17 Hz, 1H), 6.81 (dd, J=3, 8 Hz, 1H), 7.03 (d, J=2 Hz, 1H), 7.06 (dd, J=11, 17 Hz, 1H), 7.25 (d, J=8 Hz, 1H).
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[NH2:9][C:10]1[C:11]([N+:19]([O-])=O)=[C:12]([CH3:18])[C:13]([Cl:17])=[C:14]([Cl:16])[CH:15]=1.C(=O)(O)[O-].[K+]>O.CO>[NH2:19][C:11]1[C:10]([NH2:9])=[CH:15][C:14]([Cl:16])=[C:13]([Cl:17])[C:12]=1[CH3:18]
Reactant: Cc1c(Cl)c(Cl)cc(N)c1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1c(N)c(N)cc(Cl)c1Cl
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
A solution of sodium dithionite (94 g, 0.54 mol) in water (1 L) was added to a stirred mixture of 3-amino-5,6-dichloro-2-nitrotoluene (39.7 g, 0.18 mol) and potassium bicarbonate (94 g, 0.94 mmol) in methanol (1 L) at room temperature. After 30 minutes, the mixture was concentrated under reduced pressure and the resulting suspension extracted with ethyl acetate (total of 700 mL). The extracts were dried (MgSO4) and concentrated under reduced pressure to give 2,3-diamino-5,6-dichlorotoluene (26.1 g, 38% over 2 steps) as a brown solid. 1H NMR (300 MHz, CDCl3) 2.28 (3H, s), 3.36 (2H, br s), 3.42 (2H, br s), 6.72 (1H, s).
Reaction SMILES: II.O[PH2]=O.[CH3:6][N:7]1[CH:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([CH:21]([C:23]4[CH:24]=[C:25]5[C:30](=[CH:31][CH:32]=4)[N:29]=[CH:28][CH:27]=[CH:26]5)O)=[CH:19][N:20]=3)[N:17]=2)[CH:9]=[N:8]1>C(O)(=O)C.O>[CH3:6][N:7]1[CH:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([CH2:21][C:23]4[CH:24]=[C:25]5[C:30](=[CH:31][CH:32]=4)[N:29]=[CH:28][CH:27]=[CH:26]5)=[CH:19][N:20]=3)[N:17]=2)[CH:9]=[N:8]1
Reactant: Cn1cc(-c2ccc3ncc(C(O)c4ccc5ncccc5c4)n3n2)cn1
Agent: II
Agent: O=[PH2]O
Solvent: O
Solvent: CC(=O)O
Product: Cn1cc(-c2ccc3ncc(Cc4ccc5ncccc5c4)n3n2)cn1
Reaction time: 0.5 h

Procedure:
The title compound was synthesized like described in Tetrahedron Letters, 2001, 42, 831-833): iodine (207 mg, 0.82 mmol) and H3PO2 (0.44 mL of a 50% aqueous solution, 4.07 mmol) were added to a solution of (rac)-[6-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-yl]-quinolin-6-yl-methanol (Example 1, 145 mg, 0.41 mmol) in acetic acid (1 mL). The RM was subjected to MW-irradiation at 150° C. for 30 min. The RM was diluted with water and extracted with EtOAc. The organic layer was separated and washed carefully with sat. K2CO3-sol then dried filtered and concentrated. Purification by HPLC and then liberation of the free base afforded the title compound as a white solid (tR 1.055 min (conditions 1), MH+=341.2, 1H-NMR in DMSO-d6: 8.9 (d, 1H), 8.5 (s, 1H), 8.4 (d, 1H), 8.2 (d, 1H), 8.1 (s, 1H), 8.05 (s, 1H), 8.0 (d, 1H), 7.9 (d, 1H), 7.8 (s, 1H), 7.7 (d, 1H), 7.6 (dd, 1H), 4.6 (s, 2H), 4.0 (s, 3H)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15](=O)/[CH:16]=[CH:17]/[N:18](C)C)=[N:9]2)=[CH:4][CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29]N>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15]3[N:29]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[F:22])[N:18]=[CH:17][CH:16]=3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(Cl)cc2)ccc1=O
Reactant: NNc1ccccc1F
Product: O=c1ccn(-c2ccc(Cl)cc2)nc1-c1ccnn1-c1ccccc1F

Procedure:
The product was obtained starting from 1-(4-Chloro-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-24) and 2-fluoro-phenylhydrazine according to the method described for example 1. MS: M=367.1 (M+H)+