Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C([Li])CCC.[O:12]([CH2:19][CH:20]=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>C1COCC1.CCCCCC.CCOCC.CCCCCC>[O:12]([CH2:19][CH:20]([OH:21])[C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C#C[Si](C)(C)C
Reactant: O=CCOc1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: C[Si](C)(C)C#CC(O)COc1ccccc1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 41.7 %

Procedure:
To 7.2 g of trimethylsilylacetylene dissolved in 110 ml of THF and cooled to -20° C. was added 46.2 ml of 1.55M n-butyl lithium in hexane. The mixture was allowed to come to room temperature for 15 minutes, recooled to -20° C., and treated dropwise with 5.3 g of phenoxyacetaldehyde (II) in THF. After the addition was complete, the reaction mixture was stirred at 0° C. for 4 hours. The reaction mixture was then poured into a mixture of ether:hexane (1:1) over 0.5N HCl and shaken. The organic layer was separated, washed 3 times with H2O, dried (Na2SO4), and evaporated to dryness. The residue was chromatographed on a column of silica gel that was eluted with 30% ethyl acetate in hexane to yield 3.8 g of 1-phenoxy-4-trimethylsilylbut-3-yn-2-ol (III).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[Li]CCCC.[C:12](OCC)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCOC(C)=O>C1COCC1>[C:13]1([C:12](=[O:19])[CH2:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1ccccc1
Reactant: Cc1nccs1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Cc1nccs1)c1ccccc1
Reaction time: 1 h
Yield: 16.4 %

Procedure:
To a solution of 2-methylthiazole (500 mg, 5.1 mmol) in anhydrous THF (10 mL) at −78° C. under nitrogen was added dropwise n-BuLi (2.5 mol/L, 2.0 mL), after being stirred at this temperature for 1 hour, a solution of ethyl benzoate (1.1 g, 7.3 mmol) in anhydrous THF (5 mL) was added, and the reaction mixture was stirred at room temperature overnight. When TLC (PE:EtOAc=7:1) indicated that the starting materials were consumed, water was added to quench the reaction, and the aqueous layer extracted with EtOAc (10 mL×3). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, concentrated, and purified by column chromatography (PE:EtOAc=15:1) to afford Intermediate 3 as a yellow oil (170 mg, yield: 17.0%).
Reaction SMILES: N1CCCC1.[CH2:6]([CH:8]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH2:9]1)[CH3:7].C(NCC)C.[C:20](Cl)(=[O:22])[CH3:21]>O.C1C=CC=CC=1>[C:20]([CH:11]1[CH2:12][CH2:13][CH:8]([CH2:6][CH3:7])[CH2:9][C:10]1=[O:14])(=[O:22])[CH3:21]
Reactant: CCC1CCCC(=O)C1
Reactant: CC(=O)Cl
Solvent: c1ccccc1
Solvent: CCNCC
Solvent: C1CCNC1
Product: CCC1CCC(C(C)=O)C(=O)C1

Procedure:
Pyrrolidine (71.0 g.) is added to a solution of 12.6 g. of 3-ethylcyclohexanone in 12.6 ml. of benzene and the mixture is refluxed for eight hours with azeotropic removal of water. The mixture is cooled (ice bath) and 10.1 g. of diethylamine followed by 10.0 g. of acetyl chloride are added dropwise. The resulting mixture is refluxed for two hours then cooled and quenched by addition of 15.0 ml. of concentrated hydrochloric acid. The reaction mixture is refluxed an additional 15 minutes, cooled and diluted with water. The mixture is extracted with ether and the ethereal phase is washed with water, dried (MgSO4) and concentrated in vacuo to give a residue which, upon distillation in vacuo, gives 2-acetyl-5-ethylcyclohexanone.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11](O)=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH2:24][CH2:25][NH2:26])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH:11]1[C:19]2[C:18](=[CH:17][C:16]([O:15][CH3:14])=[C:21]([O:22][CH3:23])[CH:20]=2)[CH2:24][CH2:25][NH:26]1
Reactant: COc1ccc(CCN)cc1OC
Reactant: O=C(O)CCc1cccc(F)c1F
Product: COc1cc2c(cc1OC)C(CCc1cccc(F)c1F)NCC2

