Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([N:15]2[CH2:20][CH2:19][CH:18]([N:21](C)[C:22](=O)OCC3C=CC=CC=3)[CH2:17][CH2:16]2)[CH:12]=[CH:11][N:10]=1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[CH3:22][NH:21][CH:18]1[CH2:19][CH2:20][N:15]([C:13]2[CH:12]=[CH:11][NH:10][C:9](=[O:8])[CH:14]=2)[CH2:16][CH2:17]1
Reactant: CN(C(=O)OCc1ccccc1)C1CCN(c2ccnc(OCc3ccccc3)c2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CNC1CCN(c2cc[nH]c(=O)c2)CC1
Reaction time: 4 h
Yield: 87 %

Procedure:
A solution of benzyl 1-(2-(benzyloxy)pyridin-4-yl)piperidin-4-yl(methyl)carbamate (400 mg, 1.160 mmol, 1.0 eq) in MeOH (5 ml) was degassed for 15 minutes with nitrogen. Pd(OH)2 (300 mg, 60% w/w) was then added and hydrogenation was carried out for 4 hours at RT. After monitoring by TLC, the reaction mixture was filtered off over Celite, concentrated under reduced pressure and dried. Yield: 87% (210 mg, 1.014 mmol)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([C:17]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([CH3:29])[CH:23]=3)([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:14][C:13]=2[CH:30]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([C:17]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[C:24]([CH3:29])[CH:23]=3)([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:14][C:13]=2[CH:30]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)CBr
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1cc2cc(OCc3ccccc3)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2cc(OCc3ccccc3)ccc2o1
Yield: 63.5 %

Procedure:
4-[1-(5-Benzyloxy-benzofuran-2-yl)-1-ethyl-propyl]-2-methyl-phenol (4.05 g, 10.1 mmol) and 1-bromopinacolone (2.17 g, 12.1 mmol) and K2CO3 (2.79 g, 20.2 mmol) in acetone (50 mL) are reacted analogous to Example 18-E to give the title compound (3.20 g, 63%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:23])[C:9]([NH:11][C:12]([CH3:22])([CH:19]([CH3:21])[CH3:20])[C:13](=[O:18])[CH2:14]C([O-])=O)=[O:10])=[CH:4][CH:3]=1.CC(O)C.S(=O)(=O)(O)O.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:23])[C:9]([NH:11][C:12]([CH3:22])([CH:19]([CH3:20])[CH3:21])[C:13](=[O:18])[CH3:14])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C(=O)NC(C)(C(=O)CC(=O)[O-])C(C)C)c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC(=O)C(C)(NC(=O)C(C)c1ccc(Cl)cc1)C(C)C
Temperature: 60 °C
Yield: 89.7 %

Procedure:
In a reactor were placed 57.5 g (0.156 mole) of 4-[2-(4-chlorophenyl)propanoylamino]-4,5-dimethyl-3-oxohexanoate, 156 ml of 2-propanol, 62.4 ml of water and 15.6 ml of concentrated sulfuric acid. The mixture was refluxed for 7 hours with heating, to give rise to a reaction. After the completion of the reaction, the reaction mixture was cooled to 60° C. 446 ml of water was added for further cooling. The mixture was neutralized with a 23% aqueous sodium hydroxide solution. The precipitated crystals were collected by filtration to obtain 41.5 g (0.14 mole) of 2-(4-chlorophenyl)-N-[1-methyl-1-(methylethyl)-2-oxopropyl]propanamide (yield=90%).
Reaction SMILES: [CH2:1]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S(Cl)([Cl:20])=O>>[CH2:1]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([Cl:20])=[O:17])[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCC[C@H]1CC[C@H](C(=O)O)CC1
Product: CCCCCCCC[C@H]1CC[C@H](C(=O)Cl)CC1
Temperature: 60 °C

Procedure:
1.16 g (4.82 mM) of trans-4-n-octylcyclohexane-carboxylic acid was added to thionyl chloride, and the mixture was heated at 60° C. for 3 hours, followed by distilling-off of an excess of the thionyl chloride, to obtain 1.00 g (3.86 mM) of trans-4-n-octylcyclohexane-carboxylic acid chloride.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.I[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1>>[N:1]1([C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: N#Cc1ccc(I)cc1
Product: N#Cc1ccc(-n2ccc3ccccc32)cc1

