Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)C=O.ClC1C=C(C=CC=1)C(OO)=[O:17]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([OH:17])[CH:9]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(Br)cc1C=O
Solvent: ClCCl
Product: COc1ccc(Br)cc1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 369.1 %

Procedure:
To a solution of 5-bromo-2-methoxy-benzaldehyde (8 g, 4.67 mmol) dissolved in methylene chloride (24 mL) at 0° C. is slowly added a solution of m-chloroperoxybenzoic acid (10.90 g, 5.60 mmol) in methylene chloride (80 mL). The reaction mixture is slowly warmed up to room temperature and stirred for 72 h. The white solid is filtered off and the filtrate is stirred for 2 h with 2 M sodium sulfite (32 mL). The organic layer is concentrated in vacuo then the residue is dissolved in diethyl ether and washed with 1 M sodium sulfite and a half-saturated sodium bicarbonate solution. The organic phase is extracted with 2 M sodium hydroxide. The combined basic extract is acidified to pH 3-4 with concentrated HCl, and extracted with diethyl ether. The combined organic extracts are washed with a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo to provide 3.5 g (37%) of the title compound as a brown solid. 1H NMR (CDCl3): δ 7.10 (d, J=2 Hz, 1H), 7.00 (dd, J=8, 2 Hz, 1H), 6.70 (d, J=8 Hz, 1H), 3.95 (s, 3H).
Reaction SMILES: [NH2:1][C:2]([C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24](F)[CH:23]=1)([C:16]1[N:17]([CH3:21])[CH:18]=[N:19][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[NH2:1][C:2]1([C:16]2[N:17]([CH3:21])[CH:18]=[N:19][CH:20]=2)[C:22]2=[CH:29][C:28](=[C:25]([C:26]#[N:27])[CH:24]=[CH:23]2)[O:15][C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=2)[CH2:8][O:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Cn1cncc1C(N)(CCCCOCc1cccc(O)c1)c1ccc(C#N)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1cncc1C1(N)CCCCOCc2cccc(c2)Oc2cc1ccc2C#N
Reaction time: 18 h

Procedure:
4-[1-Amino-5-(3-hydroxy-benzyloxy)-1-(3-methyl-3H-imidazol-4-yl)-pentyl]-2-fluoro-benzonitrile (0.214 g, 0.443 mmol) was dissolved in DMF (44 mL) at ambient temperature and treated with Cs2CO3 (0.577 g, 1.77 mmol). After 18 h, the reaction mixture was concentrated to dryness, and partitioned between a minimum amount of H2O and CH2Cl2. The aqueous layer was washed with CH2Cl2 (2×), the organics combined, dried (MgSO4), filtered and concentrated to give the title compound after purification on the ISCO Combiflash eluting with 1-3% MeOH/CH2Cl2w/NH4OH. MS (M+1) 389.
Reaction SMILES: C(OCC)(=O)CC(OCC)=O.[H-].[Na+].C1(CBr)CC1.[CH2:19]([O:21][C:22](=[O:33])[CH:23]([CH2:29][CH2:30][CH:31]=[CH2:32])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:20]>C1COCC1>[CH2:19]([O:21][C:22](=[O:33])[CH:23]([CH2:29][CH:30]1[CH2:32][CH2:31]1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:20]
Reactant: C=CCCC(C(=O)OCC)C(=O)OCC
Agent: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(=O)CC(=O)OCC
Solvent: C1CCOC1
Product: CCOC(=O)C(CC1CC1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an ice-cooled solution of diethyl malonate (3.0 g, 18.7 mmol) in THF (30 mL) was added, portionwise over 15 min, sodium hydride (0.824 g, 60% in oil, 20.6 mmol). The mixture was stirred at RT for 30 min, and then cooled in an ice bath. Cyclopropylmethyl bromide (2.36 mL, 24.3 mmol) was added and the reaction mixture stirred at RT for 1 h and then refluxed for 6 h. The cooled mixture was concentrated in vacuo, the residue was partitioned between diethyl ether and dilute aqueous NH4Cl; and the aqueous phase was extracted with diethyl ether. The combined organic phases were washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 2-8% EtOAc in cyclohexane) affording a mixture of the title compound and 2-but-3-enylmalonic acid diethyl ester (3.24 g, 10:1 ratio respectively). This mixture was dissolved in DCM (150 mL) and a solution of mCPBA (0.77 g, 4.46 mmol) in DCM (5 mL) added. The reaction mixture was stirred at RT for 16 h, and then washed with a saturated solution of NaHCO3, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 2-8% EtOAc in cyclohexane) affording the title compound as a colourless oil (2.68 g, 67%). 1H NMR (CDCl3, 300 MHz): δ 4.20 (4H, q, J=7.1 Hz), 3.44 (1H, t, J=7.5 Hz), 1.81 (2H, t, J=7.3 Hz), 1.27 (6H, t, J=7.1 Hz), 0.80-0.67 (1H, m), 0.48-0.42 (2H, m), 0.12-0.07 (2H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.[CH3:27][CH2:28][CH2:29][C:30](Cl)=[O:31]>N1C=CC=CC=1>[C:30]([O:15][C:10]1[CH:11]=[C:12]2[C:7]3=[C:8]([C:16](=[O:26])[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)=[CH:18][N:6]3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:14][C:13]2=3)[CH:9]=1)(=[O:31])[CH2:29][CH2:28][CH3:27]
Reactant: O=c1c(Cc2cccnc2)cn2c3ccc(F)cc3c3cc(O)cc1c32
Reactant: CCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCC(=O)Oc1cc2c(=O)c(Cc3cccnc3)cn3c4ccc(F)cc4c(c1)c23
Reaction time: 0.83 h
Yield: 70 %

