Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]([I:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:13]([N:19]=[C:20]=[S:21])[CH:14]1[O:18][CH2:17][CH2:16][CH2:15]1.C(N(CC)CC)C>C(O)C>[I:12][C:8]1[CH:7]=[C:3]2[C:2](=[C:10]([I:11])[CH:9]=1)[NH:1][C:20](=[S:21])[N:19]([CH2:13][CH:14]1[CH2:15][CH2:16][CH2:17][O:18]1)[C:4]2=[O:6]
Reactant: Nc1c(I)cc(I)cc1C(=O)O
Reactant: S=C=NCC1CCCO1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=c1c2cc(I)cc(I)c2[nH]c(=S)n1CC1CCCO1
Temperature: 25 °C

Procedure:
A mixture of 2-amino-3,5-diiodobenzoic acid (1.09 g, 2.57 mmol), tetrahydrofurfuryl isothiocyanate (0.35 g, 2.43 mmol) and triethylamine (0.26 g, 2.57 mmol) in 3.5 mL of ethanol was heated to reflux for about 6 h, and then was allowed to cool to room temperature. The ensuing precipitate was filtered and washed with ethanol (1×20 mL), hexanes (1×mL), and then dried to deliver 0.86 g of the title compound of Step A. 1H NMR (400 MHz, Me2SO-d6): δ 1.64-1.75 (m,1H), 1.75-1.85 (m,1H), 1.86-2.0 (m,2H), 3.57-3.65 (m,1H), 3.70-3.81 (m,1H), 4.26-4.34 (m,1H), 4.36-4.44 (m,1H), 4.52-4.60 (m,1H), 8.19 (d,1H), 8.56 (d,1H), 10.1 (br s,1H).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16](=[C:18]([C:23]2[CH:28]=[CH:27][C:26]([O:29]C)=[CH:25][CH:24]=2)[S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>ClCCl>[CH:1]([N:14]1[CH2:15][C:16](=[C:18]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)[S:19]([CH3:22])(=[O:21])=[O:20])[CH2:17]1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COc1ccc(C(=C2CN(C(c3ccccc3)c3ccccc3)C2)S(C)(=O)=O)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CS(=O)(=O)C(=C1CN(C(c2ccccc2)c2ccccc2)C1)c1ccc(O)cc1
Yield: 44.3 %

Procedure:
On carrying out the operation according to the procedure of Example 32 starting with 1.4 g of 1-benzhydryl-3-[(4-methoxyphenyl)(methylsulfonyl)methylene]azetidine, 10 cm3 of a 1 M boron tribromide solution and 100 cm3 of dichloromethane, the residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 3.5 cm, height 24 cm) at a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (50/50 by volume) as eluents and collecting 25 cm3 fractions. Fractions 21 to 37 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from a mixture of 30 cm3 of ethyl ether. 0.6 g of 1-benzhydryl-3-[(4-hydroxyphenyl)(methylsulfonyl)methylene]azetidine is obtained melting at 211° C. [NMR spectrum in DMSO-d6, T=300K, δ in ppm (300 MHz): 2.90 (3H, s, SCH3), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.75 (1H, s, NCH), 6.80 (2H, d, J=7 Hz, 2CH arom.), between 7.10 and 7.35 (8H, m, 8CH arom.), 7.48 (4H, d, J=7 Hz, 4CH arom.), 9.80 (1H, s, OH)].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16][CH2:15]1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[C:32]([CH:35]=O)[S:33][CH:34]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[O:20]=[S:17]1(=[O:21])[CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:30]4[CH:31]=[C:32]([CH2:35][N:7]([CH2:6][CH3:5])[CH3:8])[S:33][CH:34]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15][CH2:16]1
Reactant: CC1(C)OB(c2csc(C=O)c2)OC1(C)C
Reactant: NC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCS(=O)(=O)CC4)c3c2)cs1
Temperature: 150 °C
Yield: 5.4 %

