Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.CN.Cl.[CH3:23][N:24](C)CCCC(N=C=N)C>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:9][C:10]([NH:24][CH3:23])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(O)CC(c1ccc(Cl)cc1)c1ccc(Br)cc1
Reactant: CC(CCCN(C)C)N=C=N
Agent: CN
Agent: Cl
Solvent: ClCCl
Product: CNC(=O)CC(c1ccc(Cl)cc1)c1ccc(Br)cc1
Reaction time: 16 h

Procedure:
A mixture of 3-(4-bromo-phenyl)-3-(4-chloro-phenyl)-propionic acid (0.25 g, 0.74 mmol) and 1-hydroxybenatriazole (0.12 g, 0.88 mmol) in dichloromethane (3 ml) was stirred for 15 minutes before addition of methylamine (40% solution in water, 0.110, 1.47 mmol) and 1-(3-dimethylaminopropyl)-ethylcarbodiimide hydrochloride (0.17 g, 0.88 mmol). The reaction mixture was stirred for 16 hours, solvent removed under reduced pressure and the residue partitioned between ethyl acetate and 1N HCl. The organic layer was separated, washed with saturated sodium hydrogen carbonate, brine, dried (MgSO4), filtered and concentrated to yield the title compound which was used in the next step without further purification. LC/MS: (PS-A2) Rt 3.20 [M+H]+ 353.95.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[C:4]#[C:5][CH3:6].[OH:8][CH:9]([CH2:12][OH:13])[CH2:10][NH2:11]>C(O)C>[OH:8][CH:9]([CH2:12][OH:13])[CH2:10][NH:11][C:5]([CH3:6])=[CH:4][C:3]([O:2][CH3:1])=[O:7]
Reactant: NCC(O)CO
Reactant: CC#CC(=O)OC
Solvent: CCO
Product: COC(=O)C=C(C)NCC(O)CO

Procedure:
To 5.0 g (0.051 m) methyl-2-butynoate in 25 ml absolute ethanol is added 5.0 g (0.055 m), 2,3-dihydroxypropylamine. This solution is heated at 75°-80° for 18 hours and the solvent is then removed at reduced pressure. The residue oil is chromatographed on silica gel, eluting with 10% methanol/chloroform to afford the desired product as a white solid. m.p. 109°-111°. The yield is 5.6 g (59%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11]O)=[CH:5][CH:4]=1.P(Br)(Br)[Br:14]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][Br:14])=[CH:5][CH:4]=1
Reactant: BrP(Br)Br
Reactant: COc1ccc(CCCO)cc1
Product: COc1ccc(CCCBr)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.1 %

Procedure:
To a solution of 3-(p-methoxyphenyl)-1-propanol (16.6 g; 0.1 mol) in 250 mL of tolune, cooled to 0° C., was added dropwise 26 mL of phosphorus tribromide (0.27 mol). Following completion of the addition the reaction was stirred at room temperature for 1 hour, then refluxed for an additional hour. The reaction was cooled and poured onto ice, the layers were separated, and the organic phase washed with saturated sodium bicarbonate (3×) and brine (3×). The crude material obtained upon drying and evaporation of the solvent was chromatographed, eluting with 10%, EtOAc/hexane, to obtain 14 g (61%) of 3-(p-methoxyphenyl)-1-propylbromide.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:37](Cl)(=[O:46])[CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:40]1([CH2:39][CH2:38][C:37]([N:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:14][CH:13]=2)[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)=[CH:19][CH:18]=2)=[O:46])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: c1cc(OC2CCCCO2)ccc1CNc1ccc(OCCN2CCCC2)cc1
Reactant: O=C(Cl)CCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCc1ccccc1)N(Cc1ccc(OC2CCCCO2)cc1)c1ccc(OCCN2CCCC2)cc1
Reaction time: 1 h

