Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][CH:9]2[O:13][C:12](=[O:14])[CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=1.[CH:15]#[C:16][CH:17]([OH:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C(N(CC)CC)C.O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[OH:26][CH:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:16]#[C:15][C:2]1[N:7]=[C:6]([CH2:8][CH:9]2[O:13][C:12](=[O:14])[CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=1
Reactant: C#CC(O)CCCCCCCC
Reactant: O=C1CCC(Cc2cccc(Br)n2)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCC(O)C#Cc1cccc(CC2CCC(=O)O2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 43.8 %

Procedure:
A solution of 500 mg of 5-[(6-bromo-2-pyridyl)-methyl]-tetrahydrofuran-2-one in 13 ml of triethylamine and 2 ml of tetrahydrofuran is mixed with 350 mg of (3RS)-1-undecin-3-ol, 37 mg of bis-(triphenylphosphine)-palladium(II) chloride and 5 mg of copper(I) iodide and the mixture is stirred for 3 days at room temperature. The reaction mixture is evaporated to dryness, distributed between water and ethyl acetate, dried on sodium sulfate, concentrated by evaporation and the residue is chromatographed on silica gel with hexane/0-35% ethyl acetate. 294 mg of 5-{6-[(3RS)-3-hydroxy-1-undecinyl]-2-pyridyl-methyl}-tetrahydrofuran-2-one is obtained as oil.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([SH:15])=[CH:11][CH:10]=1.Br[CH:17]([CH2:19][CH3:20])[CH3:18].O>CN(C=O)C>[CH3:18][CH:17]([S:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH3:7])=[CH:10][CH:11]=1)[CH2:19][CH3:20]
Reactant: CCC(C)Br
Reactant: COc1ccc(S)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)Sc1ccc(OC)cc1
Reaction time: 8 h

Procedure:
Potassium t-butoxide (30.6 g, 275.0 mmol) is added to a solution of 4-methoxybenzenethiol (30.0 ml, 250.0 mmol) in 250 ml of DMF. The mixture is heated at 80° until homogeneous, after which 2-bromobutane (30.0 ml, 275.0 mmol) in 30 ml of DMF is added dropwise over approx. 30 min. The mixture is stirred at 60° overnight, after which it is cooled and is then poured into water and the aqueous phase is extracted with ether (3X). The combined ether extracts are washed with water, with 5% sodium hydroxide, with water and with brine, dried, and the solvent removed to give 4-(1-methylpropylthio)anisole.
Reaction SMILES: C[NH:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:41])/[CH:31]=[CH:32]/[C:33]3[CH:38]=CC(CCl)=[CH:35][CH:34]=3)=[CH:25][CH:24]=2)=[CH:19][CH:18]=1>CN(C=O)C>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[CH:25][C:26]([NH:29][C:30](/[CH:31]=[CH:32]/[CH:33]([CH2:38][NH:2][CH:3]3[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]3)[C:34]3[CH:5]=[CH:4][CH:3]=[CH:8][CH:35]=3)=[O:41])=[CH:27][CH:28]=2)=[CH:19][CH:18]=1
Reactant: O=C(/C=C/c1ccc(CCl)cc1)Nc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(NCC(/C=C/C(=O)Nc2ccc(-c3ccc(Cl)cc3)cc2)c2ccccc2)CC1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
0.5 g (2.34 mmol) of tert-butyl 4-methylaminopiperidine-1-carboxylate is added to a suspension of 300 mg (0.79 mmol) of (E)-N-(4′-chlorobiphenyl-4-yl)-3-(4-chloromethylphenyl)acrylamide in 5 mL of DMF and the mixture is stirred for 18 hours at 80° C. Then the reaction mixture is poured onto water and the precipitate formed is suction filtered. Further purification is carried out by stirring out from a little methanol. Yield: 200 mg (45% of theory); C33H38ClN3O3 (M=560.13); melting point: 168° C.-169° C.; calc.: molecular ion peak (M+H)+: 560/562 (Cl); found: molecular ion peak (M+H)+: 560/562 (Cl).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O=[C:20]1[CH2:25][CH2:24][CH:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.ClCCCl.C(O)(=O)C>[CH:1]1([NH:4][CH:20]2[CH2:25][CH2:24][CH:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]2)[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)C1CCC(NC2CC2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 90.5 %

