Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[CH:9]([CH3:11])[CH3:10].FC(F)(F)C(O)=O.[CH2:19]([O:26][C:27](=[O:55])[N:28]([CH2:53][CH3:54])[CH2:29][CH2:30][N:31]1[CH:35]=[C:34]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[C:38]([C:43]([F:46])([F:45])[F:44])[CH:37]=2)[N:33]=[C:32]1[CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[CH2:19]([O:26][C:27](=[O:55])[N:28]([CH2:29][CH2:30][N:31]1[CH:35]=[C:34]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[C:38]([C:43]([F:45])([F:46])[F:44])[CH:37]=2)[N:33]=[C:32]1[CH:47]1[CH2:48][CH2:49][N:50]([C:2]2[C:3]([CH:9]([CH3:11])[CH3:10])=[C:4]([NH2:8])[N:5]=[CH:6][N:7]=2)[CH2:51][CH2:52]1)[CH2:53][CH3:54])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCN(CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCNCC1)C(=O)OCc1ccccc1
Reactant: CC(C)c1c(N)ncnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCN(CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(C)C)CC1)C(=O)OCc1ccccc1
Temperature: 120 °C
Reaction time: 48 h

Procedure:
A reaction mixture of 6-chloro-5-isopropyl-pyrimidin-4-ylamine (40.0 mg; 0.23 mmol; 1.0 eq.), ethyl-{2-[4-(4-fluoro-3-trifluoromethyl-phenyl)-2-piperidin-4-yl-imidazol-1-yl]-ethyl}-carbamic acid benzyl ester trifluoroacetate (2) (174.0 mg; 0.23 mmol; 1.0 eq.), and Cs2CO3 (303.7 mg; 0.93 mmol; 4.0 eq.) in DMSO (1.5 ml) was stirred at 120° C. for 48 hr. The crude was purified by prep HPLC to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[O:9][C:8]([C:10]3[N:11]=[C:12]4[N:16]([CH:17]=3)[N:15]=[C:14]([O:18][CH3:19])[S:13]4)=[CH:7][C:6]2=[C:20]([OH:22])[CH:21]=1.[C:23]1([C:29]2[S:33][N:32]=[C:31]([CH2:34]O)[N:30]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1.CCOC(C)=O>[CH3:19][O:18][C:14]1[S:13][C:12]2=[N:11][C:10]([C:8]3[O:9][C:5]4[CH:4]=[C:3]([O:2][CH3:1])[CH:21]=[C:20]([O:22][CH2:34][C:31]5[N:30]=[C:29]([C:23]6[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=6)[S:33][N:32]=5)[C:6]=4[CH:7]=3)=[CH:17][N:16]2[N:15]=1
Reactant: OCc1nsc(-c2ccccc2)n1
Reactant: COc1cc(O)c2cc(-c3cn4nc(OC)sc4n3)oc2c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(OCc2nsc(-c3ccccc3)n2)c2cc(-c3cn4nc(OC)sc4n3)oc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.5 %