Procedure:
Prepared by Procedure C and Scheme O using 1H-indole and 4-iodobenzonitrile: ESMS m/e: 219.0 (M+H)+.
Reaction SMILES: [O:1]=[P:2]12[O:13][P:11]3([O:14]P(OP([O:10]3)([O:9]1)=O)(=O)[O:3]2)=[O:12].[CH2:15]([O:19][CH2:20][CH2:21]O)[CH2:16][CH2:17][CH3:18]>C(Cl)Cl>[CH2:15]([O:19][CH2:20][CH2:21][O:10][P:11]([O:13][P:2]([OH:9])([OH:3])=[O:1])([O:14][CH2:21][CH2:20][O:19][CH2:15][CH2:16][CH2:17][CH3:18])=[O:12])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCOCCO
Reactant: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: CCCCOCCOP(=O)(OCCOCCCC)OP(=O)(O)O

Procedure:
To a reaction flask containing 500 ml of methylene chloride under a nitrogen atmosphere is added with stirring phosphorus pentoxide (270 g, 1.9 moles). 2-Butoxyethanol (425 g, 3.6 moles) is added from a dropping funnel over about 2 hr, during which a gentle reflux occurs. At the end of the addition, only a small amount of unreacted P2O5 remains. The contents of the flask are a clear yellow solution. At the end of 24 h additional reaction, the contents of the flask are darker in color and no P2O5 is observed.
Reaction SMILES: O.O.[C:3]([O-:15])(=[O:14])[CH2:4][C:5]([CH2:10][C:11]([O-:13])=[O:12])([C:7]([O-:9])=[O:8])[OH:6].[Na+].[Na+].[Na+].[Na+].[Cl-].[Cl-].[Cl-].[Ca+2]>[Cl-].[Na+].O>[C:3]([OH:15])(=[O:14])[CH2:4][C:5]([CH2:10][C:11]([OH:13])=[O:12])([C:7]([OH:9])=[O:8])[OH:6]
Reactant: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=C(O)CC(O)(CC(=O)O)C(=O)O