Procedure:
The compound is prepared from 3-(2,3-difluoro-phenyl)-propionic acid and 2-(3,4-dimethoxy-phenyl)-ethylamine according to the method of example A8.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([OH:13])[CH:12]=1)[CH:5]=[CH:6][C:7]([OH:9])=[O:8].[CH3:14]O>>[CH3:14][O:8][C:7](=[O:9])[CH:6]=[CH:5][C:4]1[CH:3]=[C:2]([OH:1])[CH:12]=[C:11]([OH:13])[CH:10]=1
Reactant: O=C(O)C=Cc1cc(O)cc(O)c1
Reactant: CO
Product: COC(=O)C=Cc1cc(O)cc(O)c1

Procedure:
FIG. 8 illustrates examples of synthetic schemes for producing alkylated derivatives of 3,5-dihydroxycinnamic acid. In the illustrated synthetic schemes, 3,5-dihydroxycinnamic acid 51 is first esterified in MeOH to produce 3,5-dihydroxycinnamic acid methyl ester 52, which is then reacted with 1 or 2 eq. of an alkylating agent RX in the presence of TBAI and K2CO3 to produce the mono-alkylated intermediate 53 or the dialkylated intermediate 55. The esters 53 and 55 are then hydrolyzed under basic conditions to produce the corresponding acids 54 and 56, respectively.
Reaction SMILES: [CH3:1][C@@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[CH3:21][N:22]([CH3:32])[C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1.Cl>CN(C)C1C=CN=CC=1.ClCCl>[CH3:21][N:22]([CH3:32])[C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:31])=[CH:25][CH:24]=1
Reactant: CN(C)c1ccc(N=C=O)cc1
Reactant: CC1(C)C2CC[C@]1(C)C(=O)CC2=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)c1ccc(NC(=O)C2C(=O)C3CC[C@](C)(C2=O)C3(C)C)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To an ice-cooled solution of (1S)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.36 g, 2.0 mmole), triethylamine (0.20 g, 2.0 mmole) and 4-(dimethylamino)pyridine (0.24 g, 2.0 mmole) in dry dichloromethane (25 mL) was added a solution of 4-(dimethylamino)phenyl isocyanate (0.32 g, 2.0 mmole) in dry dichloromethane (5 mL). The resulting reaction mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature. It was then stirred at 30° C. for seven hours. The resulting mixture was treated with 2N aqueous HCl (30 mL) and the layers were separated. The acidic aqueous layer was extracted with two additional portions of dichloromethane (50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The desired product was isolated by chromatography on silica gel (10% ethyl acetate/hexane) and recrystallized from 95% ethanol to yield the title compound as a light gray solid (0.16 g, 23% yield), mp=93–95° C.; MS (−) ESI m/z=341 (M−H)−; [α]D25=−23.8° (c=1, EtOH).
Reaction SMILES: [C:1]([C:3]1[C:4]([O:9][C:10]2[CH:11]=[CH:12][C:13]3[O:17][C:16]([CH:18]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([C:32]([N:34]([CH3:42])[CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])=[O:33])=[CH:28][CH:27]=4)[CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)=[C:15]([CH3:43])[C:14]=3[CH:44]=2)=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[OH-].[Na+]>C(O)C.O1CCCC1>[C:1]([C:3]1[C:4]([O:9][C:10]2[CH:11]=[CH:12][C:13]3[O:17][C:16]([CH:18]([NH:25][C:26]4[CH:27]=[CH:28][C:29]([C:32]([N:34]([CH3:42])[CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:33])=[CH:30][CH:31]=4)[CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)=[C:15]([CH3:43])[C:14]=3[CH:44]=2)=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(Oc4ncccc4C#N)cc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)oc2ccc(Oc3ncccc3C#N)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32.7 %

Procedure:
Ethyl 3-{[(4-{[{5-[(3-cyanopyridin-2-yl)oxy]-3-methyl-1-benzofuran-2-yl}(cyclohexyl)methyl]amino}phenyl)carbonyl](methyl)amino}-propanoate (234 mg) obtained in Example A197 was dissolved in ethanol (1.5 mL) and tetrahydrofuran (1.5 mL), 1N aqueous sodium hydroxide solution (0.78 mL) was added to the solution, and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure, water (4 mL) was added, and the mixture was neutralized with 1N hydrochloric acid (0.78 mL) under ice-cooling. The resulting precipitate was collected by filtration and dried. The obtained residue was purified by preparative HPLC “instrument: Gilson Inc., preparative HPLC system; column: Develosil ODS-UG-10, S-5 μm, 50×100 mm; solvent: SOLUTION A; 0.1% trifluoroacetic acid-containing water, SOLUTION B; 0.1% trifluoroacetic acid-containing acetonitrile, (SOLUTION A:SOLUTION B=95:5-0:100); flow rate: 150 mL/min; detection method: UV 220 nm”. To the fractionated fraction was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to give the title compound (73 mg, 33%) as a colorless amorphous form.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][O:15]C(=O)C)[C:9]=1[CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[Na+]>>[CH2:1]([O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][OH:15])[C:9]=1[CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1ccnc(COC(C)=O)c1C
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCOc1ccnc(CO)c1C
Yield: 87.5 %