Procedure:
To a solution of [4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-[4-(tetrahydro-pyran-2-yloxy)-benzyl]-amine (0.125 g, 0.34 mmol) and triethylamine (0.18 mL, 1.36 mmol) in 2 mL methylene chloride was added hydrocinnamoyl chloride (0.152 mL, 1.02 mmol), dropwise. The reaction mixture was stirred for 1 hr. at room temperature. Saturated aqueous sodium bicarbonate was added and the layers were separated. The aqueous layer was washed with an additional 2 mL of methylene chloride. The combined organic layers were concentrated to give the title compound of Step A. MS 529.2 (M+1)+
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1([OH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O-]CCCC.[F:19][C:20]([F:34])([F:33])[C:21]1[CH:22]=[C:23]([N:27]2[C:31](Cl)=[N:30][N:29]=[CH:28]2)[CH:24]=[CH:25][CH:26]=1>CN(C)C=O>[F:33][C:20]([F:19])([F:34])[C:21]1[CH:22]=[C:23]([N:27]2[C:28]([O:13][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:29][N:30]=[CH:31]2)[CH:24]=[CH:25][CH:26]=1
Reactant: FC(F)(F)c1cccc(-n2cnnc2Cl)c1
Reactant: Oc1ccccc1
Agent: CC(C)(C)[O-]
Agent: CCCC[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(-n2cnnc2Oc2ccccc2)c1
Temperature: 75 °C

Procedure:
0.8 g of potassium tert-butoxide was added to a solution of 0.53 g of phenol in 10 ml of dry dimethyl formamide. When all the butoxide had dissolved, a solution of 1.4 g of 25B in 10 ml of dry dimethylformamide (10 ml) was added and the stirred mixture was heated to 75° C. for 90 minutes. The reaction mixture was poured into a large excess of ice-water, the solid product filtered off and recrystallized from hexane/ethyl acetate to give 25, as a solid, m.p.: 83°-85° C.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][C:10]([CH2:13]O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[N:1]1([C:7]2[N:12]=[CH:11][C:10]([CH2:13][N:19]3[C:15](=[O:25])[C:16]4[C:17](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:18]3=[O:20])=[CH:9][CH:8]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCc1ccc(N2CCOCC2)nc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(N2CCOCC2)nc1
Temperature: 25 °C
Yield: 71.3 %

Procedure:
To a THF (200 mL) solution of (6-(morpholin-4-yl)pyridine-3-yl)methanol (CA 388088-73-1) (3.2 g), phthalimide (3.64 g) and triphenylphosphine (6.49 g), diisopropylazodicarboxylate (5.43 mL) was added at 0° C. for 5 minutes. The reaction solution was concentrated under reduced pressure after 12-hour stirring at room temperature. 3.8 g of the title compound was obtained by the residue was purified by silica gel chromatography (heptane-ethyl acetate system).
Reaction SMILES: [CH2:1]([Li])CCC.[CH2:6]([Si:8]([CH2:18][CH3:19])([CH2:16][CH3:17])[C:9]1[O:10][CH:11]=[C:12]([CH:14]=O)[CH:13]=1)[CH3:7]>CCCCCC.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:6]([Si:8]([CH2:18][CH3:19])([CH2:16][CH3:17])[C:9]1[O:10][CH:11]=[C:12]([CH:14]=[CH2:1])[CH:13]=1)[CH3:7]
Reactant: [Li]CCCC
Reactant: CC[Si](CC)(CC)c1cc(C=O)co1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=Cc1coc([Si](CC)(CC)CC)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
n-Butyl lithium (a 2.5 M solution in hexane; 4.4 ml, 11.0 mmol) was added dropwise to a suspension of methyltriphenylphosphonium bromide (3.93 g, 11 mmol) in THF (40 ml) at 0 degrees C. under argon. After 2 hours stirring at 0 degrees C., a solution of 2-triethylsilyl-4-furaldehyde (1.54 g, 7.33 mmol) in THF (2 ml) was added. Stirring was continued at room temperature for 14 hours and the mixture was quenched with methanol/water 40 ml (1:1). Extraction (pentane) and evaporation of the dried (magnesium sulfate) extracts gave a residue, which was purified by flash chromatography on silica using pentane to give the titled furan. Rf (pentane) 0.75.
Reaction SMILES: [O:1]1CCCC1.[CH3:6][CH:7]([CH3:16])[SiH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9].[H][H]>[Pd].O>[CH3:6][CH:7]([CH3:16])[Si:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:9])[OH:1]
Reactant: [H][H]
Reactant: C1CCOC1
Reactant: CC(C)[SiH](C)c1ccccc1
Agent: [Pd]
Solvent: O
Product: CC(C)[Si](C)(O)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
All the dehydrated tetrahydrofuran solution containing dimethylphenyldimethylsilane was placed in a 1-liter flask equipped with an Allihn condenser, thermometer, and stirrer, and 20 ml of water deionized by ion exchange and 0.3 g of a 5 wt % palladium-on-active carbon catalyst (the quantity of metallic palladium: 0.023 wt % of dimethylphenyldimethylsilane) were added with stirring at room temperature: 23° C. Then, hydrogen gas began evolving immediately. Measurement with a wet type of gas meter attached to the outlet of the Allihn condenser indicated that 9.75 l (0.394 mole) at 23° C. of hydrogen gas evolved until the evolution ceased 2.5 hours after the initiation of reaction. The reaction product mixture was filtered to remove the palladium catalyst, and also the lower aqueous layer was removed, giving a tetrahydrofuran solution of dimethylphenyldimethylhydroxysilane.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([CH:23]([CH3:25])[CH3:24])[CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C(C1C=CC=CC=1B1OC(C)(C)C(C)(C)O1)(C)C>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([CH:23]([CH3:25])[CH3:24])[CH:20]=[C:21]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1B(O)O
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C(C)C)cc(Br)c3O2)cc1
Agent: CC(C)c1ccccc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C(C)C)cc(-c4ccccc4)c3O2)cc1
Yield: 46 %

