Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:17][CH3:18])[C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][N:9]([CH2:13][C:14]([OH:16])=O)[CH2:8]1)=[O:6])[CH3:3].[NH2:19][C@@H:20]([CH2:38][O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)=[O:22]>>[CH2:40]([O:39][CH2:38][C@H:20]([NH:19][C:14](=[O:16])[CH2:13][N:9]1[CH2:10][CH2:11][CH2:12][CH:7]([C:5]([N:4]([CH2:2][CH3:3])[CH2:17][CH3:18])=[O:6])[CH2:8]1)[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)=[O:22])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CCN(CC)C(=O)C1CCCN(CC(=O)O)C1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: CCN(CC)C(=O)C1CCCN(CC(=O)N[C@@H](COCc2ccccc2)C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)C1
Yield: 41.8 %

Procedure:
Proceeding as in Example 1, but substituting 2-(3-(diethylcarbamoyl)piperidin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 231, 1-(2-((S)-3-(benzyloxy)-1-(4-(4-fluorophenoxy)phenylamino)-1-oxopropan-2-ylamino)-2-oxoethyl)-N,N-diethylpiperidine-3-carboxamide (20.2 mg, 41.8%). 1H-NMR (400 MHz, DMSO-D6): σ 10.22 (s, 1H), 8.01 (t, 1H), 7.61 (d, 2H), 7.27 (m, 6H), 7.00 (m, 4H), 4.70 (m, 1H), 4.52 (s, 2H), 3.71 (m, 2H), 3.27 (m, 4H), 3.02 (m, 6H), 2.15 (m, 2H), 1.63 (m, 3H), 1.35 (m, 1H), 1.06 (m, 3H), 0.93 (m, 3H). MS (EI) for C34H41FN4O5: 605.8 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[CH:12]=[C:11](C=O)[O:10][C:9]=2[C:8]([O:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:7][CH:6]=1)=[O:4].[C:22](O)(=O)[CH2:23][C:24]([OH:26])=[O:25].N1CCCCC1.Cl>C1(C)C=CC=CC=1>[CH:17]1([O:16][C:8]2[C:9]3[O:10][C:11](/[CH:22]=[CH:23]\[C:24]([OH:26])=[O:25])=[CH:12][C:13]=3[C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: COC(=O)c1ccc(OC2CCCC2)c2oc(C=O)cc12
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: COC(=O)c1ccc(OC2CCCC2)c2oc(/C=C\C(=O)O)cc12
Temperature: 25 °C
Yield: 66.3 %

Procedure:
To a well stirred solution of Methyl-2-formyl-7-cyclopentyloxybenzo[b]furan-4-carboxylate (21.0 g, 0.0868 moles) in toluene (250.0 mL) was added malonic acid (13.5 g, 0.1302 moles) and Piperidine (5.0 ml). The reaction mixture was then refluxed for 3-4 hours. Reaction mixture was cooled to room temperature, acidified with 10% aqueous HCl solution and extracted with ethyl acetate (2×250 mL). The combined organic layers were washed with water (2×100 mL) and dried over anhydrous sodium sulfate. Removal of solvent under vacuo gave product (19 g) as light yellow solid.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Br[CH2:9][CH2:10][CH2:11][CH2:12][Cl:13].C(N(CC)CC)C>C(O)C>[Cl:13][CH2:12][CH2:11][CH2:10][CH2:9][S:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: Sc1ccncc1
Reactant: ClCCCCBr
Solvent: CCN(CC)CC
Solvent: CCO
Product: ClCCCCSc1ccncc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.7 %