Procedure:
Trisodium citrate dihydrate was added to the dilution brine consisting of 500 ppm NaCl containing 2770 ppm CaCl2 (1000 ppm Ca+2). The chelating agent was added to give concentrations equivalent to 1,000, 3,000 and 5,000 ppm of citric acid; i.e., a citric acid (molecular weight=192) concentration of 1,000 ppm was prepared by adding 1531 ppm of trisodium citrate dihydrate (molecular weight=294).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:16][C@H:12]2[CH2:13][NH:14][CH2:15][C@@:11]2([C:17]([O:19][CH3:20])=[O:18])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:16][C@H:12]2[CH2:13][N:14]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH2:15][C@@:11]2([C:17]([O:19][CH3:20])=[O:18])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)[C@@]12CNC[C@@H]1C[C@@H](NC(=O)OC(C)(C)C)C2
Solvent: ClCCl
Product: COC(=O)[C@]12C[C@H](NC(=O)OC(C)(C)C)C[C@H]1CN(C(=O)OCc1ccccc1)C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the product from Step D (21.5 g, 75.6 mmol) in DCM (400 mL) was added TEA (31.6 mL, 226.8 mmol) and benzyl chloroformate (14.5 mL, 95%, 98.3 mmol) at 0° C. under Ar. The mixture was stirred at rt for 3 h and quenched by the addition of aqueous NaHCO3 solution. The aqueous phase was extracted with DCM (3×) and the combined organic phases were dried over Na2SO4. Evaporation and purification by column chromatography (eluent: 20% EtOAc in hexanes to 30%) gave the product as a colorless gel. 1H-NMR (400 MHz, CDCl3): δ 1.43 (s, 9H), 1.89 (br. s., 2H), 2.13 (br. s., 2H), 2.99 (d, J=1.0 Hz, 1H), 3.22-3.57 (m, 2H), 3.59-3.83 (m, 4H), 3.99 (d, J=11.6 Hz, 1H), 4.23 (d, J=5.8 Hz, 1H), 4.85 (br. s., 1H), 5.12 (d, J=3.0 Hz, 2H), 7.28-7.42 (m, 5H). LC/MS: C22H30N2O6: m/z 441.2 (M+Na).
Reaction SMILES: CC1O[C:6](=[O:8])[C:5]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:4]=2[N:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([Mg]Br)=[CH:18][CH:17]=1>C1(C)C=CC=CC=1.CCOCC>[NH2:3][C:4]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:5]=1[C:6]([C:19]1[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=1)=[O:8]
Reactant: COc1ccc2nc(C)oc(=O)c2c1
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COc1ccc(N)c(C(=O)c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-methyl-6-(methyloxy)-4H-3,1-benzoxazin-4-one (for a preparation see Reference compound A) (40.0 g, 0.21 mol) in a toluene/ether (2/1) mixture (760 mL) at 0° C. was added dropwise a solution of 4-chlorophenylmagnesium bromide (170 mL, 1M in Et2O, 0.17 mol). The reaction mixture was allowed to warm to room temperature and stirred for 1 h before being quenched with 1N HCl (200 mL). The aqueous layer was extracted with EtOAc (3×150 mL) and the combined organics were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude compound was then dissolved in EtOH (400 mL) and 6N HCl (160 mL) was added. The reaction mixture was refluxed for 2 h before being concentrated to one-third in volume. The resulting solid was filtered and washed twice with ether before being suspended in EtOAc and neutralised with 1N NaOH. The aqueous layer was extracted with EtOAc (3×150 mL) and the combined organics were washed with brine (150 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The title compound was obtained as a yellow solid (39 g, 88% yield); LC/MS (Method A): m/z 262 [M+H]+, Rt 2.57 min.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[CH2:28][N:27]([C:29](=[O:31])[CH3:30])[CH2:26][CH2:25][C:9]=2[N:10]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][CH:23]=[N:22][CH:21]=3)=[CH:16][CH:15]=2)[N:12]=1)(=O)=O.[NH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][C@@H:35]1[CH2:43][OH:44]>CS(C)=O>[OH:44][CH2:43][C@H:35]1[CH2:36][C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:34]1[C:7]1[C:8]2[CH2:28][N:27]([C:29](=[O:31])[CH3:30])[CH2:26][CH2:25][C:9]=2[N:10]=[C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[O:24][CH:23]=[N:22][CH:21]=3)=[CH:18][CH:19]=2)[N:12]=1
Reactant: OC[C@H]1Cc2ccccc2N1
Reactant: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(OS(=O)(=O)C(F)(F)F)c2C1
Solvent: CS(C)=O
Product: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N3c4ccccc4C[C@@H]3CO)c2C1
Reaction time: 8 h
Yield: 37.6 %

Procedure:
6-Acetyl-2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl trifluoromethanesulfonate (35 mg, 0.07 mmol, Example 26a) in DMSO (1 mL) was dispensed in a library plate. (R)-indolin-2-ylmethanol (10.44 mg, 0.07 mmol) was added to it and the reaction mixture was left to shake overnight at 80° C. before filtered and purified by preparative HPLC to yield (R)-1-(4-(2-(Hydroxymethyl)indolin-1-yl)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (12.7 mg, 36%).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6](CN)=[CH:5][CH:4]=1)#[N:2].[C:11](=[O:14])([O-])[O-:12].[Na+].[Na+].Cl[O-].[Na+].NC(N)=O.S(=O)(=O)(O)O>[Ru](Cl)(Cl)Cl.O.O1CCOCC1>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([C:11]([OH:12])=[O:14])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(CN)cc1
Agent: Cl[Ru](Cl)Cl
Agent: NC(N)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccc(C(=O)O)cc1
Temperature: 50 °C
Yield: 183.5 %