Procedure:
To a mixture of 3.35 g of cyclopropylamine, 1.0 mL of acetic acid, 9.34 g of sodium triacetoxyborohydride, and 30 mL of 1,2-dichloroethane was added dropwise 5.00 g of ethyl 4-oxocyclohexane carboxylate at room temperature. After stirring at room temperature for 14 hours, to the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution to quench the reaction. To the reaction mixture was added chloroform, followed by extraction and then the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (aqueous ammonia-methanol-chloroform) to obtain 5.62 g of ethyl 4-(cyclopropylamino)cyclohexane carboxylate as a colorless oily substance.
Reaction SMILES: C1(C)C=CC=CC=1.CC1(C)C(C)(C)OB([C:16]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:17]=2[CH2:18][CH2:19][C:20]3=[O:25])O1.Cl[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N+:34]([O-:36])=[O:35].C([O-])([O-])=O.[Na+].[Na+]>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.CCOC(C)=O.O>[N+:34]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH2:18][CH2:19][C:20]2=[O:25])([O-:36])=[O:35]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: CC1(C)OB(c2cccc3c2CCC3=O)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1CCc2c1cccc2-c1ccccc1[N+](=O)[O-]
Yield: 91.1 %

Procedure:
Degassed toluene (0.5 L), borolan 88 (10 g, 39 mmol), 2-chloro-1-nitrobenzene (6.3 g, 40 mmol), Pd(PPh3)4 (3 g, 2.6 mmol) and 2M Na2CO3 (200 mL) were mixed under a rapid flow of argon, and the resulting mixture was refluxed overnight. Water (200 mL) and EtOAc (500 mL) were added. The aqueous layer was separated and extracted with EtOAc (2×500 mL), and the combined extracts dried over Na2SO4. The solvent was evaporated at reduced pressure and the crude product purified by column chromatography (20% EtOAc in hexanes) to give 9 g (91%) of the biphenyl intermediate 89 as a yellow solid.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9])[CH2:3][CH3:4].CCN(CC)CC.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[CH3:20][S:21]([O:1][CH:2]([C:5]1[CH:12]=[CH:11][CH:10]=[C:7]([C:8]#[N:9])[CH:6]=1)[CH2:3][CH3:4])(=[O:23])=[O:22]
Reactant: CCC(O)c1cccc(C#N)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(OS(C)(=O)=O)c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71.3 %

Procedure:
A mixture of 3-(1-hydroxypropyl)benzonitrile (0.273 g, 1.694 mmol; ref. Synlett (2002), (11), 1922-1924), Et3N (0.354 mL, 2.54 mmol) and MsCl (0.198 mL, 2.54 mmol) in CH2Cl2 (5 mL) was stirred at rt. After 90 min, an additional 0.75 eq each of Et3N and MsCl were added. After 1 h, the reaction mixture was concentrated to dryness, and the residue was partitioned between EtOAc (20 mL) and 0.1N HCl (20 mL). The organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed over silica gel using a 5-30% EtOAc-hexane gradient to give 1-(3-cyanophenyl)propyl methanesulfonate (0.289 g, 68% yield) (the product is somewhat unstable, and it needs to be used shortly thereafter or stored at low temperatures).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]([C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[C:12]([O:18]C)=[C:11]([O:20]C)[CH:10]=1)=[O:8].[BrH:22]>>[BrH:22].[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]([C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[C:12]([OH:18])=[C:11]([OH:20])[CH:10]=1)=[O:8]
Reactant: COc1cc(C(=O)c2nccn2C)cc([N+](=O)[O-])c1OC
Agent: Br
Product: Cn1ccnc1C(=O)c1cc(O)c(O)c([N+](=O)[O-])c1

