Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:12]([OH:13])=[C:11]2[C:4]([C:5]([CH:7]=[CH:8][C:9]2=[O:10])=[O:6])=[C:3]([OH:14])[CH:2]=1.[OH-].[Na+].Cl.[C:18]([O:21][CH2:22][CH3:23])(=O)C>C(Cl)Cl.O.CCCCCC>[OH:14][C:3]1[CH:2]=[CH:1][C:12]([OH:13])=[C:11]2[C:4]=1[C:5](=[O:6])[C:7]1[CH:2]3[CH2:3][CH2:23][C:22]([O:21][CH3:18])([C:8]=1[C:9]2=[O:10])[CH:12]=[CH:1]3
Reactant: CCOC(C)=O
Reactant: O=C1C=CC(=O)c2c(O)ccc(O)c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CCCCCC
Product: COC12C=CC(CC1)C1=C2C(=O)c2c(O)ccc(O)c2C1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 83 %

Procedure:
20.9 g (0.11 mol) of naphthazarin (8) and 28.4 g of 1-methoxy-1,3-chclohexadiene (19) (technical grade, 70%, 0.177 mol) were refluxed in 330 ml of methylene chloride (temperature oil bath 50° C.). The course of the reaction was followed by means of TLC (ethyl acetate:n-hexane, 2:5). After evaporation 330 ml of pentane was added to the residue and the solution was stirred for 5 minutes. The solution was cooled to 0° C. and filtrated. The filtrate was rinsed with 2×50 ml of petroleum ether. The yield of the yellow/brown product was 30.0 g (91%). The crystals were taken up in a solution of 22.0 g (0.55 mol) of caustic soda in 825 ml of water. During half an hour air was passed through the solution while the solution was stirred. The colour of the solution changed from green to blue. The course of the reaction was followed by means of TLC (ethyl acetate:n-hexane, 2:5). After the reaction 46.2 ml of concentrated HCl (37%) was added to the solution. The product precipitated as a red solid which was filtered off. This compound was dried on a film evaporator (2 mm Hg) and in a vacuum dessicator (over P2O5) during at least one night. The yield of the red compound (20) was 27.0 g (91%). The overall yield was 83%. Melting point 239°-241° C. 1H-NMR (90 MHz, CDCl3, TMS internal standard): δ=1.39-1.92 ppm (4H, m, CH2 --CH2), δ=3,69 ppm (3H, s, OMe), δ=4,53 ppm (1H, m, H4), δ=6.40 ppm (1H, dd, J=5.6 Hz and J=8 Hz), δ=6.64 ppm (1H, dd, J=8 Hz and J=1.5 Hz), δ=7.12 ppm (2H, s, ArH), δ=12.60 ppm (1H, s, ArOH), δ=13.06 ppm (1H, s, ArOH).
Reaction SMILES: Br[C:2]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]2[O:6][CH2:7][C:8]([CH3:10])([CH3:9])[C:4]=2[CH:3]=1.C([Li])CCC.C(=O)=O>C1COCC1>[C:13]([C:11]1[C:5]2[O:6][CH2:7][C:8]([CH3:10])([CH3:9])[C:4]=2[CH:3]=[CH:2][CH:12]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1cc(Br)cc2c1OCC2(C)C
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1cccc2c1OCC2(C)C
Temperature: -20 °C
Reaction time: 1 h

