Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.[CH2:17]([O:19][C:20](=[O:31])/[CH:21]=[CH:22]/[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[CH3:18].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:17]([O:19][C:20]([CH:21]1[CH:22]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[CH2:3][N:4]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:5]1)=[O:31])[CH3:18]
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CCOC(=O)/C=C/c1ccc(Cl)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 63 %

Procedure:
A solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (2.46 g, 10.4 mmol) in CH2Cl2 (15 mL) was added dropwise, over a 30 minutes period, to a stirred solution of (E)-3-(3,4-dichloro-phenyl)-acrylic acid ethyl ester (2.40 g, 10.4 mmol) and trifluoroacetic acid (0.08 mL, 1 mmol) in CH2Cl2 (10 mL) at 0° C. The ice bath was removed, and the solution was stirred at 25° C. for an additional 48 h. It was then concentrated and purification by flash chromatography (SiO2, EtOAc/H 1:4) afforded 2.48 g (66%) of the title compound as a yellow oil. ES-MS m/e: 379.3 (M+H+).
Reaction SMILES: C(N(CC)CC)C.Cl[CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([N:16]([CH3:18])[CH3:17])[CH:11]=1.[C:19]([C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:38])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[SH:37])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>CN(C)C=O.C(OCC)(=O)C>[C:19]([C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:38])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[S:37][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([N:16]([CH3:18])[CH3:17])[CH:11]=2)=[CH:25][CH:24]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CN(C)c1cc(CCl)ccn1
Reactant: CC(C)(C)c1ccc(NC(=O)c2ccccc2S)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)c1cc(CSc2ccccc2C(=O)Nc2ccc(C(C)(C)C)cc2)ccn1
Reaction time: 68 h
Yield: 34.8 %

