Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C(O)CO.[F:14][C:15]([F:20])([F:19])[C:16]([OH:18])=[O:17]>C(#N)C>[F:14][C:15]([F:20])([F:19])[C:16]([O-:18])=[O:17].[NH2:1][CH2:2][CH2:3][NH+:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1
Reactant: O=C(O)C(F)(F)F
Reactant: NCCN1CCNCC1
Solvent: OCCO
Solvent: CC#N
Product: NCC[NH+]1CCNCC1
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
12.92 g (0.1 mol) of 1-(2-aminoethyl)piperazine and 50 g of ethylene glycol or acetonitrile as an organic solvent were put into a 250 ml two-necked flask equipped with a condenser, and 11.4 g (0.1 mol) of trifluoroacetic acid was slowly added dropwise thereto. The resulting solution was stirred at room temperature for 4 hours, washed with diethyl ether several times, and then dried under vacuum, thus obtaining 1-(2-aminoethyl)piperazinium trifluoroacetate (yield: 86%).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.[NH2:13][C:14]1[N:19]=[CH:18][N:17]=[C:16](Cl)[CH:15]=1>CS(C)=O>[NH:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([O:3][C:16]3[N:17]=[CH:18][N:19]=[C:14]([NH2:13])[CH:15]=3)[CH:12]=2)[CH:8]=[CH:9]1
Reactant: Oc1ccc2cc[nH]c2c1
Reactant: Nc1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Nc1cc(Oc2ccc3cc[nH]c3c2)ncn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 35.5 %

Procedure:
Sodium hydride (200 mg, 5.00 mmol) was suspended in dimethyl sulfoxide (8 ml); while stirring at room temperature, 6-hydroxyindole (666 mg, 5.00 mmol) and 6-amino-4-chloropyrimidine (518 mg, 4.00 mmol) were added thereto one by one; and the reaction mixture was stirred at 60° C. for 2 hours, at 80° C. for 1 hour, and at 100° C. for 1.5 hours. After cooled down to room temperature, the reaction mixture was partitioned between ethyl acetate and water; and the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Fuji Silysia BW-300, hexane:ethyl acetate=1:1, ethyl acetate, then ethyl acetate:methanol=98:2); the obtained crystals were suspended in ethyl acetate (50 ml) and stirred at room temperature overnight, filtered off, washed with diethyl ether, and dried to yield the title compound (322 mg, 1.42 mmol, 35.6%) as pale yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:11])[C:9]=1[OH:10])[CH:5]=O.[NH:12]1[CH2:18][C:16](=[O:17])[NH:15][C:13]1=[S:14].C([O-])(=O)C.[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:18]2[NH:12][C:13](=[S:14])[NH:15][C:16]2=[O:17])[CH:7]=[C:8]([Br:11])[C:9]=1[OH:10]
Reactant: O=Cc1cc(Br)c(O)c(Br)c1
Reactant: O=C1CNC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NC(=S)NC1=Cc1cc(Br)c(O)c(Br)c1
Yield: 24.7 %

Procedure:
Prepared according to the procedure described in Example 1 using 3,5-dibromo-4-hydroxybenzaldehyde (4.5 g, 16 mmoles), 2-thiohydantoin (1.7 g, 15 mmoles), sodium acetate (4.5 g, 55 mmoles), and acetic acid (35 ml). Recrystallization from ethanol gave the pure product (1.4 g), mp 267° C. (dec).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:5]=2[N:6]=1.[Cl:15][CH2:16][S:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([I:24])[C:19]=1[Cl:25]>>[Cl-:15].[NH2:1][C:2]1[N:3]([CH2:16][S:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([I:24])[C:19]=2[Cl:25])[C:4]2[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:5]=2[N+:6]=1[CH2:16][S:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([I:24])[C:19]=1[Cl:25]
Reactant: COc1cc2nc(N)[nH]c2cc1OC
Reactant: ClCSc1cccc(I)c1Cl
Product: COc1cc2c(cc1OC)[n+](CSc1cccc(I)c1Cl)c(N)n2CSc1cccc(I)c1Cl
Product: [Cl-]