Procedure:
A solution of 5-bromo-7-tert-butyl-3,3-dimethyl-2,3-dihydrobenzo[b]furan (12.4 g, 44.0 mmol) in freshly distilled THF (44 mL) is cooled to -78° C. under Ar, and a solution of n-butyl lithium (2.5M in hexane; 15.0 mL, 37.5 mmol) is added dropwise via syringe. A slight exotherm is apparent, and a milky suspension results. The suspension is allowed to warm to -20° C., and then is cooled to -50° C. To the resulting suspension is added a large excess of freshly pulverized solid CO2. The resulting mixture is allowed to warm to 0° C. After 1 h, the mixture is partitioned between 0.1N NaOH (40 mL) and hexane (3×30 mL). The hexane layer is dried (MgSO4), filtered and evaporated to yield 7-tert-butyl-3,3-dimethyl-2,3-dihydrobenzo[b]furan. The aqueous layer is acidified to pH 2 with 1N HCl, and is extracted with Et2O (3×20 mL). The Et2O layers are combined, dried (MgSO4), filtered and evaporated to provide the desired carboxylic acid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].C1OCCOCCOCCOCCOCCOC1.[CH3:36][O:37][C:38](=[O:53])[C:39]1[CH:44]=[CH:43][C:42]([CH2:45]Br)=[CH:41][C:40]=1[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>COCCOC.C1(C)C=CC=CC=1.O>[CH3:36][O:37][C:38](=[O:53])[C:39]1[CH:44]=[CH:43][C:42]([CH2:45][O:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:41][C:40]=1[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: Oc1cccnc1
Reactant: COC(=O)c1ccc(CBr)cc1-c1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1ccc(COc2cccnc2)cc1-c1ccccc1
Reaction time: 0.25 h
Yield: 48.4 %

Procedure:
To a mechanically-stirred 0° C. solution of 3-hydroxypyridine (4.4 g, 46 mmol) in DME (20 mL) was added potassium hexamethyldisilazide (0.5 M in toluene, 88.5 mL, 44 mmol) and the mixture was stirred for 15 minutes. 18-Crown-6 (1.46 g, 5.5 mmol) and a solution of 4-bromomethyl-2-phenylbenzoic acid methyl ester (6.8 g, 22 mmol) in toluene (25 mL) was added and the reaction mixture was vigorously stirred overnight. The reaction mixture was poured into 200 mL of water and the layers were separated. The aqueous phase was extracted with 2 portions of ethyl acetate and the combined organic phases were extracted with water and brine, dried (MgSO4), filtered and concentrated. The resulting oil was purified by flash chromatography (65% ethyl acetate-hexane) to give 4-(3-pyridyloxymethyl)-2-phenylbenzoic acid methyl ester (3.4 g).
Reaction SMILES: C1(N)CCC1.[Cl-:6].[N+](C1C=[C:14]([N+]([O-])=O)[CH:13]=[CH:12][C:11]=1[N+:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=1)([O-])=O>C(O)CCC>[Cl-:6].[CH:11]1([N+:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=2)[CH2:12][CH2:13][CH2:14]1
Reactant: Cc1ccc[n+](-c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])c1
Agent: NC1CCC1
Agent: [Cl-]
Solvent: CCCCO
Product: Cc1ccc[n+](C2CCC2)c1
Yield: 56.2 %

Procedure:
Cyclobutylamine (2.3 g, 32 mmol) was added to 1-(2,4-dinitrophenyl)-3-methylpyridinium chloride (J. Org. Chem. 1997, 62, 729-33) (8.0 g, 31 mmol) in n-butanol (120 mL) at 20° C. and the deep red solution was refluxed overnight. Concentration under vacuum left a residue that was treated with water (20 mL) and the precipitate was removed by filtration, and the operation was repeated twice. The combined aqueous phase was basified with concentrated ammonia (2 mL) and washed twice with EtOAc. Evaporation of the water to gave the title compound (3.2 g, 70%) as a brown oil. LCMS: 148 M+
Reaction SMILES: Br[CH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([Br:11])[C:5]=2[O:4][C:3]1([CH3:13])[CH3:12].[C:14]([O-:17])(=[O:16])[CH3:15].[K+]>CN(C)C=O>[C:14]([O:17][CH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([Br:11])[C:5]=2[O:4][C:3]1([CH3:13])[CH3:12])(=[O:16])[CH3:15]
Reactant: CC(=O)[O-]
Reactant: CC1(C)Oc2c(Br)cccc2C1Br
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OC1c2cccc(Br)c2OC1(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 7.6 grams (0.025 mole) of 3,7-dibromo-2,3-dihydro-2,2-dimethylbenzofuran and 11.3 grams (0.115 mole) of powdered potassium acetate in 125 mL of dry N,N-dimethylformamide is stirred at ambient temperature for about 24 hours. After this time, the reaction mixture is concentrated under reduced pressure to a residue. The residue is poured into about 350 mL of water and the mixture is extracted with diethyl ether. The ether extract is concentrated under reduced pressure, yielding 3-acetoxy-7-bromo-2,3-dihydro-2,2-dimethylbenzofuran.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:9]2[C:10]([Cl:15])=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[S:7][CH:6]=1.[CH3:17][N:18]1[C:22]([CH2:23]O)=[CH:21][C:20]([C:25]([F:28])([F:27])[F:26])=[N:19]1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.C(P(CCCC)CCCC)CCC>C1COCC1>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:9]2[C:10]([Cl:15])=[CH:11][C:12]([O:14][CH2:23][C:22]3[N:18]([CH3:17])[N:19]=[C:20]([C:25]([F:28])([F:26])[F:27])[CH:21]=3)=[CH:13][C:8]=2[S:7][CH:6]=1
Reactant: COC(=O)Cc1csc2cc(O)cc(Cl)c12
Reactant: Cn1nc(C(F)(F)F)cc1CO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)Cc1csc2cc(OCc3cc(C(F)(F)F)nn3C)cc(Cl)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.5 %

Procedure:
To a mixture of methyl(4-chloro-6-hydroxy-1-benzothiophen-3-yl)acetate (750 mg) and THF (dry) (10 mL) were added (1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanol (632 mg), ADDP (958 mg) and tri-n-butylphosphine (1.442 mL) at room temperature. The mixture was stirred at room temperature for 16 h. The insoluble material was removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane). The product was crystallized from EtOAc-hexane to give the title compound (1132 mg).
Reaction SMILES: S(Cl)(Cl)=O.[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH2:10][C:11]([OH:13])=[O:12].[C:14](=O)(O)[O-].[Na+]>CO>[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH2:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: O=C([O-])O
Reactant: O=C(O)Cc1cccs1
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)Cc1cccs1
Yield: 98 %

Procedure:
Thionyl chloride (10.20 ml, 140.7 mmol) was added to a solution of thiophen-2-yl-acetic acid (10.0 g, 70.3 mmol) in MeOH (100 ml) at 0° C. The reaction mixture was heated to reflux for 18 h, the volatiles were evaporated and the crude reaction mixture was basified with aqueous sodium bicarbonate solution, extracted with DCM, washed with brine and dried over anhydrous sodium sulfate. After filtration the organic solvent was evaporated and dried to afford 10.75 g (98%) of methyl 2-(thiophen-2-yl)acetate as color less liquid.
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([C:18]2[CH:19]=[N:20][C:21]([OH:24])=[N:22][CH:23]=2)=[O:17])[CH2:9][C@@H:10]([OH:14])[C:11](O)=[O:12])=[CH:3][CH:2]=1.C[N:32](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N.CCN(C(C)C)C(C)C>CN(C=O)C.O1CCOCC1>[C:1]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([C:18]2[CH:23]=[N:22][C:21]([OH:24])=[N:20][CH:19]=2)=[O:17])[CH2:9][C@H:10]([C:11](=[O:12])[NH2:32])[OH:14])=[CH:3][CH:2]=1
Reactant: O=C(N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@H](O)C(=O)O)c1cnc(O)nc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)[C@H](O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnc(O)nc1
Reaction time: 0.03 h
Yield: 13.8 %

Procedure:
(2R,4R)-5-Biphenyl-4-yl-2-hydroxy-4-[(2-hydroxypyrimidine-5-carbonyl)amino]pentanoic acid (14.5 mg, 35.6 μmol, 1.0 eq.) and HATU (13.5 mg, 35.6 μmol, 1.0 eq.) were combined in DMF (5 mL), and the resulting mixture was stirred for 2 minutes. 0.5 M ammonia in dioxane was added, followed by DIPEA (12.4 μL). The resulting mixture was stirred for 1 hour then dried under vacuum. The product was purified using reverse phase chromatography (10-70% MeCN/H2O; 0.05% TFA over 70 minutes) to yield the title compound (2 mg). MS m/z [M+H]+ calc'd for C22H22N4O4, 407.16. found 407.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH2:5][OH:6].[CH3:11][S:12](Cl)(=[O:14])=[O:13].C(N(CC)CC)C>ClCCl>[CH3:11][S:12]([O:6][CH2:5][C:4]1[CH:3]=[C:2]([Cl:1])[CH:9]=[C:8]([Cl:10])[CH:7]=1)(=[O:14])=[O:13]
Reactant: OCc1cc(Cl)cc(Cl)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cc(Cl)cc(Cl)c1

Procedure:
To a solution of 3.5 g of 3,5-dichlorobenzyl alcohol (Aldrich) in 75 mL of dichloromethane at 0° C. was added 1.8 mL of methane sulfonylchloride followed by 3.5 mL of triethylamine added dropwise. After 2 hours the solution was diluted to 150 mL with dichloromethane, washed with 3N HCl, saturated aqueous NaHCO3 dried with Na2SO4 and the solvents removed to yield the desired 3,5-dichlorobenzyl methanesulfonate as a yellow oil that was used without purification.
Reaction SMILES: C1(C2C=CC(C[NH:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15](F)=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=3)=CC=2)CC1.[CH3:25][O:26][C:27]1([C:31]2[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=2)[CH2:30][CH2:29][CH2:28]1.FC(F)(F)C1C=C(CCN)C=CC=1.[BH4-].[Na+]>>[CH3:25][O:26][C:27]1([C:31]2[CH:38]=[CH:37][C:34]([CH2:35][NH:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:19]([F:20])([F:21])[F:22])[CH:13]=3)=[CH:33][CH:32]=2)[CH2:30][CH2:29][CH2:28]1
Reactant: COC1(c2ccc(C=O)cc2)CCC1
Reactant: Fc1ccc(CCNCc2ccc(C3CC3)cc2)cc1C(F)(F)F
Agent: NCCc1cccc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Product: COC1(c2ccc(CNCCc3cccc(C(F)(F)F)c3)cc2)CCC1
Yield: 77 %

Procedure:
The title compound was synthesized in analogy to (4-cyclopropylbenzyl)-[2-(4-fluoro-3-trifluoromethylphenyl)-ethyl]-amine (described in example S53) using 4-(1-methoxycyclobutyl)-benzaldehyde (76 mg, 0.40 mmol), 2-(3-trifluoromethylphenyl)-ethylamine (76 mg, 0.40 mmol) and sodium borohydride (17 mg, 0.44 mmol). The isolated residue was purified by flash column chromatography (2%-5% MeOH in EtOAc) to give the desired product (112 mg, 77%) as a colorless oil. MS (ISP) 364.3 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:26][N:25]([C:27]([CH3:31])([CH3:30])[C:28]#[N:29])[CH2:24]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C(=O)([O-])[O-:33].[K+].[K+].OO.O>CS(C)=O>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:26][N:25]([C:27]([CH3:31])([CH3:30])[C:28]([NH2:29])=[O:33])[CH2:24]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C(C)(C)C#N)C3)ccc1-2
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C(C)(C)C(N)=O)C3)ccc1-2
Temperature: 45 °C
Yield: 49.7 %

Procedure:
A solution of 2-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-2-methyl-propionitrile (0.26 g, 0.6 mmol) in DMSO (5 mL) was treated with potassium carbonate (16 mg, 0.12 mmol) followed by hydrogen peroxide (30% aq., 0.33 mL) and the mixture was heated at 45° C. for 18 hours then at 50° C. for a few more hours. Further hydrogen peroxide (33 mL, 30% aq.) was added and the mixture heated at 50° C. for 18 hours. After cooling, water was added and the mixture was extracted with EtOAc (×5). The combined organic extracts were dried (Na2SO4), and concentrated in vacuo and the residue purified by flash chromatography (SiO2, first time with 0-10% MeOH in EtOAc then second time with 0-5% MeOH in DCM). Further purification was by reverse-phase preparative HPLC (Gemini C18 column, gradient 30-40% MeOH in H2O+0.1% HCO2H). A solution of the product in a mixture of chloroform and DCM was treated with 0.2M HCl in ether (0.32 mL) and then concentrated in vacuo to give 446 (27 mg, 9%). LCMS: RT=7.41 min, [M+H]+=453. 1H NMR δ (ppm) (DMSO-d6): 10.79 (1 H, s), 8.34-8.28 (1 H, m), 8.06 (1 H, s), 7.82 (1 H, d, J=17.45 Hz), 7.65 (1H, d, J=4.94 Hz), 7.27-7.16 (1 H, m), 7.07 (1 H, d, J=1.80 Hz), 5.80-5.72 (1 H, m), 4.47 (1 H, td, J=10.76, 4.67 Hz), 4.37-4.26 (3 H, m), 4.20-3.94 (3H, m), 3.41 (2 H, q, J=4.96 Hz), 1.55-1.45 (12 H, m)
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](F)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[NH2:19][CH:20]1[CH2:23][CH2:22][CH:21]1[NH2:24]>N1C=CC=CC=1>[NH2:19][CH:20]1[CH2:23][CH2:22][CH:21]1[NH:24][C:10]1[CH:11]=[C:12]2[C:7]([C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4][N:3]2[CH2:1][CH3:2])=[CH:8][C:9]=1[F:14]
Reactant: NC1CCC1N
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(NC3CCC3N)cc21

Procedure:
A mixture of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid and 1,2 diaminocyclobutane [The American Chemical Society, Vol. 64, p. 2696 (1942)] in pyridine is reacted as described in Example 1 giving the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[C:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)=[C:11]([CH:28]=[O:29])[CH:10]=1)[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)=[C:11]([CH:28]=[O:29])[CH:10]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)CCCOc1ccc(C#CCCCCOC2CCCCO2)c(C=O)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCOc1ccc(CCCCCCOC2CCCCO2)c(C=O)c1

Procedure:
A 1.2 g (2.88 mmol) sample of rac-4-[3-formyl-4-[6-[(tetrahydro-2H-pyran-2-yl)oxy]-1-hexyn-1-yl]phenoxy]butanoic acid ethyl ester from example 49 was hydrogenated in ethyl acetate using 80 mg of 10% palladium on carbon, at room temperature, under 1 atmosphere of hydrogen. When the reduction was complete, the catalyst was filtered with suction and the filtrate concentrated under reduced pressure giving rac-4-[3-formyl-4-[6-[(tetrahydro-2H-pyran-2-yl)oxy]hexyl]phenoxy]butanoic acid ethyl ester as a pale-yellow oil, in quantitative yield.
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Br.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:16][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:8]=[CH:9]2
Reactant: BrCCCCCCBr
Reactant: Oc1ccc2c(ccn2-c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: BrCCCCCCOc1ccc2c(ccn2-c2ccccc2)c1
Yield: 52.4 %

Procedure:
864 mg (4.1 mmol) 1-Phenyl-1H-indol-5-ol in 10 ml acetone were treated with 2.44 g (10 mmol) 1,6-dibromohexane and 2.8 g (20 mmol) K2CO3 at reflux for 4 h. The solution was filtered, concentrated and purified by column chromatography on silica gel with hexane/EtOAc 39:1 to yield 800 mg (52%) 5-(6-Bromo-hexyloxy)-1-phenyl-1H-indole as colorless oil, MS: 371 (M, 1Br).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[Cl:7][C:8]1[S:12][C:11]([S:13](Cl)(=[O:15])=[O:14])=[CH:10][CH:9]=1.C(N(CC)CC)C>C1COCC1>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][S:13]([C:11]1[S:12][C:8]([Cl:7])=[CH:9][CH:10]=1)(=[O:15])=[O:14]
Reactant: CN(C)CCN
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)CCNS(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.3 %

Procedure:
To a stirred solution of 2-dimethylamino-ethylamine (1.61 g, 13.8 mmol) in THF (20 mL) was added at 0° C. (ice water bath) commercially available 5-chloro-thiophene-2-sulfonyl chloride (1.0 g, 4.61 mmol) and triethylamine (0.71 mL, 5.07 mmol). The reaction mixture was stirred at room temperature for 16 h and evaporated. The crude product was further purified by flash chromatography (ethyl acetate/MeOH) to yield the title compound (1.23 g, 99%) as a light yellow oil. MS (ISP) 269.0 [(M+H)+].
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[C:6]([C:8]([O:10]CC)=[O:9])[N:5]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:4]=1.[CH3:21][O-:22].[Na+]>CO.O>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([N:5]2[C:6]([C:8]([OH:10])=[O:9])=[CH:7][C:3]([CH2:2][O:22][CH3:21])=[N:4]2)=[CH:18][CH:17]=1
Reactant: C[O-]
Reactant: CCOC(=O)c1cc(CBr)nn1-c1ccc(OC)cc1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCc1cc(C(=O)O)n(-c2ccc(OC)cc2)n1
Yield: 61 %

