Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:6]=2[N:7]=1.[CH:25]1([CH2:28][NH2:29])[CH2:27][CH2:26]1>O>[CH:25]1([CH2:28][NH:29][C:2]2[N:3]=[C:4]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[C:5]3[C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:9][S:8][C:6]=3[N:7]=2)[CH2:27][CH2:26]1
Reactant: Clc1nc(NCc2ccccn2)c2c(-c3ccccc3)csc2n1
Reactant: NCC1CC1
Solvent: O
Product: c1ccc(-c2csc3nc(NCC4CC4)nc(NCc4ccccn4)c23)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
In a 10 ml glass tube were placed 2-chloro-N-(2-pyridyl)methyl-5-phenylthieno[2,3-d]pyrimidin-4-ylamine (0.03 g, 0.0852 mmol) and cyclopropylmethylamine (0.5 ml). The vessel was sealed with a septum and placed in the microwave cavity. Microwave irradiation of 200 W was used, the temperature being ramped from room temperature to 200° C. Once 200° C. was reached, the reaction mixture was held at this temperature for 40 minutes. After cooling to ambient temperature, water (4 ml) was added and the mixture stirred for 2.5 hours. The resulting solid was collected by filtration, washed with water and dried under reduced pressure to give N2-Cyclopropylmethyl-5-phenyl-N4-pyridin-2-ylmethyl-thieno[2,3-d]pyrimidine-2,4-diamine (0.025 g) as a yellow solid, m.p.t. 109-111° C.
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[CH:11]1[C:16]([CH:17]([CH:20]=O)[CH:18]=O)=[CH:15][CH:14]=[C:13]([Cl:22])[CH:12]=1>N1C=CC=CC=1>[Cl:22][C:13]1[CH:14]=[CH:15][C:16]([C:17]2[CH:18]=[N:9][C:2]([C:3]3[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=3)=[N:10][CH:20]=2)=[CH:11][CH:12]=1
Reactant: N=C(N)c1ccncc1
Reactant: O=CC(C=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Clc1ccc(-c2cnc(-c3ccncc3)nc2)cc1
Yield: 55.9 %

Procedure:
Isonicotinamidine, hydrochloride (0.488 g) and 2-(4-chlorophenyl)malondialdehyde (0.566 g) were combined in anhydrous pyridine (10 ml) and heated to reflux under nitrogen, for 18 h. The resultant dark solution was cooled and poured onto ice-water (150 ml) and the mixture extracted with ethyl acetate (150 ml, then 50 ml). The combined organic extracts were washed with water (3×10 ml), saturated brine (20 ml), dried (Na2SO4), evaporated to dryness under reduced pressure and the residue purified by silica gel column chromatography with 3.5% methanol/dichloromethane as eluent, to give the title compound as a white solid (0.463 g, 56%).
Reaction SMILES: [CH3:1][CH:2]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)=[O:4].[CH:20]1[C:25]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=[CH:24][CH:23]=[C:22](O)[CH:21]=1.C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[CH3:1][CH:2]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)=[O:4].[OH:32][C:29]1[CH:28]=[CH:27][C:26]([C:25]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:31][CH:30]=1
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCCCCCC(C)C(=O)c1ccc(C(=O)O)cc1
Solvent: c1ccncc1
Product: Oc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Into a flask were charged 151.0 mg (0.58 mmol) of 4-(2-methyloctanoyl) benzoic acid, 321.3 mg (1.74 mmol) of p,p'-biphenol, N,N'-dicyclohexyl-carbodiimide (0.66 mmol) and 6 ml of dried pyridine, which was stirred at room temperature for 6 hours. The resulting solid was filtered off and the solvent was distilled off, and the resulting oily matter was purified by a column chromatography of silica gel to obtain 122.3 mg (yield 49%) of 4-(2-methyloctanoyl) benzoic acid-4-hydroxy biphenyl.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.C[CH2:12][N:13]=[C:14]=NCCCN(C)C.[CH2:22]([O:29][C:30]([NH:32][C:33]([CH3:39])([CH3:38])[CH2:34][C:35](O)=[O:36])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N(C)C>C(Cl)Cl>[CH2:22]([O:29][C:30](=[O:31])[NH:32][C:33]([CH3:39])([CH3:38])[CH2:34][C:35](=[O:36])[N:13]([CH3:14])[CH3:12])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(CC(=O)O)NC(=O)OCc1ccccc1
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CN(C)C(=O)CC(C)(C)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
HOBt (1.242 g, 9.193 mmol) and EDCI (2.35 g, 12.26 mmol) were added to a solution of 3-benzyloxycarbonylamino-3-methyl-butyric acid (1.54 g, 6.129 mmol) in DCM (45 mL) at 0° C. The resulting mixture was stirred at 0° C. for 30 min, and a solution of Me2NH (2 M in THF, 12.26 mL, 24.51 mmol) was added. The reaction mixture was warmed up to RT and stirred overnight. The solvent was evaporated under reduced pressure, and the residue partitioned between EtOAc and a mixture of water, brine and NaHCO3 (sat aq). The organic layer was separated, washed with HCl (1 M), dried over anhydrous MgSO4, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (EtOAc/hexane) to afford (2-dimethylcarbamoyl-1,1-dimethyl-ethyl)-carbamic acid benzyl ester (1.14 g, 67% yield).