Procedure:
To a suspension of 33.35 g (0.30 mol) of 4-mercaptopyridine and 51.44 g (0.30 mol) of 1-bromo-4-chlorobutane in 500 ml of ethanol, 41.9 ml (0.30 mol) of triethylamine was added, and the mixture was stirred at room temperature for 5 hours. The solvent was distilled off and chloroform was added to the residue. The mixture was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography (eluent: ethyl acetate/n-hexane =1:1) to give 54.27 g of the desired compound (89.7% yield, colorless oil).
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[C:10](=[C:20]3[CH2:26][CH:25]4[NH:27][CH:22]([CH2:23][CH2:24]4)[CH2:21]3)[C:11]3[C:16]([O:17][C:18]=2[CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].C(O)C.C[Si](I)(C)C>C(Cl)(Cl)Cl>[CH2:28]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[CH:10]([CH:20]3[CH2:26][CH:25]4[NH:27][CH:22]([CH2:23][CH2:24]4)[CH2:21]3)[C:11]3[C:16]([O:17][C:18]=2[CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:29]
Reactant: CCN(CC)C(=O)c1ccc2c(c1)Oc1ccccc1C2=C1CC2CCC(C1)N2
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCN(CC)C(=O)c1ccc2c(c1)Oc1ccccc1C2C1CC2CCC(C1)N2
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 9-(8-aza-bicyclo[3.2.1]oct-3-ylidene)-9H-xanthene-3-carboxylic acid diethylamide, 8a (3 g, 7.7 mmol) in chloroform (50 mL) were added ethanol (2.25 mL, 38.6 mmol) and trimethylsilyl iodide (5.25 mL, 38.6 mmol). The mixture was stirred at 100° C. for 2 h in a sealed tube. The reaction was allowed to cool to rt and washed with 1 N NaOH, aqueous Na2S2O4, and brine. The organic phase was dried over sodium sulfate, filtered, and concentrated, to yield title compound 9-(8-aza-bicyclo[3.2.1]oct-3-yl)-9H-xanthene-3-carboxylic acid diethylamide, 9a (3.0 g, 0.53 mmol). MS m/z=391.4 (MH+)
Reaction SMILES: [C:1]([CH:4]1[N:9]([CH3:10])[CH2:8][CH2:7][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5]1)(=O)[NH2:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>C1(C)C=CC=CC=1>[C:1]([CH:4]1[N:9]([CH3:10])[CH2:8][CH2:7][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5]1)(=[S:27])[NH2:2]
Reactant: CN1CCN(C(=O)OC(C)(C)C)CC1C(N)=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CN1CCN(C(=O)OC(C)(C)C)CC1C(N)=S
Yield: 79.9 %

Procedure:
tert-Butyl 3-carbamoyl-4-methylpiperazine-1-carboxylate (400 mg, 1.64 mmol) was dissolved in toluene (20 mL) and Lawesson reagent (332 mg, 0.82 mmol) was added. The reaction mixture was heated to reflux for 5 h. Solvent was removed under reduced pressure and the crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 10-15% MeOH in CHCl3) to afford tert-butyl 3-carbamothioyl-4-methylpiperazine-1-carboxylate (0.17 g, yield 40%) as pale yellow liquid. 1H NMR (300 MHz, CDCl3) δ 8.16 (br s, 1H), 7.47 (br s, 1H), 4.28-4.21 (m, 1H), 4.06-3.99 (m, 1H), 3.62 (m, 1H), 3.18-3.13 (dd, J=10.2 Hz, 4.1 Hz, 1H), 2.89-2.82 (m, 2H), 2.52-2.47 (dd, J=11.5 Hz, 3.4 Hz, 1H), 2.26 (s, 3H), 1.47 (s, 9H). MS (ESI) m/z: Calculated for C11H21N3O2S: 259.14. found: 260.2 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH2:9][CH:8]([CH3:12])[CH2:7][C:5]=2[N:6]=1.C1CCN2C(=NCCC2)CC1.C1N=[CH:27][N:26]([C:29](N2C=NC=C2)=[O:30])[CH:25]=1.CNC>CC#N>[CH3:25][N:26]([CH3:27])[C:29]([NH:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH2:9][CH:8]([CH3:12])[CH2:7][C:5]=2[N:6]=1)=[O:30]
Reactant: CC1CC(=O)c2sc(N)nc2C1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC1CC(=O)c2sc(NC(=O)N(C)C)nc2C1
Temperature: 110 °C
Reaction time: 8 h
Yield: 76.8 %

Procedure:
To a solution of 2-amino-5-methyl-5,6-dihydro-4H-benzothiazol-7-one (30.0 g, 0.165 mol) in MeCN (750 mL) are added DBU (75.2 g, 0.495 mol) and CDI (80.1 g, 0.495 mol) at RT. The reaction mixture is stirred at 110° C. overnight. Dimethylamine (93.5 g, 1.15 mol) and another portion of DBU (175 g, 1.15 mol) are added to the mixture at RT and the stirring is continued overnight at 110° C. After cooling to RT, the reaction mixture is evaporated in vacuo and the residue is poured into ice water. The reaction mixture is treated with HCl (6 M) to pH to 5. The aqueous mixture is extracted with EtOAc (3×300 mL). The combined organic phase is washed with brine and dried over anhydrous Na2SO4. The solvent is evaporated and the residue is recrystallized from hexane to give 1,1-dimethyl-3-(5-methyl-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-urea (32.1 g, 77% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[Cl:15][C:16]1[C:17]([C:26]([F:29])([F:28])[F:27])=[N:18][N:19]([CH2:22][C:23](O)=[O:24])[C:20]=1[CH3:21]>>[Cl:15][C:16]1[C:17]([C:26]([F:28])([F:27])[F:29])=[N:18][N:19]([CH2:22][C:23]([N:12]2[CH2:13][CH2:14][N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:10][CH2:11]2)=[O:24])[C:20]=1[CH3:21]
Reactant: COc1cccc(N2CCNCC2)c1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Product: COc1cccc(N2CCN(C(=O)Cn3nc(C(F)(F)F)c(Cl)c3C)CC2)c1

