Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>ClCCl>[CH3:18][S:19]([O:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:6][C:3]=1[CH:4]=[O:5])(=[O:21])=[O:20]
Reactant: O=Cc1cc(O)ccc1O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Oc1ccc(OS(C)(=O)=O)c(C=O)c1
Reaction time: 0.5 h

Procedure:
To a solution of 2,5-dihydroxybenzaldehyde (8.22 g, 59.5 mmol) in 100 mL of dichloromethane at 0° C. was added triethylamine (24.8 mL, 178 mmol), followed by dropwise addition of methanesulfonyl chloride (10.1 mL, 130 mmol). After 30 minutes, the solution was concentrated in vacuo, then partitioned between EtOAc and saturated NaHCO3 solution. The organic layer was washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The product was isolated as a brown oil which was used without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:18][NH2:19].O>CS(C)=O>[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:18][NH:19][C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1
Reactant: Cc1cc(Cl)c2cccc(O)c2n1
Reactant: NCc1ccc(Cl)c(Cl)c1
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(O)c2n1
Yield: 40.7 %

Procedure:
4-Chloro-8-hydroxy-2-methylquinoline (500 mg, 2.58 mmole) and 3,4-dichlorobenzylamine (910 mg, 5.16 mmole) in dimethylsulfoxide (5 mL) were stirred at 140° C. for 90 min in a microwave oven. Water was added and the mixture was decanted to obtain an oily residue. The residue was washed with ethyl acetate to give a brownish solid (350 mg, 41%). ESI-MS [M+H]+=333.1/337.0 calculated for C17H14Cl2N2O=333 g/mole
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]([S:13][CH3:14])[C:6](=[O:12])[NH:7]2.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].N1C=CN=C1>CN(C=O)C.CCCCCC.CCOC(C)=O>[CH3:14][S:13][CH:5]1[C:4]2[C:8](=[CH:9][CH:10]=[CH:11][C:3]=2[CH2:2][O:1][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[NH:7][C:6]1=[O:12]
Reactant: CSC1C(=O)Nc2cccc(CO)c21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CSC1C(=O)Nc2cccc(CO[Si](C)(C)C(C)(C)C)c21
Reaction time: 24 h
Yield: 95.1 %

Procedure:
A solution of 0.82 g (3.9 mmol) of 4-hydroxymethyl-3-methylsulfanyl-1,3-dihydro-indol-2-one in DMF (20 mL) was treated with 0.65 g (4.3 mmol) of t-butyldimethylsilyl chloride and 0.3 g (4.4 mmol) of imidazole and stirred for 24 h. The solution was diluted with 75 mL of hexane and 75 mL of EtOAc. The organic phase was washed with brine, dried over MgSO4 and concentrated to give 1.2 g (95%) of 3-methylsulfanyl-4-(t-butyldimethylsilyloxy)methyl-1,3-dihydro-indol-2-one as a clear oil which crystallised upon storage at rt: 1H NMR (DMSO-d6): δ0.051 (s, 3H), 0.064 (s, 3H), 0.881 (s, 9H), 1.87 (s, 3H), 4.43 (s, 1H), 4.79 (d, J=14.2 Hz, 1H), 4.88 (d, J=14.2 Hz, 1H), 6.70 (d, J=7.9 Hz, 1H), 7.00 (d, J=7.9 Hz, 1H), 7.19 (t, J=7.9 Hz, 1H), 10.48 (s, 1H); APCI−MS m/z 346 (M+23)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:5][CH:4]=1.CN(C)[CH:17]=[O:18].O.O.O.O.O.O.O.O.O.[S-2:29].[Na+].[Na+]>O>[S:29]([CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:17](=[O:18])[C:10]([CH3:12])([CH3:11])[CH3:9])=[CH:7][CH:8]=1)[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:5][CH:4]=1
Reactant: CC(C)(C)C(=O)c1ccc(CBr)cc1
Reactant: [S-2]
Reactant: CN(C)C=O
Agent: [Na+]
Solvent: O
Product: CC(C)(C)C(=O)c1ccc(CSCc2ccc(C(=O)C(C)(C)C)cc2)cc1
Temperature: 0 °C