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:32])[CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][C:21]([OH:31])([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[CH:10][CH:9]=1>[O-2].[O-2].[O-2].[Cr+6].O>[OH:31][C:21]1([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][CH2:15][C:14]([C:11]2[CH:12]=[CH:13][C:8]([F:7])=[CH:9][CH:10]=2)=[O:32])[CH2:19][CH2:20]1
Reactant: Cc1ccc(C2(O)CCN(CCCC(O)c3ccc(F)cc3)CC2)cc1
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(C2(O)CCN(CCCC(=O)c3ccc(F)cc3)CC2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
One gram of chromium trioxide was added with stirring to 40 ml of pyridine cooled to 0°C. The mixture was stirred at room temperature for 1 hour, and then again cooled to 0°C. Into the said mixture was added 1.1 g of 1-(p-fluorophenyl)-4-[4-hydroxy-4-(p-methylphenyl)-piperidino]-1-butanol, and the mixture was stirred for 1 hour under cooling with ice. The reaction mixture was poured into 300 ml of cold water to separate an oily substance. The oily substance is extracted with ethyl acetate, and the ethyl acetate layer was washed 4 times with each 60 ml of water, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was recrystallized from aqueous acetone to obtain γ-(4-hydroxy-4-p-methylphenylpiperidino)-p-fluorobutyrophenone, melting at 119° - 120°C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.C1C(=O)N([Br:46])C(=O)C1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15](=[O:17])[CH2:16][Br:46])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CBr)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(4-(benzyloxy)-phenyl)-ethanone (49.12 g; 217.1 mmol) in CH2Cl2 (750 mL) was added drop wise DIPEA (45.37 mL; 260.5 mmol) and TMSOTf (45.18 mL; 249.6 mmol), both at 0° C. The resulting solution was maintained at 0° C. for 1 h, and then NBS (42.50 g; 238.8 mmol) was added in four portions. The resulting mixture was allowed to warm to RT and stirred 1 hour. Subsequently, the mixture was concentrated in vacuo and the residue was treated with EtOAc and washed twice with water, and brine. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O) and crystallization from iPr2O to afford 1-(4-benzyloxy-phenyl)-2-bromo-ethanone.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[S:5])#[N:2].[C:7]([C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:18]=1)[CH:14]=O)([CH3:10])([CH3:9])[CH3:8]>>[C:1]([C:3](=[CH:14][C:13]1[CH:12]=[C:11]([C:7]([CH3:9])([CH3:8])[CH3:10])[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=1)[C:4](=[S:5])[NH2:6])#[N:2]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1
Reactant: N#CCC(N)=S
Product: CC(C)(C)c1cc(C=C(C#N)C(N)=S)cc(C(C)(C)C)c1

Procedure:
Following the procedure as set forth in Example 11 above, cyanothioacetamide was condensed with 3,5-di-tert butylbenzaldehyde to yield the title compound, m.p. 172°-174° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[O:15][CH3:16])[C:5]([F:17])=[CH:4][N:3]=1.[F:18][C:19]1[CH:20]=[C:21]([CH:23]=[C:24]([CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=1)[NH2:22]>>[F:17][C:5]1[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[O:15][CH3:16])=[N:7][C:2]([NH:22][C:21]2[CH:23]=[C:24]([CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=[C:19]([F:18])[CH:20]=2)=[N:3][CH:4]=1
Reactant: COc1cc(F)ccc1-c1nc(Cl)ncc1F
Reactant: CS(=O)(=O)Cc1cc(N)cc(F)c1
Product: COc1cc(F)ccc1-c1nc(Nc2cc(F)cc(CS(C)(=O)=O)c2)ncc1F

Procedure:
Example 12 was prepared under similar conditions as described in the preparation of Example 1 using 2-chloro-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidine and 3-fluoro-5-[(methylsulfonyl)methyl]aniline. The batch was purified by preparative HPLC.