Procedure:
Title compound was prepared following protocol P, wherein 1-(3-methoxyphenyl)piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a white solid: 1H NMR (DMSO-d6, 400 MHz) 7.15 (t, 1H), 6.65 (d, 1H), 6.60 (s, 1H), 6.47 (d, 1H), 5.38 (s, 2H), 3.72 (s, 3H), 3.65 (m, 4H), 3.28 (m, 2H), 3.19 (m, 2H), 2.18 (s, 3H) ppm; MS (ES) M+H expect=417.1, found=417.1.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=3[CH3:23])[C:6]=2[CH:5]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:3]=1.[CH3:30]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.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>[CH3:11][C:8]1[N:7]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:22])[F:21])[C:14]=2[CH3:23])[C:6]2[CH:5]=[C:4]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[CH:3]=[C:2]([CH3:30])[C:10]=2[N:9]=1
Reactant: CB1OB(C)OB(C)O1
Reactant: Cc1c(Cn2c(C)nc3c(Br)cc(N4CCOCC4)cc32)cccc1C(F)(F)F
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: Cc1c(Cn2c(C)nc3c(C)cc(N4CCOCC4)cc32)cccc1C(F)(F)F
Yield: 42.5 %

Procedure:
A mixture of 4-bromo-2-methyl-1-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-1H-benzimidazole, prepared as described in Example 62 (200 mg, 0.427 mmol), trimethylboroxine (0.239 mL, 1.708 mmol), Pd(Ph3P)4 (49.4 mg, 0.043 mmol) and potassium carbonate (118 mg, 0.854 mmol) in 1,4-Dioxane (2.5 mL)/Water (0.25 mL) was irradiated at 120° C. in a microwave synthesizer for 40 min, then cooled and poured into water. The mixture was extracted with ethyl acetate. The extracts were washed with brine, dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by RP-HPLC (25-45% AcCN in water plus 0.1% TFA) to give the desired compound (77 mg, 0.181 mmol, 42.5% yield) as a white solid (contains 3-5% of the 4-H compound). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.58 (d, J=8.08 Hz, 1 H), 7.12 (t, J=7.83 Hz, 1 H), 6.80 (d, J=1.01 Hz, 1 H), 6.51 (d, J=7.83 Hz, 1 H), 6.40 (d, J=1.77 Hz, 1 H), 5.26 (s, 2 H), 3.78-3.91 (m, 4 H), 3.01-3.15 (m, 4 H), 2.67 (s, 3 H), 2.56 (s, 3 H), 2.50 (s, 3 H). MS(ES+) m/e 404.1 [M+H]+. (NOTE: The reaction was repeated using PdCl2(dppf) as catalyst. Less (to negligible) reduction was observed).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:12])=[C:4]([N:13]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=2)[S:14]([C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23]CC)=[O:22])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[N:3]=1.[H-].[Na+].[CH3:42][CH:43]([OH:45])[CH3:44].Cl>O1CCCC1.C(Cl)(Cl)Cl>[CH:43]([O:45][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:12])=[C:4]([N:13]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]([F:38])([F:39])[F:37])=[CH:31][CH:30]=2)[S:14]([C:17]2[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:26][CH:27]=2)(=[O:16])=[O:15])[N:3]=1)([CH3:44])[CH3:42]
Reactant: CC(C)O
Reactant: CCOC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(OC(F)(F)F)cc2)c2nc(Br)c3ccccc3c2C)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: Cc1c(N(Cc2ccc(OC(F)(F)F)cc2)S(=O)(=O)c2ccc(C(=O)O)cc2)nc(OC(C)C)c2ccccc12
Yield: 61.6 %