Procedure:
10-fluoro-2-hydroxy-5-(3-pyridylmethyl)-4H-pyrido[3,2,1-jk]carbazole-4-one (150 mg) produced in Example 236 was suspended in pyridine (12 ml), and n-butyryl chloride (74 μl) was added dropwise to the suspension in an ice bath. After stirring for 50 minutes, the solvent was evaporated under reduced pressure. The residue was washed with ether to obtain the title compound (126 mg, 70%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([Cl:19])[C:8]([O:12][CH2:13][CH:14](OC)OC)=[CH:9][CH:10]=2)[N:5]=[C:4]([C:20]2[N:21]=[C:22]([CH:25]([CH3:27])[CH3:26])[S:23][CH:24]=2)[CH:3]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CC(O)=O.Cl.CCOC(C)=O.C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([Cl:19])[C:8]([O:12][CH2:13][CH2:14][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:9][CH:10]=2)[N:5]=[C:4]([C:20]2[N:21]=[C:22]([CH:25]([CH3:26])[CH3:27])[S:23][CH:24]=2)[CH:3]=1
Reactant: C1COCCN1
Reactant: COC(COc1ccc2c(Cl)cc(-c3csc(C(C)C)n3)nc2c1Cl)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)c1nc(-c2cc(Cl)c3ccc(OCCN4CCOCC4)c(Cl)c3n2)cs1
Reaction time: 1 h
Yield: 85.3 %

Procedure:
4,8-Dichloro-7-(2,2-dimethoxy-ethoxy)-2-(2-isopropyl-thiazol-4-yl)-quinoline (250 mg, 0.565 mmol) was dissolved in AcOH (5.0 mL) and 2N HCl(aq). The reaction mixture was placed in a 60° C. oil bath and stirred for 1 h. Remove solvent under reduced pressure. The crude material was taken up in EtOAc and washed with ½ sat NaHCO3(aq). Organics were dried over Na2SO4, filtered and was concentrated. The crude material was then taken up in CH2Cl2. Morpholine (77 μL, 0.88 mmol) was added to the reaction mixture and stirred for 15 min. NaBH(OAc)3 (161 mg, 0.761 mmol) and AcOH (1 drop) were added and the reaction was monitored by LC/MS. After 5 min the reaction was determined to be complete. The mixture was diluted with DCM and washed with ½ sat brine, dried with Na2SO4, filtered and was concentrated. 4,8-dichloro-2-(2-isopropyl-thiazol-4-yl)-7-(2-morpholin-4-yl-ethoxy)-quinoline (218 mg, 86%) was isolated by silica gel chromatography as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([O:13][CH3:14])[CH:8]=2)=[CH:4][CH:3]=1.[CH2:17]([C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1)[CH3:18]>>[CH3:14][O:13][C:9]1[CH:8]=[C:7]([O:6][C:5]2[CH:15]=[CH:16][C:2]([NH:1][C:26]([NH:25][C:22]3[CH:23]=[CH:24][C:19]([CH2:17][CH3:18])=[CH:20][CH:21]=3)=[O:27])=[CH:3][CH:4]=2)[CH:12]=[CH:11][N:10]=1
Reactant: CCc1ccc(N=C=O)cc1
Reactant: COc1cc(Oc2ccc(N)cc2)ccn1
Product: CCc1ccc(NC(=O)Nc2ccc(Oc3ccnc(OC)c3)cc2)cc1