Procedure:
A solution of 20.0 g. (0.078 mole) of α-bromo-p-pivaloyl toluene in 40 ml. dimethylformamide is warmed to 50° C. and treated dropwise with 9.4 g. (0.0392 mole) of sodium sulfide nonahydrate in 11 ml. water for about 15 minutes. The resulting solution is refluxed for 18 hours, cooled and poured onto 1 liter of ice/water. The aqueous solution is extracted twice with ether and the ether washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated. The residue is recrystallized from methanol to give 4',4'"-(thiodimethylene) bis(pivalophenone); m.p. 64°-65° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH2:10](O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH2:10]([C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OCc1ccccc1
Reactant: COc1ccc(C)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COc1ccc(C)cc1Cc1ccccc1
Temperature: 167.5 °C
Reaction time: 2 h

Procedure:
A mixture of 4-methylanisole (200 g, 1.64 mol), benzyl alcohol (40.0 g, 0.37 mol) and p-toluenesulfonic acid monohydrate (8.0 g, 0.042 mol) was stirred at 160 to 175° C. for two hours while eliminating water generated by the reaction. After excess 4-methylanisole was distilled off under reduced pressure (inner temperature, 132° C./25 mmHg (3.3 kPa), the residue was dissolved in toluene (50 ml) and then the organic layer was successively washed with water (20 ml), 10% aqueous caustic soda (20 ml) and water (20 ml). After the washed organic layer was concentrated, the residue was distilled under reduced pressure to collect a component fractionated at boiling point of 120-138° C. at 0.7 mmHg (0.09 kPa) as a main fraction (52.75 g, 67.2%). The component was analyzed by NMR to identify 2.7:1 mixture of 2-benzyl-4-methylanisole and 3-benzyl-4-methylanisole.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[BH4-].[Na+]>CO>[O:13]1[CH2:14][CH2:15][N:10]([CH2:5][C:4]2[CH:3]=[C:2]([OH:1])[CH:9]=[CH:8][CH:7]=2)[CH2:11][CH2:12]1
Reactant: O=Cc1cccc(O)c1
Reactant: C1COCCN1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Oc1cccc(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
To a solution of 3-hydroxybenzaldehyde (1 g, 8.19 mmol) in methanol (15 mL) was added morpholine (1.42 g, 16.4 mmol). Then the mixture was stirred at room temperature for 1 h. The mixture was cooled to −5° C., and sodium borohydride (403 mg, 10.6 mmol) was added in small portions. The resulting mixture was stirred at room temperature for 4 h. The mixture was quenched with diluted hydrochloride acid and concentrated. The aqueous solution was washed with ethyl acetate and then made basic by addition of ammonium hydroxide. The basic aqueous slurry was extracted with ethyl acetate and this organic layer was dried and concentrated to give 3-(morpholinomethyl)phenol (0.76 g, 48.2%) as white solid. LCMS retention time 0.871 min, LCMS MH+ 194.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:5]([N+:14]([O-:16])=[O:15])[C:4](=C)[CH:3]=1.[C:18](=O)([O-])[O-].[Na+].[Na+].[Br:24][C:25](Br)=[N:26][OH:27]>CCOC(C)=O>[Br:24][C:25]1[CH2:18][C:11]2([CH2:10][CH2:9][N:8]([C:6]3[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=3)[CH2:13][CH2:12]2)[O:27][N:26]=1
Reactant: ON=C(Br)Br
Reactant: C=C1C=C(C)N=C(N2CCCCC2)C1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1ccc([N+](=O)[O-])c(N2CCC3(CC2)CC(Br)=NO3)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 70.8 %