Procedure:
Triethylamine (6 μL, 0.44 mmol) was added to a solution of 4-chloromethyl-2-dimethylaminopyridine (36 mg, 0.21 mmol) and N-(4-tert-butylphenyl)-2-mercaptobenzamide (36 mg, 0.13 mmol) in N,N-dimethylformamide (1.0 mL) at room temperature, and the mixture was stirred for 68 hours. The mixture was diluted with ethyl acetate (30 mL), the whole was washed with saturated aqueous sodium hydrogen carbonate solution (30 mL) and brine (30 mL) successively, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give 19 mg of the target compound as a pale yellow oil. (Yield 22%)
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][CH:11]3[C:26](=[O:27])[N:14]4[CH2:15][CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18][CH:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[F:29][C:30]([F:42])([F:41])[C:31]1[CH:32]=[C:33]([S:37](Cl)(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1.C(N(CC)CC)C>O1CCOCC1.C(Cl)Cl>[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][CH:11]3[C:26](=[O:27])[N:14]4[CH2:15][CH2:16][N:17]([S:37]([C:33]5[CH:34]=[CH:35][CH:36]=[C:31]([C:30]([F:42])([F:41])[F:29])[CH:32]=5)(=[O:39])=[O:38])[CH2:18][CH:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)C(Oc3cnc(C4CC4)cn3)CC2C1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C1C(Oc2cnc(C3CC3)cn2)CC2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)CCN12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
To a solution of the product from Example 207C (40 mg, 0.107 mmol) in 1,4-dioxane (0.5 mL) was added a 4 M solution of hydrogen chloride in 1,4-dioxane (0.5 mL, 2.0 mmol). The resulting mixture was stirred at room temperature for 90 minutes and then concentrated in vacuo. To the residue was added CH2Cl2 (1 mL), 3-(trifluoromethyl)-benzene-1-sulfonyl chloride (0.021 mL, 0.130 mmol) and triethylamine (0.045 mL, 0.324 mmol), and the resulting mixture was stirred at room temperature for 90 minutes. The mixture was partitioned between water and CH2Cl2, and the organic layer was dried over Na2SO4. The drying agent was removed by filtration, and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-5% CH3OH in CH2Cl2 to give the title compound (47 mg, 90%). 1H NMR (300 MHz, CDCl3) δ ppm 0.84-1.04 (m, 4H) 1.55-1.65 (m, 0.6H) 1.89-2.50 (m, 4H) 2.85-2.98 (m, 0.4H) 3.00-3.20 (m, 1H) 3.69-3.84 (m, 0.4H) 3.83-3.96 (m, 1.6H) 3.95-4.07 (m, 1H) 4.20 (dd, J=13.22, 2.37 Hz, 1H) 5.43 (dd, J=8.14, 5.09 Hz, 0.6H) 5.57 (t, J=7.63 Hz, 0.4H) 7.74 (t, J=7.80 Hz, 1H) 7.86-7.99 (m, 3H) 8.00-8.04 (m, 1H) 8.07-8.13 (m, 1H); MS (ESI) m/z 483 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH:32]([CH3:34])[CH3:33])=[CH:27][N:26]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH:32]([CH3:34])[CH3:33])=[CH:27][N:26]=1)=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)Oc1ccc(Br)nc1
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Product: CC(C)Oc1ccc(C(=O)C(NC(=O)OC(C)(C)C)c2ccc(Cl)c(Cl)c2)nc1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and 2-bromo-5-isopropoxy-pyridine (Intermediate 30) in analogy to Example 1a): MS (ISP): 439.2 and 441.1 (M+H)+, 383.2 and 385.1 ((M-isobutene)+H)+ (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.C(NC(C)C)(C)C.C([Li])CCC.[I:21]I>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[C:7]([I:21])=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)c1
Reactant: II
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Clc1ccnc(Cl)c1I
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2,4-dichloropyridine (5.2 g, 35.14 mmol) and diisopropylamine (3.91 g, 38.65 mmol) in dry THF (40 mL) cooled at −78° C. under a nitrogen atmosphere, was added n-butyllithium (24.16 mL, 38.65 mmol, 1.6 M in hexanes) dropwise. The resulting reaction mixture was stirred at −78° C. for 45 min. and then a solution of iodine (9.81 g, 38.651 mmol) in dry THF (20 mL) was added dropwise. The mixture was stirred at −78° C. for 1 h., allowed to warm to r.t., diluted with EtOAc and quenched with NH4Cl (aqueous sat. solution) and Na2S2O3 (aqueous sat. solution). The organic layer was separated, washed with NaHCO3 (aqueous sat. solution), dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; DCM in heptane 0/100 to 20/80). The desired fractions were collected and concentrated in vacuo to yield intermediate compound I-1 (7.8 g, 81%).
Reaction SMILES: CS(O)(=O)=O.[CH3:6][C:7]1([CH3:17])[O:12][CH2:11][C:10]([CH2:15][CH3:16])([CH2:13]O)[CH2:9][O:8]1.[I-:18].[Na+]>CC(CC)=O>[CH3:6][C:7]1([CH3:17])[O:12][CH2:11][C:10]([CH2:15][CH3:16])([CH2:13][I:18])[CH2:9][O:8]1
Reactant: [I-]
Reactant: CCC1(CO)COC(C)(C)OC1
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCC1(CI)COC(C)(C)OC1

Procedure:
A mixture of 2,2-dimethyl-5-ethyl-5-hydroxymethyl-1,3-dioxane methylsulphonate (6.0 g.) and sodium iodide (9.0 g.) in ethyl methyl ketone was refluxed, with stirring, for forty-eight hours. The solvent was removed in vacuo and the resulting oil was poured into water. The aqueous mixture was extracted with ether. The ethereal extracts were washed with 5% aqueous sodium thiosulphate solution and then water. The ethereal extracts were dried over anhydrous magnesium sulphate and then evaporated in vacuo. The residue was purified by column chromatography on silica, eluting with 1:10 ether: hexane. 2,2-Dimethyl-5-ethyl-5-iodomethyl-1,3-dioxane was obtained as a colourless oil (5.0 g.)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1.Cl[C:31]1[N:36]=[C:35]([NH:37][C@H:38]2[CH2:43][CH2:42][CH2:41][C@@H:40](O)[C@H:39]2[OH:45])[C:34]([F:46])=[CH:33][N:32]=1.C(=O)([O-])[O-:48].[Na+].[Na+]>C(#N)C.CCOC(C)=O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:31]3[N:36]=[C:35]([NH:37][C:38]4([OH:48])[CH2:43][CH2:42][CH2:41][CH2:40][CH:39]4[OH:45])[C:34]([F:46])=[CH:33][N:32]=3)=[CH:9][N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(Cl)cnc32)cc1
Reactant: O[C@@H]1[C@H](O)CCC[C@@H]1Nc1nc(Cl)ncc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC4(O)CCCCC4O)n3)c3cc(Cl)cnc32)cc1
Temperature: 120 °C