Reaction SMILES: COC1C=CC(C2SC3C=CC(OC)=CC=3C=2)=C(N)C=1.Cl.[F:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C:26](O)=O.FC1C=[C:44](C=CC=1OCCN1CCCCC1)[CH2:45][NH:46][C:47]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:48]=1[C:55]1[S:59][C:58]2[CH:60]=[CH:61][C:62]([O:64][CH3:65])=[CH:63][C:57]=2[CH:56]=1>>[CH2:45]([N:46]([CH2:26][C:25]1[CH:29]=[CH:30][C:31]([O:32][CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[C:23]([F:22])[CH:24]=1)[C:47]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:48]=1[C:55]1[S:59][C:58]2[CH:60]=[CH:61][C:62]([O:64][CH3:65])=[CH:63][C:57]=2[CH:56]=1)[CH3:44]
Reactant: O=C(O)c1ccc(OCCN2CCCCC2)c(F)c1
Reactant: COc1ccc(-c2cc3cc(OC)ccc3s2)c(NCc2ccc(OCCN3CCCCC3)c(F)c2)c1
Agent: COc1ccc(-c2cc3cc(OC)ccc3s2)c(N)c1
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1cc(OC)ccc1-c1cc2cc(OC)ccc2s1

Procedure:
Synthesized from 5-methoxy-2-(5-methoxybenzo[b]thiophen-2-yl)phenylamine and 3-fluoro-4-(2-piperidin-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 114, [3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl][5-methoxy-2-(5-methoxybenzo[b]thiophen-2-yl)phenyl]amine (236 mg) was used according to an analogous synthetic method to Example 36 to provide ethyl[3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl][5-methoxy-2-(5-methoxybenzo[b]thiophen-2-yl)phenyl]amine (202 mg). The total amount of this compound was used according to an analogous synthetic method to Example 111 to provide the title compound (136 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH:10]([N:17]1[CH:21]=[C:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:19]=[C:18]1[C:28]([O:30]CC)=O)[C:11]2=O)=[O:5])[CH3:2].C([O-])(=O)C.[NH4+:37]>C(O)(=O)C>[O:30]=[C:28]1[NH:37][C:11]2[C:12]3[CH:13]=[CH:14][CH:15]=[C:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:8]=3[CH2:9][C:10]=2[N:17]2[CH:21]=[C:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:19]=[C:18]12
Reactant: CCOC(=O)Cc1cn(C2Cc3c(CC(=O)OCC)cccc3C2=O)c(C(=O)OCC)n1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CCOC(=O)Cc1cn2c3c([nH]c(=O)c2n1)-c1cccc(CC(=O)OCC)c1C3
Temperature: 0 °C
Reaction time: 2 h
Yield: 54.9 %

Procedure:
A mixture of 1.63 g of ethyl 1-[4-(ethoxycarbonylmethyl)-1-oxoindan-2-yl]-4-(ethoxycarbonylmethyl)imidazole-2-carboxylate, 15 ml of acetic acid and 2.83 g of ammonium acetate is heated at reflux for 5 hours. The heating is stopped, 1.4 g of ammonium acetate are added and the refluxing is continued for 2 hours. The reaction mixture is poured over 100 ml of crushed ice and extracted with 3×50 ml of dichloromethane. The organic phase is dried over magnesium sulphate, filtered and evaporated in a rotary evaporator. The evaporation residue is suspended in 15 ml of ethyl acetate to give 0.8 g of diethyl 4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-2,9-diacetate in the form of a beige solid [1H NMR spectrum in DMSO-d6, T=300K, δ in ppm, (250 MHz): 1.25 (6H, m, 2 CH3), 3.80 (4H, s, 2 CH2CO2Et), 4.00 (2H, s, CH2), 4.15 (4H, q, J=6 Hz 2 OCH2), 7.15 (1H, d, J=8 Hz, arom. CH), 7.40 (1H, t, J=8 Hz, arom. CH), 7.80 (1H, d, J=8 Hz, arom. CH), 7.90 (1H, s, arom. CH), 12.4 (1H, s, CONH)].