Procedure:
To a solution of 4-isopropylphenol (13.38 g, 98.0 mmol) with N-bromosuccinimide (17.5 g, 98 mmol) generally according to the procedure described for Example 305 afforded 13.78 g (65%) of 2-bromo-4-isopropylphenol. Treatment of 2-bromo-4-isopropylphenol (13.74 g, 41.0 mmol) with potassium carbonate (22.0 g, 160 mmol) and allyl bromide (9.23 g, 76.8 mmol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 2-allyl-6-bromo-4-isopropylphenol. Treatment of 2-allyl-6-bromo-4-isopropylphenol (6.85 g, 27.0 mmol) with 3-chloroperoxybenzoic acid (7.72 g, 27.0 mmol, 77%) followed by potassium carbonate (9.3 g, 67.5.0 mmol) generally according to the procedure described for Intermediate 9 afforded 1.12 g, (17%) of (±)-(7-bromo-5-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methanol. Treatment of (±)-(7-bromo-5-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methanol (1.12 g, 4.6 mmol) with p-toluenesulfonyl chloride (1.32 g, 6.9 mmol) generally according to the procedure described for Intermediate 10 gave 1.90 g (97%) of (±)-(7-bromo-5-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a colorless oil. Treatment of (±)-(7-bromo-5-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.4 g, 0.94 mmol) and 2-methylphenylboronic acid (0.38 g, 2.82 mmol) generally according to the procedure described for Intermediate 35 afforded 0.19 g, (46%) of (5-isopropyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (0.141 g, 2.17 mmol) generally according to the procedure described for Intermediate 98 afforded 0.11 g (83%) of (±)-2-(azidomethyl)-5-isopropyl-7-phenyl-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-5-isopropyl-7-phenyl-2,3-dihydro-1-benzofuran with polymer-supported triphenylphosphine (0.188 g, 0.716 mmol) according to the procedure described in Example 154 afforded 0.055 g (48%) of (±)-[(5-isopropyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl]amine as a white solid, hydrochloride salt. mp 221-222° C. (dec).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([N:20]([CH3:25])[S:21]([CH3:24])(=[O:23])=[O:22])[CH:19]=1)[C:5]([NH:7][C@@H:8]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[CH3:9])=[O:6].[CH3:26][N:27](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[C:26]([C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([N:20]([CH3:25])[S:21]([CH3:24])(=[O:23])=[O:22])[CH:19]=1)[C:5]([NH:7][C@@H:8]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[CH3:9])=[O:6])#[N:27]
Reactant: CN(C)C=O
Reactant: C[C@@H](NC(=O)c1cc(Br)cc(N(C)S(C)(=O)=O)c1)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: C[C@@H](NC(=O)c1cc(C#N)cc(N(C)S(C)(=O)=O)c1)c1ccc(F)cc1

