Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2OC)=CSC=1C([O:39][CH3:40])=O.C(OCC)(OCC)OCC.[Cl:51]C1C=CC(N)=CC=1>C(O)(=O)C>[Cl:51][C:4]1[CH:5]=[CH:6][C:1]([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=4[O:39][CH3:40])[C:10]=3[N:9]=[CH:8]2)=[CH:2][CH:3]=1
Reactant: COC(=O)c1scc(-c2ccccc2OC)c1N
Reactant: Nc1ccc(Cl)cc1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: COc1ccccc1-c1csc2c(=O)n(-c3ccc(Cl)cc3)cnc12
Yield: 70.5 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(2-methoxyphenyl)thiophene-2-carboxylate (50 mg, 0.21 mmol), triethyl orthoformate (0.41 ml), 4-chloroaniline (45.05 mg, 0.35 mmol), and acetic acid (0.05 ml) were used to give 49.4 mg (0.13 mmol, 70.5% yield) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][C:9]([O:11]C)=[O:10])=[C:6]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:5]=[C:4]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26]([C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=3)=[O:27])=[CH:21][CH:20]=2)[N:3]=1.[OH-].[Na+].CCOCC.Cl>C1COCC1>[CH3:1][C:2]1[C:7]([CH2:8][C:9]([OH:11])=[O:10])=[C:6]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:5]=[C:4]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([NH:25][C:26]([C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=3)=[O:27])=[CH:23][CH:24]=2)[N:3]=1
Reactant: COC(=O)Cc1c(C)nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc1N1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc(N2CCCC2)c1CC(=O)O
Temperature: 60 °C
Reaction time: 13 h
Yield: 31.2 %

Procedure:
A solution of methyl {4-methyl-2-[4-(2-naphthoylamino)benzyl]-6-pyrrolidin-1-ylpyrimidin-5-yl}acetate (0.018 g, 0.04 mmol) in THF (1 mL) at room temperature was treated with 1N NaOH (0.5 mL) and the resulting biphasic mixture was stirred at 60° C. for 13 hours. After cooling to room temperature, Et2O was added and the organic layer siphoned off The remaining aqueous layer was acidified with 6N HCl and the separated solids were collected by suction, rinsed with water, and dried under high vacuum for 4 hours to give (4-methyl-2-[4-(2-naphthoyl-amino)benzyl]-6-pyrrolidin-1-ylpyrimidin-5-yl)acetic acid (0.006 g, 37% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:24])[CH:5]=[C:6]([Cl:23])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=1.[Cl:25][C:26]([Cl:30])=[CH:27][CH2:28]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:24][CH2:28][CH:27]=[C:26]([Cl:30])[Cl:25])[CH:5]=[C:6]([Cl:23])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][N:14]=1
Reactant: ClCC=C(Cl)Cl
Reactant: Oc1cc(Cl)c(OCCCOc2ccc(C(F)(F)F)cn2)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.7 %

Procedure:
A mixture of 0.5 g of 3,5-dichloro-4-[3-(5-trifluoromethylpyridin-2-yloxy)-propyloxy]phenol, 0.25 g of 1,1,3-trichloropropene, 0.2 g of potassium carbonate and 3 ml of N,N-dimethylformamide was stirred at room temperature overnight. The reaction mixture was subjected to silica gel chromatography, which afforded 0.3 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-[3-(5-trifluoromethylpyridin-2-yloxy)propyloxy]benzene (47% yield), nD20.5 1.5377.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8](=[O:14])OC(C)(C)C.C(N(CC)CC)C.[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1C(Cl)=O.Cl.O1CCOCC1>C(Cl)Cl>[ClH:22].[NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8](=[O:14])[C:24]1[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=1[Cl:22]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: ClCCl
Product: N[C@H]1CCC[C@@H]1NC(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of tert-butyl N-[(1S,2S)-2-aminocyclopentyl]carbamate (CAS number 586961-34-4; 500 mg, 2.497 mmol) in dry DCM (8.3 ml) was added triethylamine (1.74 ml, 12.48 mmol) and 2-chlorobenzoyl chloride (CAS number 609-65-4; 476 μl, 3.74 mmol). The reaction was stirred at room temperature for 72 hours. The reaction was partitioned between DCM and a saturated solution of sodium bicarbonate, filtered through a hydrophobic frit and concentrated in vacuo. The resulting residue was purified by column chromatography (silica, 0-100% ethyl acetate/petrol). The Boc protect intermediate was dissolved in 1,4-dioxane (8 ml) and to this was added HCl in 1,4-dioxane (4 M, 6.0 ml, 23.91 mmol). The reaction was stirred at room temperature for 17 hours and then concentrated in vacuo, azeotropically distilled with toluene to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.O>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:3]=1
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc(Cl)cc1N1CCCCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 96.8 %