Procedure:
To a suspension of ethyl 4-({(1-bromo-4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)-benzyl]amino}sulfonyl)benzoate (93.5 mg, 0.15 mmol) prepared in Example 9-(1) and sodium hydride (60.0 mg, 1.5 mmol) in tetrahydrofuran (2 mL) was added 2-propanol (0.115 mL, 1.5 mmol) under argon atmosphere, and the mixture was heated to reflux for 4 hours. The mixture was neutralized by 2 mol/L hydrochloric acid, and then thereto was added chloroform. The mixture was stirred, and then separated. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/chloroform=2%→10%) to give 4-({(1-isopropoxy-4-methylisoquinolin-3-yl) [4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoic acid (53.1 mg, 58%) as a brown powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[C:21](Cl)(=[O:23])[CH3:22]>C(Cl)(Cl)Cl>[C:21]([NH:13][CH2:12][CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:23])[CH3:22]
Reactant: COc1ccc(CCN)cc1OC
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(CCNC(C)=O)cc1OC
Reaction time: 8 h
Yield: 91 %

Procedure:
To a stirred solution of β-(3,4-dimethoxyphenyl)ethylamine (100 g, 0.552 m) and triethylamine (66.6 g, 0.66 m) in CHCl3 (1 liter) was added acetyl chloride (47.1 g, 0.60 mole) dropwise over a period of 30 min. and the mixture stirred overnight. The mixture was washed with 3×500 ml H2O, dried over MgSO4 and evaporated to a solid. The solid was dissolved in 500 ml hot CCl4, 300 ml cyclohexane added and allowed to cool slowly. The crystallized solid was collected by filtration and dried to afford N-acetyl-3,4-dimethoxyphenethylamine as a white solid, 112.1 g (91% yield). m.p. 99°-100°.
Reaction SMILES: [CH2:1]([O:5][CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]#[CH:4].[C:10]([C:14]1([CH2:18]O)[CH2:17][O:16][CH2:15]1)([CH3:13])([CH3:12])[CH3:11]>>[C:10]([C:14]12[CH2:15][O:16][C:7]([CH2:6][O:5][CH2:1][CH2:2][C:3]#[CH:4])([O:9][CH2:18]1)[O:8][CH2:17]2)([CH3:13])([CH3:12])[CH3:11]
Reactant: C#CCCOCC(=O)O
Reactant: CC(C)(C)C1(CO)COC1
Product: C#CCCOCC12OCC(C(C)(C)C)(CO1)CO2

Procedure:
4-t-Butyl-1-(but-3-ynyloxymethyl)-2,6,7-trioxabicyclo[2.2.2]octane was prepared from 2-(but-3-ynyloxy)acetic acid and 3-t-butyl-3-hydroxymethyloxetane using methodology described in Example I
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:9]([CH3:10])[C:8]2[CH:11]=[CH:12][C:13]([NH2:15])=[CH:14][C:7]=2[N:6]=1)([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[Cl:21][C:22]1[N:27]=[C:26](Cl)[CH:25]=[CH:24][N:23]=1>C1COCC1.C(O)C>[Cl:21][C:22]1[N:27]=[C:26]([NH:15][C:13]2[CH:12]=[CH:11][C:8]3[N:9]([CH3:10])[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[N:6][C:7]=3[CH:14]=2)[CH:25]=[CH:24][N:23]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)Nc1nc2cc(N)ccc2n1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)Nc1nc2cc(Nc3ccnc(Cl)n3)ccc2n1C
Temperature: 75 °C
Reaction time: 5 h