Procedure:
To 5-bromo-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indole-7-carboxamide (400 mg, 1.08 mmol) in dioxane and water (4 mL/1 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thiophenecarbaldehyde (462 mg, 1.94 mmol), Pd(PPh3)4 (100 mg) and K2CO3 (447 mg, 3.24 mmol). The reaction mixture was heated to 150° C. for 20 minutes by microwave irradiation. The organic phase was concentrated and redissolved in DMSO (10 mL). The resulting solution was split to eight. NaBH3CN (30 mg), ZnCl2 (30 mg) and methyl ethylamine (50 mg) were added. The mixture was heated at 100° C. for 30 minutes which was then filtered and purified by HPLC with TFA to afford the title compound (13 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C@H:5]([C:7]1[C:8]([CH3:22])=[N:9][C:10]2[N:11]([N:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:16]=2)[C:12]=1[I:13])[OH:6])[CH3:2].Cl(O)(=O)(=O)=O>C(Cl)Cl.C(OC(C)(C)C)(=O)C>[C:7]([O:6][C@@H:5]([C:7]1[C:8]([CH3:22])=[N:9][C:10]2[N:11]([N:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:16]=2)[C:12]=1[I:13])[C:4]([O:3][CH2:1][CH3:2])=[O:23])([CH3:8])([CH3:12])[CH3:5]
Reactant: CCOC(=O)c1cc2nc(C)c([C@H](O)C(=O)OCC)c(I)n2n1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Solvent: CC(=O)OC(C)(C)C
Product: CCOC(=O)c1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(I)n2n1
Reaction time: 3 h
Yield: 135.7 %

Procedure:
To a stirred solution of (S)-ethyl 6-(2-ethoxy-1-hydroxy-2-oxoethyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (5.3 g, 12.2 mmol) in CH2Cl2 (150 mL) and t-butyl acetate (105 mL) at rt was added perchloric acid (3.15 mL, 36.7 mmol). The reaction flask was sealed. After stirring for 3 h, the reaction mixture was diluted with CH2Cl2 (100 mL), carefully quenched with sat. aq. NaHCO3 (50 mL). The organic layer was separated and washed with brine (100 mL), dried (Na2SO4), filtered and concentrated in vacuo to give a yellow liquid. This crude product was purified by flash column chromatography on a silica gel column using (10-50% EtOAc/Hex as eluant) to afford the desired (S)-ethyl 6-(1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (4.5 g, 8.28 mmol, 67.7% yield) as viscous oil. In addition, 700 mg of starting material was recovered. 1H NMR (500 MHz, CDCl3) δ 7.31 (s, 1H), 5.56 (s, 1H), 4.51 (q, J=7.1 Hz, 2H), 4.26-4.16 (m, 2H), 2.71 (s, 3H), 1.48 (t, J=7.2 Hz, 3H), 1.30 (s, 9H), 1.23 (t, J=7.0 Hz, 3H). LCMS (M+H)=490.0.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]=[CH:13][O:14]C)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(C1C=CC(C=O)=CC=1)(C)(C)C>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][CH:13]=[O:14])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC=CCc1ccc(C(C)(C)C)cc1
Agent: CC(C)(C)c1ccc(C=O)cc1
Product: CC(C)(C)c1ccc(CCC=O)cc1

Procedure:
4-Tert-butyl 1-(3-methoxy-2-propen-1-yl)benzene was similarly prepared as described in Examples I and II. First, 4-tert-butyl benzaldehyde (commercially available from TCI Company) was used to obtain 3-(4-tert-butyl-phenyl)-propionaldehyde (1.1 Kg), which was consequently used to afford 4-tert-butyl 1-(3-methoxy-2-propen-1-yl)benzene (636 g). The product 4-tert-butyl 1-(3-methoxy-2-propen-1-yl)benzene has a boiling point of 98° C. at a pressure of 1.2 mmHg.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[CH:6][C:5]=2[C:9]([C:11]2[CH:21]=[CH:20][C:14]3[O:15][C:16]([F:19])([F:18])[O:17][C:13]=3[C:12]=2[S:22]([CH3:24])=[O:23])=[O:10])[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:33])C=1>ClCCl>[CH:1]1([C:4]2[O:8][N:7]=[CH:6][C:5]=2[C:9]([C:11]2[CH:21]=[CH:20][C:14]3[O:15][C:16]([F:19])([F:18])[O:17][C:13]=3[C:12]=2[S:22]([CH3:24])(=[O:33])=[O:23])=[O:10])[CH2:2][CH2:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CS(=O)c1c(C(=O)c2cnoc2C2CC2)ccc2c1OC(F)(F)O2
Solvent: ClCCl
Product: CS(=O)(=O)c1c(C(=O)c2cnoc2C2CC2)ccc2c1OC(F)(F)O2
Yield: 89.9 %