Procedure:
A suspension of 1-(6-methyl-4-methylen-3-nitro-2-pyridyl)piperidine (Compound 3a, 350 mg, 1.5 mmol), sodium carbonate (1.26 g, 15 mmol) and dibromoformaldoxime (608 mg, 3 mmol) in 25 mL of EtOAc was stirred at r.t. for 2 days. Afterwards, the reaction mixture was washed with water, dried over sodium sulphate and evaporated to dryness in vacuo. The crude was purified by automated flash chromatography (SP1®TM-Biotage; gradient Petroleum Ether-EtOAc from 9:1 to 6:4) giving 377 mg of the title product. Yield: 70.8%.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=[O:27].[Cl-].[NH4+]>CCCCCC.O1CCCC1>[F:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=1[CH:26]([C:25]1[CH:28]=[CH:29][CH:30]=[C:23]([F:22])[CH:24]=1)[OH:27]
Reactant: O=Cc1cccc(F)c1
Reactant: N#Cc1ccc(F)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: N#Cc1ccc(F)c(C(O)c2cccc(F)c2)c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
In an atmosphere of nitrogen gas, 76.3 ml of 1.56 M solution of n-butyllithium in hexane was added to a solution of 11.1 g of N,N-diisopropylamine in 200 ml tetrahydrofuran under ice-cooling, and the mixture was stirred at the same temperature for 15 minutes. After cooling to −78° C., a solution of 12.1 g of 4-fluorobenzonitrile in 40 ml tetrahydrofuran was added dropwise. After stirring at the same temperature for 45 minutes, 10.6 ml of 3-fluorobenzaldehyde was added dropwise. After stirring at the same temperature for 25 minutes, saturated aqueous ammonium chloride solution was added and the solvent was removed. To the residue was added 150 ml of ethyl acetate, and the mixture was sequentially washed with 1 N hydrochloric acid, water, saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:toluene=3:97 to 1:19), and the resulting crystals were recrystallized from diisopropyl ether-hexane, to give 12.7 g of the title compound as pale yellow needles.
Reaction SMILES: [I:1][CH3:2].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]2=[S:16])=[CH:6][CH:5]=1>CC(C)=O>[I-:1].[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([N+:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[S:16][CH3:2])=[CH:8][CH:9]=1
Reactant: CI
Reactant: Nc1ccc(N2CCCCC2=S)cc1
Solvent: CC(C)=O
Product: CSC1=[N+](c2ccc(N)cc2)CCCC1
Product: [I-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1.25 ml (20.0 mmol) of iodomethane are added to a solution of 3.74 g (18.1 mmol) of 1-(4-aminophenyl)piperidine-2-thione in 30 ml of acetone, and the mixture is stirred at room temperature for 48 hours. The reaction mixture is evaporated, giving 1-(4-aminophenyl)-6-methylsulfanyl-2,3,4,5-tetrahydropyridinium iodide as a brownish solid; ESI 221.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:15][CH3:16])=[C:6]([CH:8]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)O)[CH:7]=1.CC(C)=[O:19]>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:15][CH3:16])=[C:6]([CH:8]2[C:12](=[O:11])[CH:13]=[CH:14][CH:10]2[OH:19])[CH:7]=1
Reactant: CCc1ccc(Br)cc1C(O)c1ccco1
Reactant: CC(C)=O
Solvent: O
Product: CCc1ccc(Br)cc1C1C(=O)C=CC1O
Temperature: 55 °C
Reaction time: 44 h

Procedure:
A solution of (5-bromo-2-ethylphenyl)furan-2-ylmethanol (40.73 g, 145 mmol) in acetone (1150 ml) and water (170 ml) is heated to 55° C. and 30 drops of polyphosphoric acid are added. The mixture is stirred at 55° C. for 44 hours, then cooled to room temperature. The reaction mixture is concentrated under reduced pressure to remove most of the acetone then ethyl acetate (500 ml) is added, and the reaction mixture is partitioned. The aqueous phase is extracted into ethyl acetate and the organic solutions are combined, washed with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to give 5-(5-bromo-2-ethylphenyl)-4-hydroxycyclopent-2-enone (33.67 g).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][N:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([O-:17])=[O:16])=[N:8][C:7]=12)=O.[S:21]1[CH2:25][C:24](=[O:26])[NH:23][C:22]1=[O:27].N1CCCC[CH2:29]1>CCO>[O:27]=[C:22]1[NH:23][C:24](=[O:26])[C:25](=[CH:1][C:3]2[CH:4]=[N:5][N:6]3[CH:11]=[CH:10][C:9]([C:12]4[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=4)[C:15]([O:17][CH3:29])=[O:16])=[N:8][C:7]=23)[S:21]1
Reactant: C1CCNCC1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1cnn2ccc(-c3cccc(C(=O)[O-])c3)nc12
Solvent: CCO
Product: COC(=O)c1cccc(-c2ccn3ncc(C=C4SC(=O)NC4=O)c3n2)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 73.9 %