Procedure:
To a deoxygenated solution of 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (0.22 g, 0.51 mmol) and (1R,2S,3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexane-1,2-diol, 31b, (0.08 g, 0.24 mmol) in acetonitrile (6 ml) was added 2M sodium carbonate (0.45 mL of 2 M solution, 0.894 mmol) and Pd(PPh3)4 (34.5 mg, 0.030 mmol). The reaction was sealed and heated to 120° C. for 15 minutes in the microwave. The r×n was diluted with EtOAc and filtered thru florisil. The solution was concentrated to crude and purified via silica gel chromatography (DCM to 20% MeOH/DCM) to give compound 31c (0.11 g) as a pink solid.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6]CO)[CH2:2][CH3:3].[CH:9]([Cl:12])(Cl)[Cl:10]>S(Cl)(Cl)=O>[ClH:10].[CH2:1]([NH:4][CH2:5][CH2:6][CH2:9][Cl:12])[CH2:2][CH3:3]
Reactant: CCCNCCCO
Reactant: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CCCNCCCCl
Product: Cl

Procedure:
There was added to about 124 parts of the above N-propyl-3-amino propanol dissolved in 1194 parts of chloroform under an atmosphere of nitrogen and at a temperature of about 0° C., 189 parts of thionyl chloride at a rate which was sufficient to maintain the temperature of the resulting reaction mixture below 20° C. When the addition was complete, the solution was brought to reflux for 30 minutes. The reaction mixture was then quenched with excess ethanol and concentrated to provide a yellow viscous oil. There was obtained a quantitative yield of N-propylamino-3-chloro propane hydrochloride after the aforementioned yellow viscous oil was crystallized from ethanol in the form of a white crystalline solid; (M.P. 246°-247° C.).
Reaction SMILES: [CH2:1](O)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[CH:35]1([CH2:38][N:39]([CH2:60][CH:61]2[CH2:63][CH2:62]2)[C:40]2[C:41]([S:58][CH3:59])=[N:42][N:43]3[C:48]([C:49]4[C:54]([CH3:55])=[CH:53][C:52]([CH3:56])=[CH:51][C:50]=4[OH:57])=[CH:47][CH:46]=[CH:45][C:44]=23)[CH2:37][CH2:36]1>O1CCCC1.C(OCC)(=O)C.O>[CH:35]1([CH2:38][N:39]([CH2:60][CH:61]2[CH2:63][CH2:62]2)[C:40]2[C:41]([S:58][CH3:59])=[N:42][N:43]3[C:48]([C:49]4[C:54]([CH3:55])=[CH:53][C:52]([CH3:56])=[CH:51][C:50]=4[O:57][CH2:1][CH3:2])=[CH:47][CH:46]=[CH:45][C:44]=23)[CH2:36][CH2:37]1
Reactant: CCO
Reactant: CSc1nn2c(-c3c(C)cc(C)cc3O)cccc2c1N(CC1CC1)CC1CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc(C)cc(C)c1-c1cccc2c(N(CC3CC3)CC3CC3)c(SC)nn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After adding ethanol (2 μL), triphenylphosphine (15 mg) and diethyl azodicarboxylate (9 μL) to a solution of 2-[3-[di(cyclopropylmethyl)amino]-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-7-yl]-3,5-dimethylphenol (15 mg) in tetrahydrofuran (0.45 mL) under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The reaction mixture was added to water, extraction was performed with ethyl acetate, and the organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and the title compound (3.7 mg) was obtained from the n-hexane:ethyl acetate (9:1) fraction as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:38]1(=[O:48])[NH:42][C:41](=[O:43])[C:40]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:39]12.C(OC(N=NC(OCC)=O)=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:42]2[C:38](=[O:48])[C:39]3[C:40](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:41]2=[O:43])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC(CCCCO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCCCN2C(=O)c3ccccc3C2=O)CC1
Temperature: 15 °C
Reaction time: 8 h