Procedure:
To a solution of 3-bromo-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[methyl(methylsulfonyl)amino]benzamide (Intermediate X) (0.033 g, 0.077 mmol) in 0.80 mL degassed DMF (degassed by bubbling a stream of argon through solvent for 5 min) was added Zn(CN)2 (0.011 g, 0.092 mmol) and Pd(PPh3)4 (0.009 g, 0.008 mmol). The reaction vessel was purged thoroughly with argon, then sealed and microwaved at 180° C. for 30 min. The reaction was diluted with EtOAc, and the organics were washed with 3M aqueous LiCl. The aqueous washed with fresh EtOAc (2×), the combined organics were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (5->75% EtOAc/hexanes) to afford 3-cyano-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[methyl(methylsulfonyl)amino]benzamide as a white foam. 1H NMR (CDCl3, 400 MHz) δ 8.04 (t, J=2.0 Hz, 1H), 7.91 (t, J=1.3 Hz, 1H), 7.78 (t, J=1.5 Hz, 1H), 7.36-7.7.31 (m, 2H), 7.05-7.00 (m, 2H), 6.67 (d, J=7.5 Hz, 1H), 5.25 (q, J=7.1 Hz, 1H), 3.34 (s, 3H), 2.87 (s, 3H), 1.59 (d, J=7.0 Hz, 3H). LCMS [M+H]+=376.
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[CH:7]=[N:8][N:9]([C:11]2([C:14](=[NH:18])OCC)[CH2:13][CH2:12]2)[CH:10]=1.[S].C(N(CC)CC)C.Cl.Cl.[NH2:29][C:30]1[CH:31]=[CH:32][C:33]([N:37]2[CH2:42][CH2:41][CH2:40][C@@H:39]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:38]2)=[N:34][C:35]=1N>C(O)C>[Cl:5][C:6]1[CH:7]=[N:8][N:9]([C:11]2([C:14]3[NH:18][C:35]4=[N:34][C:33]([N:37]5[CH2:42][CH2:41][CH2:40][C@@H:39]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:38]5)=[CH:32][CH:31]=[C:30]4[N:29]=3)[CH2:12][CH2:13]2)[CH:10]=1
Reactant: CCOC(=O)[C@@H]1CCCN(c2ccc(N)c(N)n2)C1
Reactant: CCOC(=N)C1(n2cc(Cl)cn2)CC1
Agent: Cl
Agent: [S]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)[C@@H]1CCCN(c2ccc3nc(C4(n5cc(Cl)cn5)CC4)[nH]c3n2)C1
Yield: 48.9 %