Procedure:
To 3-(3-formylpyrazolo[1,5-a]pyrimidin-5-yl)benzoate (27 mg, 0.096 mmol) in 0.5 mL EtOH was added 2,4-thiazolidinedione (11 mg, 0.096 mmol) and piperidine (9.5 μL, 0.096 mmol). The mixture was stirred at 50° C. overnight. The solid formed was isolated by filtration and air dried to yield 27 mg methyl 3-(3-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-5-yl)benzoate as an orange solid (74% yield). LCMS (M+1=381)
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[C:7]([Cl:14])[C:5]=1[NH2:6])([O-])=O.[Se].[OH2:16].[CH2:17](N(CC)CC)C>O1CCCC1>[Cl:14][C:7]1[C:5]2[C:4](=[N:1][C:17](=[O:16])[N:6]=2)[CH:10]=[C:9]([NH2:11])[CH:8]=1
Reactant: CCN(CC)CC
Reactant: O
Reactant: Nc1c(Cl)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Se]
Solvent: C1CCOC1
Product: Nc1cc(Cl)c2c(c1)=NC(=O)N=2
Temperature: 80 °C
Reaction time: 5 h
Yield: 84 %

Procedure:
2,4-Dinitro-6-chloroaniline 2.7 g (12.5 m moles), selenium 1.98 g (25.0 m moles), water 1.6 ml (89 m moles), triethylamine 5.0 g (50 m moles) and tetrahydrofuran 100 ml were placed in a 200-ml capacity autoclave, and stirred at a temperature of 80° C. for five hours under carbon monoxide of 20 Kg/cm2. The reaction mixture obtained was worked up in the same manner as in EXAMPLE 1, to provide 4-chloro-6 -aminobenzimidazolone in 84% yield.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][CH2:9][CH2:10][CH:11]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([NH:8][CH2:9][CH2:10][CH:11]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(CCN)c1ccc(Cl)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NCCC(NC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 16 h
Yield: 61.2 %

Procedure:
Acetic anhydride (0.084 mL, 0.89 mmol) was added dropwise to tert-butyl 3-amino-1-(4-chlorophenyl)propylcarbamate (Intermediate 25) (203 mg, 0.71 mmol) and N,N-diisopropylethylamine (0.248 mL, 1.43 mmol) in DCM (5 mL) at 20° C. The resulting solution was stirred at 20° C. for 16 hours. The reaction mixture was quenched with NaHCO3 (2M) (10 mL) and water (10 mL) and extracted with DCM (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 2.5% MeOH in DCM. Pure fractions were evaporated to dryness to afford tert-butyl 3-acetamido-1-(4-chlorophenyl)propylcarbamate (142 mg, 61.0%) as a white solid. 1H NMR (399.9 MHz, DMSO-d6) δ1.36 (9H, s), 1.67-1.82 (2H, m), 1.79 (3H, s), 2.97 (2H, q), 4.50 (1H, d), 7.32 (2H, d), 7.38 (2H, d), 7.43-7.45 (1H, m), 7.79 (1H, s). m/z (ESI+) (M+H)+=327; HPLC tR=2.03 min.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:34])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([NH2:33])=[CH:14][C:15]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:16]=2[CH:32]=1)([CH3:3])[CH3:2].[CH3:35][C:36]1[CH:37]=[C:38]([S:42](Cl)(=[O:44])=[O:43])[CH:39]=[CH:40][CH:41]=1>>[CH:1]([O:4][C:5](=[O:34])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([NH:33][S:42]([C:38]2[CH:39]=[CH:40][CH:41]=[C:36]([CH3:35])[CH:37]=2)(=[O:44])=[O:43])=[CH:14][C:15]2[N:19]=[C:18]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:17]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:16]=2[CH:32]=1)([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)CCCCCOc1cc2c(cc1N)nc(-c1ccccc1)n2-c1ccccc1
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Product: Cc1cccc(S(=O)(=O)Nc2cc3nc(-c4ccccc4)n(-c4ccccc4)c3cc2OCCCCCC(=O)OC(C)C)c1