Procedure:
5.0 g of 3,4-dimethoxy-5-nitrophenyl (1-methylimidazol-2-yl) ketone are treated with 50 ml of hydrobromic acid (48%), whereupon the mixture is stirred under reflux temperature for 2 hours. After cooling the separated precipitate is filtered under suction, washed with ice-water and recrystallized from ethanol. There is obtained 3,4-dihydroxy-5-nitrophenyl (1-methyl- imidazol-2-yl) ketone hydrobromide in the form of yellow crystals of decomposition point >240°.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:4]=2[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=1.CC(C)([O-])C.[K+].[Br:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Br.N1CCNCC1>O1CCCC1>[Br:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][CH:7]1[C:6](=[O:9])[N:5]([CH3:10])[C:4]2[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:3]=2[C:2]([Cl:1])=[N:8]1
Reactant: BrCc1ccccc1Br
Reactant: CN1C(=O)CN=C(Cl)c2cc(Cl)ccc21
Agent: C1CNCCN1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN1C(=O)C(Cc2ccccc2Br)N=C(Cl)c2cc(Cl)ccc21
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 64.7 %

Procedure:
(E)-5,7-Dichloro-1-methyl-1H-benzo[e][1,4]diazepin-2(3H)-one (400 mg, 1.65 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL) under a nitrogen atmosphere, cooled to −78° C., then a 1 M solution of potassium tert-butoxide in tetrahydrofuran (1.7 mL, 1.7 mmol) was added dropwise. The reaction mixture was stirred for 10 minutes before a solution of the 2-bromobenzyl bromide (411 mg, 1.65 mmol) in tetrahydrofuran (2 mL) was added dropwise. The mixture was stirred at −78° C. for 20 minutes then the cooling bath removed and the mixture was allowed to warm to ambient temperature and stirred at ambient temperature for 18 hours. piperazine (283 mg, 3.29 mmol) was added to remove excess 2-bromobenzyl bromide and the mixture was stirred at ambient temperature for 30 minutes, diluted with ethyl acetate, and washed with cold 1 M aqueous hydrogen chloride (2×40 mL). The organic layers were dried with sodium sulfate, decanted and concentrated in vacuo to approximately 20 mL of a red liquid. The product was purified on a short pad of silica gel eluting with 100 mL of ethyl acetate:hexanes (1:2) to yield (E)-3-(2-bromobenzyl)-5,7-dichloro-1-methyl-1H-benzo[e][1,4]diazepin-2(3H)-one (0.44 g, 65%). 1H NMR (300 MHz, CDCl3) δ 3.40 (s, 3H) 3.75 (m, 2H), 4.15 (m, 1H), 7.05-7.55 (m, 7H).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH:10]2[CH2:13][C:12](=[CH2:14])[CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[Cl:15][C:16]([Cl:21])(Cl)[C:17](Cl)=[O:18]>>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH:10]2[CH2:13][C:12]3([CH2:14][C:17](=[O:18])[C:16]3([Cl:21])[Cl:15])[CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: C=C1CC([C@H]2CC[C@H](CCC)CC2)C1
Product: CCC[C@H]1CC[C@H](C2CC3(CC(=O)C3(Cl)Cl)C2)CC1

Procedure:
35 mmol of 4C are reacted with trichloroacetyl chloride in analogy to Example 1B.
Reaction SMILES: [CH2:1]([N:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:16]3[O:17][C:18]4([C:28]([CH3:30])([CH3:29])[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:21]4[CH3:31])[CH:19]=[N:20][C:15]=3[CH:14]=2)=[CH:9][CH:8]=1)[CH2:4][CH2:5][OH:6])[CH3:2].C(N(CC)CC)C.[C:45](Cl)(=[O:48])[CH2:46][CH3:47]>C(Cl)Cl>[C:45]([O:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:16]3[O:17][C:18]4([C:28]([CH3:29])([CH3:30])[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:21]4[CH3:31])[CH:19]=[N:20][C:15]=3[CH:14]=2)=[CH:9][CH:8]=1)(=[O:48])[CH2:46][CH3:47]
Reactant: CCN(CCO)c1ccc(-c2cc3c(c4ccccc24)OC2(C=N3)N(C)c3ccccc3C2(C)C)cc1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)OCCN(CC)c1ccc(-c2cc3c(c4ccccc24)OC2(C=N3)N(C)c3ccccc3C2(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2-(ethyl(4-(1,3,3-trimethylspiro[indoline-2,2′-naphtho[1,2-b][1,4]oxazine]-6′-yl)phenyl)amino)ethanol (Example 8, Step 3) (0.085 g, 0.17 mmol) in DCM (5 ml) was treated with triethylamine (0.026 g, 0.26 mmol) in one portion followed by propionyl chloride (0.019 g, 0.21 mmol) and stirred at RT for 18 hrs. The solvent was then evaporated in vacuo and the crude residue purified by column chromatography (silica gel) eluting with 0-10% EtOAc/Petroleum ether, which gave the pure product, 2-(ethyl(4-(1,3,3-trimethylspiro[indoline-2,2′-naphtho[1,2-b][1,4]oxazine]-6′-yl)phenyl)amino)ethyl propionate, as a pale green foam upon evaporation of the solvent in vacuo (0.08 g, 84%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:11])[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.[CH2:12]=O.Cl.[CH3:15][NH:16][CH3:17].Cl>O.C(O)(C)C>[CH3:15][N:16]([CH3:17])[CH2:10][CH:9]([CH3:12])[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=1)=[O:11]
Reactant: CCC(=O)c1cccc(O)c1
Reactant: CNC
Reactant: C=O
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: CC(CN(C)C)C(=O)c1cccc(O)c1
Temperature: 27.5 °C
Yield: 55.5 %