Procedure:
Following the procedure of Example 2 and replacing 2-aminobenzimidazole with 2-amino-5,6-dimethoxybenzimidazole and replacing 2-bromo-4-chlorophenyl chloromethyl ether with 2-chloro-3-iodophenyl chloromethyl sulfide, the title compound is obtained.
Reaction SMILES: [CH2:1]([C:5]1[C:9](=[NH:10])[S:8][N:7]([C:11]([CH3:15])([CH3:14])[CH2:12][F:13])[CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:16][O:17][C:18]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:19]=1[C:20](Cl)=[O:21].C(N(CC)CC)C>C1COCC1>[CH2:1]([C:5]1=[CH:6][N:7]([C:11]([CH3:14])([CH3:15])[CH2:12][F:13])[S:8]/[C:9]/1=[N:10]\[C:20](=[O:21])[C:19]1[CH:23]=[C:24]([C:27]([F:29])([F:30])[F:28])[CH:25]=[CH:26][C:18]=1[O:17][CH3:16])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cn(C(C)(C)CF)sc1=N
Reactant: COc1ccc(C(F)(F)F)cc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCc1cn(C(C)(C)CF)s/c1=N\C(=O)c1cc(C(F)(F)F)ccc1OC
Temperature: 60 °C
Reaction time: 14 h
Yield: 8.7 %

Procedure:
To a solution of Example 152C (0.46 g, 2.0 mmol) in THF (10 mL) were added 2-methoxy-5-(trifluoromethyl)benzoyl chloride (0.52 g, 2.2 mmol, JRD Fluorochemicals Ltd) and triethylamine (0.84 mL, 6.0 mmol). After stirring at 60° C. for 14 hr, the reaction mixture was cooled to room temperature, quenched with saturated NaHCO3 (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% ethyl acetate in dichloromethane) to afford 75 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.93 (t, J=7.3 Hz, 3 H), 1.22-1.46 (m, 2 H), 1.65 (s, 2 H), 1.65 (s, 6 H), 2.63-2.83 (m, 2 H), 3.89 (s, 3 H), 4.60 (d, J=47.1 Hz, 2 H), 7.31 (d, J=8.8 Hz, 1 H), 7.80 (dd, J=8.6, 2.5 Hz, 1 H), 8.10 (d, J=2.4 Hz, 1 H), 8.63 (s, 1 H); MS (ESI+) m/z 433 (M+H)+; Anal. Calculated C20H24F4N2O2S: C, 55.54; H, 5.59; N, 6.48. Found: C, 55.75; H, 5.23; N, 6.43.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([O-:24])=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Na+].[CH2:28](Br)[CH:29]=[CH2:30]>CN(C)P(N(C)C)(N(C)C)=O>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:30][CH:29]=[CH2:28])=[O:23])=[CH:25][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)[O-])cc1
Reactant: C=CCBr
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=CCOC(=O)c1ccc(NCCCCCCCCCCCCCCCC)cc1

Procedure:
A solution of 7.66 g. of sodium 4-(n-hexadecylamino)benzoate and 12.1 g. of allyl bromide in 100 ml. of dry hexamethylphosphoramide is added to a reaction flask. After 6 hours the solution is poured into 100 ml. of water and the solid collected and recrystallized from 50 ml. of acetonitrile. This material is recrystallized from hexanol to yield the title compound, m.p. 81°-83° C.
Reaction SMILES: Br[CH2:2][C:3](Br)=[O:4].[CH2:6]([NH:13][CH2:14][CH3:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1)(=[O:25])=[O:24]>>[CH2:6]([N:13]([CH2:14][CH3:15])[C:3](=[O:4])[CH2:2][N:26]([S:23]([C:18]1[C:17]([CH3:16])=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:24])=[O:25])[C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Cc1ccc(NS(=O)(=O)c2ccccc2C)cc1
Reactant: CCNCc1ccccc1
Reactant: O=C(Br)CBr
Product: CCN(Cc1ccccc1)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccccc1C

Procedure:
prepared by reaction of 2-bromoacetyl bromide with N-benzyl-N-ethylamine and 2-methyl-N-p-tolyl-benzenesulfonamide
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[C:5](I)=[CH:4][N:3]=1.[F:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18](B(O)O)[CH:19]=1.[NH2:23][C:24]1[S:25][CH:26]=[C:27]([CH3:29])[N:28]=1>>[F:13][C:14]1[CH:19]=[C:18]([C:5]2[C:6]3[S:10][C:9]([CH3:11])=[N:8][C:7]=3[C:2]([NH:23][C:24]3[S:25][CH:26]=[C:27]([CH3:29])[N:28]=3)=[N:3][CH:4]=2)[CH:17]=[N:16][CH:15]=1
Reactant: OB(O)c1cncc(F)c1
Reactant: Cc1nc2c(Cl)ncc(I)c2s1
Reactant: Cc1csc(N)n1
Product: Cc1csc(Nc2ncc(-c3cncc(F)c3)c3sc(C)nc23)n1