Procedure:
A solution of 5-cyclopropyl-4-(2,2-difluoro-4-methylsulphinyl-1,3-benzodioxol-5-oyl)isoxazole (1.0 g) in dichloromethane was stirred with m-chloroperbenzoic acid (55%, 1.33 g) for 5 hours, then washed in turn with sodium metabisulphite solution, saturated sodium bicarbonate solution and water. The solution was dried (magnesium sulphate), evaporated to dryness and the residue recrystallised from toluene/cyclohexane to give 5-cyclopropyl-4-(2,2-difluoro-4-methylsulphonyl-1,3-benzodioxol-5-oyl)isoxazole (compound 6, 0.94 g) as a colourless solid, m.p. 162°-163° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](OC)=[O:9])=[CH:4][C:3]=1[CH3:12].CC(C[AlH]CC(C)C)C>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[CH3:12]
Reactant: COC(=O)c1cnc(Cl)c(C)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: Cc1cc(CO)cnc1Cl
Reaction time: 8 h
Yield: 88.3 %

Procedure:
To a solution of methyl 6-chloro-5-methyl-3-pyridinecarboxylate (84 mg, 0.453 mmol) in DCM (2 ml), DIBAL-H (1.5 M solution in toluene, 0.905 ml, 1.358 mmol) was added dropwise under N2 at −78° C. The reaction mixture was allowed to attain rt and stirred overnight. After 18 h, TLC showed no starting material. The reaction was quenched by addition of sodium-potassium tartrate saturated solution, extracted with DCM, dried, filtered, and concentrated to afford (6-chloro-5-methyl-3-pyridinyl)methanol (63 mg, 0.400 mmol, 88% yield) pure enough to be used in the next step.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](/[C:11](=[C:15](\[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)/[CH2:16][CH3:17])/[C:12]([OH:14])=O)=[CH:7][CH:6]=1.Cl.Cl.[CH3:26][N:27]([CH3:38])[CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=1.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:26][N:27]([CH3:38])[CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:12](=[O:14])/[C:11](/[C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:6][CH:7]=2)=[C:15](/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)\[CH2:16][CH3:17])=[CH:33][CH:32]=1
Reactant: CC/C(=C(\C(=O)O)c1ccc(OCOC)cc1)c1ccccc1
Reactant: CN(C)CCOc1ccc(N)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC/C(=C(\C(=O)Nc1ccc(OCCN(C)C)cc1)c1ccc(OCOC)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 65 %

Procedure:
To a mixture of 3 (2.90 g, 9.28 mmol), 4-(2-(dimethylamino)ethoxy)benzenamine dihydrochloride (2.58 g, 10.2 mmol), 4-Dimethylaminopyridine (56.7 mg, 0.464 mmol) in CH2Cl2 (100 ml) was added O-Benzotriazoyl-N,N,N′,N′-tetramethyluronium Hexafluorophosphate (3.87 g, 10.2 mmol) under ice cooling, and the mixture was stirred at 0° C. for 10 min. Then N,N-Diisopropylethylamine (4.19 g, 32.4 mmol) was added under ice cooling. The mixture was stirred at 0° C. for 5 min, and at room temperature for 15 h. The reaction was quenched with saturated aqueous NaHCO3 under ice cooling, and the whole was extracted with CHCl3, the organic layer was washed with brine, dried over Na2SO4, and then concentrated. Purification by Biotage (eluent: CH2Cl2 to CH2Cl2/MeOH, 6:1) gave the colorless solid. The solid was triturated with Et2O-hexane to give 4 (65%).
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][C:17]([Cl:21])=[C:18](Br)[CH:19]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(CC)CC.[CH3:29][Si:30]([C:33]#[CH:34])([CH3:32])[CH3:31]>C1(C)C=CC=CC=1.[I+].[Cu+].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>[C:1]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][C:17]([Cl:21])=[C:18]([C:34]#[C:33][Si:30]([CH3:32])([CH3:31])[CH3:29])[CH:19]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(Br)c1
Reactant: C#C[Si](C)(C)C
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [I+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(C#C[Si](C)(C)C)c1
Temperature: 100 °C
Yield: 75 %