Procedure:
6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol (Example 1H, 8.25 mg, 0.026 mmol) and (5-phenyl-1,2,4-thiadiazol-3-yl)methanol (Example 7B, 5 mg, 0.025 mmol) were put in a flask and this was flushed with N2. Dry THF (4 mL) was added and to this resulting suspension was added tri-n-butylphosphine (0.017 mL, 0.065 mmol) and a solution of 1,1′-(azodicarbonyl)dipiperidine (16.57 mg, 0.065 mmol) in dry THF (2.5 mL) was added dropwise via a syringe pump over 2 h. The resulting being suspension was stirred for an additional 2 hours at RT, at which time LC showed that no starting material remained. The mixture was diluted with EtOAc, washed with 0.2N HCl, sat aqueous NaHCO3 and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified on silica gel chromatography (50% dichloromethane/hexanes to 100% dichloromethane to 1% EtOAc/CH2Cl2 to 7% EtOAc/CH2Cl2) and lyophilized in MeCN/water to give the title material (6.2 mgs, 49%). LC (Method B): 2.615 min. HRMS (ESI) calcd for C23H18N5O4S2 [M+H]+ m/z 492.0795, found 492.0828. 1H NMR (CDCl3, 400 MHz) δ ppm: 8.00 (dd, J=8.02, 1.37 Hz, 2H), 7.85 (s, 1H), 7.50-7.56 (m, 3H), 7.14 (s, 1H), 6.71-6.75 (m, 1H), 6.51 (d, J=1.57 Hz, 1H), 5.51 (s, 2H), 4.21 (s, 3H), 3.84 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH:3]1[CH2:16][CH2:15][C:6]2[O:7][C:8]3[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=3[C:5]=2[CH2:4]1.C(N(CC)CC)C.[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>O1CCCC1.[OH-].[Na+]>[CH3:1][N:2]([CH3:17])[CH:3]1[CH2:16][CH2:15][C:6]2[O:7][C:8]3[CH:13]=[CH:12][C:11]([NH:14][C:30](=[O:31])[C:29]4[CH:33]=[CH:34][C:26]([F:25])=[CH:27][CH:28]=4)=[CH:10][C:9]=3[C:5]=2[CH2:4]1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CN(C)C1CCc2oc3ccc(N)cc3c2C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C1CCc2oc3ccc(NC(=O)c4ccc(F)cc4)cc3c2C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.7 %

Procedure:
To a solution of 0.132 gm (0.57 mMol) of N,N-dimethyl-8-amino-1,2,3,4-tetrahydro-2-dibenzofuranamine in 5 mL of tetrahydrofuran were added 1.5 mL of triethylamine followed by 0.10 mL (0.13 gm, 0.85 mMol) of 4-fluorobenzoyl chloride. The resulting mixture was stirred at room temperature for 90 minutes at which time the reaction mixture was diluted with 0.1 N aqueous sodium hydroxide. This aqueous solution was extracted with dichloromethane and the organic phases were washed sequentially with water and saturated aqueous sodium chloride. The dichloromethane solution was dried over sodium sulfate and concentrated under reduced pressure. This residue was dissolved in dilute aqueous tartaric acid and then washed with dichloromethane. The aqueous phase made basic with aqueous sodium carbonate and was then extracted with dichloromethane. These dichloro-methane extracts were combined and concentrated under reduced pressure. The residue was subjected to radial chromatography (silica gel, 2 mm), eluting with 5% methanol (containing 5% ammonium hydroxide) in chloro-form. Fractions containing product were combined and concentrated under reduced pressure. The residue was crystallized from toluene/hexane to provide 0.130 gm (64%) of the title compound in two crops.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].[CH3:9][C:10](=O)[CH2:11][CH2:12][C:13](=O)[CH3:14].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>ClCCl>[CH3:14][C:13]1[N:7]([CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:8])[C:10]([CH3:9])=[CH:11][CH:12]=1
Reactant: CC(=O)CCC(C)=O
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cn1c(C)ccc1C
Reaction time: 0.5 h
Yield: 55.9 %

Procedure:
Glycine ethyl ester HCl (22 g, 158 mmol) was added to a stirring mixture of hexane-2,5-dione (18 g, 158 mmol) in dichloromethane (100 mL) in an Erlenmeyer flask. To the stirring heterogeneous mixture was slowly added triethylamine (66 mL, 473 mmol). After 30 minutes, dichloromethane (50 mL) and NaHCO3 (sat. aq. 100 mL) were added and the mixture continued to stir for 20 minutes. The dichloromethane layer was injected directly onto a 330 g silica gel column and the product was eluted with 0-100% ethyl acetate in hexanes. Pertinent fractions were combined and concentrated to afford ethyl 2-(2,5-dimethyl-1H-pyrrol-1-yl)acetate as a white solid (16 g, 56%). 1H NMR (CDCl3/400 MHz) δ (ppm) 5.8 (s, 2H), 4.85 (s, 2H), 4.22 (q, 2H), 2.17 (s, 6H), 1.28 (t, 3H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][C@H:11]2[CH2:16][CH2:15][N:14](C(OCC)=O)[CH2:13][C@H:12]2[O:22][CH2:23][CH2:24][CH3:25])=[O:9])[NH:5][C:6]=1[CH3:7].[OH-].[K+].O.NN.O>C(O)CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][C@@H:11]2[CH2:16][CH2:15][NH:14][CH2:13][C@@H:12]2[O:22][CH2:23][CH2:24][CH3:25])=[O:9])[NH:5][C:6]=1[CH3:7]
Reactant: CCCO[C@@H]1CN(C(=O)OCC)CC[C@@H]1NC(=O)c1cc(Cl)c(C)[nH]1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: CCCO[C@H]1CNCC[C@H]1NC(=O)c1cc(Cl)c(C)[nH]1
Yield: 28.7 %