Procedure:
Ethyl 3-(bromomethyl)-1-(4-methoxyphenyl)-1H-pyrazole-5-carboxylate (0.50 g, 1.47 mmol) is dissolved in 12 mL of 0.5 M NaOMe in methanol and heated to reflux for 14 hours. The reaction mixture was cooled and reduced to 1/10 original volume. The reaction mixture was dissolved in 20 mL of water and extracted with EtOAc. The aqueous mixture was acidified with 1N HCl and extracted with EtOAc to give 0.236 g (61%) of desired product. A mixture of ethyl and methyl esters (˜0.05 g) was found in the first EtOAc extract. 1H NMR (CDCl3): δ7.32 (d, J=8.8, 2H); 7.11 (s, 1H); 6.94 (d, J=8.8, 2H); 4.54 (s, 2H); 3.85 (s, 3H); 3.44 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([OH:19])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22].[CH2:36](Br)[CH2:37][CH2:38][CH3:39]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:19][CH2:36][CH2:37][CH2:38][CH3:39])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22]
Reactant: COc1ccc(CC2c3c(OC)ccc(O)c3CCN2CC(=O)NCc2ccccn2)cc1OC
Reactant: CCCCBr
Product: CCCCOc1ccc(OC)c2c1CCN(CC(=O)NCc1ccccn1)C2Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-5-hydroxy-8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide with butyl bromide
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25]([NH:28][CH3:29])[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]>C1COCC1>[C:1]([N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25]([NH:28][CH2:29][CH2:23][N:30]([CH3:33])[CH3:31])[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[CH:7]=[N:6]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CNc1ncc2cc(-c3cc(NC(=O)Nc4cnn(C(C)(C)C)c4)c(F)cc3C)c(=O)n(C)c2n1
Solvent: C1CCOC1
Product: Cc1cc(F)c(NC(=O)Nc2cnn(C(C)(C)C)c2)cc1-c1cc2cnc(NCCN(C)C)nc2n(C)c1=O
Reaction time: 4 h

Procedure:
To a solution of 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea from Example 109 (0.075 g, 0.15 mmol) in THF (1 mL) was added, N1-dimethylethane-1,2-diamine (0.04 g, 0.44 mmol) and stirring continued for 4 h at RT. Solvent was removed under vacuum and crude product was purified by silica gel chromatography to provide 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(5-(2-(2-(dimethylamino)ethylamino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluoro-4-methylphenyl)urea as the hydrochloride salt (0.058, 74% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.61 (brs, 1H), 8.67-8.64 (m, 2H), 8.42 (s, 1H), 7.95-7.88 (m, 2H), 7.71 (s, 1H), 7.68 (s, 1H), 7.32 (s, 1H), 7.07 (d, J=12.4 Hz, 1H), 3.68-3.65 (m, 2H), 3.57 (s, 3H), 3.28-3.26 (m, 2H), 2.79 (s, 3H), 2.78 (s, 3H), 2.00 (s, 3H), 1.40 (s, 9H); MS (ESI) m/z: 536.2 (M+H+).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[Cu](C#N)[C:17]#[N:18]>>[Si:9]([O:8][CH2:7][C:5]1[S:6][C:2]([C:17]#[N:18])=[CH:3][CH:4]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: N#C[Cu]C#N
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(Br)s1
Product: CC(C)(C)[Si](C)(C)OCc1ccc(C#N)s1

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 3 (3a) using [(5-bromo-2-thienyl)methoxy]t-butyldimethylsilane (2.4 g, 7.8 mmol) [reference literature: Tetrahedron, vol. 39, 2531 (1983)] and copper cyanide (1.3 g, 14 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:50 to 1:7) as the eluent to afford the title compound (1.1 g) in a yield of 56% as a white crystalline solid.