Procedure:
Acetic acid (0.5 mL, 8.88 mmol), ethyl 1-(4-chloro-1H-pyrazol-1-yl)cyclopropanecarbimidate (445 mg, 1.78 mmol), a catalytic amount of sulfur, and triethylamine (0.8 mL, 5.92 mmol) were added to a suspension of (R)-ethyl 1-(5,6-diaminopyridin-2-yl)piperidine-3-carboxylate dihydrochloride (500 mg, 1.48 mmol) in ethanol (25 mL) at room temperature. The reaction mixture was heated at reflux for 18 h, then was concentrated under reduced pressure. The resulting residue was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via column chromatography (100-200 mesh silica gel, 25-70% ethyl acetate in petroleum ether) to afford (R)-ethyl 1-(2-(1-(4-chloro-1H-pyrazol-1-yl)cyclopropyl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidine-3-carboxylate (300 mg). MS (ES+) (M+H) 415.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][S:10][CH:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[N+:28]([C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1)([O-:30])=[O:29].C(N(CC)CC)C>C1COCC1.CN(C=O)C>[N+:28]([C:31]1[CH:32]=[CH:33][C:34]([CH2:35][NH:36][C:13]([CH:9]2[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:12][CH2:11][S:10]2)=[O:15])=[CH:37][CH:38]=1)([O-:30])=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCSC1C(=O)O
Reactant: NCc1ccc([N+](=O)[O-])cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCSC1C(=O)NCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
3-(t-butoxycarbonyl)thiazolidine-2-carboxylic acid (1 g, 4.3 mmol) and carbonyldiimidazole (0.7 g, 4.3 mmol) are dissolved in THF (10 ml). the mixture is agitated for 1 hour at ambient temperature. 4-nitrobenzylamine (0.81 g, 4.3 mmoles) and triethylamine (0.6 ml. 0.43 g, 4.3 mmoles) in suspension in 10 ml of a THF and DMF mixture (1/1) are added to the preceding solution and the whole is heated under reflux for 5 hours. The solvents are then evaporated off under reduced pressure. The residue is taken up in 25 ml of ethyl acetate and washed 3 times with 15 ml of water. The organic phase is dried and the solvent is evaporated off under reduced pressure. The product obtained is purified on silica gel in a dichloromethane/methanol mixture (95/5). N-(4-nitrobenzyl)-3-(t-butoxycarbonyl)thiazolidine-2-carboxamide is obtained in the form of a pale yellow oil with a yield of 80% (1.25 g).
Reaction SMILES: C([CH:3]([O:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][C:11]=1[C:18]12[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2)[CH2:4][O:5][CH3:6])#C.I[C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1.[CH2:39](N(CC)CC)[CH3:40]>O.C(OCC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu](I)I>[OH:17][CH:16]([C:13]1[CH:14]=[CH:15][C:10]([O:9][CH2:8][O:7][CH2:3][CH2:4][O:5][CH3:6])=[C:11]([C:18]23[CH2:25][CH:24]4[CH2:23][CH:22]([CH2:21][CH:20]([CH2:26]4)[CH2:19]2)[CH2:27]3)[CH:12]=1)[C:39]#[C:40][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1
Reactant: COC(=O)c1ccc(I)cc1
Reactant: CCN(CC)CC
Reactant: C#CC(COC)OCOc1ccc(CO)cc1C12CC3CC(CC(C3)C1)C2
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOCC
Product: COCCOCOc1ccc(C(O)C#Cc2ccc(C(=O)OC)cc2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2.5 g (6.7 mmol) of a-ethynyl-3-(1-adamantyl)-4-methoxyethoxymethoxyphenylmethanol, 1.2 g (6.7 mmol) of methyl 4-iodobenzoate and 50 ml of triethylamine were introduced into a three-necked flask. The reaction medium was degassed with nitrogen for 30 min, then 380 mg (0.5 mmol) of bis(triphenylphosphine)palladium (II) chloride and 190 mg (0.8 mmol) of copper iodide were successively added. The reaction medium was stirred at room temperature for four hours and was then evaporated to dryness and the residue obtained was taken up in water and ethyl ether. The organic phase was separated out after settling had taken place, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a column of silica, eluted with a mixture of ethyl acetate and heptane (20/80). 2.7 g (79%) of methyl 4-[[3-hydroxy-3-[3-(1-adamantyl)-4-methoxyethoxymethoxyphenyl]-1-propynyl]]benzoate, having a melting point of 95°-6° C., were recovered.
Reaction SMILES: [C:1](Cl)([Cl:3])=[O:2].[OH-:5].[Na+:6].[OH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)([CH3:16])[CH3:15])=[CH:10][CH:9]=1>[Cl-].[Na+].O.ClCCl>[CH3:16][C:14]([C:11]1[CH:12]=[CH:13][C:8]([OH:7])=[CH:9][CH:10]=1)([C:17]1[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=1)[CH3:15].[C:1]([OH:2])([OH:7])=[O:5].[Cl-:3].[Na+:6]
Reactant: O=C(Cl)Cl
Reactant: [OH-]
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(O)O