Procedure:
The title compound is prepared from 4-(4-amino-phenoxy)-2-methoxy-pyridine (Stage 92.1; 91 mg, 0.42 mmol) and 4-ethyl-phenyl-isocyanate (124 μl, 0.84 mmol) analogously to Example 89: m.p.: 196° C.; Anal.: CHN.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].[Br:16][CH2:17][CH2:18][CH2:19]Br.C(OCC)(=O)C>CS(C)=O.O>[Br:16][CH2:17][CH2:18][CH2:19][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc(OCCCBr)cc1
Reaction time: 0.08 h

Procedure:
In 50 ml of dimethyl sulfoxide was dissolved 10 g of 4-cyanophenol, followed by adding thereto 23 g of potassium carbonate at room temperature. The resulting mixture was stirred at the same temperature for 5 minutes and then 64 ml of 1,3-dibromopropane was added thereto, followed by stirring at room temperature for 12 hours. Subsequently, the reaction mixture was added to a mixed solvent of 200 ml of ethyl acetate and 100 ml of water, after which the organic layer was separated and the aqueous layer was extracted with 50 ml of ethyl acetate. The combined organic layer was washed successively with a 1N aqueous sodium hydroxide solution, water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent; hexane:ethyl acetate=5:1) to obtain 5.1 g of 1-bromo-3-(4-cyanophenoxy)propane as a colorless oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[CH:9]=[CH:10][CH:11]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(Cl)(Cl)Cl.CO>C(OCC)C>[OH:3][CH2:4][C:6]1[CH:7]=[C:8]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)c1cccc(-n2ccnc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Solvent: CO
Product: OCc1cccc(-n2ccnc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
230 mg of 1-(3-ethoxycarbonylphenyl)imidazole see J. Am. Chem. Soc., 79, 4922 (1957)1 was dissolved in ml of ethyl ether, and 50 mg of lithium aluminium hydride was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water. The organic layer was separated and dried over anhydrous magnesium sulfate. The desiccant was separated by filtration. The solvent was evaporated and then the residue was purified by silica gel column chromatography Wakogel C-200, 20 g; eluting solvent: chloroform/methanol=20/1) to give 160 mg (yield 92%) of the captioned compound as a colorless oil.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[O:12].C([O-])([O-])=O.[K+].[K+].O>CN(C)C(=O)C>[O:7]([C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[O:12])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccccc1F
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=Cc1ccccc1Oc1ccccc1

Procedure:
To a solution of phenol (1.8888 g, 0.0201 mol) and 2-fluorobenzaldehyde (2.14 mL, 0.0203 mol) in N,N-dimethylacetamide (20 mL) was added anhydrous K2CO3 (3.0798 g, 0.0223 mol). The resulting heterogenous mixture was refluxed for 3 h. The resulting green mixture was then treated with H2O (100 mL) and extracted with EtOAc (2×100 mL). The combined organic extracts were washed with H2O (4×100 mL), dried over Na2SO4, filtered and concentrated. The resulting dark residue was purified by flash chromatography on silica gel (10% EtOAc in hexane) to yield 2-phenoxybenzaldehyde as a light yellow oil.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[F:23][C:24]([F:63])([CH2:60][CH2:61][CH3:62])[CH2:25][C@H:26]([NH:51][C:52]([N:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1)=[O:53])[C:27](=[O:50])[NH:28][C@H:29]([CH:32]([OH:49])[C:33]1[O:34][C:35]([C:38]2[CH:43]=[CH:42][C:41]([O:44][C:45]([F:48])([F:47])[F:46])=[CH:40][CH:39]=2)=[N:36][N:37]=1)[CH2:30][CH3:31].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[F:63][C:24]([F:23])([CH2:60][CH2:61][CH3:62])[CH2:25][C@H:26]([NH:51][C:52]([N:54]1[CH2:55][CH2:56][O:57][CH2:58][CH2:59]1)=[O:53])[C:27](=[O:50])[NH:28][C@H:29]([C:32]([C:33]1[O:34][C:35]([C:38]2[CH:43]=[CH:42][C:41]([O:44][C:45]([F:46])([F:47])[F:48])=[CH:40][CH:39]=2)=[N:36][N:37]=1)=[O:49])[CH2:30][CH3:31]
Reactant: CCCC(F)(F)C[C@H](NC(=O)N1CCOCC1)C(=O)N[C@@H](CC)C(O)c1nnc(-c2ccc(OC(F)(F)F)cc2)o1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CCCC(F)(F)C[C@H](NC(=O)N1CCOCC1)C(=O)N[C@@H](CC)C(=O)c1nnc(-c2ccc(OC(F)(F)F)cc2)o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.9 %