Procedure:
6-[(5-Amino-1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanoic acid isopropyl ester was reacted according to general operating instructions 13 with 3-methylbenzenesulfonic acid chloride.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:9]([I:12])=[CH:10][N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:13][CH:14]([CH3:17])[CH2:15][NH2:16].O>CN(C)C=O>[Cl:8][C:6]1[CH:7]=[C:2]([NH:16][CH2:15][CH:14]([CH3:17])[CH3:13])[C:3]2[N:4]([C:9]([I:12])=[CH:10][N:11]=2)[N:5]=1
Reactant: Clc1cc(Br)c2ncc(I)n2n1
Reactant: CC(C)CN
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CNc1cc(Cl)nn2c(I)cnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.1 %

Procedure:
To a solution of 200 mg (0.558 mmol) 8-bromo-6-chloro-3-iodoimidazo[1,2-b]pyridazine which was prepared according to intermediate example 1c in 4 mL N,N-dimethylformamide were added 122 mg 2-methylpropan-1-amine and the mixture was stirred at rt overnight. Water was added and the mixture was extracted with dichloromethane and methanol. The organic phase was washed with water and dried over sodium sulfate. After filtration and removal of solvent the residue was purified by chromatography to give 188 mg (96%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#N)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[OH-:12].[Na+].S(=O)(=O)(O)O.[CH2:19]([OH:21])[CH3:20]>>[C:19]([O:12][CH2:10][CH2:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1)(=[O:21])[CH3:20]
Reactant: [OH-]
Reactant: CCO
Reactant: Cc1cc(Cl)cc(CC#N)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(=O)OCCc1cc(C)cc(Cl)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To [(3-chloro-5-methylphenyl)]acetonitrile (0.38 g; 2.29 mmol) were added 2N aqueous sodium hydroxide solution (2.1 ml) and ethanol (5 ml). The mixture was stirred at 80° C. for 1 hour. The reaction solution was concentrated under reduced pressure. To the residue were added water and 2N-aqueous HCl to become neutral. Ethyl acetate was added thereto and extracted. The organic layer was washed with brine, dried over anhydrous sodium sulphate, and evaporated under reduced pressure to give colorless crystal. Concentrated sulfuric acid (0.02 ml) and ethanol (2 ml) were added thereto, and the mixture was refluxed for 5 hours. The reaction solution was concentrated under reduced pressure. To the residue were added water and 2N-aqueous sodium hydroxide solution to become neutral. Ethyl acetate was added thereto and extracted. The organic layer was washed with brine, dried over anhydrous sodium sulphate, and evaporated under reduced pressure. The residue was purified by column chromatograph on silica gel (hexane:ethyl acetate=6:1) to give 3-chloro-5-methylphenylethyl acetate as colorless oil (0.31 g; 63%).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]=[C:3]1[S:9][CH3:10].[Br:11]Br>C(Cl)(Cl)Cl>[Br:11][C:6]1[C:7](=[O:8])[N:2]([CH3:1])[C:3]([S:9][CH3:10])=[N:4][CH:5]=1
Reactant: BrBr
Reactant: CSc1nccc(=O)n1C
Solvent: ClC(Cl)Cl
Product: CSc1ncc(Br)c(=O)n1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
A 0° C. solution of 3-methyl-2-(methylthio)pyrimidin-4(3H)-one (1.37 g, 8.77 mmol) in CHCl3 (15 mL) was treated with bromine (0.54 mL, 10.5 mmol), stirred at 0° C. for 1 h, quenched with satd. NaHCO3 (15 mL), warmed to RT slowly and stirred overnight. The mixture was extracted with DCM (3×) and the combined organics were dried over Na2SO4 and concentrated to dryness to afford 5-bromo-3-methyl-2-(methylthio)pyrimidin-4(3H)-one (2.0 g, 97% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.24 (s, 1H), 3.45 (s, 3H), 2.55 (s, 3H); MS (ESI) m/z: 235.0 (M+H+).
Reaction SMILES: [O:1]1[C:5]2[CH2:6][N:7]([C:10](=[O:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:8][CH2:9][C:4]=2[CH:3]=[CH:2]1.[CH3:23][NH:24][CH3:25].[CH2:26]=O>C(O)(=O)C>[CH3:23][N:24]([CH2:26][C:2]1[O:1][C:5]2[CH2:6][N:7]([C:10](=[O:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:8][CH2:9][C:4]=2[CH:3]=1)[CH3:25]
Reactant: C=O
Reactant: CNC
Reactant: O=C(CCCCCc1ccccc1)N1CCc2ccoc2C1
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CN(C(=O)CCCCCc1ccccc1)CC2
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
To a solution of 0.493 g (1.658 mmol) of 1-(5,7-dihydro-4H-furo[2,3-c]pyridin-6-yl)-6-phenylhexan-1-one in 20 ml of acetic acid, 0.18 g (2.0 mmol) of 50% aqueous dimethylamine and 0.16 g (2.0 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 15 minutes. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=4/1) to yield the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[N:12][C:13]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])=[N:14][C:15]=2[NH:17][CH2:18][CH:19]([OH:21])[CH3:20])[N:10]([CH2:31][OH:32])[N:9]=1.C(NC(C)C)(C)C.CN(C1C=CC=CN=1)C.[C:49]1(=[O:55])[O:54][C:52](=[O:53])[CH2:51][CH2:50]1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[N:12][C:13]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])=[N:14][C:15]=2[NH:17][CH2:18][CH:19]([OH:21])[CH3:20])[N:10]([CH2:31][O:32][C:49](=[O:55])[CH2:50][CH2:51][C:52]([OH:54])=[O:53])[N:9]=1
Reactant: CC(O)CNc1nc(Oc2ccc(F)cc2F)nc2c1c(-c1ccccc1Cl)nn2CO
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(O)CNc1nc(Oc2ccc(F)cc2F)nc2c1c(-c1ccccc1Cl)nn2COC(=O)CCC(=O)O
Temperature: 25 °C
Yield: 25.7 %