Procedure:
To a solution of 3-(1-BOC-2-(S)-azetidinylmethoxy)-5-bromo-6-chloropyridine (1.0 g, 2.6 mmol) in toluene (20 mL) was added NEt3 (1 mL), copper (I) iodine (50 mg, 10%), tetrakis(triphenylphosphine)palladium (0) (305 mg, 10%) and (trimethylsilyl)acetylene (0.45 mL, 3.18 mmol). The reaction mixture was stirred and heated at 100° C. for 16 h. Solvent was evaporated and the residue was chromatographed (silica gel; hexane/EtoAc, 5:1 to 2:1) to afford an oil (770 mg, 74%): 1H NMR (CDCl3, 300 MHz) δ 1.42 (s, 9H), 2.20-2.40 (m, 2H), 3.80-3.92 (m, 2H), 4.10 (m, 1H), 4.30 (m, 1H), 4.50 (m, 1H), 7.37 (d, 1H, J=3.0 Hz), 8.05 (d, 1H, J=3.0 Hz); MS (CI/NH3) m/z 395 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[CH:3]=1.C([Li])CCC.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([N+:23]([O-:25])=[O:24])=[C:19]([CH:22]=1)[CH:20]=[O:21].C(O)(=O)C>C1COCC1.CCCCCC>[N+:23]([C:18]1[CH:17]=[CH:16][C:15]([Cl:14])=[CH:22][C:19]=1[CH:20]([C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8])[OH:21])([O-:25])=[O:24]
Reactant: Clc1cccc(Cl)c1
Reactant: O=Cc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(Cl)cc1C(O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.5 %

Procedure:
To 16.75 g of 1,3-dichlorobenzene dissolved in 250 ml of THF are added dropwise, at −70° C., 68 ml of a 1.6M solution in hexane of n-butyllithium. After one hour at −70° C., 10 g of 5-chloro-2-nitrobenzaldehyde dissolved in THF are introduced and the mixture is left for 3 hours at this temperature. The resulting mixture is hydrolysed by addition of 5 ml of acetic acid and is allowed to warm to room temperature. The resulting mixture is concentrated and the residue is chromatographed on a column of silica gel, eluting with a 90/10 (v/v) cyclohexane/ethyl acetate mixture to give 7.975 g of the expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:17]=[C:16]([C:18]3[NH:22][N:21]=[N:20][N:19]=3)[CH:15]=[CH:14][C:10]=2[C:11](O)=[O:12])=[CH:4][CH:3]=1>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([S:8][C:9]3[CH:17]=[C:16]([C:18]4[NH:22][N:21]=[N:20][N:19]=4)[CH:15]=[CH:14][C:10]=3[C:11]2=[O:12])=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(-c2nnn[nH]2)cc1Sc1ccc(Cl)cc1
Solvent: O
Product: O=c1c2ccc(-c3nnn[nH]3)cc2sc2ccc(Cl)cc12

Procedure:
2-(p-Chlorophenylthio)-4-(5-tetrazolyl)benzoic acid (3.41g) was heated with polyphosphoric acid (70g) on a steam bath for 1 hr. The reaction mixture was decomposed by warming with water, and the product filtered off, washed with water, recrystallised from dimethylformamide, and dried at 156° C. in vacuo, giving 7-chloro-3-(5-tetrazolyl)thioxanthone, decomposes without melting.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([NH:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[C:16][C:17]2([OH:21])[CH2:20][CH2:19][CH2:18]2)[CH:10]=1)=[O:4]>CCO>[F:1][C:2]([F:22])([F:23])[C:3]([NH:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][C:17]2([OH:21])[CH2:18][CH2:19][CH2:20]2)[CH:10]=1)=[O:4]
Reactant: O=C(NCCOc1cccc(C#CC2(O)CCC2)c1)C(F)(F)F
Solvent: CCO
Product: O=C(NCCOc1cccc(CCC2(O)CCC2)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2,2,2-Trifluoro-N-(2-(3-(2-(1-hydroxy cyclobutyl)ethynyl)phenoxy)ethyl)acetamide (0.45 g, 1.9 mmol) in EtOH (20 mL) was degassed and purged with nitrogen. To this was added Pd on C (0.09 g, 10%) and the flask was evacuated and filled with hydrogen. The resulting reaction mixture was stirred at room temperature under hydrogen balloon overnight. This was followed by filtration through a pad of Celite. The filter cake was washed with ethanol and the filtrate concentrated to afford 2,2,2-trifluoro-N-(2-(3-(2-(1-hydroxycyclobutyl)ethyl)phenoxy)ethyl)acetamide as yellow oil. Yield (0.3 g, 66%): 1H NMR (400 MHz, DMSO-d6) δ 7.20-7.25 (m, 1H), 6.87 (d, J=7.6 Hz, 1H), 6.78 (s, 1H), 6.72 (dd, J=8.0, 2.4 Hz, 1H), 4.11 (t, J=5.0 Hz, 2H), 3.76-3.81 (m, 2H), 2.67-2.72 (m, 2H), 2.01-2.14 (m, 4H), 1.92-1.96 (m, 2H), 1.22-1.26 (m, 2H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:15]=[C:16]([C:19]2[NH:20][C:21]3[CH:27]=[C:26]([Cl:28])[C:25]([Cl:29])=[CH:24][C:22]=3[N:23]=2)[S:17][CH:18]=1.CN(C)[CH:32]=[O:33].Cl>O1CCCC1.O>[Br:13][C:14]1[CH:15]=[C:16]([C:19]2[NH:23][C:22]3[CH:24]=[C:25]([Cl:29])[C:26]([Cl:28])=[CH:27][C:21]=3[N:20]=2)[S:17][C:18]=1[CH:32]=[O:33]
Reactant: CN(C)C=O
Reactant: Clc1cc2nc(-c3cc(Br)cs3)[nH]c2cc1Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: O=Cc1sc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)cc1Br
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 54.7 %