Procedure:
17.3 g (0.065 mol, 1.0 eq.) of 4-hexyloxy-2-acetoxymethyl-3-methylpyridine was added dropwise to a 25% aqueous solution of sodium hydroxide at 5 to 22° C., and the mixture was allowed to react for one hour at room temperature, and then extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate, and then concentrated to dryness, to obtain 12.7 g of 4-hexyloxy-2-hydroxymethyl-3-methylpyridine as a brown oily matter (yield 87.6%).
Reaction SMILES: C(OC([C:6]1([CH:14]=[O:15])[S:13][C:12]2[CH:11]=[CH:10][NH:9][C:8]=2[CH2:7]1)=O)C.[O-]S([O-])(=O)=O.[Mg+2].[C:22]([O:25]CC)(=[O:24])C>>[CH:14]([C:6]1[S:13][C:12]2[CH:11]=[C:10]([C:22]([OH:25])=[O:24])[NH:9][C:8]=2[CH:7]=1)=[O:15]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)C1(C=O)Cc2[nH]ccc2S1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: O=Cc1cc2[nH]c(C(=O)O)cc2s1

Procedure:
2-Formyl-4H-thieno[3,2-b]pyrrole-carboxylic acid ethyl ester (see, for example, Gale, W. W. et al., J. Org. Chem., 29: 2160-2165 (1964)) was hydrolyzed according to Procedure F (50° C. overnight; acidified aqueous phase extracted with ethyl acetate; combined organic phases dried over MgSO4, concentrated).
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[CH:20]=[N:21][C:22]([C:30]4[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:31]=4[F:38])=[C:23]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH:24]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[CH:20]=[N:21][C:22]([C:30]4[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:31]=4[F:38])=[C:23]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH:24]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1cc(OCc2cnc(-c3cc(OC)ccc3F)c(OCC(C)C)c2)ncn1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(F)c(-c2ncc(COc3cc(C(CC(=O)O)C4CC4)ncn3)cc2OCC(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(6-((6-(2-fluoro-5-methoxyphenyl)-5-isobutoxypyridin-3-yl)methoxy)pyrimidin-4-yl)propanoate (890 mg) in THF (5.0 mL) and methanol (2.5 mL) was added 1N aqueous sodium hydroxide solution (5.0 mL), and the mixture was stirred at room temperature for 1 hr. 1N Hydrochloric acid (5.0 mL) was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After silica gel filtration, the solvent was evaporated under reduced pressure, and the obtained crude crystals were recrystallized (ethyl acetate/hexane) to give the title compound (688 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[N:4][C:5]([F:10])=[C:6]([Cl:9])[C:7]=1F.[NH2:12]C1C(F)=C(F)N=C(F)C=1Cl>>[NH2:12][C:7]1[C:2]([Cl:1])=[C:3]([F:11])[N:4]=[C:5]([F:10])[C:6]=1[Cl:9]
Reactant: Fc1nc(F)c(Cl)c(F)c1Cl
Reactant: Nc1c(F)c(F)nc(F)c1Cl
Product: Nc1c(Cl)c(F)nc(F)c1Cl