Procedure:
A solution of ethyl (3R,4S)-4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-propoxypiperidine-1-carboxylate (Intermediate 73, 2.8 g, 7.547 mmol) potassium hydroxide (4.2 g, 75.47 mmol), and Hydrazine hydrate (3.6 mL, 75.47 mmol) in ethylene glycol (100 mL) was stirred for 60 h at 120° C. The reaction mixture was poured into water (300 mL) and extracted with ethyl acetate (2×300 mL). The combined organic extracts were dried over anhydrous sodium sulphate, filtered, and concentrated under vacuum to afford 4-chloro-5-methyl-N-[(3S,4R)-3-propoxypiperidin-4-yl]-1H-pyrrole-2-carboxamide 650 mg, 30% as solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([Cl:25])=[C:6]([N:8]2[C:13](=[O:14])[N:12]([CH3:15])[C:11](=[O:16])[N:10]([CH2:17][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[C:9]2=[O:24])[CH:7]=1.[F:27][C:28]1[CH:38]=[CH:37][CH:36]=[C:30]2[C:31]([O:33][C:34](=O)[C:29]=12)=[O:32]>C(O)(=O)C>[Cl:25][C:5]1[CH:4]=[C:3]([F:26])[C:2]([N:1]2[C:34](=[O:33])[C:29]3=[C:28]([F:27])[CH:38]=[CH:37][CH:36]=[C:30]3[C:31]2=[O:32])=[CH:7][C:6]=1[N:8]1[C:13](=[O:14])[N:12]([CH3:15])[C:11](=[O:16])[N:10]([CH2:17][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[C:9]1=[O:24]
Reactant: CC(C)OC(=O)Cn1c(=O)n(C)c(=O)n(-c2cc(N)c(F)cc2Cl)c1=O
Reactant: O=C1OC(=O)c2c(F)cccc21
Solvent: CC(=O)O
Product: CC(C)OC(=O)Cn1c(=O)n(C)c(=O)n(-c2cc(N3C(=O)c4cccc(F)c4C3=O)c(F)cc2Cl)c1=O
Temperature: 25 °C

Procedure:
A solution of isopropyl 3-(5-amino-2-chloro-4-fluorophenyl)tetrahydro-5-methyl-2,4,6-trioxo-s-triazine-1(2H)-acetate (1.0 g, 2.6 mmol) and 3-fluorophthalic anhydride (0.51 g, 3.1 mmol) in acetic acid is refluxed for 6 hours, stirred at room temperature for several days and poured onto ice. The resultant aqueous mixture is filtered to obtain a solid. The solid is dried and chromatographed (silica gel/2.5% ether in methylene chloride solution) to give the title product as a yellow foam, mp 119°-125° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([NH2:26])[CH2:24][CH3:25])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:35]([O:37][CH3:38])=[O:36].O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([NH:26][C:35](=[O:36])[O:37][CH3:38])[CH2:24][CH3:25])=[CH:4][CH:3]=1
Reactant: COC(=O)Cl
Reactant: CCC(N)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(NC(=O)OC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 27.9 %

Procedure:
To a solution of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-amine (100 mg, 0.24 mmol) and triethylamine (0.10 mL, 0.72 mmol) in tetrahydrofuran (5.0 mL) was added methyl chloroformate (0.0377 mL, 0.488 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hr. Water was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 35-65% ethyl acetate/n-hexane gradient mixture and recrystallization from ethyl acetate/n-hexane to give the title compound (31.5 mg, 0.067 mmol, 28%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12]([NH:15][C:16]1[C:17](Cl)=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[CH:23][CH:22]=[C:21]2[O:26][CH3:27])(=[O:14])=[O:13].C([O-])=O.[NH4+]>[Pd].C(O)(=O)C.CCOC(C)=O>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:5]=[CH:4][C:3]=1[S:12]([NH:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[CH:23][CH:22]=[C:21]2[O:26][CH3:27])(=[O:13])=[O:14]
Reactant: COc1ccnc2c(NS(=O)(=O)c3ccc(C(F)(F)F)cc3N)c(Cl)ccc12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccnc2c(NS(=O)(=O)c3ccc(C(F)(F)F)cc3N)cccc12
Yield: 101.3 %