Reaction SMILES: Br[C:2]1[C:3]([O:15][CH3:16])=[C:4]([C:13]#[N:14])[C:5](=[O:12])[N:6]([CH:8]([CH2:10][CH3:11])[CH3:9])[CH:7]=1.[CH3:17][N:18]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[N:19]1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:8]([N:6]1[CH:7]=[C:2]([C:20]2[CH:21]=[CH:22][N:18]([CH3:17])[N:19]=2)[C:3]([O:15][CH3:16])=[C:4]([C:13]#[N:14])[C:5]1=[O:12])([CH2:10][CH3:11])[CH3:9]
Reactant: CCC(C)n1cc(Br)c(OC)c(C#N)c1=O
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCC(C)n1cc(-c2ccn(C)n2)c(OC)c(C#N)c1=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
To a mixture of 5-bromo-1-(sec-butyl)-4-methoxy-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step B (130 mg), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (114 mg), 2M aqueous sodium carbonate solution (1.37 mL) and 1,2-dimethoxyethane (2.5 mL) was added tetrakis(triphenylphosphine)palladium(0) (52.7 mg), and the mixture was stirred with microwave irradiation at 100° C. for 1 hr. The reaction mixture was diluted with water, and the mixture was extracted twice with ethyl acetate. The extracts were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate/hexane) to give the title compound (90 mg).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.[Cl:7][C:8]1[S:12][C:11]([S:13](Cl)(=[O:15])=[O:14])=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18].C(N(CC)CC)C>C1COCC1>[Cl:7][C:8]1[S:12][C:11]([S:13]([N:1]2[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]2)(=[O:14])=[O:15])=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)sc1Cl
Reactant: OC1CCNC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(S(=O)(=O)N2CCC(O)C2)sc1Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 36.3 %

Procedure:
To a stirred solution of (RS)-3-pyrrolidinol (0.75 g, 8.6 mmol) in THF (18 ml) was added at room temperature 5-chloro-4-nitrothiophene-2-sulfonyl chloride (1.5 g, 5.72 mmol) and triethylamine (0.88 ml, 6.3 mmol). The light yellow suspension was stirred at room temperature for 17 h, and evaporated. The crude product was further purified by column chromatography on silica gel (ethyl acetate), and subsequent crystallization from dichloromethane/MeOH/hexane to yield (RS)-1-(5-chloro-4-nitro-thiophene-2-sulfonyl)-pyrrolidin-3-ol (0.65 g, 36%) as a yellow solid. MS (EI) 312.0 [(M)+], mp 96° C.
Reaction SMILES: [F:1][C:2]([F:10])(S(F)(=O)=O)C(O)=O.[OH:11][C:12]1[N:17]=[C:16]([CH:18]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]3[C:26]([N:31]4[CH2:36][CH2:35][CH2:34][CH2:33][C:32]4=[O:37])=[N:27][CH:28]=[CH:29][CH:30]=3)[CH2:19]2)[CH:15]=[CH:14][CH:13]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].O>C(#N)C>[F:1][CH:2]([F:10])[O:11][C:12]1[N:17]=[C:16]([CH:18]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]3[C:26]([N:31]4[CH2:36][CH2:35][CH2:34][CH2:33][C:32]4=[O:37])=[N:27][CH:28]=[CH:29][CH:30]=3)[CH2:19]2)[CH:15]=[CH:14][CH:13]=1
Reactant: O=C1CCCCN1c1ncccc1CCN1CCC(c2cccc(O)n2)C1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C1CCCCN1c1ncccc1CCN1CCC(c2cccc(OC(F)F)n2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.8 %

Procedure:
2,2-Difluoro-2-(fluorosulfonyl)acetic acid (9.72 mg, 0.054 mmol, 1 eq) is added slowly, under stirring, to a mixture of 1-(3-{2-[3-(6-hydroxypyridin-2-yl)pyrrolidin-1-yl]ethyl}pyridin-2-yl)piperidin-2-one a16-1 (20 mg, 0.054 mmol, 1 eq) and dry sodium sulfate (0.78 mg, 0.005 mmol, 0.1 eq) in dry acetonitrile (400 μl). The reaction is stirred for 2 h at room temperature, then water (100 μl) is added. The resulting solution is concentrated in vacuo. The residue is purified by basic reverse phase chromatography (gradient: H2O/acetonitrile/NH4OH from 50/50/0.1 to 20/80/0.1) to afford 9.4 mg of 1-[3-(2-{3-[6-(difluoromethoxy)pyridin-2-yl]pyrrolidin-1-yl}ethyl)pyridin-2-yl]piperidin-2-one 109.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[CH:11]=[C:12]2[C:17]([NH:18][C@H:19]([CH3:24])[C:20]([F:23])([CH3:22])[CH3:21])=[C:16]([C:25]([NH2:27])=[O:26])[CH:15]=[N:14][N:13]2[CH:28]=1.[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:23][C:20]([CH3:22])([CH3:21])[C@H:19]([NH:18][C:17]1[C:12]2[N:13]([CH:28]=[C:10]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:11]=2)[N:14]=[CH:15][C:16]=1[C:25]([NH2:27])=[O:26])[CH3:24]
Reactant: OB(O)c1ccccc1
Reactant: C[C@@H](Nc1c(C(N)=O)cnn2cc(Br)cc12)C(C)(C)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: C[C@@H](Nc1c(C(N)=O)cnn2cc(-c3ccccc3)cc12)C(C)(C)F
Temperature: 120 °C
Yield: 51.2 %

Procedure:
Potassium phosphate (2M aqueous solution, 0.22 mL, 0.44 mmol) was added in one portion to a stirred solution of 6-bromo-4-(((1R)-2-fluoro-1,2-dimethylpropyl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (Intermediate 3, 20 mg, 0.058 mmol), phenyl boronic acid (11 mg, 0.087 mmol), X-Phos ligand (2.8 mg, 0.0058 mmol) and palladium acetate (0.7 mg, 0.0029 mmol) in anhydrous 1,4-dioxane (0.25 mL). The resulting biphasic mixture was then heated in the CEM microwave at 120° C. for 10 min. The reaction was allowed to cool to rt and the phases separated. The aqueous phase was extracted with ethyl acetate (2×5 mL). The combined organics were then dried (MgSO4) and evaporated in vacuo before purifying by reverse-phase Prep HPLC (condition A). The fraction containing the major product was concentrated on the rotovap to afford 10.1 mg (45%) of the title compound as a white solid. HPLC (condition B): retention time=3.84 min. LCMS (condition B): MH+m/z 341.2. 1H NMR (400 MHz, MeOD) δ ppm 8.38 (1 H, d, J=3.52 Hz), 8.15 (1 H, d, J=1.76 Hz), 7.76-8.03 (3 H, m), 7.61-7.76 (1 H, m), 7.53 (1 H, br. s.), 7.38 (1 H, br. s.), 4.87 (1 H, buried s.), 1.60-2.06 (9 H, m).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:14][O:15][C@H:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([O:22][CH2:23][CH:24]=O)[CH2:17]1.[BH4-].[Na+].C[OH:29]>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:14][O:15][C@H:16]1[CH2:21][CH2:20][CH2:19][CH:18]([O:22][C@@H:23]([OH:29])[CH3:24])[CH2:17]1
Reactant: CO
Reactant: Cc1cccc(-c2nc(CO[C@H]3CCC[C@@H](OCC=O)C3)c(C)o2)c1
Agent: [BH4-]
Agent: [Na+]
Product: Cc1cccc(-c2nc(CO[C@H]3CCCC(O[C@H](C)O)C3)c(C)o2)c1
Reaction time: 1.5 h

Procedure:
2.3 g of 4-((1R,3S)-3-(allyloxycyclohexyloxymethyl)-5-methyl-2-m-tolyloxazole are dissolved in 65 ml of methyl tert-butyl ether and, at 0° C., 65 ml of water, 4.4 g of sodium metaperiodate and 3.3 ml of a 2.5% strength solution of osmium tetroxide in tert-butanol are added. After 20 min, the mixture is slowly warmed to 40° C. After 2 h, a further 700 mg of sodium metaperiodate were added and the mixture was stirred at 45° C. for 2 h. 140 ml of sat. sodium thiosulfate solution were added and the mixture was extracted with methyl tert-butyl ether. The combined organic phases are dried over sodium sulfate and the solvent is removed under reduced pressure. This gives 2-((1R,3S)-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]acetaldehyde as a colorless oil. C20H25NO4 (343.43), MS (ESI): 344 (M+H+). 2-((1R,3S)-[3-(5-Methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]acetaldehyde is, as a crude product, taken up in 60 ml of dry methanol, and 300 mg of sodium borohydride are added. After 1.5 h, the mixture is quenched with 3 ml of acetone and concentrated. The residue is taken up in 50 ml of ethyl acetate/50 ml of sat. sodium bicarbonate solution, and the org. phase is dried over sodium sulfate. The solvent is removed under reduced pressure and the residue is then purified by flash chromatography on silica gel (n-heptane/ethyl acetate=1:3). This gives 1.6 g of 2-((1R,3S)-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]ethanol as a colorless oil. C20H27NO4 (345.44), MS (ESI): 346 (M+H+).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[O:12][C:11]2([CH3:20])[CH3:19])[CH:7]=[N:8][CH:9]=1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:19][C:11]1([CH3:20])[CH:10]([N:6]2[C:5]([CH2:3][OH:2])=[CH:9][N:8]=[CH:7]2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[O:12]1
Reactant: COC(=O)c1cncn1C1c2ccccc2OC1(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)Oc2ccccc2C1n1cncc1CO
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-(2,2-dimethyl-2,3-dihydro-benzofuran-3-yl)-3H-imidazole-4-carboxylic acid methyl ester (2.2 g, 8.1 mmol), which can be prepared as described in Example 11, in THF (80 mL) at 0° C. is added LiAlH4 (310 mg, 8.1 mmol). After 30 minutes the reaction is quenched at 0° C. by the consecutive addition of 9:1 THF/H2O (3.5 mL), 2M aqueous NaOH (1.4 mL), and H2O (2.6 mL). The reaction is warmed to room temperature and diluted with THF (30 mL). After the addition of MgSO4 (3.75 g), the heterogeneous mixture is stirred for 15 min and then filtered through a pad of Celite®. The pad of Celite® is washed with ethyl acetate and the combined filtrate is concentrated. The resulting residue is purified by silica gel flash chromatography (methanol-dichloromethane, 0:1 to 1:20) to afford 3-(2,2-dimethyl-2,3-dihydro-benzofuran-3-yl)-3H-imidazol-4-yl]-methanol; HRMS: (ESI) m/z 245.1296 [(M+H)+: Calcd for C14H17N2O2: 245.1290]; 1H NMR (400 MHz, CDCl3) δ ppm 1.10 (s, 3 H), 1.54 (s, 3 H), 4.57-4.87 (m, 2 H), 5.60 (s, 1 H), 6.81-7.06 (m, 4 H), 7.22 (d, J=7.45 Hz, 1 H), 7.34 (t, J=7.45 Hz, 1 H).
Reaction SMILES: [C:1]([O-:12])(=[O:11])[C:2]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH2:13]([N+](CC)(CC)CC)[CH3:14].NC1C=CC=CC=1.C(OC(=O)C(OCC)=O)C>[Pt]>[CH2:13]([O:11][C:1](=[O:12])[C:2]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3])[CH3:14]
Reactant: O=C([O-])C(=O)Nc1ccccc1
Reactant: CC[N+](CC)(CC)CC
Agent: [Pt]
Solvent: CCOC(=O)C(=O)OCC
Solvent: Nc1ccccc1
Product: CCOC(=O)C(=O)Nc1ccccc1
Yield: 90 %

Procedure:
The electrochemical oxidation of tetraethylammonium oxanilate was carried out in an one-compartment cell (graphite anode, platinum cathode). The starting material was prepared by firstly reacting aniline and diethyloxalate to give ethyloxanilate which compound was then saponified with tetraethylammonium hydroxide; the yield was more than 90%.