Procedure:
This compound was prepared from 3,5-dichloro-2,4,6-trifluoropyridine (24.5 g) by a procedure similar to that described for compound 2: yield, 23.7 g (98%); mp 110° C. (Lit., Chambers et al., J. Chem. Soc. 1964, 5634-5640 mp 112-113° C.).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[C:13]3[CH:38]=[CH:37][N:36](S(C4C=CC(C)=CC=4)(=O)=O)[C:14]=3[N:15]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:30][CH2:29][N:28]([CH:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]4)=[CH:21][C:20]=3[O:34][CH3:35])[N:17]=2)[C:3]=1[C:4]([NH2:6])=[O:5].C([O-])([O-])=O.[K+].[K+]>CO.O1CCCC1>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:26][CH2:27][N:28]([CH:31]([CH3:33])[CH3:32])[CH2:29][CH2:30]4)=[CH:21][C:20]=3[O:34][CH3:35])[NH:15][C:14]3=[N:36][CH:37]=[CH:38][C:13]=23)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: COc1cc(N2CCN(C(C)C)CC2)ccc1Nc1nc(Nc2cccc(F)c2C(N)=O)c2ccn(S(=O)(=O)c3ccc(C)cc3)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(N2CCN(C(C)C)CC2)ccc1Nc1nc(Nc2cccc(F)c2C(N)=O)c2ccnc-2[nH]1
Temperature: 85 °C
Reaction time: 6 h
Yield: 92.3 %

Procedure:
To a suspension of the 2-fluoro-6-({2-{[4-[4-(1-methylethyl)-1-piperazinyl]-2-(methyloxy)phenyl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzamide (15.7 g, 23.4 mmol) in methanol (250 mL) and tetrahydrofuran (125 ml) was added K2CO3 (32.3g 234 mmol in 125 ml of water), The reaction mixture was stirred at 85° C. for 6 hours. The organic layer was subsequently washed with water and brine, dried over sodium sulfate, filtered, stripped onto celite, and purified by chromatography on SiO2 (400 g SiO2, 0% to 10% MeOH/CH2CL2 with 0.1% added NH3) to afford the 2-fluoro-6-[(2-{[4-[4-(1-methylethyl)-1-piperazinyl]-2-(methyloxy)phenyl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]benzamide (11.2 g, 92%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.01 (d, J=6.59 Hz, 6 H), 2.59 (d, J=3.85 Hz, 4 H), 2.67 (m, J=6.41 Hz, 1 H), 3.10 (br. s., 4 H), 3.81 (s, 3H), 6.22 (s., 1 H), 6.47 (d, J=8.79 Hz, 1 H), 6.63 (d, J=1.28 Hz, 1 H), 6.89-6.98 (m, 2 H), 7.36-7.46 (m, 2 H), 7.90 (d, J=8.61 Hz, 1 H), 8.02 (s., 1 H), 8.10 (s, 1 H), 8.50 (d, J=8.42 Hz, 1 H), 10.47 (s, 1 H), 11.31 (s., 1 H). MS(ESI): m/z 519 (M+1)+.
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1.[CH2:19]([O:21][C:22]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][N:34]2[CH2:41][CH2:40][CH2:39][NH:38][CH2:37][CH2:36][CH2:35]2)=[CH:28][CH:27]=1)=[O:23])[CH3:20].C([O-])(O)=O.[Na+]>C(O)CCC>[CH2:19]([O:21][C:22]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][N:34]2[CH2:35][CH2:36][CH2:37][N:38]([C:2]3[N:6]([CH2:7][C:8]4[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=4)[C:5]4[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=4[N:3]=3)[CH2:39][CH2:40][CH2:41]2)=[CH:28][CH:27]=1)=[O:23])[CH3:20]
Reactant: CCOC(=O)CCc1ccc(CCN2CCCNCCC2)cc1
Reactant: Fc1ccc(Cn2c(Br)nc3ccccc32)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: CCOC(=O)CCc1ccc(CCN2CCCN(c3nc4ccccc4n3Cc3ccc(F)cc3)CCC2)cc1
Yield: 85 %

Procedure:
To a solution of 2-bromo-1-(4-fluorophenylmethyl)-1H-benzimidazole (0.244 g) in n-butanol (1 ml) was added 1-[2-[4-(2-ethoxycarbonylethyl)phenyl]ethyl]-1,5-diazacyclooctane (1.00 g), and the mixture was refluxed for 2 hours. To the reaction mixture was added a saturated aqueous NaHCO3 solution (50 ml), and the mixture was extracted with methylene chloride (30 ml). The extract was washed with water, and dried over anhydrous MgSO4. The solvent was removed under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on a silica gel column using a mixture of methylene chloride, diethyl ether and methanol (1:1:0.25) as eluent to give a mixture (0.369 g) of 5-[2-[4-(2-ethoxycarbonylethyl)phenyl]ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctane and 5-[2-[4-(2-n-butoxycarbonylethyl)phenyl]ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctane.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[O:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1)([CH3:4])([CH3:3])[CH3:2].C(N1CCC(OC2C=C(C(F)(F)F)C=C(N[C:46]([C:48]3[C:49]([Cl:54])=[N:50][CH:51]=[CH:52][CH:53]=3)=[O:47])C=2)CC1)(OC(C)(C)C)=O>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:46](=[O:47])[C:48]2[CH:53]=[CH:52][CH:51]=[N:50][C:49]=2[Cl:54])=[CH:7][C:6]=1[O:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCC(COc2cc(N)ccc2C(C)(C)C)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(NC(=O)c3cccnc3Cl)cc(C(F)(F)F)c2)CC1
Product: CN1CCC(COc2cc(NC(=O)c3cccnc3Cl)ccc2C(C)(C)C)CC1