Procedure:
The title compound, MS: m/e=358.2 (M+H+), was prepared in accordance with the general method of example 2, step 1 and step 2 from 4-chloro-7-iodo-2-methyl-thiazolo[4,5-c]pyridine (Example B), 3-fluoro-5-pyridineboronic acid and 2-amino-4-methylthiazole.
Reaction SMILES: [CH2:1]([C:13]1([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:23]2[CH:22]=[CH:21][S:20][C:19]=2[C:15]2[S:16][CH:17]=[CH:18][C:14]1=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C([Li])(C)(C)C.[CH3:41][Sn:42](Cl)([CH3:44])[CH3:43].O>C1COCC1.CCCCC>[CH2:24]([C:13]1([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:14]2[CH:18]=[C:17]([Sn:42]([CH3:44])([CH3:43])[CH3:41])[S:16][C:15]=2[C:19]2[S:20][C:21]([Sn:42]([CH3:44])([CH3:43])[CH3:41])=[CH:22][C:23]1=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCCCCCCC1(CCCCCCCCCCCC)c2ccsc2-c2sccc21
Reactant: C[Sn](C)(C)Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCC
Product: CCCCCCCCCCCCC1(CCCCCCCCCCCC)c2cc([Sn](C)(C)C)sc2-c2sc([Sn](C)(C)C)cc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
A dry three-neck round bottom flask was equipped with a Schlenk adapter, dropping funnel, and rubber septum. Under nitrogen, 4,4-didodecyl-4H-cyclopenta[1,2-b:5,4-b′]dithiophene (0.51 g, 1 mmol) was dissolved in dry THF (12 ml) and cooled −78° C. using a dry ice/acetone cold bath. Under nitrogen, a solution of t-butyllithium (1.7 M in pentane, 2.35 ml, 4 mmol) was added dropwise over 15 minutes to the reaction vessel. The reaction was stirred at −78° C. under nitrogen for one hour and stirred at room temperature for 3 hours. Under nitrogen, a solution of trimethyltin chloride (1.0 g, 5 mmol) in dry pentane (2 ml) was added dropwise over 5 minutes to the reaction vessel at −78° C. The reaction was stirred at −78° C. under nitrogen for 1 hour and subsequently warmed to room temperature and stirred overnight. The mixture was then poured into deionized water (3×100 ml) and the organic phase extracted with hexanes (3×50 ml). The organic phases were collected and washed with deionized water (3×50 ml), dried over sodium sulphate, filtered, and concentrated. The product was dried under high vacuum with agitation for 48 hours to give 0.80 g of product as colorless oil, yield 95%. 1H NMR (500 MHz, CD2Cl2) δ (ppm): 6.94 (s, 2H), 1.79-1.76 (m, 4H), 1.29-1.15 (m, 36H), 1.08-1.02 (m, 4H), 0.88 (t, J=6.0 Hz, 6H), 0.39 (s, 18H).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[CH:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:1]([N:3]([CH2:4][CH3:5])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCCCCCC=O
Reactant: CCNCC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCCCCCN(CC)CC
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.7 %

Procedure:
Dissolve 50.90 ml (0.5 moles) diethylamine and 57.10 g (0.5 mole) heptaldehyde in 500 ml methanol and stir at room temperature for one hour. Slowly add 31.42 g sodium cyanoborohydride in 500 ml methanol to the stirred reaction mixture. Add glacial acetic acid to the reaction mixture until pH=6. Stir at room temperature overnight. Concentrate reaction mixture volume to 300 ml and then add 500 ml distilled water. Add concentrated hydrochloric acid until pH=1. Extract with 5×250 ml methylene chloride. Evaporate organic solvent and then dissolve the residue in 400 ml 0.1N HCl. Wash aqueous solution with 3×200 ml diethyl ether and then add 2N NaOH until solution is basic (pH=12). Extract with 3×200 ml diethyl ether. Dry over MgSO4, filter and evaporate, the distill in vacuo to obtain 46.0 g (53.7%) title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[CH3:9][NH:10][C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1>>[CH3:9][N:10]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=1)[C:2]1[CH:7]=[C:6]([N:10]([CH3:9])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=2)[N:5]=[CH:4][N:3]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CNc1cccc(O)c1
Product: CN(c1cccc(O)c1)c1cc(N(C)c2cccc(O)c2)ncn1
Yield: 43 %

