Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>CN(C1C=CN=CC=1)C.ClCCl>[C:10]([O:8][CH2:7][CH:5]1[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]1)(=[O:12])[CH3:11]
Reactant: CC1(C)OCC(CO)O1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCC1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 28.1 g (212 mmol) of 2,2-dimethyl-1,3-dioxolane-4-methanol and 44 g (361 mmol) of DMAP in 1 L of dichloromethane was added 36 mL (382 mmol) of acetic anhydride dropwise. The resulting mixture was stirred at rt for 0.5 h. The reaction mixture was then quenched with NH4Cl (aq), the organic layer separated and washed with saturated NaHCO3. The organic layer was then dried (Na2SO4), filtered and concentrated in vacuo to give an oil which was used without further purification. 1H NMR (500 MHz, acetone-d6): δ 4.30-4.25 (m, 1H), 4.09-4.01 (m, 1H), 3.72 (dd, 1H), 2.01 (s, 3H), 1.33 (s, 3H), 1.27 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:3]=1[C:4]#[N:5].[NH:13]([CH2:17][CH2:18][OH:19])[CH2:14][CH2:15][OH:16]>>[NH2:10][C:7]1[CH:8]=[CH:9][C:2]([N:13]([CH2:17][CH2:18][OH:19])[CH2:14][CH2:15][OH:16])=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: OCCNCCO
Product: N#Cc1cc(N)ccc1N(CCO)CCO
Yield: 77.7 %

Procedure:
By the reaction and treatment in the same manner as in Starting Material Synthetic Example 4 using 2-chloro-5-nitrobenzonitrile (25.5 g) and diethanolamine (102 g), the title compound (24 g) was obtained. melting point: 38° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[N:30]=[C:31]([N:39]2[CH2:44][CH2:43][N:42]([CH2:45][CH3:46])[CH2:41][CH2:40]2)[C:32]2[C:37]([CH:38]=1)=[CH:36][CH:35]=[CH:34][CH:33]=2>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C.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>[CH2:45]([N:42]1[CH2:41][CH2:40][N:39]([C:31]2[C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:38]=[C:29]([C:11]3[CH:12]=[C:13]4[C:8](=[CH:9][CH:10]=3)[CH2:7][CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:14]4)[N:30]=2)[CH2:44][CH2:43]1)[CH3:46]
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc2c(c1)CC(C(=O)OCC)C2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: CCOC(=O)C1Cc2ccc(-c3cc4ccccc4c(N4CCN(CC)CC4)n3)cc2C1
Yield: 90.8 %

Procedure:
2-Ethoxycarbonyl-5-(Tributylstannyl)indane (3.04 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (0.87 g) were heated under reflux overnight in the presence of tetrakistriphenylphosphinepalladium(0) (0.12 g) in xylene in nitrogen atmosphere. After cooling, the reaction solution was diluted with ethyl acetate and filtered. The filtrate was extracted with 2N hydrochloric acid, and the resulting aqueous layer was washed with ethyl acetate, adjusted to pH 10 with a 8N aqueous solution of sodium hydroxide, and then extracted with ethyl acetate. The extract was washed with a 10% aqueous solution of sodium carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, to give 1-(4-ethylpiperazin-1-yl)-3-(2-ethoxycarbonylindan-5-yl)isoquinoline (1.06 g) as a brown viscous oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:22][CH2:23][CH2:24][O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[C:11]=1[O:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[Cl:21])[C:5]([O:7][CH3:8])=[O:6].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>N1C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:21][C:14]1[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:13]=1[O:12][C:11]1[C:10]([O:22][CH2:23][CH2:24][O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[NH:1][S:40]([C:37]1[CH:36]=[CH:35][C:34]([O:33][CH3:32])=[CH:39][CH:38]=1)(=[O:42])=[O:41]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1cc(N)c(Oc2cc(OC)ccc2Cl)c(OCCOC2CCCCO2)c1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)c1cc(NS(=O)(=O)c2ccc(OC)cc2)c(Oc2cc(OC)ccc2Cl)c(OCCOC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
135 mg of methyl 3-amino-4-(2-chloro-5-methoxy-phenoxy)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate were dissolved in pyridine (3 ml), treated while cooling with ice with a solution of 111 mg of 4-methoxy-benzenesulphonyl chloride in toluene (1 ml) and subsequently stirred at RT for 20 hours. The reaction mixture was poured on to ice/3M HCl, the product was extracted with ethyl acetate and the organic phase was washed with water and dried over magnesium sulphate. After removing the solvent there was obtained methyl 4-(2-chloro-5-methoxy-phenoxy)-3-(4-methoxy-benzenesulphonylamino)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate as a foam.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[N+:9]([O-])=O.[H][H]>CO.[Ni]>[CH3:1][NH:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[NH2:9]
Reactant: [H][H]
Reactant: CNc1ccncc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: CNc1ccncc1N
Yield: 83.8 %