Procedure:
1-[3-(2-Chloro-phenyl)-6-(2,4-difluoro-phenoxy)-1-hydroxymethyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-propan-2-ol (2.0 g, 4.3 mmol) was dissolved in 80 mL THF, and diisopropylamine (0.78 g, 5.6 mmol), dimethyamino pyridine (52 mg, 0.4 mmol) and succinic anhydride (703 mg, 7.0 mmol) were added while stirring at room temperature. The reaction mixture was stirred for 16 hours at room temperature, then partitioned between water and ethyl acetate, and the organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was dissolved in EtOAc and purified by flash chromatography (silica gel, hexanes/EtOAc 1:1 to EtOAc/AcOH 100:1) to give 0.62 g of succinic acid mono-[3-(2-chloro-phenyl)-6-(2,4-difluoro-phenoxy)-4-(2-hydroxy-propylamino)-pyrazolo[3,4-d]pyrimidin-1-ylmethyl]ester, MS (M+H)=562
Reaction SMILES: [O:1]1[C:5]2([CH2:21][CH2:20][CH2:19][C:7]3([CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][C:15]([CH3:18])([OH:17])[CH3:16])[CH2:8]3)[CH2:6]2)OCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[OH:17][C:15]([CH3:18])([CH3:16])[CH2:14][CH2:13][CH2:12][CH:9]1[CH2:10][CH2:11][C:7]2([CH2:19][CH2:20][CH2:21][C:5](=[O:1])[CH2:6]2)[CH2:8]1
Reactant: CC(C)(O)CCCC1CCC2(CCCC3(C2)OCCO3)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(O)CCCC1CCC2(CCCC(=O)C2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(1,4-dioxa-dispiro[4.1.4.3]tetradec-9-yl)-2-methyl-pentan-2-ol (28′) (290 mg, 0.97 mmol) in acetone (6 mL) was added H2O (catalytic amount) and p-toluenesulfonic acid (catalytic amount). The reaction mixture is stirred at room temperature overnight and then dried over anhydrous MgSO4. The solution is filtered through silica and the filtrate concentrated under reduced pressure. The resulting residue is purified over silica (isooctane/EtOAc, 7:3) to afford the desired product as a colorless oil which was characterized as follows: