Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:3]([C@@H:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([OH:14])[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[C:24]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)=[O:25].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1>[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[C:24]([C:26]1[CH:31]=[CH:30][C:29]([O:32][C:2]2[C:3]([C@H:8]3[CH2:13][CH2:12][CH2:11][C@@H:10]([OH:14])[CH2:9]3)=[N:4][CH:5]=[CH:6][N:7]=2)=[CH:28][CH:27]=1)=[O:25]
Reactant: O[C@H]1CCC[C@@H](c2nccnc2F)C1
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: O=C(c1ccc(Oc2nccnc2[C@H]2CCC[C@@H](O)C2)cc1)c1nc2ccccc2[nH]1
Temperature: 180 °C

Procedure:
A mixture of (rac)-cis-3-(3-fluoropyrazin-2-yl)cyclohexanol (140 mg, 0.713 mmol), (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (340 mg, 1.427 mmol), and cesium carbonate (465 mg, 1.427 mmol) in NMP (1.8 ml) was heated in a Biotage™ microwave reactor at 180° C. for 45 min. The mixture was partitioned between H2O(10 ml) and CH2Cl2 (20 ml), the layers were separated, and the aqueous layer was extracted with CH2Cl2 (3×20 ml). The combined organic layers were dried (MgSO4), concentrated under reduced pressure, and the resulting brown oil was purified by reversed phase HPLC (Gilson Gemini-NX 10u C18 110A, 100×50.0 mm, 10% to 95% H2O/MeCN, 0.1% TFA). The product containing fractions were combined, neutralized by the addition of solid Na2CO3, and extracted with CH2Cl2 (3×20 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to deliver (rac)-cis-(1H-benzo[d]imidazol-2-yl)(4-(3-(3-hydroxycyclohexyl)pyrazin-2-yloxy)phenyl)methanone as a brown foam. MS (ESI, pos. ion) m/z: 415.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13]>C(N(CC)CC)C.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]>[F:10][C:5]1[CH:4]=[CH:3][C:2]([C:16]#[C:15][Si:12]([CH3:14])([CH3:13])[CH3:11])=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: C#C[Si](C)(C)C
Reactant: N#Cc1cc(Br)ccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(F)c(C#N)c1
Temperature: 100 °C

Procedure:
5-Bromo-2-fluorobenzonitrile (5.01 g, 25.0 mmol), dichlorobis(triphenylphosphine)palladium(II) (652 mg, 0.929 mmol), and copper (J) iodide (413 mg, 2.17 mmol) were combined in triethylamine (15 mL) under an atmosphere of nitrogen. Trimethylsilyl acetylene (4.2 mL, 29.7 mmol) was added and the mixture was heated to 100° C. The mixture solidified and was monitored by LC/MS. After completion, the mixture was diluted with methylene chloride and washed with 1 N HCl. The organic layer was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of ethyl acetate in hexanes (5-45%) to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.09 (dd, J=6.10, 2.03 Hz, 1H) 7.77-7.97 (m, 1H) 7.54 (t, J=9.15 Hz, 1H) 0.15-0.32 (m, 9H).
Reaction SMILES: [O:1]=[C:2]1[CH:7]([CH2:8][C:9]([OH:11])=[O:10])[S:6](=[O:13])(=[O:12])[C:5]2[S:14][C:15]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:16][C:4]=2[NH:3]1.S(=O)(=O)(O)O.[CH3:26]O>>[O:1]=[C:2]1[CH:7]([CH2:8][C:9]([O:11][CH3:26])=[O:10])[S:6](=[O:13])(=[O:12])[C:5]2[S:14][C:15]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:16][C:4]=2[NH:3]1
Reactant: CO
Reactant: NS(=O)(=O)c1cc2c(s1)S(=O)(=O)C(CC(=O)O)C(=O)N2
Agent: O=S(=O)(O)O
Product: COC(=O)CC1C(=O)Nc2cc(S(N)(=O)=O)sc2S1(=O)=O

Procedure:
A mixture of (2,3-dihydro-2,4,4-trioxo-6-sulfamoyl-1H-thieno-[2,3-b][1,4]thiazin-3-yl)acetic acid (5 g) and concentrated sulfuric acid (3 ml) in methanol (50 ml) was heated to reflux for 5 hours. The solvent was removed and the residue was treated with ice cold water. The resulting solid was collected, rinsed with additional cold water and dried at 50° C. to yield 4.05 g. Recrystallization from water gave methyl (2,3-dihydro-2,4,4-trioxo-6-sulfamoyl-1H-thieno-[2,3-b][1,4]thiazin-3-yl)acetate, mp 223°-225° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([OH:17])=[C:14]([C:18]#[N:19])[C:13](=[O:20])[NH:12][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1.C1C=C[NH+]=CC=1.[Br:27][Br-]Br>CC(O)=O.O>[Br:27][C:9]1[S:10][C:11]2[NH:12][C:13](=[O:20])[C:14]([C:18]#[N:19])=[C:15]([OH:17])[C:16]=2[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: N#Cc1c(O)c2c(-c3ccc(Cl)cc3)csc2[nH]c1=O
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1c(O)c2c(-c3ccc(Cl)cc3)c(Br)sc2[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3-(4-chlorophenyl)-4-hydroxy-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carbonitrile (0.17 g, 0.55 mmol) in AcOH (6 mL) was added pyridine hydrobromide perbromide (0.18 g, 0.6 mmol) in a single portion at room temperature. The reaction was stirred at room temperature for 1 h, diluted with water (25 mL). The resultant solid was filtered and dried to give the title compound. MS (ESI) m/e 380.79 (M−H)+; 1H NMR (300 MHz, DMSO-d6): ppm 7.45 (d, 2H), 7.33 (d, 2H).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl[C:11]1[S:12][CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:15]=1.C(N(CC)CC)C>CN(C)C=O>[CH2:1]([NH:9][C:11]1[S:12][CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCOC(=O)c1csc(Cl)n1
Reactant: CCCCCCCCN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCCCCNc1nc(C(=O)OCC)cs1

Procedure:
The reaction described in Preparation 26 was repeated, but using 2.7 g of octylamine, 4.0 g of ethyl 2-chlorothiazole-4-carboxylate, 4.2 g of triethylamine and 15 ml of dimethylformamide, giving the title compound as a pale yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[CH:13]2[N:16](C)[CH:10]([CH2:11][CH2:12]2)[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH+]1C=CC=CC=1>O>[CH2:1]([N:8]1[C:9](=[O:18])[CH:10]2[NH:16][CH:13]([CH2:12][CH2:11]2)[C:14]1=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1C2CCC1C(=O)N(Cc1ccccc1)C2=O
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: O
Product: O=C1C2CCC(N2)C(=O)N1Cc1ccccc1

Procedure:
A mixture of 3-benzyl-2,4-dioxo-8-methyl-3,8-diazabicyclo(3.2.1)octane (U.S. Pat. No. 3,328,396) (1.05 g) and pyridinium hydrochloride (5 g) was heated in an oil-bath at 220° C. for 25 minutes. After cooling, the mixture was taken up with water (30 mL) and extracted with ether. The organic layer was dried over magnesium sulfate, evaporated to give 0.45 g of crude product which was chromatographed over silica gel using dichloromethane - ethyl acetate 80:20 as eluent to give 0.3 g of crystallized titled product. MP 72° C.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.N12CCN(CC1)CC2.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[C:35]([CH2:36][OH:37])=[CH:34][C:33]2[C:28](=[C:29]([CH3:38])[CH:30]=[CH:31][CH:32]=2)[N:27]=1.[H-].[Na+]>CS(C)=O.O>[N:10]1[C:2]([O:37][CH2:36][C:35]2[C:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[Cl:19])=[N:27][C:28]3[C:33]([CH:34]=2)=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:38])=[C:3]2[C:7]([NH:6][CH:5]=[N:4]2)=[N:8][CH:9]=1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: Cc1cccc2cc(CO)c(-c3ccccc3Cl)nc12
Agent: C1CN2CCN1CC2
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cccc2cc(COc3ncnc4[nH]cnc34)c(-c3ccccc3Cl)nc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Prepared according to procedure L A mixture of 6-chloropurine (75 mg, 0.49 mmol) and 1,4-diazabicyclo[2.2.2]octane (109 mg, 0.97 mmol) in DMSO (0.5 mL) was stirred at rt for 5 h and was then added via cannula to a mixture of (2-(2-chlorophenyl)-8-methylquinolin-3-yl)-methanol (69 mg, 0.24 mmol) and sodium hydride, 60% dispersion in mineral oil (39 mg, 0.97 mmol) in DMSO (0.5 mL) that had been stirred at rt for 15 min prior to the addition. The mixture was stirred at rt for 3.5 h, cooled to 0° C., and H2O (5 mL) was added carefully. The mixture was extracted with EtOAc (3×10 mL), and the combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The resulting yellow oil was dissolved in CH2Cl2, evaporated onto silica gel (deactivated with 2M NH3 in MeOH), and purified by flash chromatography (Biotage® Si 25+M) eluting with 2M NH3 in MeOH/CH2Cl2 (5%) to provide a white solid [PI3Kδ IC50=25 nM]. MS (ESI+) m/z=402.0 (M+1).
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@H:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:2]2.C(N(CC)CC)C.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>C(Cl)(Cl)Cl>[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([S:29]([N:2]2[C@@H:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:4]3[CH2:5][CH2:6][CH:1]2[CH2:8][CH2:7]3)(=[O:31])=[O:30])=[CH:27][CH:28]=1
Reactant: CCOC(=O)[C@@H]1NC2CCC1CC2
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H]1C2CCC(CC2)N1S(=O)(=O)c1ccc(OC)cc1
Yield: 37.5 %

Procedure:
To a solution of ethyl (3R)-2-azabicyclo[2.2.2]octane-3-carboxylate (362 mg, 1.97 mmol) in chloroform (4.0 ml) were added triethylamine (0.30 ml, 2.17 mmol) and 4-methoxybenzenesulfonyl chloride(448 mg, 2.17 mmol) while being cooled with ice. After a reaction at room temperature for 2 hours, the reaction mixture was washed with 1N hydrochloric acid, saturated sodium bicarbonate water and saturated brine successively, and dried over magnesium sulfate. The solvent was evaporated and the residue was recrystallized (hexane/ethyl acetate), to give ethyl (3R)-2-[(4-methoxyphenyl)sulfonyl]-2-azabicyclo[2.2.2]octane-3-carboxylate (261 mg). Further, mother liquid was concentrated, and the resulting residue was purified by silica gel column chromatography (1%–5% methanol/chloroform), to give the same compound (137 mg, total 399 mg, 57%).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C(Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Ic1ccc(OCc2ccccc2)cc1
Yield: 88.1 %

Procedure:
4-iodoanisole (10.12 g, 0.046 mole), benzyl bromide (8.00 g, 0.046 mole), and potassium carbonate (6.31 g, 0.046 mole) in acetone (20 ml) were refluxed for 24 hours. Water was added and the aqueous layer extracted with ether (3×100 ml). The combined organic layers were washed with 2M NAOH (2×150 ml) and dried over anhydrous potassium carbonate. Evaporation of the solvent followed by crystallisation from methanol yielded 12.57 g (88%) benzyl 4-iodophenyl ether.
Reaction SMILES: [F:1][C@:2]12[C@@H:21]([OH:22])[CH2:20][C@@:19]3([CH3:23])[C@@H:12]([CH2:13][CH:14]=[C:15]3[C:16](=[O:18])[CH3:17])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:25])[CH2:4][CH2:5][C:6](=[O:24])[CH:7]=1.[OH2:26]>CS(C)=O.CO.Cl>[C:21]([C@@H:14]1[CH2:13][C@@H:12]2[C@:19]([CH3:23])([CH2:20][C@H:21]([OH:22])[C@@:2]3([F:1])[C@H:11]2[CH2:10][CH2:9][C:8]2[C@:3]3([CH3:25])[CH2:4][CH2:5][C:6](=[O:24])[CH:7]=2)[C@H:15]1[C:16](=[O:18])[CH3:17])(=[O:26])[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:3]=1
Reactant: O
Reactant: CC(=O)C1=CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Agent: Cl
Solvent: CS(C)=O
Solvent: CO
Product: CC(=O)[C@H]1[C@H](C(=O)c2ccccc2)C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1-Phenyl-1-tetrahydropyranyloxyacetonitrile (1.3 g.) is added to a suspension of 57% sodium hydride-paraffin (275 mg.) in dry dimethylsulfoxide (20 ml.) in a nitrogen atmosphere. The mixture is stirred at room temperature for 90 minutes to yield a homogeneous solution of the anion. To the anion is added a solution of 9-fluoro-11β-hydroxypregna-4,16-diene-3,20-dione (1.04 g.) in dry dimethylsulfoxide. After 30 minutes, the mixture is poured into water and extracted with ethyl acetate. The extracts are combined, washed with water, dried over magnesium sulfate and evaporated to afford 2.55g. of a gum. This is dissolved in methanol (25 ml.), conc. hydrochloric acid (2 drops) is added and the solution is maintained in a bath at 55°-60°C for 5.0 hours. The methanol is evaporated in vacuo, the residue is dissolved in ethyl acetate, washed with a diluted sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated to afford the crude product as a gum. This is absorbed on a dry column of silica gel (40 g.) and the column is eluted successively with chloroform, ethyl acetate-chloroform (1:9) and ethyl acetate. Crystallization of the material (1.1 g.) eluted with ethyl acetate-chloroform from acetone-hexane affords the analytical specimen (690 mg.), melting point 250° -252°C, dec.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]([C:18](=O)[CH:19]([CH3:21])[CH3:20])=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)=[CH:5][CH:4]=1.Cl.[NH2:24][OH:25].[OH-].[Na+].Cl>CCO.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]([C:18](=[N:24][OH:25])[CH:19]([CH3:21])[CH3:20])=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2nn3ccccc3c2C(=O)C(C)C)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2nn3ccccc3c2C(=NO)C(C)C)cc1
Temperature: 0 °C
Yield: 50.5 %

Procedure:
To a solution of 4.4 (14.9 mmol) of 1-(2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one in 32 ml of anhydrous EtOH was added 4.15 g of hydroxylamine hydrochloride, followed by a solution of 13.73 g (14.9 mmol) of NaOH in 10 ml water dropwise. The mixture was stirred and refluxed over night. After cooling, the solution was poured into a solution of 6 ml 6N HCl and 100 ml ice water with stirring for 30 minutes. The mixture was extracted with ethyl acetate three times. The organic phase was washed with brine and dried over MgSO4. After evaporation of the solvent under vacuum, 5 g of crude product was obtained. Purification on an aluminum oxide column with hexane-dichloromethane-ethyl acetate as eluant afforded 2.33 g (50.5%) of 1-(2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one oxime. Compound 1022.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH3:11][N:12]([CH3:25])[CH2:13][CH2:14][CH2:15][C:16]1[C:17]([CH3:24])=[C:18]([CH:22]=O)[NH:19][C:20]=1[CH3:21]>>[CH3:25][N:12]([CH3:11])[CH2:13][CH2:14][CH2:15][C:16]1[C:17]([CH3:24])=[C:18]([CH:22]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])[NH:19][C:20]=1[CH3:21]
Reactant: O=C1Cc2ccccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CCCN(C)C
Product: Cc1[nH]c(C=C2C(=O)Nc3ccccc32)c(C)c1CCCN(C)C
Yield: 52 %

Procedure:
2-Oxindole (133 mg, 1.0 mmol) was condensed with 4-(3-dimethylaminopropyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (208 mg, 1.0 mmol) using method B to give 168.3 mg (52%) of 3-[4-(3-dimethylaminopropyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[C:7]([CH2:12]O)=[CH:6][C:5]=1[N:14]([CH3:16])[CH3:15].N12CCCN=C1CCCCC2.C1(P([N:43]=[N+:44]=[N-:45])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[CH3:1][NH:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[C:7]([CH2:12][N:43]=[N+:44]=[N-:45])=[CH:6][C:5]=1[N:14]([CH3:16])[CH3:15]
Reactant: CNC(=O)c1cc(C#N)c(CO)cc1N(C)C
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CNC(=O)c1cc(C#N)c(CN=[N+]=[N-])cc1N(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 81.2 %

Procedure:
After dissolving N1-methyl-5-cyano-2-(dimethylamino)-4-(hydroxymethyl)benzamide (849 mg, 3.6 mmol) in tetrahydrofuran (20 ml), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.77 ml, 5.1 mmol) and diphenylphosphoryl azide (1.1 ml, 5.1 mmol) were added and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (755 mg) as a faint yellow powder. (80% yield)
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][NH:7][NH2:8])[CH3:2].C([O:14][C:15](=O)[CH:16]=[C:17]([NH2:21])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:21][C:17]1[NH:8][N:7]([CH2:6][C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([CH2:1][CH3:2])[CH:4]=2)[C:15](=[O:14])[CH:16]=1
Reactant: CCOC(=O)C=C(N)OCC
Reactant: CCc1cccc(CNN)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCc1cccc(Cn2[nH]c(N)cc2=O)c1
Reaction time: 8 h

Procedure:
14.2 g of 3-ethylbenzylhydrazine were added dropwise to a solution of 15.1 g of β-amino-β-ethoxyacrylic acid ethyl ester and a pinch of p-toluenesulphonic acid in 80 ml of ethanol, in the course of which the temperature rose from 22° to 30°. After stirring overnight, the solvent was distilled off in vacuo and the solid residue was recrystallised from ethanol. The product was the compound identified above. Melting point: 73°, 5 g (24%).
Reaction SMILES: [CH2:1]([Li])CCC.[C:6]1([CH2:12][CH2:13][C:14](=O)[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.CCCCCC>[C:6]1([CH2:12][CH2:13][C:14]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH2:1])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [Li]CCCC
Reactant: O=C(CCc1ccccc1)CCc1ccccc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C(CCc1ccccc1)CCc1ccccc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
A suspension of 1.59 g (4.45 mmol) of methyltriphenylphosphonium bromide in 100 ml of tetrahydrofuran was cooled to -78° C., treated with 2.2 ml (4.5 mmol) of n-butyllithium, warmed to 0° C., and recooled to -78° C. The resulting solution was treated via cannula with a solution of 1.59 g (4.45 mmol) of 1,5-diphenyl-3-pentanone in 20 ml of tetrahydrofuran. After being allowed to stir at ambient temperature for 2 h, the solution was diluted with hexane, washed sequentially with water and saturated brine, dried over MgSO4, and concentrated in vacuo. The mixture was purified by flash chromatography to give 0.90 g (86%) of the desired compound as a colorless oil. 1H NMR (CDCl3) δ 2.37 (t, J=8 Hz, 4H), 2.76 (t, J=8 Hz, 4H), 4.81 (s, 2H), 7.15-7.3 (m, 10H). Mass spectrum (M+NH4)+ =254.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:6][C@@H:5]([C:7]([O:9]C)=[O:8])[CH2:4][O:3]1.[OH-].[K+:13]>CO.CCOCC>[K+:13].[CH3:1][C:2]1([CH3:11])[O:6][C@@H:5]([C:7]([O-:9])=[O:8])[CH2:4][O:3]1
Reactant: COC(=O)[C@H]1COC(C)(C)O1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: CC1(C)OC[C@H](C(=O)[O-])O1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93.9 %

Procedure:
To a solution of methyl (R)-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (0.16 mL, 1.0 mmol) in MeOH (2 mL), 2 N KOH (0.5 mL, 1 mmol) was added. The resulting solution was stirred at RT for 20 min and concentrated in vacuo. The residue obtained was suspended in ether (10 mL) and sonicated for 5 min. The ether was then removed and the resulting residue was dried in vacuo for 4 h to obtain (R)-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxylic acid potassium salt (173 mg, 94%) which was directly used in the next step without purification.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[I-].[CH3:19][O:20][C:21]1[CH:29]=[C:28]2[C:24]([C:25]([CH2:31][N+](C)(C)C)=[CH:26][N:27]2[CH3:30])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([CH2:31][C:25]2[C:24]3[C:28](=[CH:29][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)[N:27]([CH3:30])[CH:26]=2)[CH2:14][CH2:13]1
Reactant: COc1ccc2c(C[N+](C)(C)C)cn(C)c2c1
Reactant: c1ccc2[nH]c(NCC3CCNCC3)nc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc2c(CN3CCC(CNc4nc5ccccc5[nH]4)CC3)cn(C)c2c1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
After adding anhydrous acetonitrile (2 ml) to a mixture of (1H-benzimidazol-2-yl)-piperidin-4-ylmethyl-amine (20 mg, 0.09 mmol), (6-methoxy-1-methyl-1H-indol-3-ylmethyl)-trimethylammonium iodide (0.1 mmol) and anhydrous potassium carbonate (5 mg, 0.11 mmol), the mixture was stirred at 50° C. for 12 hours. The mixture was cooled to room temperature and then passed through a silica gel short column and purified by preparative HPLC to obtain (1H-benzimidazol-2-yl)-[1-(6-methoxy-1-methyl-1H-indol-3-ylmethyl)-piperidin-4-ylmethyl]-amine. The compound was identified by LC-MS.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[F:47][C:48]1[CH:55]=[CH:54][C:51]([CH2:52][NH2:53])=[CH:50][CH:49]=1>ClCCl>[F:47][C:48]1[CH:55]=[CH:54][C:51]([CH2:52][NH:53][C:8]([C:4]2[S:3][C:2]([Br:1])=[N:6][C:5]=2[CH3:7])=[O:10])=[CH:50][CH:49]=1
Reactant: Cc1nc(Br)sc1C(=O)O
Reactant: NCc1ccc(F)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc(Br)sc1C(=O)NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 57.4 %

Procedure:
Part A. To a solution of 2-bromo-4-methyl-thiazole-5-carboxylic acid (10 g, 45.0 mmol, 1.0 equiv) and diisopropylethylamine (15.6 mL, 90.0 mmol, 2.0 equiv) in anhydrous dichloromethane (400 mL) was added benzotriazol-1-yloxytris-(dimethylamino)phosphonium hexafluorophosphate (BOP reagent, 22 g, 49.5 mmol, 1.1 equiv) and 4-fluorobenzylamine (5.7 mL, 49.5 mmol, 1.1 equiv). The resulting mixture was stirred at ambient temperature for 12 hr. The reaction mixture was diluted with dichloromethane, washed with water then brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by column chromatography [SiO2, ethyl acetate/hexanes, 10:90 to 40:60, v/v], followed by stirring in pentane and filtering the solid to afford 2-bromo-4-methyl-thiazole-5-carboxylic acid 4-fluoro-benzylamide (8.5 g, 57% yield). MS (M+H)+=330.1, Rt=1.36 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([O:13][C:14]2[CH:19]=[C:18](Cl)[N:17]=[C:16]([NH2:21])[N:15]=2)[C:9]([F:12])([F:11])[F:10])=[C:4]([N:22]2[CH:26]=[CH:25][C:24]([CH3:27])=[N:23]2)[CH:3]=1.[CH2:28]1[C:32]2([CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH2:31][C@@H:30]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[N:29]1[C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[NH2:21][C:16]1[N:17]=[C:18]([N:35]2[CH2:34][CH2:33][C:32]3([CH2:28][N:29]([C:43]([O:45][CH2:46][C:47]4[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=4)=[O:44])[C@H:30]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:31]3)[CH2:37][CH2:36]2)[CH:19]=[C:14]([O:13][C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[N:22]2[CH:26]=[CH:25][C:24]([CH3:27])=[N:23]2)[C:9]([F:12])([F:11])[F:10])[N:15]=1
Reactant: Cc1ccn(-c2cc(Br)ccc2[C@@H](Oc2cc(Cl)nc(N)n2)C(F)(F)F)n1
Reactant: CCOC(=O)[C@@H]1CC2(CCNCC2)CN1C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Br)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 90 °C

Procedure:
To a solution of 4-[(1R)-1-[4-bromo-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoro-ethoxy]-6-chloro-pyrimidin-2-amine (125 mg, 0.3 mmol, Step 1) in dioxane (3 mL) was added (S)-2-benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (95 mg, 0.3 mmol) and Na2CO3 (182 mg, 0.35 mmol). The reaction was heated to 90° C. for 130 h, then cooled to RT, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.