Procedure:
To a solution of diisopropylamine (0.67 mL, 4.8 mmol) in tetrahydrofuran (6 mL) was added n-butyllithium (1.6 mol/L in hexanes; 2.7 mL, 4.3 mmol) at 0° C. under nitrogen atmosphere, and the reaction mixture was cooled to −78° C. 2-(4-Bromothiophen-2-yl)-5,6-dichlorobenzimidazole (500 mg, 1.44 mmol) in tetrahydrofuran (14 mL) was added dropwise followed by the addition of dimethylformamide (0.33 mL, 4.3 mmol), and the mixture was stirred for 30 min. Water and hydrochloric acid (1 mol/L) were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was triturated with ethyl acetate to afford 2-(3-bromo-2-formylthiophen-5-yl)-5,6-dichlorobenzimidazole (296 mg, 55%).
Reaction SMILES: S=C1[N:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18](=[O:20])[CH3:19])=[C:13]([O:21][CH3:22])[CH:12]=2)=[O:8])[CH2:5][CH2:4]S1.NCC[N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C1COCC1>[C:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][O:9][C:7](=[O:8])[NH:6][CH2:5][CH2:4][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[CH:12][C:13]=1[O:21][CH3:22])(=[O:20])[CH3:19]
Reactant: NCCN1CCOCC1
Reactant: COc1cc(COC(=O)N2CCSC2=S)ccc1OC(C)=O
Solvent: C1CCOC1
Product: COc1cc(COC(=O)NCCN2CCOCC2)ccc1OC(C)=O
Reaction time: 2 h
Yield: 71.2 %

Procedure:
Compound VII (219.1 mg, 0.642 mmol) was dissolved in anhydrous THF (3.2 mL, 5 mL/mmol of 6). To the yellow solution was added 4-(2-aminoethyl)morpholine (83.5 mg, 84 μL, 0.642 mmol). The reaction solution was stirred for two hours, after which time the solution was colorless. The solvent was removed under reduced pressure. The crude material was purified by column chromatography on silica gel using CH2Cl2/MeOH (96:4, v/v) to give 161 mg (71%) of 17 as a white solid: mp=82-83° C. (uncorrected); Rf=0.16 (CH2Cl2/MeOH, 96:4, v/v); 1HNMR (CDCl3) δ 6.99 (d, 3J=8 Hz, 1H), 6.96 (d, 4J=1.65 Hz, 1H), 6.94 (dd, 3J=8 Hz, 4J=1.8 Hz, 1H), 5.23 (bs, 1H), 5.05 (s, 2H), 3.82 (s, 3H), 3.67 (m, 4H), 3.29 (m, 2H), 2.46 (t, 3J=5.9 Hz, 2H), 2.42 (bs, 41-1) and 2.29 (s, 3H). Exact mass (ESI) calculated for C17H25N2O6 [M+H]=353.1707. found 353.1705.
Reaction SMILES: [CH3:1][C@@:2]1([C:18]([F:21])([F:20])[F:19])[CH2:17][N:5]2[C:6](=[O:16])[CH:7]=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:9]=[C:4]2[NH:3]1.Br[CH2:23][CH2:24][S:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:1][C@@:2]1([C:18]([F:21])([F:19])[F:20])[CH2:17][N:5]2[C:6](=[O:16])[CH:7]=[C:8]([N:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)[N:9]=[C:4]2[N:3]1[CH2:23][CH2:24][S:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CCOCC3)cc2=O)N1
Reactant: BrCCSc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CCOCC3)cc2=O)N1CCSc1ccccc1