Procedure:
10% palladium on carbon (82 mg) was added to a solution of 2-amino-N-(7-chloro-4-methoxy-quinolin-8-yl)-4-trifluoromethyl-benzenesulfonamide (Intermediate 195) (670 mg, 1.5 mmol) and ammonium formate (481 mg, 7.5 mmol) in 50% acetic acid (5 ml) and the reaction was heated under reflux for 30 min. After cooling the mixture was diluted with EtOAc (100 ml), washed sat sodium bicarbonate solution, dried (MgSO4) concentrated in vacuo. The crude residue was purified by column chromatography with DCM/MeOH (98:2) as the eluent to give the title compound (604 mg, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([S:8]([N:11]2[C:15]3[CH:16]=[C:17]([C:21](O)=[O:22])[CH:18]=[C:19]([F:20])[C:14]=3[O:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=1.[NH2:26][C:27]1[CH:37]=[CH:36][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:29][CH:28]=1>>[CH2:34]([O:33][C:31](=[O:32])[C:30]1[CH:29]=[CH:28][C:27]([NH:26][C:21]([C:17]2[CH:18]=[C:19]([F:20])[C:14]3[O:13][CH2:12][N:11]([S:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[O:24][CH3:25])(=[O:10])=[O:9])[C:15]=3[CH:16]=2)=[O:22])=[CH:37][CH:36]=1)[CH3:35]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1COc2c(F)cc(C(=O)O)cc21
Product: CCOC(=O)c1ccc(NC(=O)c2cc(F)c3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CO3)cc1

Procedure:
Reaction of 3-(5-chloro-2-methoxy-benzenesulfonyl)-7-fluoro-2,3-dihydro-benzooxazole-5-carboxylic acid with ethyl 4-aminobenzoate in analogy with example 30, step 4 gave 4-{[3-(5-chloro-2-methoxy-benzenesulfonyl)-7-fluoro-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoic acid ethyl ester. White solid, MS (ISP)=535.2 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.I[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1>>[N:14]1[CH:15]=[CH:16][C:11]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[CH:12][CH:13]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: Ic1ccncc1
Product: c1ccc2c(c1)ccn2-c1ccncc1

Procedure:
Prepared by Procedure C and Scheme O using 1H-indole and 4-iodopyridine: ESMS m/e: 195 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][N:10]2[CH3:19])=[CH:5][CH:4]=1.[Cl-].[Al+3].[Cl-].[Cl-].O>C1C=CC=CC=1>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][N:10]2[CH3:19])=[CH:5][CH:4]=1
Reactant: COc1ccc(C2Cc3ccccc3CN2C)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: O
Product: CN1Cc2ccccc2CC1c1ccc(O)cc1

Procedure:
To 30 ml of 3-(4-methoxyphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline (Compound No. 19) in benzene, 0.85 g of aluminum chloride was added and the resulting mixture was heated to reflux for 5 hours. After completion of the reaction, the reaction mixture was allowed to cool and water was added thereto. The generated precipitates were removed by filtration through Celite. The filtrate was made alkaline with saturated aqueous sodium hydrogen carbonate solution, and the resultant was extracted with ethyl acetate. After drying the combined organic layers over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [hexane/ethyl acetate (1/1)] to obtain 0.28 g of 3-(4-hydroxyphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[C:14]([NH:16][C:17]2[S:18][CH:19]=[CH:20][N:21]=2)[CH:13]=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:22]N1C(=O)CCC1=O>O1CCOCC1.C(OCC)(=O)C>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[C:14]([NH:16][C:17]2[S:18][C:19]([Cl:22])=[CH:20][N:21]=2)[CH:13]=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(Nc2nccs2)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCc1cccc(Nc2ncc(Cl)s2)n1
Temperature: 25 °C