Procedure:
2.3 g methyl-(3-nitropyridin-4-yl)-amine are hydrogenated in 50 ml of methanol for and with 0.8 g Raney nickel for 2.5 h at 50° C. and 50 psi hydrogen pressure. The catalyst is filtered off and the filtrate is evaporated to dryness. The product is purified by chromatography (Alox, dichloromethane/methanol from 99/1 to 19/1). 1.55 g product are obtained as a solid.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[F:4][C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH2:11]/[C:12]/2=[CH:15]\[C:16](Cl)=[O:17])=[CH:7][CH:6]=1>ClCCl.C(OCC)(=O)C>[F:4][C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH2:11]/[C:12]/2=[CH:15]\[C:16]([N:2]([CH3:3])[CH3:1])=[O:17])=[CH:7][CH:6]=1
Reactant: O=C(Cl)/C=C1\CCCc2ccc(F)cc21
Reactant: CNC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(C)C(=O)/C=C1\CCCc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69.4 %

Procedure:
Dimethylamine (3 ml, 0.045 mol, Kodak) was added to a chilled (ice bath) solution of (E)-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthylidene)acetyl chloride (2.3 g, 0.010 mol) in dichloromethane (35 ml). The reaction was warmed to 25° C. and stirred for 1.5 h. The volatiles were removed by spin evaporation in vacuo to give a beige residue. This residue was dissolved in ethyl acetate (200 ml), washed with deionized water (50 ml), and the organic layer was concentrated by spin evaporation in vacuo. The residue was chromatographed on Silica Gel 60 using a step gradient from ethyl acetate-hexanes/1:5 to ethyl acetate. Fractions containing (E)-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthylidene)-N,N-dimethylacetamide were combined and concentrated by spin evaporation in vacuo to a white solid. Recrystallization from dichloromethane-hexanes gave 1.62 g (70%) of (E)-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthylidene)-N,N-dimethylacetamide as a white crystalline solid; m.p., 66°-70° C.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1)#[N:2].S(Cl)([Cl:14])=O>ClCCl>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:14])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: N#Cc1ccc(C(=O)Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of 4-cyanobenzoic acid (5 g, 33.98 mmol, 1.00 equiv) in dichloromethane (50 mL) was added thionyl chloride (25 mL) dropwise with stirring. The resulting solution was refluxed for 4 h. The reaction mixture was cooled to room temperature and concentrated under vacuum to give 3 g of crude 4-cyanobenzoyl chloride as a brown solid. The crude was used in the next step without further purification.
Reaction SMILES: [CH3:1][CH2:2]N=C=NCCCN(C)C.C(O)C.[Br:15][C:16]1[CH:20]=[CH:19][O:18][C:17]=1[C:21]([OH:23])=[O:22]>CN(C)C1C=CN=CC=1.ClCCl>[Br:15][C:16]1[CH:20]=[CH:19][O:18][C:17]=1[C:21]([O:23][CH2:1][CH3:2])=[O:22]
Reactant: O=C(O)c1occc1Br
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1occc1Br
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.7 %

Procedure:
WSC (17.3 g), 4-dimethylaminopyridine (1.1 g) and ethanol (5.2 ml) were added to a dichloromethane solution (100 ml) of 17.2 g 3-bromo-2-furancarboxylic acid and stirred for 5 hours at 25° C. The reaction solution was washed with saturated brine and dried over MgSO4. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/30), thereby giving 17.5 g of the desired compound.
Reaction SMILES: [C:1]([C:9]1[N:13]([CH3:14])[C:12]([CH:15]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)C(OCC)=O)=[CH:11][C:10]=1[CH3:30])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>CO.C1COCC1>[C:1]([C:9]1[N:13]([CH3:14])[C:12]([CH2:15][C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[CH:11][C:10]=1[CH3:30])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(c1ccc([N+](=O)[O-])cc1)c1cc(C)c(C(=O)c2ccccc2)n1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(Cc2ccc([N+](=O)[O-])cc2)n(C)c1C(=O)c1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
Ethyl 2-(5-benzoyl-1,4-dimethylpyrrol-2-yl)-2-(4-nitrophenyl)acetate (8.2 g, 20.2 mmol) [prepared by proceeding as described in Example 1, Steps (a) and (b)] was dissolved in a 1:1 mixture of methanol/THF (200 ml). An aqueous solution of LiOH (250 ml, 0.4M, 100.9 mmol) was added and the mixture was stirred at 60° C. for 2 h. The organic solvents were evaporated in vacuo, the aqueous residue was acidified with 10% HCl, and the product was extracted into ethyl acetate. The organic phase was washed with water, dried over sodium sulfate, and concentrated under vacuum. Purification on a Florisil® column (hexane-ethyl acetate, 4:1) gave 4-[5-benzoyl-1,4-dimethyl-1H-pyrrol-2-ylmethyl]-nitrobenzene (6.68 g, 99%) as a yellow solid. ##STR22##
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[C:14]2[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]2)[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[H][H]>[Pd].C(OCC)(=O)C.CO>[F:8][C:6]1[CH:5]=[C:4]([CH:9]([CH:14]2[CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17]2)[C:10]([CH3:11])([CH3:12])[CH3:13])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(=C(c2cc(F)cc(F)c2)C(C)(C)C)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(C(c2cc(F)cc(F)c2)C(C)(C)C)C1