Procedure:
The product is prepared according to the procedure described in Example 1, using 100 mg of (S)-2-methyl-7-morpholin-4-yl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one (Example 1j) and 143 mg of 2-bromoethylphenyl sulphide, replacing the sodium hydride with caesium carbonate. After purification by silica column chromatography (eluent: dichloromethane/methanol 97/03), 96 mg of (S)-2-methyl-7-morpholin-4-yl-1-(2-phenylsulfanylethyl)-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one are obtained, the characteristics of which are the following:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O)#[N:2].FC(F)(F)C(O)=O.[CH2:19]([O:26][C:27](=[O:40])[CH2:28][CH2:29][NH:30][C:31](=[O:39])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([NH2:38])[CH:33]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:26][C:27](=[O:40])[CH2:28][CH2:29][NH:30][C:31](=[O:39])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([NH:38][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=2)[CH:33]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N#Cc1cccc(C(=O)O)c1
Reactant: Nc1cccc(C(=O)NCCC(=O)OCc2ccccc2)c1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(C(=O)Nc2cccc(C(=O)NCCC(=O)OCc3ccccc3)c2)c1

Procedure:
For the preparation of the starting material, m.p. 182°-183° C., 3-cyanobenzoic acid and N-(m-aminobenzoyl)-β-alanine benzyl ester trifluoroacetate are coupled to give N-[m-(m-cyanobenzamido)benzoyl]-β-alanine benzyl ester, MS: 428 (100, M+H), and this is converted with hydrogen sulphide and triethylamine in pyridine into N-[m-[m-(thiocarbamoyl)benzamido]benzoyl]-β-alanine benzyl ester, m.p. 128°-131° C. The latter is then reacted with methyl iodide in acetone and subsequently with ammonium acetate in methanol and treated with benzyl chloroformate and triethylamine in THF.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:8]=[C:7]2I)(=[O:3])[NH2:2].C([Sn](CCCC)(CCCC)[C:26]1[N:31]=[C:30]([N:32]2[CH2:37][CH2:36][CH:35]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[CH2:34][CH2:33]2)[CH:29]=[N:28][CH:27]=1)CCC>CN(C=O)C.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>[C:41]([O:40][C:39]([NH:38][CH:35]1[CH2:36][CH2:37][N:32]([C:30]2[N:31]=[C:26]([C:7]3[C:6]4[C:10](=[CH:11][CH:12]=[C:4]([C:1](=[O:3])[NH2:2])[CH:5]=4)[N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:8]=3)[CH:27]=[N:28][CH:29]=2)[CH2:33][CH2:34]1)=[O:45])([CH3:44])([CH3:42])[CH3:43]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(N2CCC(NC(=O)OC(C)(C)C)CC2)n1
Reactant: CC(C)(C)OC(=O)n1cc(I)c2cc(C(N)=O)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(c2cncc(-c3cn(C(=O)OC(C)(C)C)c4ccc(C(N)=O)cc34)n2)CC1
Temperature: 90 °C
Reaction time: 1 h
Yield: 26.2 %

Procedure:
A mixture of tert-butyl 5-carbamoyl-3-iodo-1H-indole-1-carboxylate (460 mg, 1.42 mmol) and tert-butyl 1-(6-(tributylstannyl)pyrazin-2-yl)piperidin-4-ylcarbamate (1d) (807 mg, 1.42 mmol) in DMF (4.6 mL) was purged with argon gas for 5 min, added Cut (405 mg, 2.13 mmol), palladium tetrakis (170 mg, 0.14 mmol) and again purged with argon gas for 5 min. The reaction mixture was stirred at 90° C. under nitrogen atmosphere for 1 h. The reaction mixture was then poured into water. The resulting precipitate was collected by filtration. The filtrate was extracted with diethyl ether. The organic layer was concentrated and combined with the above precipitate to give the crude product, which was purified by column chromatography to obtain the title compound as a brown solid (200 mg, 31%). MS (ESI, pos. ion) m/z: 537.0 (M+1).