Procedure:
2 g of 6-(((tert-butyl(dimethyl)silyl)oxy)methyl)-N-thiazol-2-ylpyridin-2-amine obtained in Example 5-(2) was dissolved in 20 ml of 1,4-dioxane, and then 832 mg of N-chlorosuccinimide was added thereto at room temperature. The reaction mixture was heated under reflux for 2 hours, cooled to room temperature, diluted with ethyl acetate, and then washed with water and brine. The resulting organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated in vacuo to give the title compound.
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][CH2:5][NH:6][C:7](=[O:38])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:22]C2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)[CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:10][CH:9]=1.Br[C:41]1[C:46]([CH:47]([CH3:49])[CH3:48])=[CH:45][C:44]([CH:50]([CH3:52])[CH3:51])=[CH:43][C:42]=1[CH:53]([CH3:55])[CH3:54]>>[CH:53]([C:42]1[CH:43]=[C:44]([CH:50]([CH3:52])[CH3:51])[CH:45]=[C:46]([CH:47]([CH3:49])[CH3:48])[C:41]=1[O:22][CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:39])=[O:2])=[O:38])=[CH:9][CH:10]=1)[CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])([CH3:55])[CH3:54]
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCCC(F)(F)F)Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1
Reactant: CC(C)c1cc(C(C)C)c(Br)c(C(C)C)c1
Product: CC(C)c1cc(C(C)C)c(OC(CCCC(F)(F)F)c2ccc(C(=O)NCCC(=O)O)cc2)c(C(C)C)c1

Procedure:
The title compound is prepared in a manner substantially similar to Example 359 starting from 3-(4-{5,5,5-trifluoro-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-pentyl}-benzoylamino)-propionic acid methyl ester and 2-bromo-1,3,5-triisopropyl-benzene. MS: 610.2 [M−H]−.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:16][N:15](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:14][CH2:13][N:12](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:11][CH2:10][N:9](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:8][CH2:7][N:6](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:5][CH2:4][N:3]1S(C1C=CC(C)=CC=1)(=O)=O.OS(O)(=O)=O.C(O)C>C(OCC)C>[CH3:1][C@H:2]1[CH2:16][NH:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7][NH:6][CH2:5][CH2:4][NH:3]1
Reactant: Cc1ccc(S(=O)(=O)N2CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)C[C@H](C)N(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CCOCC
Product: C[C@H]1CNCCNCCNCCNCCN1
Temperature: 100 °C
Reaction time: 71 h
Yield: 12 %