Procedure:
To a cooled (0° C.) solution of 1.75 g (10.0 mmol) of 4-chloro-2-fluoronitrobenzene in 15 mL of EtOH was added 2.97 mL (30.0 mmol) of piperidine dropwise over 5 min. The solution stirred at 0° C. for 10 min and then at 23° C. for 30 min. The mixture was poured into water (225 mL) and extracted with EtOAc (2×30 mL). The combined extracts were washed with saturated aq NaHCO3 and brine (30 mL each) and then dried (Na2SO4) Concentration afforded 2.33 g (97%) of the title compound as an orange oil which crystallized on standing: Mass spectrum (ESI, m/z): Calcd. for C11H13ClN2O2, 241.1 (M+H), found 241.1.
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([C:7]([NH:9][NH:10][C:11](=[O:29])[C@H:12]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=2)[C@H:13]([OH:15])[CH3:14])=[O:8])=[CH:5][CH:4]=1)#[N:2].N1C=CN=C1.[CH3:37][C:38]([Si:41](Cl)([CH3:43])[CH3:42])([CH3:40])[CH3:39]>CN(C=O)C>[Si:41]([O:15][C@H:13]([CH3:14])[C@@H:12]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=1)[C:11]([NH:10][NH:9][C:7](=[O:8])[C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:31][CH:30]=1)=[O:29])([C:38]([CH3:40])([CH3:39])[CH3:37])([CH3:43])[CH3:42]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@@H](O)[C@@H](Nc1ccc(C#N)c(C(F)(F)F)c1)C(=O)NNC(=O)c1ccc(C#N)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c(C(F)(F)F)c1)C(=O)NNC(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 79 %

Procedure:
To a pre-cooled (0° C.) solution of 4-cyano-N′-((2R,3R)-2-(4-cyano-3-(trifluoromethyl)phenylamino)-3-hydroxybutanoyl)benzohydrazide (1.57 g, 3.64 mmol) in DMF (100 mL) was added imidazole (1.98 g, 29.4 mmol) then TBSCl (2.20 g, 14.58 mmol). The reaction was warmed slowly to room temperature, stirred for 19 h, cooled to 0° C. and quenched with H2O (300 mL). The solution was extracted with EtOAc (250 mL). The organic extract was washed with H2O (2×100 mL) and 5% aq. citric acid (3×80 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a brown oil, which was purified by flash chromatography over silica gel (20-30% EtOAc in hexanes) to provide the title compound as a colourless solid (1.57 g, 79%): 1H NMR (400 MHz, acetone-d6, δ in ppm) 8.06 (dm, J=8.6 Hz, 2H), 7.91 (dm, J=8.6 Hz, 2H), 7.73 (d, J=8.8 Hz, 1H), 7.36 (d, J=2.2 Hz, 1H), 7.14 (dd, J=2.4, 8.6 Hz, 1H), 6.52 (d, J=7.6 Hz, 1H), 4.49-4.39 (m, 2H), 1.36 (d, J=6.1 Hz, 3H), 0.85 (s, 9H), 0.12 (s, 3H), 0.09 (s, 3H).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].N1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C[OH:12]>>[NH2:1][C:2]1[S:3][C:8]([C:9](=[O:12])[CH3:10])=[C:7]([CH3:6])[N:4]=1
Reactant: CO
Reactant: NC(N)=S
Reactant: c1ccncc1
Product: CC(=O)c1sc(N)nc1C
Reaction time: 4 h