Procedure:
Dess-Martin Periodinane (15 wt % in DCM, 0.58 gm, 0.21 mmol) is added to a solution of morpholine-4-carboxylic acid [(S)-3,3-difluoro-1-((S)-1-{hydroxy-[5-(4-trifluoromethoxy-phenyl)-1,3,4-oxadiazol-2-yl]-methyl}-propylcarbamoyl)-hexyl]-amide (61 mg, 0.10 mmol) in dry methylene chloride (8 mL) and stirred at room temperature for 3 hrs. The reaction is quenched with a solution of Na2S2O3 (81.43 mg, 0.50 mmol) in aqueous NaHCO3. The organic layer is separated and the aqueous extracted with dichloromethane. The organic extracts are dried over sodium sulfate and concentrated under reduced pressure. Column chromatography on silica eluting with a mixture of methylene chloride and ethyl acetate gives morpholine-4-carboxylic acid ((S)-3,3-difluoro-1-{(S)-1-[5-(4-trifluoromethoxy-phenyl)-1,3,4-oxadiazole-2-carbonyl]-propylcarbamoyl}-hexyl)-amide as a powder (39 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH:9]=[N:10][O:11][CH2:12][CH2:13][CH3:14])[CH:3]=1.[C:15]([O-])(=[O:17])[CH3:16].[Na+]>C(OC(=O)C)(=O)C>[C:15]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[CH:9]=[N:10][O:11][CH2:12][CH2:13][CH3:14])(=[O:17])[CH3:16]
Reactant: CC(=O)[O-]
Reactant: CCCON=Cc1cc(Cl)ccc1O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCCON=Cc1cc(Cl)ccc1OC(C)=O
Temperature: 25 °C
Yield: 70.4 %

Procedure:
To a stirred solution of 6.4 grams (0.03 mole) of 4-chloro-2-[(propoxyimino)methyl]phenol (prepared in the manner of Example 1) in 50 ml of acetic anhydride was added in one portion 2.5 grams (0.03 mole) of sodium acetate. The reaction mixture was heated at 90°-100° for two hours, cooled to ambient temperature, and poured into 200 ml of ice-water. The mixture was stirred until the ice melted. A colorless oil separated and was extracted with portions of methylene chloride. The combined extracts were dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was distilled under reduced pressure to give 5.4 grams of 4-chloro-2-[(propoxyimino)methy]phenyl acetate; bp 95°-107°/3.333 Pa.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[C:7]3[C:20]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N:14]4[C:8]=3[C:9]3[N:10]([C:28]5[C:33]([C:34]=3[C:5]=2[C:4](=[O:35])[N:3]1[Si](C(C)C)(C(C)C)C(C)C)=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH:11]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[S:12](=[O:22])(=[O:21])[CH2:13]4.CS(C)=O.C([O-])(=O)C.[Na+]>O>[O:1]=[C:2]1[C:6]2[C:7]3[C:20]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N:14]4[C:8]=3[C:9]3[N:10]([C:28]5[C:33]([C:34]=3[C:5]=2[C:4](=[O:35])[NH:3]1)=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH:11]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[S:12](=[O:22])(=[O:21])[CH2:13]4
Reactant: CCOC(=O)C1n2c3ccccc3c3c4c(c5c6ccccc6n(c5c32)CS1(=O)=O)C(=O)N([Si](C(C)C)(C(C)C)C(C)C)C4=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C1n2c3ccccc3c3c4c(c5c6ccccc6n(c5c32)CS1(=O)=O)C(=O)NC4=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.5 %