Procedure:
The manufacture of condensation polymers often produces a brine solution as a by-product. For example, a brine solution is produced in the manufacture of polycarbonate resins through the reaction of phosgene with at least one bisphenol compound in an organic solvent in the presence of aqueous sodium hydroxide. A common example is the reaction of bisphenol A with phosgene in dichloromethane in the presence of aqueous sodium hydroxide to produce bisphenol A polycarbonate and sodium chloride solution.
Reaction SMILES: Br[C:2]1[C:25](=[O:26])[N:24]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:5]2[N:6]=[C:7]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)=[CH:13][N:12]=3)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:32].C1(C)C=CC=CC=1.C([Sn](CCCC)(CCCC)[C:45]([O:47][CH2:48][CH3:49])=[CH2:46])CCC>C(Cl)(Cl)Cl.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>[CH:27]1([N:24]2[C:5]3[N:6]=[C:7]([NH:10][C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]5)=[CH:13][N:12]=4)[N:8]=[CH:9][C:4]=3[C:3]([CH3:32])=[C:2]([C:45]([O:47][CH2:48][CH3:49])=[CH2:46])[C:25]2=[O:26])[CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCN(C)CC4)cn3)ncc12
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: C=C(OCC)c1c(C)c2cnc(Nc3ccc(N4CCN(C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 110 °C
Reaction time: 12 h
Yield: 90.6 %

Procedure:
A 6-dram vial was charged with 6-bromo-8-cyclopentyl-5-methyl-2-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-8H-pyrido[2,3-d]pyrimidin-7-one (266 mg, 0.53 mmol) and tetrakis(triphenylphosphine)palladium(0) (61 mg, 0.053 mmol) and the atmosphere replaced with argon. Toluene (5 ml) was added followed by tributyl-(1-ethoxy-vinyl)-stannane (289 mg, 0.80 mmol). The vial was heated to 110° C. and stirred for 12 h. The reaction mixture was diluted with chloroform (25 ml) and adsorbed onto silica gel. Chromatographic purification on silica gel (chloroform/2-propanol+1% TEA gradient) gave the 8-cyclopentyl-6-(1-ethoxy-vinyl)-5-methyl-2-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-8H-pyrido[2,3-d]pyrimidin-7-one (237 mg, 0.48 mmol). MS (APCI+) 490 (M+1, 100).
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[C:28]([CH3:36])=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(O[N:47]1N=[N:54][C:49]2C=CC=C[C:48]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.NCC#N>CN(C=O)C>[C:48]([CH2:49][NH:54][C:30](=[O:32])[C:29]1[CH:33]=[CH:34][CH:35]=[C:27]([C:10]2[C:11]3[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]4[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=4[F:25])[C:12]=3[N:13]=[C:8]([NH:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:37][CH3:38])[CH2:1][CH3:2])[N:9]=2)[C:28]=1[CH3:36])#[N:47]
Reactant: CCN(CC)CCCNc1nc(-c2cccc(C(=O)O)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CCN
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CCCNc1nc(-c2cccc(C(=O)NCC#N)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.5 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-2-methylbenzoic acid (26 mg, 0.05 mmol) in DMF (0.5 mL) were added HBTU (28 mg, 0.075 mmol), triethylamine (21.1 uL, 0.15 mmol) and aminoacetonitrile (9.3 mg, 0.1 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (9.1 mg, 33%). LC-MS m/z 560 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[CH2:9]([N:16]1[CH2:21][CH2:20][CH:19]([NH:22][CH3:23])[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH3:23][N:22]([CH:19]1[CH2:18][CH2:17][N:16]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:21][CH2:20]1)[CH:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CNC1CCN(Cc2ccccc2)CC1
Reactant: CN1CCC(=O)CC1
Product: CN1CCC(N(C)C2CCN(Cc3ccccc3)CC2)CC1
Yield: 66 %

Procedure:
In operating analogously to preparation LXXI, starting with N-methyl-4-piperidinone and 1-benzyl-4-(methylamino)piperidine, the product sought after is obtained as a yellow oil (yield=66%).