Procedure:
A mixture of thiourea (5.18 g, 0.068 mol) in dry MeOH (20 mL) was stirred and cooled on an ice bath. Pyridine (2 mL) was added, followed by 3-chloro-2,4-pentadione (9.15 g, 0.068 mol) dropwise. After completion of the addition the reaction mixture was allowed to warm to r. t. and stirring was continued for 4 h. The precipitates were filtered and washed with EtOAc to afford white solid 1-(2-amino-4-methyl-thiazol-5-yl)-ethanone.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[OH:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]1.C(N(CC)CC)C>CN(C=O)C>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[N:14]1[CH2:15][CH2:16][CH2:17][C@@H:12]([OH:11])[CH2:13]1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: O[C@@H]1CCCNC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnccc1N1CCC[C@@H](O)C1

Procedure:
Method 1 of Example 1 was followed using 1 equivalent each of 4-chloro-3-nitropyridine, (R)-3-hydroxypiperidine and triethylamine in DMF yielding (R)-1-(3-nitropyridin-4-yl)piperidin-3-ol, LCMS (m/z): 224.1 (MH+); LC Rt=1.06 min.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:35][C:19]3=[N:20][CH:21]=[C:22]([C:24]4[CH:25]=[C:26]([CH:31]=[CH:32][C:33]=4[CH3:34])[C:27]([O:29][CH3:30])=[O:28])[CH:23]=[C:18]3[CH:17]=2)=[CH:12][CH:11]=1>[Al].ClC(Cl)C.CCOC(C)=O>[Br:8][C:17]1[C:18]2[C:19](=[N:20][CH:21]=[C:22]([C:24]3[CH:25]=[C:26]([CH:31]=[CH:32][C:33]=3[CH3:34])[C:27]([O:29][CH3:30])=[O:28])[CH:23]=2)[O:35][C:16]=1[C:13]1[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(C)c(-c2cnc3oc(-c4ccc(F)cc4)cc3c2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: [Al]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: COC(=O)c1ccc(C)c(-c2cnc3oc(-c4ccc(F)cc4)c(Br)c3c2)c1
Reaction time: 8 h

Procedure:
The reaction flask was wrapped in aluminum foil. NBS (175 mg, 0.983 mmol) was added to a stirring solution of methyl 3-(2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)-4-methylbenzoate (289 mg, 0.800 mmol) in dichloroethane (8 mL) at room temperature. It was allowed to stir overnight. The mixture was diluted with EtOAc and quenched with 10% sodium metabisulfate and washed with sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) the expected product consistent by LCMS and NMR. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.41 (1H, d, J=2.01 Hz), 8.16-8.26 (2H, m), 8.06 (1H, d, J=2.26 Hz), 7.95 (1H, dd, J=8.03, 1.76 Hz), 7.87 (1H, d), 7.45-7.57 (3H, m), 3.86 (3H, s), 2.34 (3H, s). LC-MS retention time: 2.85 min; m/z (MH+): 440, 442. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]1([CH:11]([CH:14]([CH3:16])[CH3:15])[C:12]#[N:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>S(=O)(=O)(O)O>[N+:1]([C:8]1[CH:9]=[CH:10][C:5]([CH:11]([CH:14]([CH3:16])[CH3:15])[C:12]#[N:13])=[CH:6][CH:7]=1)([O-:4])=[O:2]
Reactant: CC(C)C(C#N)c1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(C)C(C#N)c1ccc([N+](=O)[O-])cc1
Reaction time: 1.17 h