Procedure:
In a 10 mL flask were placed 0.07 g of the compound from Example 44, 4.0 mL of dimethyl sulfoxide, 1.0 mL of water and 0.05 g of sodium acetate. The resulting mixture was stirred at room temperature for 16 hours, cooled and poured in to ice and water. The resulting yellow precipitate was collected, washed with water and dried in vacuo (2.0 mm Hg) for 2 days to give 0.04 g of the title compound. mp: 298°-300° C.; HRMS: calc'd: 487.0838; measured: 487.0831 ##STR69##
Reaction SMILES: [NH2-].[Na+].[C:3]1([CH2:13][C:14]#[N:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[N:16]1([CH2:22][CH2:23]Cl)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CCOCC.O>[C:3]1([CH:13]([CH2:23][CH2:22][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:14]#[N:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: ClCCN1CCCCC1
Reactant: N#CCc1cccc2ccccc12
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: N#CC(CCN1CCCCC1)c1cccc2ccccc12
Reaction time: 5 h

Procedure:
8.2 g of sodium amide are added in small quantities on a solution of 33.4 g of 1-naphthyl acetonitrile in 450 ml of anhydrous ether. The mixture is heated for 2 hours to reflux, then 29.5 g of 2-piperidino-1-chloroethane are added, a heating to reflux is repeated for 5 hours. The mixture is then cooled, poured in water, and the organic phase is extracted 3 times with 600 ml of hydrochloric acid at 10%. The aqueous phase is washed with ether and neutralized with soda at 30%. The decanting oil is extracted, washed with sodium chloride-saturated water and dried over magnesium sulphate. After evaporation of the solvent, the resulting oil is distilled under reduced pressure (vane pump).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][N:23]=1)[CH3:20]>>[CH2:19]([NH:21][C:22]1[N:23]=[CH:24][C:25]([NH:28][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:26][CH:27]=1)[CH3:20]
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: CCNc1ccc(N)cn1
Product: CCNc1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 16 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-ethylamino-pyridin-3-yl)-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N2-ethyl-pyridine-2,5-diamine. LCMS calcd for C18H15F3N4O2 (m/e) 376, obsd 377 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.C([O-])(=[O:28])C.[Na+]>C(O)(=O)C>[OH:28][C:2]1[N:7]=[N:6][C:5]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCC(CNc2ccc(Cl)nn2)CC1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(OCc1ccccc1)N1CCC(CNc2ccc(O)nn2)CC1
Temperature: 100 °C

Procedure:
Benzyl 4-{[(6-chloro-3-pyridazinyl)amino]methyl}-1-piperidinecarboxylate (EXAMPLE 22) (37 mg, 0.10 mmol) was dissolved in acetic acid (5 mL) with sodium acetate (82 mg, 1.00 mmol) and was heated to 100° C. for 18 h. The volatiles were removed under reduced pressure and the residue partitioned between sat. NaHCO3 and ethyl acetate. The organics were dried over Na2SO4, filtered and concentrated under reduced pressure, affording the title compound as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[OH:11].[Br:12]Br>C(Cl)(Cl)(Cl)Cl>[Br:12][C:8]1[C:3]([O:2][CH3:1])=[C:4]([OH:11])[C:5]([O:9][CH3:10])=[CH:6][CH:7]=1
Reactant: COc1cccc(OC)c1O
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(Br)c(OC)c1O
Reaction time: 2 h

Procedure:
To a stirring solution of 2,6-dimethoxy-phenol (2 g, 12.98 mmol) in carbon tetrachloride (70 mL) at −10° C. was added bromine (2 g, 12.98 mmol) in carbon tetrachloride and stirred for 2 h. The reaction mixture was diluted with carbon tetrachloride, washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 3-Bromo-2,6-dimethoxy-phenol as a mixture (2 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C@@H:12]([O:21][CH2:22][O:23][CH3:24])[CH2:11][CH:10]4[CH2:25]OS(CC3C=CC=CC=3)(=O)=O)[CH2:7][CH2:6][C:5]=2[CH:4]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C@@H:12]([O:21][CH2:22][O:23][CH3:24])[CH2:11][C@@H:10]4[CH3:25])[CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: COCO[C@H]1CC(COS(=O)(=O)Cc2ccccc2)[C@H]2[C@@H]3CCc4cc(OC)ccc4[C@H]3CC[C@]12C
Solvent: C1CCOC1
Product: COCO[C@H]1C[C@H](C)[C@H]2[C@@H]3CCc4cc(OC)ccc4[C@H]3CC[C@@]21C
Temperature: 65 °C
Yield: 97.1 %