Procedure:
A mixture of 1-(3-hydroxy-phenyl)-propan-1-one (5 g, 0.03 mol), paraformaldehyde (1 g, 0.03 mol), dimethylamine hydrochloride (3 g, 0.04 mol), hydrochloric acid (3.4 ml, 30%) and isopropanol (15 ml) was refluxed for 16 hours. Isopropanol was distilled off from the reaction mixture and resulting reaction mass was cooled to 25-30° C. Water (15 ml) was added to the reaction mass and washed with isopropyl ether (2×15 ml). Layers were separated and aqueous layer was added to a stirred mixture of aqueous sodium hydroxide solution (1.2 g in 16 ml water) and methyl tert-butyl ether (25 ml). Layers were separated. Organic layer was washed with water (10 ml), dried and solvent was distilled to give 3.45 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:12]=1[C:13]([O:15][CH3:16])=[O:14].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[CH:3]=2)[C:12]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1c(C)cccc1CBr
Reactant: Oc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1c(C)cccc1COc1cccc(O)c1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3-hydroxy-phenol (1.5 g, 13.6 mmol) in acetonitrile (50 mL) is added methyl 2-(bromomethyl)-6-methyl-benzoate (0.82 g, 3.4 mmol, example 2) followed by K2CO3 (3.76 g, 27.2 mmol). The resulting mixture is heated to 50° C. and stirred at this temperature for 90 min. then cooled, filtered and the filtrate concentrated under vacuum. The residue is purified by flash chromatography (silica, 5% ethyl acetate in dichloromethane) to give the title compound as a white solid. MS (EI) 272 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]([C:11]2[C:12](=[O:22])[O:13][C:14]3[C:19]([C:20]=2[OH:21])=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.[CH2:23]([S:25](Cl)(=[O:27])=[O:26])[CH3:24]>C(Cl)Cl.N1C=CC=CC=1.C(Cl)(Cl)Cl>[OH:21][C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:13][C:12](=[O:22])[C:11]=1[CH:8]([C:4]1[CH:3]=[C:2]([NH:1][S:25]([CH2:23][CH3:24])(=[O:27])=[O:26])[CH:7]=[CH:6][CH:5]=1)[CH2:9][CH3:10]
Reactant: CCS(=O)(=O)Cl
Reactant: CCC(c1cccc(N)c1)c1c(O)c2ccccc2oc1=O
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCC(c1cccc(NS(=O)(=O)CC)c1)c1c(O)c2ccccc2oc1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
14.75 mg of 3-[1-(3-aminophenyl)propyl]-4 hydroxy-coumarin is dissolved in 1 ml of methylene chloride with 8.1 microliters of pyridine added. To this solution, at room temperature with protection from moisture, is added 5.14 microliters of ethylsulfuryl chloride. The reaction is allowed to stir, at room temperature, for 18 hours. 5 ml of methylene chloride is added to the reaction mixture, the resulting mixture is washed twice with 1 ml of water, and the methylene chloride solution is separated, dried over anhydrous sodium sulfate and evaporated to dryness to yield 28 mg of crude title product. Chromatography over 15 g of silica gel using 5% methanol in chloroform as solvent gives 6.8 mg of pure title product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:18]=[CH:19][CH:20]=1)[O:8][C:9]1[N:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)=[O:4].[NH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([OH:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N(CC)CCCl)C>CN(C)C=O.O>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:20]=[CH:19][CH:18]=[C:7]([O:8][C:9]2[C:10]([C:11](=[O:13])[NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([OH:32])([CH3:30])[CH3:31])=[CH:25][CH:24]=3)=[CH:14][CH:15]=[CH:16][N:17]=2)[CH:6]=1
Reactant: CC(C)(O)c1ccc(CN)cc1
Reactant: COC(=O)c1cccc(Oc2ncccc2C(=O)O)c1
Agent: CCN(CC)CCCl
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(Oc2ncccc2C(=O)NCc2ccc(C(C)(C)O)cc2)c1