Procedure:
A mixture containing p-cyanobenzylamine (13.2 g), dioxane (70 g), sodium carbonate (5.3 g), water (50 g), and ruthenium trichloride (0.1 g) was stirred, and a 14 wt. % aqueous solution (200 g) of sodium hypochlorite was added dropwise thereto over three hours while the inside temperature of a reactor was maintained at 50° C. or lower. The reaction mixture was further stirred for two hours. Subsequently, water (100 g) and urea (4 g) were added to the mixture, and the resultant mixture was further stirred for 20 minutes. The pH of the mixture was adjusted to four through addition of 98 wt. % sulfuric acid. Precipitated crystals were collected through filtration, washed with water, and dried, to thereby obtain 13.5 g of p-cyanobenzoic acid (yield 92%, based on p-cyanobenzylamine). The p-cyanobenzoic acid obtained had a purity of 96%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:13])[CH:5]=[C:6]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:20](I)[CH3:21]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]2[O:9][CH2:10][CH2:11][O:12]2)[CH:5]=[C:4]([O:13][CH2:20][CH3:21])[CH:3]=1
Reactant: Oc1cc(Br)cc(C2OCCO2)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(Br)cc(C2OCCO2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.2 %

Procedure:
To a solution of 3-bromo-5-[1,3]dioxolan-2-yl-phenol (0.53 g, 2.16 mmol, 1.0 equiv) in DMF (2 mL) was added K2CO3 (0.33 g, 2.38 mmol, 1.1 equiv) and ethyl iodide (0.19 mL, 0.37 g, 2.38 mmol, 1.1 equiv) and the reaction mixture stirred under Ar at rt for 18 h. The K2CO3 was removed by filtration, the filtrate extracted with cyclohexane (3×50 mL), the combined organic phases washed with water (2×50 ml) and dried over MgSO4. The solvent was removed by evaporation under reduced pressure and the crude material purified with column chromatography on silica eluting with hexane/ethyl acetate (6:1) providing 0.42 g (72%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.40 (t, J=7.0 Hz, 3H), 4.01-4.10 (m, 6H), 5.75 (s, 1H), 6.93-6.94 (m, 1H), 7.02-7.04 (m, 1H), 7.19-7.20 (m, 1H). MS (EI): 273.0 [M]+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[O:8]=[C:9]1[C@@H:16]2[C@@H:12]([CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15]2)[CH2:11][CH2:10]1>>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH:16]2[C:9]([OH:8])([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)[CH2:10][CH2:11][CH:12]2[CH2:13]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: Brc1cccnc1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CCC(=O)[C@H]2C1
Product: CC(C)(C)OC(=O)N1CC2CCC(O)(c3cccnc3)C2C1
Yield: 26.6 %

Procedure:
3-Bromopyridine (4.36 g, 27.6 mmol) and the product from Example 44A (2.07 g, 9.19 mmol) were processed as described in Example 1E to afford the title compound (0.743 g, 27%). MS (DCI/NH3) m/z 305 (M+H)+.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[F:26][C:27]([F:34])([F:33])[C@H:28]([OH:32])[C:29](O)=[O:30]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:29](=[O:30])[C@@H:28]([OH:32])[C:27]([F:34])([F:33])[F:26])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)[C@@H](O)C(F)(F)F
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1)[C@@H](O)C(F)(F)F

Procedure:
The title compound, white solid (17 mg, 54.7%), MS (ISP) m/z=457.2 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (25 mg, 0.0681 mmol) and (R)-3,3,3-trifluoro-2-hydroxypropanoic acid
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16]#[C:17][C:18]3[CH:30]=[CH:29][C:21]4[S:22][C:23]([C:25]([O:27]C)=[O:26])=[CH:24][C:20]=4[CH:19]=3)=[N:14][CH:15]=2)=[CH:6][CH:5]=1.Cl>CCO>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16]#[C:17][C:18]3[CH:30]=[CH:29][C:21]4[S:22][C:23]([C:25]([OH:27])=[O:26])=[CH:24][C:20]=4[CH:19]=3)=[N:14][CH:15]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1cc2cc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)ccc2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc2cc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)ccc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
22.3 mL of 1N NaOH was added to a suspension of 3.0 g (7.43 mmol) of methyl 5-[5-(4-chlorophenyl)pyridin-2-ylethynyl]benzo[b]thiophen-2-carboxylate in 100 mL of EtOH and the reaction mixture was stirred overnight at RT. The reaction solution was cooled to 0° C. and adjusted to pH 6 by the dropwise addition of 1N HCl. The precipitated product was filtered off, washed with EtOH, and dried in the air. As the product still contained educt, the hydrolysis described above was repeated. Yield: 2.7 g (93% of theoretical); C22Hl2ClNO2S (M=389.855); calc.: molpeak (M+H)+: 390/392 (Cl); found: molpeak (M+H)+: 390/392 (Cl); Rf value: 0.89 (silica gel, PE/EtOAc 1:1).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][C:25]3[NH:26][CH:27]=[CH:28][N:29]=3)[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>FC(F)(F)C(O)=O>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][C:25]3[NH:29][CH:28]=[CH:27][N:26]=3)[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(Cc2ncc[nH]2)no1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C[C@@H](CCCC1CCCCC1)c1nc(Cc2ncc[nH]2)no1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 133.2 %