Procedure:
136.0 g (<528 mmol) 4-(1-tert-butoxycarbonylpiperidin-4-yl)-butan-1-ol (crude product), 135.3 g (516 mmol) triphenylphosphine and 75.9 g (516 mmol) phthalimide are suspended in THF and 89.9 g (516 mmol) azodicarboxylic acid diethyl ester are added dropwise within 3 hours under protective atmosphere and light cooling (ca. 15° C.). The mixture is left to stand at RT overnight without further cooling. Subsequently, the solvent is removed under vacuum and the oily residue is dissolved in 500 ml acetic acid ethyl ester and held overnight at 0° C. The sedimented precipitate is filtered and discarded. The solution is concentrated under vacuum and the oily residue is chromatographically purified over silica gel with CHCl3 and crystallized from 200 ml isopropanol after drawing off the solvent. Colorless crystals with a MP of 100-102° C. were recovered; yield: 108.5g (57%).
Reaction SMILES: [C:1]1([CH2:7][SH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18](F)[C:17]=1[Cl:23]>CN(C=O)C.C(OCC)(=O)C.O>[CH2:7]([S:8][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([Br:15])[C:17]=1[Cl:23])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Fc1cccc(Br)c1Cl
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Clc1c(Br)cccc1SCc1ccccc1
Reaction time: 0.17 h

Procedure:
To stirred phenyl-methanethiol (14.8 g, 119.36 mmol) in 175 ml DMF was added Cs2CO3 (38.89 g, 119.36 mmol) under argon. After 10 min. 1-bromo-2-chloro-3-fluoro-benzene (25 g, 119.36 mmol) in 25 ml DMF was added and stirring was continued overnight at RT and then 3 h at 80° C. After cooling the mixture was diluted with ethyl acetate/water and washed subsequently with 1 N HCl and brine. The organic layer was dried with MgSO4, filtered and evaporated. Purification by chromatography on silica gel yielded 22 g (59%) as an amorphous, colorless solid.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[O:12][CH2:13][C:14](=[O:21])[C:15]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][N:29]=2)[C:24]([CH:31]=O)=[CH:23]1.N1CCCCC1>C(O)C>[NH:22]1[C:30]2=[N:29][CH:28]=[CH:27][CH:26]=[C:25]2[C:24]([CH:31]=[C:13]2[O:12][C:11]([NH:10][C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=3)=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:14]2=[O:21])=[CH:23]1
Reactant: CCOC(=O)C1=C(Nc2ccc(C(C)C)cc2)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)C1=C(Nc2ccc(C(C)C)cc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 34.6 %

Procedure:
To a solution of ethyl 2-[(4-isopropylphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.26 g, 0.90 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.13 g, 0.90 mmol) in ethanol (6.0 mL), piperidine (0.045 mL, 0.45 mmol) was added at ambient temperature. The mixture was refluxed for 16 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol then dried to afford the titled compound as solid (0.13 g, y. 35%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[NH:10][C:9]2=[O:17])[N:3]=1.[CH3:18][C:19]([CH3:21])=O.[OH-].[K+].C(Br)C=C>O>[CH2:21]([N:10]1[C:11]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[N:8]([C:4]2[N:3]=[C:2]([CH3:1])[CH:7]=[CH:6][CH:5]=2)[C:9]1=[O:17])[CH:19]=[CH2:18]
Reactant: CC(C)=O
Reactant: Cc1cccc(-n2c(=O)[nH]c3cccnc32)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C=CCBr
Product: C=CCn1c(=O)n(-c2cccc(C)n2)c2ncccc21
Reaction time: 8 h