Procedure:
Into mixed acids (5 ml of 90% nitric acid and 60 ml of concentrated sulfuric acid), held at -2° to -3° with a dry-ice/acetone bath, was dripped 15.92 g of 2-phenyl-3-methylbutyronitrile, causing a very exothermic reaction during the 7-minutes addition period. After an additional 70 minutes at -5° to 0°, the dark reddish orange reaction mixture was poured into excess ice. The thick oil which formed was extracted into butyl chloride, and the butyl chloride extract washed twice each with water and saturated sodium bicarbonate solution. Drying (MgSO4) and evaporation of the butyl chloride solution provided an orange-yellow oil. Vacuum distillation gave 17.1 g of yellow oil, bp 118°-130°/(0.2-0.3 Torr). Crystallization from butyl chloride/hexane provided white 2-(4-nitrophenyl)-3-methylbutyronitrile of m.p. 69°-71°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].I[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1.COCCOCCOC>[Cu]I.O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Ic1ccncc1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOCCOC
Solvent: C1COCCO1
Product: c1ccc(COc2ccc(Oc3ccncc3)cc2)cc1
Yield: 86.5 %

Procedure:
The same procedure from Example 143, step 1 was followed using p-benzyloxyphenol (500 mg, 2.5 mmol), Cs2CO3 (1.58 g, 4.85 mmol), 4-iodo pyridine (780 mg, 3.805 mmol), anhydrous dioxane (15 ml), diglyme (34 mg, 0.24 mmol), CuI (17 mg, 0.089 mmol) to give the title compound (600 mg, 57%).
Reaction SMILES: [CH:1]([C:3]1[C:8](=[O:9])[C:7]2[CH:10]=[C:11]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:12]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:6]=2[O:5][CH:4]=1)=[O:2].[CH3:26][Mg]I>>[OH:2][CH:1]([C:3]1[C:8](=[O:9])[C:7]2[CH:10]=[C:11]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:12]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:6]=2[O:5][CH:4]=1)[CH3:26]
Reactant: CS(=O)(=O)Nc1cc2occ(C=O)c(=O)c2cc1Oc1ccccc1
Reactant: C[Mg]I
Product: CC(O)c1coc2cc(NS(C)(=O)=O)c(Oc3ccccc3)cc2c1=O

Procedure:
3-Formyl-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one was reacted with methylmagnesium iodide to obtain 3-(1-hydroxyethyl)-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Br[C:13]1[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[N:17][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:13]2[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[N:17][CH:18]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccc(Cl)c([N+](=O)[O-])c2)cn1
Yield: 52.4 %