Procedure:
A solution of 15.8 mg (0.0269 mmol) of 58 in anhydrous THF (500 μL) was stirred at rt as 108 μL of a 1 M solution of LiEt3BH in THF (0.108 mmol) was added and the reaction was stirred and heated at 65° C. for 5 h then quenched at rt with EtOH (1 mL). To the reaction mixture was added diglyme (2 mL), 48 mg (0.431 mmol) Et3NO and the reaction was stirred and heated at 150° C. for 1 h allowing the THF to evaporate. The reaction mixture was allowed to cool to rt, poured into H2O (50 mL) and extracted with EtOAc (3×, 50 mL). Combined organic extracts were washed with 10% Na2S2O5 (30 mL), H2O (30 mL), dried over Na2SO4 and concentrated in vacuo giving a colorless oil. Purification by flash chromatography on a 2×17 cm column of silica gel using 4:1 hexanes/EtOAc as eluent gave 9 mg (97%) of 59. Data for 59: TLC, T-1, Rf 0.73; 1H NMR (400 MHz, CDCl3) δ 0.86 (s, 3H, H-18), 0.90 (t, 1H, J=10.2 Hz, H-14), 1.12 (d, 3H, J=6.2 Hz, 15α-CH3), 3.38 (s, 3H, CH2OCH3), 3.64 (t, 1H, J=8.6 Hz, H-17α), 3.79 (s, 3H, ArOCH3), 4.65–4.67 (AB quartet, 2H, JAB=6.6 Hz, OCH2O), 6.62 (d, 1H, J=2.8 Hz, H-4), 6.72 (dd, 1H, J=8.6, 2.8 Hz, H-2), 7.22 (d, 1H, J=8.6 Hz, H-1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH2:10](P(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2)[CH2:11]CC.Cl>C1COCC1.[Cl-].[Zn+2].[Cl-].CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:10]#[CH:11])=[CH:3][CH:4]=1
Reactant: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Reactant: COc1ccc(Cl)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Product: C#Cc1ccc(OC)cc1
Temperature: 25 °C
Yield: 76 %

Procedure:
50 mmol of anhydrous zinc chloride (dissolved in 40 ml of THF) were added at 0° C to a suspension of 50 mmol of ethynyllithium-ethylenediamine complex in 40 ml of THF. After heating to RT for half an hour, the solution was again cooled to 0° C. and 40 mmol of 4-chloroanisole, 0.05 mol % of Pd(OAc)2 and 0.1 mol % of butyldiadamantylphosphine were added. The reaction mixture was stirred at 25 to 50° C. until conversion was complete. 2 M HCl solution was then added to the reaction solution. After extraction with ether, washing of the ether phase and distillation, 76% of p-methoxyphenylacetylene is obtained.
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].CCN(C(C)C)C(C)C.[N:23]1([C:29](=[O:31])[CH3:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(#N)C>[C:29]([N:23]1[CH2:28][CH2:27][N:26]([CH:2]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:25][CH2:24]1)(=[O:31])[CH3:30]
Reactant: CCOC(=O)C(Br)c1ccccc1
Reactant: CC(=O)N1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(c1ccccc1)N1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
Ethyl 2-bromo-2-phenylacetate (0.22 ml, 1.23 mmol) was dissolved in acetonitrile (4 ml) and DIPEA (0.28 ml, 1.60 mmol) and 1-(piperazin-1-yl)ethanone (0.21 g, 1.60 mmol) were sequentially added. The reaction was stirred at room temperature overnight. The solvent was evaporated and the residue was purified by flash chromatography (DCM/Acetone=9/1) to obtain ethyl 2-(4-acetylpiperazin-1-yl)-2-phenylacetate (341 mg, 95% yield) as a pale yellow oil.