Procedure:
This compound was obtained (yield 43%) based on the method described in Production Example 2B using 4,6-dichloropyrimidine instead of the 4,6-dichloro-2-ethylpyrimidine, and using 3-methylaminophenol instead of the 3-aminophenol.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[N:10]=[C:9](I)[S:8][C:6]=2[N:7]=1.[CH3:18][S:19]([NH:22][CH2:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)(=[O:21])=[O:20].O>C(#N)C.C(=O)([O-])[O-].[Na+].[Na+].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>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[N:10]=[C:9]([C:28]3[CH:29]=[C:24]([CH:25]=[CH:26][CH:27]=3)[CH2:23][NH:22][S:19]([CH3:18])(=[O:21])=[O:20])[S:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2nc(I)sc2n1
Reactant: CS(=O)(=O)NCc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CS(=O)(=O)NCc1cccc(-c2nc3c(N4CCOCC4)nc(Cl)nc3s2)c1
Temperature: 100 °C
Yield: 90.9 %

Procedure:
A mixture of 4-(5-chloro-2-iodothiazolo[5,4-d]pyrimidin-7-yl)morpholine 18 (400 mg, 1 mmol), 3-methanesulphonylaminomethyl benzeneboronic acid (260 mg, 1.1 mmol), bis(triphenylphosphine)palladium(II) dichloride (37 mg, 0.052 mmol) in 4 ml of acetonitrile and 4 mL of 1.0 M of sodium carbonate aqueous solution was heated to 100° C. in a microwave for 10 min. Water (5 mL) was added and the resulting solid was filtered and washed with water and ethyl acetate to yield crude N-[3-(5-Chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidin-2-yl)-benzyl]-methanesulfonamide (400 mg).
Reaction SMILES: [CH:1]([C@@H:14]1[CH2:20][C@@H:19]2[C@@H:17]([O:18]2)[CH2:16][O: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.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1)[CH2:26][NH2:27]>>[CH:1]([C@@H:14]1[CH2:20][C@@H:19]([OH:18])[C@H:17]([NH:27][CH2:26][C:25]2[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=[C:23]([O:22][CH3:21])[CH:24]=2)[CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(CN)cc(OC)c1
Reactant: c1ccc(C(c2ccccc2)[C@@H]2C[C@H]3O[C@H]3CO2)cc1
Product: COc1cc(CN[C@@H]2CO[C@H](C(c3ccccc3)c3ccccc3)C[C@H]2O)cc(OC)c1
Yield: 95 %

Procedure:
(1S,4S,6R)-4-benzhydryl-3,7-dioxa-bicyclo[4.1.0]-heptane 28a (0.020 g, 0.075 mmol) was reacted with 3,5-dimethoxybenzylamine (0.25 g, 1.50 mmol) (Procedure E) to yield (2S,4R,5R)-2-benzhydryl-5-(3,5-dimethoxy-benzylamino)-tetrahydropyran-4-ol, (−)-29f, 0.03 g (Yield; 95%, [α]D=(−)58.60, c=1, CHCl3).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[CH2:10][CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=2)[C:12]1=[O:23])(=[O:3])[CH3:2].[CH3:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][Br:29]>>[Br-:29].[C:1]([C:4]1[CH:5]=[N+:6]([CH2:24][C:25]2[CH:26]=[C:27]([CH3:28])[CH:30]=[CH:31][CH:32]=2)[CH:7]=[CH:8][C:9]=1[CH2:10][CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=2)[C:12]1=[O:23])(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)CCC(Cc1ccncc1C(C)=O)C2=O
Reactant: Cc1cccc(CBr)c1
Product: COc1ccc2c(c1)CCC(Cc1cc[n+](Cc3cccc(C)c3)cc1C(C)=O)C2=O
Product: [Br-]