Procedure:
A mixture of 1 g. of 1,3-dihydro-3-(2-methylpyridin-6-yl)imidazo[4,5-b]pyridin-2-one in 100 ml. of acetone and 450 mg. of powdered potassium hydroxide was stirred 10 minutes and 1.1 g. of allyl bromide was added. After refluxing for 1.5 hours, the mixture was allowed to stand overnight at room temperature. The mixture was diluted with water and the acetone was evaporated causing crystallization of 325 mg. of 1-allyl-1,3-dihydro-3-(2-methylpyridin-6yl)imidazo[4,5-b]pyridin-2-one, m.p. 111°-112° C.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]([N:7]1[C:13](=[O:14])[CH:12]([CH3:15])[C:11]2[CH:16]=[CH:17][CH:18]=[CH:19][C:10]=2[C:9]2[C:20]([NH2:24])=[CH:21][CH:22]=[CH:23][C:8]1=2)=[O:6])[CH3:4].N1C=CC=CC=1.[F:31][C:32]1[CH:33]=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1>C1COCC1>[F:31][C:32]1[CH:33]=[C:34]([S:38]([NH:2][C@H:3]([C:5]([N:7]2[C:13](=[O:14])[CH:12]([CH3:15])[C:11]3[CH:16]=[CH:17][CH:18]=[CH:19][C:10]=3[C:9]3[C:20]([NH2:24])=[CH:21][CH:22]=[CH:23][C:8]2=3)=[O:6])[CH3:4])(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: CC1C(=O)N(C(=O)[C@H](C)N)c2cccc(N)c2-c2ccccc21
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC1C(=O)N(C(=O)[C@H](C)NS(=O)(=O)c2cccc(F)c2)c2cccc(N)c2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.6 %

Procedure:
To 5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (Example 7B) (0.1500 g, 0.434 mmol) in THF (4 ml) was added pyridine (0.088 ml, 1.09 mmol) and 3-fluorobenzenesulfonyl chloride (Fluorochem Limited) (0.0928 ml, 0.477 mmol), stirred at RT overnight. The reaction mixture was evaporated to dryness. Water was added, filtered. The solid was purified with flash chromatography (silica, 6% MeOH/CH2Cl2, crystallized with CH2Cl2/hexane and washed with Et2O/hexane (1:1, v/v) to give the title compound (0.0580 g, 29%) as a white solid.
Reaction SMILES: Cl.[S:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:17][C:18]1[CH:31]=[CH:30][CH:29]=[CH:28][C:19]=1[CH:20](Br)[C:21](=[O:26])[C:22]([F:25])([F:24])[F:23].C(OCC)(=O)C>C(Cl)Cl>[Cl:17][C:18]1[CH:31]=[CH:30][CH:29]=[CH:28][C:19]=1[CH:20]([N:7]1[CH2:8][CH2:9][C:10]2[S:2][CH:3]=[CH:4][C:5]=2[CH2:6]1)[C:21](=[O:26])[C:22]([F:24])([F:25])[F:23]
Reactant: O=C(C(Br)c1ccccc1Cl)C(F)(F)F
Reactant: c1cc2c(s1)CCNC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(C(c1ccccc1Cl)N1CCc2sccc2C1)C(F)(F)F
Temperature: 25 °C
Yield: 39.2 %