Procedure:
tert-butyl (3R)-6cyclohexyl-3-[3-(1H-imidazol-2-ylmethyl)-1,2,4-oxadiazol-5-yl]hexanoate (Preparation 102) (530 mg, 1.32 mmol) was treated with trifluoroacetic acid (10 ml) and stirred at room temperature for 1.5 hours. The solvent was removed under reduced pressure and the residue azeotroped from toluene (3×30 ml) and dichloromethane (2×30 ml) to afford the title compound (609 mg).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(C(C)C)CC)(C)C.[F:24][C:25]([F:41])([F:40])[C:26]1[CH:30]=[CH:29][N:28]([C:31]2[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=2)[N:27]=1>ClCCl>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:35]([C:34]3[CH:33]=[CH:32][C:31]([N:28]4[CH:29]=[CH:30][C:26]([C:25]([F:41])([F:24])[F:40])=[N:27]4)=[CH:39][CH:38]=3)=[O:36])[CH2:6][C:5]=12
Reactant: O=C(Cl)c1ccc(-n2ccc(C(F)(F)F)n2)cc1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(-n2ccc(C(F)(F)F)n2)cc1)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.3 %

Procedure:
To a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]-benzodiazepine (0.88 g) and diisopropylethylamine (0.66 g) in dichloromethane (50 ml) was added the 4-(3-trifluoromethylpyrazol-1-yl)benzoyl chloride (1.40 g). After stirring at room temperature for 18 hours, the reaction mixture was washed with water and saturated aqueous sodium bicarbonate. The dichloromethane solution was dried over anhydrous sodium sulfate and filtered through a short column of hydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until crystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (1.70 g), m.p. 166-167° C.; MS, m/z: 423.3 (M+H)+, 845.4 (2M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1([N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH2:10][CH2:9]1)=[O:6].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:11]1([C:8]2([N:7]3[CH2:2][CH2:3][CH2:4][C:5]3=[O:6])[CH2:10][CH2:9]2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: O=C(CCCBr)NC1(n2ccnc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCCN1C1(n2ccnc2)CC1
Temperature: 25 °C

Procedure:
In a 50 ml three necked flask fitted with a magnetic stirrer, under inert atmosphere, the crude 4-bromo-N-(1-imidazol-1-yl-cyclopropyl)-butyramide a18 (2.76 g), K2CO3 (1.26 g, 9.1 mmol) and KI (0.0075 g) in DMF (25 ml) are heated 3 h at 60° C., 17 h at 80° C., cooled down to room temperature and concentrated in vacuo. The reaction mixture is diluted with CH2Cl2, filtered and concentrated in vacuo to give the crude pyrrolidone (1.7 g). The residue is purified by chromatography on silicagel (CH2Cl2/MeOH/NH4OH: 95/4.5/05 (v/v/v)) to give, after treatment with HCl in ether (1 eq) and recrystallization in MeCN, 1-[1-(1H-imidazol-1-yl)cyclopropyl]pyrrolidin-2-one 23 (0.033 g, 7.5%) as an hydrochloride.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:15]=1[CH:14]([CH3:16])[N:13]=[C:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])[C:11]1[CH:24]=[C:25](Br)[CH:26]=[CH:27][C:10]2=1)=[O:5])[CH3:2].[CH3:29][Si:30]([C:33]#[CH:34])([CH3:32])[CH3:31]>C(#N)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:15]=1[CH:14]([CH3:16])[N:13]=[C:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])[C:11]1[CH:24]=[C:25]([C:34]#[C:33][Si:30]([CH3:32])([CH3:31])[CH3:29])[CH:26]=[CH:27][C:10]2=1)=[O:5])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)c1ncn2c1C(C)N=C(c1ccccc1F)c1cc(Br)ccc1-2
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CCOC(=O)c1ncn2c1C(C)N=C(c1ccccc1F)c1cc(C#C[Si](C)(C)C)ccc1-2
Temperature: 25 °C
Yield: 80 %