Procedure:
N-[4-tert-Butyl-3-(1-methyl-piperidin-4-ylmethoxy)-phenyl]-2-chloro-nicotinamide was prepared from 4-tert-butyl-3-(1-methyl-piperidin-4-ylmethoxy)-phenylamine by a procedure similar to that described in the preparation of 1-Boc-4-{3-[(2-chloro-pyridine-3-carbonyl)-amino]-5-trifluoromethyl-phenoxy}-piperidine.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[S:8][C:9]3[CH:15]=[C:14]([O:16][S:17]([C:20]4[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=4)(=[O:19])=[O:18])[CH:13]=[CH:12][C:10]=3[N:11]=2)=[O:5])[CH2:3][CH2:2]1.[CH:27]([N:30]([CH:34]([CH3:36])[CH3:35])[CH2:31][CH2:32][NH2:33])([CH3:29])[CH3:28]>CN1C(=O)CCC1>[CH:1]1([C:4]([NH:6][C:7]2[S:8][C:9]3[CH:15]=[C:14]([O:16][S:17]([C:20]4[CH:25]=[CH:24][C:23]([NH:33][CH2:32][CH2:31][N:30]([CH:34]([CH3:36])[CH3:35])[CH:27]([CH3:29])[CH3:28])=[CH:22][CH:21]=4)(=[O:19])=[O:18])[CH:13]=[CH:12][C:10]=3[N:11]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1)C1CC1
Reactant: CC(C)N(CCN)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)N(CCNc1ccc(S(=O)(=O)Oc2ccc3nc(NC(=O)C4CC4)sc3c2)cc1)C(C)C

Procedure:
A solution of 4-fluorobenzenesulfonic 2-(cyclopropanecarbonylamino)benzo-thiazol-6-yl ester (example 7) (100 mg, 255 μmol) and N,N-diisopropyl-ethane-1,2-diamine (147 mg, 1.02 mmol) in 2 ml of NMP is heated at 110° C. by microwave for 10 minutes. The crude reaction product is purified by preparative LC/MS (basic medium (pH 9)) to give after freeze-drying 66 mg of 4-(2-hydroxy-2-methylpropylamino)benzenesulfonic 2-(cyclopropanecarbonyl-amino)benzothiazol-6-yl ester (beige-colored solid).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[C:4]([CH3:9])[C:3]=1[CH3:10].[CH3:11][S-:12].[Na+]>C(O)C>[CH3:9][C:4]1[C:3]([CH3:10])=[C:2]([S:12][CH3:11])[N:7]=[N:6][C:5]=1[NH2:8]
Reactant: Cc1c(N)nnc(Cl)c1C
Reactant: C[S-]
Agent: [Na+]
Solvent: CCO
Product: CSc1nnc(N)c(C)c1C
Yield: 42.3 %

Procedure:
6-Chloro-4,5-dimethylpyridazin-3-amine (CAS-Nr. 76593-36-7, 400 mg, 2.54 mmol, 1.0 eq) and sodium methanethiolate (196 mg, 2.79 mmol, 1.1 eq) in 10.4 mL ethanol were heated for 1 h to 130° C. in a single mode microwave oven. The reaction mixture was partitioned between DCM and water. The organic phase was washed with brine and dried with sodium sulfate. The resulting mixture was filtered through a Whatman filter and the volatile components were removed in vacuo. The crude mixture was purified via MPLC (Biotage Isolera; 50 g SNAP cartridge: DCM/ethanol 95/5→DCM/ethanol 4/1) to give 182 mg (21% yield) of the title compound in 50% purity (UPLC, area-%).
Reaction SMILES: [CH3:1][C:2]1O[C:4]([CH3:7])=[N:5][N:6]=1.[CH2:8]([CH2:10][NH2:11])[OH:9]>CN1CCCC1=O>[CH3:1][C:2]1[N:11]([CH2:10][CH2:8][OH:9])[C:4]([CH3:7])=[N:5][N:6]=1
Reactant: Cc1nnc(C)o1
Reactant: NCCO
Solvent: CN1CCCC1=O
Product: Cc1nnc(C)n1CCO
Temperature: 160 °C
Yield: 49585.2 %