Procedure:
10 ml of methylene chloride were added to 0.39 g (2.6 mmole) of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride and 0.28 g (2.6 mmole) of sodium carbonate, and then a solution of 0.67 g (2.2 mmole) of 2-chloro-α-trifluoroacetylbenzyl bromide in 10 ml of methylene chloride was slowly added to the resulting mixture, whilst stirring at room temperature. The mixture was then stirred at room temperature for 3 hours. At the end of this time, 200 ml of ethyl acetate were added to the reaction mixture, and the organic layer was separated, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was subjected to silica gel column chromatography, using a 100:4 by volume mixture of toluene and ethyl acetate as the eluent, to give 0.31 g of the title compound as a colorless oil.
Reaction SMILES: [C:1](Cl)(=[O:3])C.C[OH:6].[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[C:8]1=NO>CC(C)=O>[OH:7][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:9](=[O:16])[C:8]([O:3][CH3:1])=[O:6]
Reactant: CC(=O)Cl
Reactant: O=C1C(=NO)Oc2ccccc21
Reactant: CO
Solvent: CC(C)=O
Product: COC(=O)C(=O)c1ccccc1O

Procedure:
27 g of acetyl chloride (0.344 mol) are added dropwise to a mixture of 245 ml of methanol and 245 ml of acetone. 20 g (0.123 mol) of benzofuran-2,3-dione 2-oxime are dissolved in this mixture and the mixture is subsequently heated under reflux for 1 hour. The solvent is distilled off under reduced pressure, the residue is poured into water, the product is extracted with diethyl ether, the organic phase is dried over sodium sulphate and the solvent is distilled off under reduced pressure. This gives 20.8 g of crude product which, according to HPLC, contains 92.4% methyl 2-hydroxyphenylglyoxylate of log p=1.87.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[C:6]([C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[C@@H:11]([NH2:13])[CH3:12])[CH:7]=[CH:8][CH:9]=1)#[N:3].[CH3:22][C:23]([O:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=1)([CH3:27])[C:24](O)=[O:25].Cl.C(N=C=NCCCN(C)C)C.N1C=CC=CC=1>C(#N)C>[C:2]([C:4]1[CH:5]=[C:6]([CH:10]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=2)[CH:11]([NH:13][C:24](=[O:25])[C:23]([O:28][C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=2)([CH3:27])[CH3:22])[CH3:12])[CH:7]=[CH:8][CH:9]=1)#[N:3]
Reactant: C[C@H](N)[C@@H](Cc1ccc(O)cc1)c1cccc(C#N)c1
Reactant: Cc1ccc(OC(C)(C)C(=O)O)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: Cc1ccc(OC(C)(C)C(=O)NC(C)C(Cc2ccc(O)cc2)c2cccc(C#N)c2)nc1
Temperature: 25 °C

Procedure:
To a solution of N-(1S, 2S)-[2-(3-cyanophenyl)-3-(4-hydroxyphenyl)-1-methylpropyl]amine hydrochloride (Reference Example 8, 0.17 g, 0.49 mmol), 2-methyl-2-(5-methyl-2-pyridyloxy)propionic acid (Reference Example 12, 96 mg, 0.49 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (0.11 g, 0.59 mmol) in acetonitrile (2 mL) at 0° C. was added pyridine (91 uL, 1.1 mmol). The reaction was allowed to warm up to room temperature overnight, and was quenched with saturated with sodium bicarbonate (2 mL). The resulting mixture was partitioned between tert-butyl methyl ether (20 mL) and water (20 mL). The organic layer was separated, washed with 1 M hydrochloric acid, water and brine and concentrated to dryness. The residue was purified by flash column chromatography on silica gel eluting with 10 to 70% ethyl acetate in hexane to afford N-[2-(3-Cyano-phenyl)-3-(4-hydroxyphenyl)-1-methylpropyl]-2-(5-methyl-2-pyridyloxy)-2-methylpropanamide. 1H NMR (500 MHz, CD3OD): δ 7.85 (br d, 1H), 7.81 (d, 1H), 7.53-7.80 (m, 2H), 7.38 (t, 1H), 7.34 (br d, 1H), 7.32 (br s, 1H), 6.80 (d, 1H), 6.51 (ABq, 4H), 4.26 (m, 1H), 3.01 (dd, 1H), 2.81 (td, 1H), 2.54 (dd, 1H), 2.12 (s, 3H), 1.73 (s, 3H), 1.67 (s, 3H), 0.83 (d, 3H). LC-MS: m/e 444 (M+H)+ (3.3 min).