Procedure:
A mixture of 138 (69.3 mg, 0.16 mmol) and bis(triphenylphosphine)palladium (II) acetate (11.68 mg, 0.015 mmol) was dissolved in a mixed solvent system of acetonitrile (120 mL) and TEA (80 mL). The mixture was degassed under vacuum and argon gas was added, after which trimethylsilylacetylene (0.044 mL, 0.31 mmol) was added into the mixture. The mixture was degassed again under vacuum (argon) and heated to reflux. The mixture was heated at reflux until analysis by TLC (EtOAc) indicated that all of the starting material 138 had been consumed. The mixture was cooled to rt and the precipitate which formed was removed by filtration through celite. The filtrate was concentrated under reduced pressure and partitioned between H2O and EtOAc. The combined layers of EtOAc were washed with brine and dried (Na2SO4), after which the solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica gel, EtOAc:hexane 1:1). The conditions for TLC were EtOAc on silica gel. A white solid 139 (58.8 mg, 80%) was obtained. mp 186-187° C.; IR (KBr, cm−1) 2410, 2358, 1716, 1497, 1253; 1H NMR (CDCl3) δ 7.92 (s, 1 H), 7.72 (dd, J=8.5, 1.5 Hz, 1 H), 7.6 (t, J=6.9 Hz, 1H), 7.48 (d, J=8.5 Hz, 1 H), 7.42-7.49 (m, 2H), 7.23-7.29 (m, 1 H), 7.05 (t, J=9.3 Hz, 1H), 6.71 (q, J=7.3 Hz, 1 H), 4.41 (m, 2 H), 1.42 (t, J=7.1 Hz, 3 H), 1.29 (d, J=7.2, 3 H), 0.24 (s, 9 H). MS (EI) m/e (relative intensity) 459 (M+, 28), 445 (32), 399 (51), 371 (100), 235 (71), 178 (75); [α]26D=28.2 (c 0.48, EtOAc).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:10]([C:22]([NH:24][C:25]3[S:29][N:28]=[C:27]([CH3:30])[N:26]=3)=[O:23])=[N:11][C:12]([S:15][C:16]3[N:20]([CH3:21])[CH:19]=[N:18][N:17]=3)=[CH:13][CH:14]=2)=[CH:4][CH:3]=1.Br.Br[CH2:33][CH2:34][CH2:35][N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH3:30][C:27]1[N:26]=[C:25]([NH:24][C:22]([C:10]2[C:9]([S:8][C:5]3[CH:4]=[CH:3][C:2]([O:1][CH2:33][CH2:34][CH2:35][N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)=[CH:7][CH:6]=3)=[CH:14][CH:13]=[C:12]([S:15][C:16]3[N:20]([CH3:21])[CH:19]=[N:18][N:17]=3)[N:11]=2)=[O:23])[S:29][N:28]=1
Reactant: BrCCCN1CCCC1
Reactant: Cc1nsc(NC(=O)c2nc(Sc3nncn3C)ccc2Sc2ccc(O)cc2)n1
Agent: Br
Product: Cc1nsc(NC(=O)c2nc(Sc3nncn3C)ccc2Sc2ccc(OCCCN3CCCC3)cc2)n1
Yield: 16.9 %

Procedure:
Using 19 mg of 3-[(4-hydroxyphenyl)thio]-N-(3-methyl-1,2,4-thiadiazol-5-yl)-6-[(4-methyl-4H-1,2,4-triazol-3-yl)thio]pyridine-2-carboxamide obtained in Reference Example (step 3) and 13 mg of 1-(3-bromopropyl)pyrrolidine hydrobromide obtained in the step 1, 4 mg of the entitled compound was obtained as a pale yellow solid in the same method as in Example 2 or in accordance with the method or by combining it with an ordinary method.