Procedure:
To a stirred solution of 2-(3-Methoxycarbonyl-phenoxy)-nicotinic acid (0.400 grams, 1.463 mmole), 2-(4-Aminomethyl-phenyl)-propan-2-ol (0.266 grams, 1.61 mmole), and 1-hydroxybenzotriazole hydrate (0.237 grams, 1.755 mmole) in dry dimethylformamide (20 ml) was added 2-diethylaminoethyl chloride hydrochloride (0.365 grams, 1.90 mmole) and stirred over night. The mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over MgSO4, filtered and concentrated to give a white foam. (0.360 g); MS (m/e) 420 (M++1); 1H NMR (CDCl3) d 1.50 (6H, s), 3.90 (3H, s), 4.70 (2H, d, J=5.60 Hz), 7.20-8.65 (12H, m).
Reaction SMILES: [C:1]1([CH3:22])[CH:6]=[CH:5][C:4]([P:7]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[CH2:23]([I:25])[CH3:24].P(=O)(O)(O)O>C1(C)C=CC=CC=1>[I-:25].[CH2:23]([P+:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:22])=[CH:2][CH:3]=1)([C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[CH3:24]
Reactant: CCI
Reactant: Cc1ccc(P(c2ccc(C)cc2)c2ccc(C)cc2)cc1
Agent: O=P(O)(O)O
Solvent: Cc1ccccc1
Product: CC[P+](c1ccc(C)cc1)(c1ccc(C)cc1)c1ccc(C)cc1
Product: [I-]
Temperature: 25 °C

Procedure:
Into a 50 milliliter glass reactor equipped with a thermometer connected to a temperature controller, a heating mantle, a condenser and a magnetic stirring bar, is charged 5 gms (0.0164 mole) of tri-p-tolyl phosphine and 25 gms of toluene. The slurry is heated to 25° C., then 3 gms (0.0192 mole) of ethyl iodide is added. This reaction mass is heated to 60° C. and maintained for 14 hours, then cooled and the resulting phosphonium salt collected by filtration. After vacuum drying, there is obtained 6.85 gms of catalyst which has a melting point of 184°-187° C. and a chemical shift of 24.7 ppm (phosphoric acid reference).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([NH2:14])[CH:11]=[CH:12][CH:13]=2)[CH2:4][CH2:3]1.[CH2:15]([O:17][C:18]([C:20]1[C:21](=[O:43])[C:22]2[CH:27]=[N:26][C:25](S(C)(=O)=O)=[N:24][C:23]=2[N:32]([C:34]2[CH:35]=[C:36]3[C:40](=[CH:41][CH:42]=2)[CH2:39][CH2:38][CH2:37]3)[CH:33]=1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1[C:21](=[O:43])[C:22]2[CH:27]=[N:26][C:25]([NH:14][C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)[CH:9]=3)=[N:24][C:23]=2[N:32]([C:34]2[CH:35]=[C:36]3[C:40](=[CH:41][CH:42]=2)[CH2:39][CH2:38][CH2:37]3)[CH:33]=1)=[O:19])[CH3:16]
Reactant: CN1CCN(c2cccc(N)c2)CC1
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3cccc(N4CCN(C)CC4)c3)ncc2c1=O