Procedure:
In the same manner as in Reference Example 1 and using 4-chloro-3-nitrophenol (4.70 g, 27.1 mmol), 5-bromo-2-nitropyridine (5.00 g, 24.6 mmol), cesium carbonate (12.0 g, 36.9 mmol) and N,N-dimethylformamide (50 mL) as starting materials, the title compound (3.81 g, 52%) was obtained as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][CH2:17][NH:18][C:19]([N:21]2[C@@H:25]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=3)[CH2:24][O:23][C:22]2=[O:34])=[O:20])[CH2:11][CH2:10]1)#[N:2].C(=O)([O-])[O-].[Cs+].[Cs+].[F:41][C:42]([F:46])([F:45])[CH2:43]I>C(#N)C.ClCCl.O>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:43][C:42]([F:46])([F:45])[F:41])[CH2:16][CH2:17][NH:18][C:19]([N:21]2[C@@H:25]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=3)[CH2:24][O:23][C:22]2=[O:34])=[O:20])[CH2:11][CH2:10]1)#[N:2]
Reactant: N#Cc1ccccc1N1CCC(NCCNC(=O)N2C(=O)OC[C@@H]2c2ccc(F)c(F)c2)CC1
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: N#Cc1ccccc1N1CCC(N(CCNC(=O)N2C(=O)OC[C@@H]2c2ccc(F)c(F)c2)CC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 18 (36 mg, 0.076 mmol) and cesium carbonate (50 mg, 0.153 mmol) in acetonitrile (100 mL) was treated with 2,2,2-trifluoroethyliodide (21.3 mg, 0.101 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane and water and the aqueous layer was extracted with two additional portions of dichloromethane. The combined organic extracts were concentrated under reduced pressure and purified by PCTLC (SiO2, 4 mm, 1% NH4OEt-1% NH4OEt-10% EtOH-90% CHCl3) to afford the title compound (49) which was converted to the hydrochloride salt after treatment with EtOAc/HCl.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[C:12]([CH:19]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][CH2:22][O-:23].[Na+].[CH2:25]([OH:27])[CH3:26]>>[CH2:22]([O:23][C:25](=[O:27])/[CH:26]=[CH:19]/[C:12]1[C:13]2[CH2:14][CH2:15][CH2:16][CH2:17][C:18]=2[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][CH:11]=1)[CH3:21]
Reactant: CCO
Reactant: O=Cc1ccc(OCc2ccccc2)c2c1CCCC2
Reactant: CC[O-]
Agent: [Na+]
Product: CCOC(=O)/C=C/c1ccc(OCc2ccccc2)c2c1CCCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled suspension (−10° C.) of 0.9 g (3.38 mmol) of 4-benzyloxy-5,6,7,8-tetrahydronaphthalene-1-carboxaldehyde [PCT Int. Appl. (2002), WO2002/092084A1] in 10 ml of absolute ethanol were added successively 0.75 ml (3.7 mmol) of triethyl phosphonoacetate and 0.255 g (3.7 mmol) of powdered sodium ethylate. Then, the mixture was stirred at ambient temperature for 1 hour. Subsequently, the reaction mixture was poured onto crushed ice/diluted hydrochloric acid and the product was extracted twice with tert.-butyl methyl ether; the organic phase was washed with brine and dried over anhydrous sodium sulfate, and finally evaporated leaving 1.15 g of the title compound as light brown solid.
Reaction SMILES: N=[C:2]1[C:6]2([CH2:11][CH2:10][O:9][CH2:8][CH2:7]2)[NH:5][C:4](=[O:12])[N:3]1[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=1.C[OH:26].C(Cl)(Cl)Cl.Cl>O>[O:12]=[C:4]1[N:3]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:21]([F:24])([F:22])[F:23])[CH:14]=2)[C:2](=[O:26])[C:6]2([CH2:7][CH2:8][O:9][CH2:10][CH2:11]2)[NH:5]1
Reactant: CO
Reactant: N#Cc1ccc(N2C(=N)C3(CCOCC3)NC2=O)cc1C(F)(F)F
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: N#Cc1ccc(N2C(=O)NC3(CCOCC3)C2=O)cc1C(F)(F)F

Procedure:
1.66 g of the product of Example 1 were introduced into 30 ml of methanol, 10 ml of chloroform and 10 ml of 2N hydrochloric acid, and the mixture was refluxed for 50 minutes. 100 ml of water were added and extraction was carried out 3 times with ethyl acetate. The organic phase was washed with salt water, dried and purified on silica with methylene chloride-acetone: 85-15 as eluant. The resultant product was dissolved in 100 ml of isopropanol at about 70° C. and filtration was carried out, followed by concentrating, ice-cooling for one hour, separating and drying to obtain 1.425 g of the expected product (white crystals) melting at 192°-193° C.
Reaction SMILES: Br[C:2]1[S:3][C:4]([Cl:12])=[C:5](Cl)[C:6]=1[C:7](=[O:10])[CH2:8][Cl:9].[Cl:13]C1SC(Cl)=CC=1.ClCC(Cl)=O>>[Cl:9][CH2:8][C:7]([C:6]1[CH:5]=[C:4]([Cl:12])[S:3][C:2]=1[Cl:13])=[O:10]
Reactant: Clc1ccc(Cl)s1
Reactant: O=C(CCl)c1c(Br)sc(Cl)c1Cl
Agent: O=C(Cl)CCl
Product: O=C(CCl)c1cc(Cl)sc1Cl
Yield: 91 %