Procedure:
To a solution of N2-isopropyl-1-methyl-1H-benzimidazole-2,5-diamine (1.46 g, 7.2 mmol) in THF (7 ml) and ethanol (21 ml) was added NaHCO3 (1.81 g, 21.6 mmol) and 2,4-dichloropyrimidine (2.68 g, 18 mmol) and the reaction was heated to 75° C. After 5 h, the reaction was filtered hot and concentrated to a gray foam. Ether was added and the solid was filtered and dried to give N5-(2-chloro-pyrimidin-4-yl)-N2-isopropyl-1-methyl-1H-benzimidazole-2,5-diamine as an off-white solid. N5-(2-chloro-pyrimidin-4-yl)-N2-isopropyl-1-methyl-1H-benzimidazole-2,5-diamine was dissolved in DMF (21 ml) and cesium carbonate (6.84 g, 21 mmol) was added After 15 min, iodomethane (0.70 ml, 11.2 mmol) was added, and the reaction was stirred at rt. After TLC showed the starting material to be consumed, the reaction was diluted with water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, dried over MgSO4 and concentrated to a red foam. The crude material was purified with silica gel to give the title compound as a white solid (1.10 g, 46% over two steps). 1H NMR (300 MHz, d6-DMSO) δ 7.87 (d, J=6.0 Hz, 1H), 7.22 (d, J=8.1 Hz, 1H), 7.11 (1.8 Hz, 1H), 6.82 (dd, J=8.1 and 1.8 Hz, 1H), 6.53 (d, J=7.5 Hz, 1H), 6.09 (d, J=6.0 Hz, 1H), 4.04 (m, 1H), 3.51 (s, 3H), 3.37 (s, 3H), 1.23 (d, J=6.6 Hz, 6H). MS (ESI) m/z=331 [M+H]+.
Reaction SMILES: [Li][CH2:2]CCC.[CH2:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[Se:21][CH:22]=[CH:23][CH:24]=3)=[C:16]([F:25])[C:15]=2[F:26])=[CH:10][CH:9]=1)[CH3:7].CI.[Cl-].[NH4+].N>C(OCC)C>[CH2:6]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[Se:21][C:22]([CH3:2])=[CH:23][CH:24]=3)=[C:16]([F:25])[C:15]=2[F:26])=[CH:12][CH:13]=1)[CH3:7]
Reactant: CCc1ccc(-c2ccc(-c3ccc[se]3)c(F)c2F)cc1
Reactant: [Li]CCCC
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CI
Product: CCc1ccc(-c2ccc(-c3ccc(C)[se]3)c(F)c2F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3.7 ml (21.7 mmol) of TMP are initially introduced at −15° C. in 10 ml of diethyl ether, and 13.0 ml (20.7 mmol, 15% soln. in hexane) of n-BuLi are metered in. After 30 min, a solution of 6.8 g (19.6 mmol) of 2-(4′-ethyl-2,3-difluorobiphenyl-4-yl)selenophene in 50 ml of diethyl ether is added. When the addition is complete, the batch is warmed to RT and stirred for 90 min. The solution is cooled to −70° C., and 6.0 ml (96.4 mmol) of methyl iodide are added. The reaction mixture is warmed to RT and stirred for 20 h. Sat. ammonium chloride soln. and conc. ammonia soln. are added successively, and the mixture is stirred vigorously for a few minutes. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed successively with water, 2 N hydrochloric acid and sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The crude product is purified by column chromatography (SiO2, n-heptane:toluene=9:1). The further purification is carried out by recrystallisation from ethanol and n-heptane. 2-(4′-Ethyl-2,3-difluorobiphenyl-4-yl)-5-methylselenophene is obtained as a solid having an m.p. of 92° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:12]([OH:18])[CH2:13][CH2:14][CH2:15][C:16]#[CH:17]>ClCCl.C(N(CC)CC)C.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>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([C:17]#[C:16][CH2:15][CH2:14][CH2:13][CH2:12][OH:18])[CH:3]=1
Reactant: C#CCCCCO
Reactant: Brc1cnc2ccccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: OCCCCC#Cc1cnc2ccccc2c1
Yield: 88.7 %