Procedure:
The title compound 120 is prepared according to the procedure reported in Example 38.1 with compound 103 (62 mg, 0.2 mmol) and 3-methylbenzyl bromide (46 μL, 0.34 mmol) as reactants. White solid. (Yield 79.3 mg, 80%).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:42]=[C:43]([CH:52]=[CH:53][CH:54]=2)[O:44][CH2:45][CH2:46][O:47]S(C)(=O)=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:55][CH:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1.C1C[O:65]CC1>>[CH:46]([OH:47])=[O:65].[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:54]=[CH:53][CH:52]=[C:43]([O:44][CH2:45][CH2:46][N:59]3[CH2:60][CH2:61][CH:56]([F:55])[CH2:57][CH2:58]3)[CH:42]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCOS(C)(=O)=O)c4)c4ccccc43)cn12
Reactant: FC1CCNCC1
Reactant: C1CCOC1
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCN5CCC(F)CC5)c4)c4ccccc43)cn12
Product: O=CO
Temperature: 60 °C
Reaction time: 24 h

Procedure:
A solution of Intermediate 154a (50.5 mg, 0.067 mmol) and 4-fluoropiperidine (34 mg, 0.33 mmol) in THF (1 mL) was stirred at 60° C. for 20 h in a sealed tube. Additional 4-fluoropiperidine (34 mg, 0.33 mmol) was added and the mixture subsequently stirred at 60° C. in a sealed tube for 24 h. The mixture was concentrated in vacuo and the residue purified by MDAP (Method 7). The title product was isolated as an off-white solid (24 mg, 47%). LCMS (Method 5): Rt 3.75 min, m/z 764.6 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.91 (3H, d, J=8.0 Hz), 1.27 (9H, s), 1.44-1.64 (2H, m), 1.59-1.72 (4H, m), 1.72-1.98 (6H, m), 1.99-2.19 (2H, m), 2.31-2.40 (2H, m), 2.55-2.64 (2H, m), 2.68 (2H, t, J=8.0 Hz), 2.87-2.95 (1H, m), 3.12-3.19 (1H, m, obscured by water), 3.30 (1H, m, completely obscured by water), 4.10 (2H, t, J=8.0 Hz), 4.51-4.59 (0.5H, m), 4.64-4.71 (0.5H, m), 4.78-4.86 (1H, m), 5.52 (1H, t, J=4.0 Hz), 6.33 (1H, s), 6.95-6.99 (1H, m), 7.06-7.13 (3H, m), 7.19 (1H, dd, J=8.0 Hz, 4.0 Hz), 7.25-7.42 (5H, m), 7.64 (1H, d, J=8.0 Hz), 7.69 (1H, d, J=4.0 Hz), 8.12 (1H, s), 8.18 (1H, s).
Reaction SMILES: [C:1]1([C:7](=[O:16])[CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[S:18]1[CH2:22][CH2:21][NH:20][CH2:19]1.[CH2:23]=O.Cl>>[CH2:9]([CH:8]([CH2:23][N:20]1[CH2:21][CH2:22][S:18][CH2:19]1)[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C=O
Reactant: O=C(CCc1ccccc1)c1ccccc1
Reactant: C1CSCN1
Agent: Cl
Product: O=C(c1ccccc1)C(Cc1ccccc1)CN1CCSC1
Yield: 50.1 %

Procedure:
A mixture containing 10.51 g (0.05 mol) of 1,3-diphenylpropan-1-one, 6.28 g (0.05 mol) of thiazolidine hydrochloride, 3.75 g (0.125 mol) of paraformaldehyde and 25 ml of 37% hydrochloric acid is stirred under reflux for 6 hours. After cooling down, 2.50 g of a white product precipitate from the reaction mixture which is unchanged thiazolidine hydrochloride. After evaporating the filtrate, the light yellow residue weighing 16.52 g is washed thoroughly 3 times with 20 ml of ether each. Thus, 7.80 g of a white powder-like substance are obtained which is suspended in water and the insoluble part is twice recrystallized from 2-propanol to obtain 3.50 g (20.1%) of hydrochloride of the title compound, m.p.: 134° C.
Reaction SMILES: [OH:1][C:2]([C@H:5]1[CH2:9][CH2:8][NH:7][C@H:6]1[CH3:10])([CH3:4])[CH3:3].[Cl:11][C:12]1[C:19]([F:20])=[C:18](F)[CH:17]=[CH:16][C:13]=1[C:14]#[N:15].C(=O)([O-])[O-].[Li+].[Li+]>CS(C)=O>[Cl:11][C:12]1[C:19]([F:20])=[C:18]([N:7]2[CH2:8][CH2:9][C@H:5]([C:2]([OH:1])([CH3:4])[CH3:3])[C@@H:6]2[CH3:10])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: C[C@@H]1NCC[C@@H]1C(C)(C)O
Reactant: N#Cc1ccc(F)c(F)c1Cl
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CS(C)=O
Product: C[C@H]1[C@@H](C(C)(C)O)CCN1c1ccc(C#N)c(Cl)c1F
Temperature: 90 °C
Reaction time: 1 h
Yield: 64.1 %