Procedure:
General procedure described for compounds 1 and 2 starting from 2,5-dichlorothiophene and chloroacetyl chloride. Purified by column chromatography column (hexane:ethyl acetate 12:1), yield 91%, m.p.: 43-44° C. (ethanol), 1H-NMR (CDCl3): δ7.1 (s, 1H, CH-Aromat), 4.6 (s, 2H, CH2); 13C-NMR (CDCl3): 186.6 (CO), 136.9 (C—Cl), 136.0 (C—CO), 130.2 (C—Cl), 129.4 (CH—Ar), 50.6 (CH2); M/z (EI): 234, 232, 230, 228 (M+, 1, 6, 16, 16%), 183, 181, 179 (M-CH2Cl, 18, 79, 100%), 155, 153, 151 (M-COCH2Cl, 3, 13, 19%), 118, 116 (M-COCH2Cl2, 5, 13%); HPLC: Delta Pak Column C18, 5 μm, 300 A, (150×3.9 mm), Purity 99%, r.t.=6.16 min, acetonitrile/H2O (0.05% H3PO4+0.04% Et3N) 50/50.
Reaction SMILES: S(Cl)(Cl)=O.[ClH:5].S(=O)=O.[C:9]([O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)(=[O:11])[CH3:10]>CN(C)C=O>[C:9]([O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([Cl:5])=[O:18])=[CH:15][CH:14]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Reactant: Cl
Agent: O=S=O
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CC(=O)Oc1ccc(C(=O)Cl)cc1

Procedure:
P-acetoxy benzoic acid 180.16 g (1.0 mol) was added to thionylchloride 500 ml, and dimethylformamide (DMF) 1 ml was dropped in as a catalyst and stirred, and when generation of hydrogen chloride and sulfur dioxide stopped and the reaction liquid cleared, p-acetoxy benzoic acid 180.16 g (1.0 mol) was added another 5 times, i.e. a total of 6.0 mol was added. After all 6.0 mol of the p-acetoxy benzoic acid was added and when the generation of hydrogen chloride and sulfur dioxide stopped, and the reaction liquid cleared, it was heated at reflux for 3 hours, then it was distilled and purified (at 173° C., 10 mmHg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][C:3]=1[NH:15][C@@H:16]1[CH2:21][CH2:20][C@H:19]([C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.[CH3:28][O:29][C:30]([NH:32][C:33](=NC(OC)=O)SC)=[O:31].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(Cl)Cl>CO>[CH:25]([NH:24][C:22]([C@@H:19]1[CH2:20][CH2:21][C@H:16]([N:15]2[C:3]3[CH:4]=[C:5]([CH2:8][N:9]4[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]4)[CH:6]=[CH:7][C:2]=3[N:1]=[C:33]2[NH:32][C:30](=[O:31])[O:29][CH3:28])[CH2:17][CH2:18]1)=[O:23])([CH3:27])[CH3:26]
Reactant: COC(=O)N=C(NC(=O)OC)SC
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(CN3CCCCC3)ccc2N)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)Nc1nc2ccc(CN3CCCCC3)cc2n1[C@H]1CC[C@@H](C(=O)NC(C)C)CC1
Temperature: 80 °C

Procedure:
To a solution of cis-4-(2-amino-5-(piperidin-1-ylmethyl)phenylamino)-N-isopropylcyclohexanecarboxamide (0.300 g, 0.805 mmol) in MeOH (4.5 mL) was added 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (0.166 g, 0.805 mmol) and p-toluenesulfonic acid monohydrate (0.168 g, 0.886 mmol). The reaction mixture was heated at 80° C. for 2 hours and then concentrated under vacuum. The residue was dissolved in DCM and was washed with saturated aqueous NaHCO3. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography, eluting with 0-100% 90:10:1 DCM/MeOH/NH4OH:DCM to afford methyl 1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2-ylcarbamate (0.239 g, 65.1% yield). MS, m/z (C25H37N5O3); calcd, 455.59. found 456.2 [M+H]. 1H NMR (400 MHz, CDCl3) δ ppm 1.23 (d, J=6.55 Hz, 6H) 1.38-1.49 (m, 2H) 1.52-1.67 (m, 4H) 1.67-1.85 (m, 6H) 2.10-2.20 (m, 2H) 2.34-2.51 (m, 4H) 2.58-2.73 (m, 2H) 3.54-3.66 (m, 1H) 3.79 (s, 3H) 4.20 (dt, J=13.70, 6.70 Hz, 1H) 4.86 (tt, J=12.79, 4.47 Hz, 1H) 5.34 (br. d, J=7.20 Hz, 1H) 7.13-7.25 (m, 2H) 7.61 (br. s., 1H) 11.29 (br. s., 1H).