Procedure:
A mixture of (S)-2-methyl-1,4,7,10,13-penta(p-toluenesulfonyl)-1,4,7,10,13-pentaazacyclopentadecane prepared as in Example 3C (22.9 g, 0.0229-mole) and concentrated H2SO4 (85 ml) was heated at 100° C. with stirring under a dry argon atmosphere for 71 h. To the resulting brown solution, ethanol (100 ml) was added dropwise with stirring at 0° C. followed by ethyl ether 1l). The dark brown solid was filtered and washed thoroughly with ethyl ether. The solid was then dissolved in H2O (100 ml) and the resulting solution washed with ethyl ether. The pH of the solution was adjusted to 11 with 10 N NaOH and the solvent was removed in vacuo. Ethanol (2×500 ml) was then added and removed in vacuo. The resulting brown oily solid was extracted with hot THF (2×500 ml) and filtered. The filtrates were combined and the solvent was removed in vacuo. The residue was dissolved in hot THF (500 ml) and was filtered. The solvent was removed in vacuo and the residue was dissolved in CHCl3. After filtering to remove cloudiness, the solvent was removed in vacuo and the crude product was purified by fractional distillation in vacuo to give a pale yellow oil which crystallized on standing. The material was further purified by recrystallization from cold (-20° C.) CH3CN to give 641 mg (12% yield) of the product as a white crystalline solid: mp 87°-9° C.; [α]d20 =+37.2° (C=0.01,C6H6); 1H NMR (CDCl3) δ1.02 (d, J=6.3 Hz, 3 H), 1.81 (br s, 5 H), 2.37 (m, 1 H), 2.75 (m, 18 H); Exact mass (M+Li)+ : calcd., 236.2426; found, 236.2425 (C11H27N5Li).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl.Cl.Cl[CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]2[N:23]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:22]3[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=3[N:20]=2)[CH2:14][CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[F:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:23]2[C:22]3[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=3[N:20]=[C:19]2[NH:18][CH:15]2[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][N:3]3[CH:4]=[CH:5][N:6]=[C:2]3[CH3:1])[CH2:17][CH2:16]2)=[CH:26][CH:27]=1
Reactant: Cc1ncc[nH]1
Reactant: Fc1ccc(Cn2c(NC3CCN(CCCl)CC3)nc3ccccc32)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nccn1CCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
A mixture of 1.64 parts of 2-methyl-1H-imidazole, 9.2 parts of N-[1-(2-chloroethyl)-4-piperidinyl]-1-(4-fluorophenylmethyl)-1H-benzimidazol-2-amine dihydrochloride, 6.4 parts of sodium carbonate and 135 parts of N,N-dimethylformamide was stirred overnight at 60° C. The reaction mixture was poured into water. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 2.6 parts (30% of 1-[(4-fluorophenyl)methyl]-N-[1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 170.5° C. (compound 20).
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[N:6][CH:5]=[CH:4][N:3]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[CH3:10][C:9]([NH:8][C:7]1[C:2]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[N:3][CH:4]=[CH:5][N:6]=1)([CH3:12])[CH3:11]
Reactant: C1CNCCN1
Reactant: CC(C)(C)Nc1nccnc1Cl
Product: CC(C)(C)Nc1nccnc1N1CCNCC1

Procedure:
Following the general procedure of PREPARATION 7 and making non-critical variations but starting with 2-chloro-3-(1,1-dimethylethylamino)pyrazine (PREPARATION 8, 0.95 g) and piperazine, the title compound is obtained, NMR (CDCl3) 1.47, 1.70, 2.99, 5.02, 7.46 and 7.69 δ.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([CH2:30][O:31][CH3:32])[N:23]=[C:22]2[CH2:33][CH2:34][CH2:35][CH3:36])=[CH:16][CH:15]=1)=[O:7])(C)(C)C.Cl>O1CCOCC1>[CH2:33]([C:22]1[N:21]([CH2:20][C:17]2[CH:16]=[CH:15][C:14]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[C:6]([OH:7])=[O:5])=[CH:19][CH:18]=2)[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([CH2:30][O:31][CH3:32])[N:23]=1)[CH2:34][CH2:35][CH3:36]
Reactant: CCCCc1nc(COC)c(C(=O)OC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCCCc1nc(COC)c(C(=O)OC)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Yield: 97.8 %

Procedure:
A solution of 0.30 g of methyl 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-(methoxymethyl)imidazole-5-carboxylate (prepared as described in Example 8) in 3 ml of a 4N solution of hydrogen chloride in dioxane was allowed no stand at room temperature for 5 hours, after which the solvent was removed by distillation under reduced pressure. The syrupy residue was triturated in diethyl ether and collected by filtration, to give 0.26 g of the title compound in the form of its hydrochloride, melting at 106°-110° C. (with softening).
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[C:3]=1[CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].[H-].[Na+].Br[CH2:19][CH2:20][C:21]([F:24])([F:23])[F:22]>CN(C)C=O>[F:1][C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[C:3]=1[CH2:4][C:5]([CH2:19][CH2:20][C:21]([F:24])([F:23])[F:22])([C:8]#[N:9])[C:6]#[N:7]
Reactant: N#CC(C#N)Cc1c(F)cc(F)cc1F
Reactant: FC(F)(F)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1c(F)cc(F)cc1F
Yield: 9.6 %

Procedure:
Using 0.50 g of (2,4,6-trifluorobenzyl)malononitrile, 10 ml of N,N-dimethylformamide, 0.11 g of sodium hydride (60% in oil), and 0.46 g of 1-bromo-3,3,3-trifluoropropane, and according to the process described in the Production Example 1, there was obtained 0.07 g of 2-(2,4,6-trifluorobenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (17)).