Procedure:
A mixture of (2S,3S)-3-(1-hydroxy-1-methylethyl)-2-methylpyrrolidine 1/2 oxalate (639 mg), 2-chloro-3,4-difluorobenzonitrile (491 mg), lithium carbonate (669 mg) and dimethyl sulfoxide (13 mL) was stirred at 90° C. for 1 hr. The reaction mixture was cooled and partitioned between water and ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (developing solvent: ethyl acetate-hexane). The obtained solid was recrystallized from ethyl acetate to give the title compound as crystals (yield: 538 mg).
Reaction SMILES: FC1C=CC(C[N:7]2C(=O)N(C3SC(C(O)=O)=C(C)N=3)C=N2)=CC=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:48][C:49]1[CH:71]=[CH:70][C:52]([CH2:53][N:54]2[C@@H:58]([CH3:59])[CH2:57][N:56]([C:60]3[S:61][C:62]([C:66]([OH:68])=O)=[C:63]([CH3:65])[N:64]=3)[C:55]2=[O:69])=[CH:51][CH:50]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>>[F:48][C:49]1[CH:71]=[CH:70][C:52]([CH2:53][N:54]2[C@@H:58]([CH3:59])[CH2:57][N:56]([C:60]3[S:61][C:62]([C:66]([NH2:7])=[O:68])=[C:63]([CH3:65])[N:64]=3)[C:55]2=[O:69])=[CH:51][CH:50]=1
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Reactant: Cc1nc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1nc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(N)=O
Yield: 67 %

Procedure:
Following the procedure as described in EXAMPLE 1, making variations as required to replace 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid and 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) with (S)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid and 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), the title compound was obtained as a colorless solid in 67% yield: mp 192-194° C. (ethyl acetate/diethyl ether); 1H NMR (300 MHz, DMSO-d5) δ 7.40-7.32 (m, 4H), 7.18 (dd, J=8.8, 8.8 Hz, 2H), 4.59 (d, J=15.6 Hz, 1H), 4.30 (d, J=15.6 Hz, 1H), 4.18 (dd, J=10.0, 9.1 Hz, 1H), 3.79-3.68 (m, 1H), 3.54 (dd, J=10.0, 6.8 Hz, 1H), 2.45 (s, 3H), 1.22 (d, J=6.2 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ 163.5, 161.5 (d, 1JC-F=243 Hz), 157.3, 154.9, 150.7, 133.1 (d, 4JC-F=3 Hz), 129.9 (d, 3JC-F=8 Hz), 118.5, 115.4 (d, 2JC-F=21 Hz), 49.4, 48.6, 43.7, 18.4, 17.0; MS (ES+) m/z 348.8 (M+1).
Reaction SMILES: FC(F)(F)C([O-])=O.[NH2:8][C:9]1[CH:17]=[CH:16][C:12]2[N:13]=[CH:14][NH:15][C:11]=2[CH:10]=1.[CH2:18]([O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1)[CH2:19][CH2:20][CH2:21][CH3:22].[Si](C#N)(C)(C)C.[N:38]1([C:43](N2C=CN=C2)=[O:44])C=CN=[CH:39]1>>[NH:13]1[C:12]2[CH:16]=[CH:17][C:9]([N:8]3[CH:28]([C:27]4[CH:30]=[CH:31][C:24]([O:23][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:25][CH:26]=4)[CH2:39][NH:38][C:43]3=[O:44])=[CH:10][C:11]=2[N:15]=[CH:14]1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCCCCOc1ccc(C=O)cc1
Agent: C[Si](C)(C)C#N
Agent: O=C([O-])C(F)(F)F
Product: CCCCCOc1ccc(C2CNC(=O)N2c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized as trifluoroacetate salt starting from 5-aminobenzimidazole (0.585 g, 4.4 mmol), 4-pentoxybenzaldehyde (0.755 mL, 4 mmol), TMSCN (0.5 mL, 4 mmol), PdC (10%, 0.02 g), TEA (1.05 mL, 7.4 mmol), di-(imidazol-1-yl)methanone (0.667 g, 4.12 mmol) as described in method 2. The product was purified by means of preparative HPLC.