Procedure:
6-(3-Quinolinyl)-5-hexyn-1-ol was prepared in the manner described above in Example 105 starting with 15.0 g of 3-bromoquinoline, 8.5 g of 5-hexyn-1-ol, 1.05 g of bis(triphenylphosphine)palladium dichloride and 0.10 g of cuprous iodide in 115 ml of dichloromethane and 28.5 ml of triethylamine. The crude product was chromatographed on a preparative high pressure liquid chromatograph eluting with 2.5% methanol-dichloromethane to give 14.4 g (89%) of 6-(3-quinolinyl)-5-hexyn-1-ol as a colorless oil. A portion was purified further on a silica thick layer plate eluting with 10% methanol-dichloromethane and solidified on drying, mp 47°-48° C.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:16]=[CH:15][C:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[C:6]([N+:17]([O-:19])=[O:18])[CH:5]=1.O.[OH-].[Li+]>C1COCC1.O>[C:11]([O:10][C:8](=[O:9])[C:7]1[CH:15]=[CH:16][C:4]([C:3]([OH:20])=[O:2])=[CH:5][C:6]=1[N+:17]([O-:19])=[O:18])([CH3:14])([CH3:12])[CH3:13]
Reactant: COC(=O)c1ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
2-Nitro-terephthalic acid 1-tert-butyl ester 4-methyl ester (21.49 mmol) was dissolved in THF (143 mL) and treated with lithium hydroxide monohydrate (1.35 g, 32.24 mmol) in water (97 mL). The reaction was stirred at room temperature for 2 hours then partially evaporated, cooled with an ice/water bath and treated with 1N HCl dropwise (35 mL). Precipitation of a solid occurred. The mixture was then extracted with DCM (150 mL and 2×50 mL) The aqueous phase was further treated with 1N HCl (10 mL) and extracted with DCM (2×50 mL). The combined organic layers were then washed with water and finally with brine. After drying over sodium sulphate and evaporation, 5.34 g of title compound were obtained as a reddish solid in 93% overall yield.
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[CH:7][N:6]=[C:5]([N:9]2[C:13](=[O:14])[C:12]([N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)=[CH:11][NH:10]2)[CH:4]=1.Cl.[F:21][C:22]1([F:26])[CH2:25][NH:24][CH2:23]1.C(N(C(C)C)C(C)C)C>O1CCCC1>[F:21][C:22]1([F:26])[CH2:25][N:24]([C:3]2[N:8]=[CH:7][N:6]=[C:5]([N:9]3[C:13](=[O:14])[C:12]([N:15]4[CH:19]=[CH:18][N:17]=[N:16]4)=[CH:11][NH:10]3)[CH:4]=2)[CH2:23]1
Reactant: FC1(F)CNC1
Reactant: O=c1c(-n2ccnn2)c[nH]n1-c1cc(Cl)ncn1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=c1c(-n2ccnn2)c[nH]n1-c1cc(N2CC(F)(F)C2)ncn1

Procedure:
100 mg (0.3 mmol) of the compound from Example 12A, 52 mg (0.4 mmol) of 3,3-difluoroazetidine hydrochloride and 174 ml (130 mg, 1.0 mmol) of N-ethyl-N-(propan-2-yl)propane-2-amine are initially charged in 2 ml of tetrahydrofuran and reacted in a single mode microwave (Emrys Optimizer) at 120° C. for 30 min. After concentration under reduced pressure, the residue is taken up in acetonitrile/water and purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). Yield: 36 mg (34% of theory)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[N:12]=2)=[CH:4][CH:3]=1.C(Cl)Cl.C(O)(C(F)(F)F)=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2oc(-c3ccc(F)cc3)nc2-c2ccccn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(-c2nc(-c3ccccn3)c(C3CCNCC3)o2)cc1

Procedure:
tert-Butyl 4-[2-(4-fluorophenyl)-4-(pyridin-2-yl)-1,3-oxazol-5-yl]piperidine-1-carboxylate (50 mg. 0.12 mmol) was stirred in 4:1 DCM/TFA (5 ml) at room temperature for 3 h. Then the volatiles were removed under vacuum, and the resulting residue was purified by reverse phase HPLC (0.05% TFA-water-acetonitrile) to give the title compound. LC-MS m/e 324.15 [M+1]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[C:8]1[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=1)[CH2:11][N:12]([CH3:20])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].[OH:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>COCCOC.O.C1(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)C=CC=CC=1>[OH:24][C:25]1[CH:30]=[CH:29][C:28]([C:8]2[CH:23]=[CH:22][CH:21]=[C:10]([CH2:11][N:12]([CH3:20])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=2)=[CH:27][CH:26]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: CN(Cc1cccc(Br)c1)C(=O)OC(C)(C)C
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CN(Cc1cccc(-c2ccc(O)cc2)c1)C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 67.7 %

Procedure:
41.6 ml (83.2 mmol) of aqueous 2M potassium carbonate solution are added dropwise to a solution of 10 g (33 mmol) of tert-butyl (3-bromobenzyl)-N-methylcarbamate and 8.3 g (60 mmol) of 4-hydroxybenzeneboronic acid in 100 ml of ethylene glycol dimethyl ether. The reaction medium is degassed and 1.9 g (1.7 mmol) of tetrakis(triphenylphosphino)palladium are added. After heating for 12 hours at 80° C., the reaction medium is cooled, diluted with water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated under vacuum. The residue obtained is purified by chromatography on a column of silica eluted with an 80/20 heptane/ethyl acetate mixture. 7 g of tert-butyl (4′-hydroxybiphenyl-3-ylmethyl)methylcarbamate are obtained in the form of a beige-colored solid, in a yield of 68%.