Procedure:
2,5-Dimethyl-1,3,4-oxadiazole (19.7 g, 0.2 mmole) and ethanolamine (18.3 g, 0.3 mole) were dissolved in 1-methyl-2-pyrrolidinone (20 ml) and the stirred reaction mixture heated at 160° C. for 24 hours, then cooled to ambient temperature. The residual gum was chromatographed on silica eluting with ethyl acetate containing from 20% to 50% methanol. Evaporation of the appropriate fractions and trituration of the residual foam with ethyl acetate gave the title product (14 g, 50%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11](OC)=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][OH:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc2ncccc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc2ncccc2c1
Reaction time: 0.33 h
Yield: 63.8 %

Procedure:
To a solution of methyl quinoline-6-carboxylate (14 g, 74.8 mmol) in THF (80 mL), was added LiAlH4 (2.84 g, 74.8 mmol) in portions. Then water (2.84 mL) and NaOH (10%, 4.26 mL) was added dropwise to quench excess reducing agent. After stirring for additional 20 min, ether was added, and the resulting mixture was filtered through celite. The filtrate was concentrated to a residue, which was purified by silica gel with hexanes:EtOAc to afford quinolin-6-ylmethanol (7.6 g) in 64% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][CH2:9][CH2:10][N:11]1[C:23]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[CH:15][C:14]=2[N:13]=[C:12]1[CH2:24][CH2:25][CH2:26][CH3:27])([CH3:4])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:34].S(=O)(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][CH2:9][CH2:10][N:11]1[C:23]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:16]([O-:34])=[CH:15][C:14]=2[N:13]=[C:12]1[CH2:24][CH2:25][CH2:26][CH3:27])([CH3:3])([CH3:2])[CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCc1nc2cnc3ccccc3c2n1CCCNC(=O)OC(C)(C)C
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCc1nc2c[n+]([O-])c3ccccc3c2n1CCCNC(=O)OC(C)(C)C
Temperature: 5 °C
Reaction time: 2 h

Procedure:
The product from step (iv) (0.9 g) was dissolved in DCM (25 mL) and cooled to 5° C. 3-Chloroperoxybenzoic acid (0.203 g) was added and the reaction was allowed to warm to rt. The reaction mixture was stirred for 2 h, more 3-chloroperoxybenzoic acid (0.30 g) was added and the reaction mixture stirred for a further 2 h. The reaction mixture was poured into saturated sodium bisulfate solution, extracted with DCM, dried, filtered and evaporated to give the subtitle (0.9 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14](C3CN(CC)C3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.NC1N=CC([O:30][CH:31]2[CH2:34][N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:32]2)=CC=1.BrC1C(=O)N(C)C=C(Br)C=1>>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[CH:13][C:14]([O:30][CH:31]3[CH2:32][N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:34]3)=[CH:15][CH:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: CCN1CC(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)C1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ccc(N)nc2)C1
Agent: Cn1cc(Br)cc(Br)c1=O
Product: Cn1cc(Br)cc(Nc2ccc(OC3CN(C(=O)OC(C)(C)C)C3)cn2)c1=O
Yield: 81 %

Procedure:
Using the same procedure as described for the preparation of 250a, reaction of 251b (1.01 g, 3.80 mmol) with 3,5-dibromo-1-methylpyridin-2(1H)-one (1.01 g, 3.80 mmol) afforded an 81% yield (1.40 mg) of 251c as a brown solid: mp 120-121° C.; 1H NMR (500 MHz, DMSO-d6) d 8.70 (s, 1H), 8.57 (d, 1H, J=2.5 Hz), 7.86 (d, 1H, J=3.0 Hz), 7.48 (d, 1H, J=2.5 Hz), 7.35 (d, 1H, J=9.0 Hz), 7.28 (m, 1H), 4.95 (m, 1H), 4.3 (m, 2H), 3.80 (m, 2H), 3.50 (s, 3H), 1.38 (s, 9H); MS (ESI+) m/z 452.3 (M+H).