Procedure:
Using the procedure outlined in Example 1(g) the title compound was prepared from 3-(4-methyl-piperazin-1-yl)-phenylamine (50 mg, 0.27 mmol) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1(e) above, 100 mg, 0.24 mmol). The title compound was obtained as a yellow solid (60 mg, 46%). 1H NMR (400 MHz, CDCl3) δ (ppm): 9.29 (s, 1H), 8.44 (s, 1H), 7.49 (br, 1H), 7.31 (d, J=7.9 Hz, 1H), 7.20 (m, 2H), 7.09 (d, J=7.8 Hz, 1H), 6.94 (d, J=7.9 Hz, 1H), 6.87 (br, 1H), 6.52 (d, J=7.9 Hz, 1H), 4.32 (q, J=7.1 Hz, 2H), 3.02-2.90 (m, 8H), 2.45 (m, 4H), 2.26 (s, 3H), 2.14 (m, 2H), 1.32 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:4](=[O:14])[N:3]=1.[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1.C1C[O:23]CC1>C(Cl)Cl>[NH2:17][CH2:18][CH2:19][NH:15][C:16]([NH:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:4](=[O:14])[N:3]=1)=[O:23]
Reactant: c1c[nH]cn1
Reactant: C1CCOC1
Reactant: CCCCCCn1ccc(N)nc1=O
Solvent: ClCCl
Product: CCCCCCn1ccc(NC(=O)NCCN)nc1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
To a solution of 4-amino-1-hexyl-1H-pyrimidin-2-one (C) (0.10 g, 0.513 mmol) in dry CH2Cl2 (7 ml) was added N,N carbonyl diimidazole (0.131 g, 0.513 mmol) and the solution was stirred at room temperature for 16 h. The solvent was evaporated and the residue redissolved in dry chloroform Hexane was then added to precipitate the intermediate, which was dried in vacuo and used directly without further purification. To a solution of the resulting imidazole intermediate (0.100 g, 0.346 mmol) was added to a solution of ethyldiamine (0.14 ml, 2.07 mmol) in dry THF (5 ml). The solution was stirred at room temperature for 16 h under N2 atmosphere. The solvents were then evaporated and the residue was dissolved in chloroform and washed with water and brine. The organic phases were combined and dried over MgSO4. The solvent was evaporated in vacuo and the crude compound was purified through flash silica gel chromatography (CHCl3/MeOH/Et3N (1:2:0.1)) to afford pure compound (L) (0.080 g, 82%)
Reaction SMILES: C([BH3-])#N.[NH2:4][C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[C:8]([CH3:15])=[CH:7][C:6]=1[OH:16].[CH2:17]([O:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([N:27]2[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]2)[CH2:23][CH2:22]1)[CH2:18][CH3:19].C(O)(=O)C>C1COCC1>[CH3:15][C:8]1[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:10][C:5]([NH:4][CH:30]2[CH2:29][CH2:28][N:27]([C@H:24]3[CH2:25][CH2:26][C@H:21]([O:20][CH2:17][CH2:18][CH3:19])[CH2:22][CH2:23]3)[CH2:32][CH2:31]2)=[C:6]([OH:16])[CH:7]=1
Reactant: CCCO[C@H]1CC[C@H](N2CCC(=O)CC2)CC1
Reactant: Cc1cc(O)c(N)cc1S(C)(=O)=O
Agent: [BH3-]C#N
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCO[C@H]1CC[C@H](N2CCC(Nc3cc(S(C)(=O)=O)c(C)cc3O)CC2)CC1
Temperature: 100 °C

Procedure:
Polymer supported cyanoborohydride (110 mg, 0.47 mmol, 4.3 mmol/g) was added to a solution of 2-amino-5-methyl-4-(methylsulfonyl)phenol (D87, 48 mg, 0.24 mmol), 1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinone (D17, 65 mg, 0.26 mmol, this specific batch contained-25% 1-[trans-4-(propyloxy)cyclohexyl]-4-piperidinone) and acetic acid (0.07 mL, 1.19 mmol) in THF (2.5 mL). The mixture was heated by microwave at 100° C. for 30 min and then for a further 3×30 min. The reaction was then filtered and concentrated by rotary evaporation to give a yellow oil, which was purified by high pH MDAP to give 5-methyl-2-({1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}amino)-4-(methylsulfonyl)phenol (D88, 49 mg, 46%) as a cream solid and 5-methyl-4-(methylsulfonyl)-2-({1-[trans-4-(propyloxy)cyclohexyl]-4-piperidinyl}amino)phenol (D89, 14 mg, 13%) as a yellow oil.