Procedure:
A mixture of 720 mg (2.14 mmol) of tert-butyl 3-[1-(3,5-difluorophenyl)-2,2-dimethylpropylidene]azetidine-1-carboxylate and 600 mg of palladium on activated carbon (10%) in 6 mL of ethyl acetate and 5 mL of MeOH was pressurized to 50 psi with hydrogen gas at room temperature for 72 h. The solution was filtered through CELITE and the filtrate was concentrated. The residue was purified by silica gel chromatography with hexanes/ethyl acetate to afford the title compound as a white solid; 1H-NMR(CDCl3) δ 0.88 (s, 9H), 1.43 (s, 9H), 2.69 (d, J=11 Hz, 1H), 3.09-3.18 (m, 2H), 3.71 (t, J=8.2 Hz, 1H), 3.81(m, 1H), 4.12 (t, J=8.5 Hz, 1H), 6.49 (br, 1H), 6.69 (m, 2);
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][N:24](COCC[Si](C)(C)C)[C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14](S(C)(=O)=O)[N:13]=2)[CH2:6]1)(=[O:4])=[O:3].[CH3:39][N:40]([CH3:44])[CH2:41][CH2:42][NH2:43].CS(C)(=O)=O>O1CCOCC1>[CH3:39][N:40]([CH3:44])[CH2:41][CH2:42][NH:43][C:14]1[N:13]=[C:12]([NH:11][C@H:7]2[CH2:8][CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6]2)[C:17]([C:18]2[N:19]=[C:20]3[CH:26]=[CH:25][NH:24][C:21]3=[N:22][CH:23]=2)=[CH:16][N:15]=1
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cnc(S(C)(=O)=O)nc3N[C@H]3CCCN(S(C)(=O)=O)C3)cnc21
Reactant: CN(C)CCN
Agent: CS(C)(=O)=O
Solvent: C1COCCO1
Product: CN(C)CCNc1ncc(-c2cnc3[nH]ccc3n2)c(N[C@H]2CCCN(S(C)(=O)=O)C2)n1

Procedure:
In a dioxane solution of ((S)-1-methanesulfonyl-piperidin-3-yl)-{2-methanesulfonyl-5-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-yl}-amine derived from Example 84, step 1, N*1*,N*1*-dimethyl-ethane-1,2-diamine was used to displace the methylsulfone similar to examples above and the de-protection step was similar to step 5, Example 76, to give N*2*-(2-dimethylamino-ethyl)-N*4*-((S)-1-methanesulfonyl-piperidin-3-yl)-5-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-pyrimidine-2,4-diamine. MS (ES+): 460.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([N:19]([CH2:34][CH3:35])[CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([CH:32]=O)=[CH:26]2)[CH3:18].N1CCCCC1>C(O)C>[CH2:34]([N:19]([CH2:17][CH3:18])[CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([CH:32]=[C:11]1[C:10]3[C:14](=[CH:15][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8][CH:9]=3)[NH:13][C:12]1=[O:16])=[CH:26]2)[CH3:35]
Reactant: CCN(CC)CCCc1ccc2[nH]c(C=O)cc2c1
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCCc1ccc2[nH]c(C=C3C(=O)Nc4cc(-c5ccccc5)ccc43)cc2c1
Temperature: 95 °C
Yield: 57.4 %

Procedure:
A mixture of 6-phenyl-2-oxindole (41 mg, 0.19 mmol)-5-(3-diethylamino-propyl)-1H-indole-2-carbaldehyde (50 mg, 0.19 mmol) and piperidine(0.1 mL) in ethanol (1 mL) was heated in a sealed tube at 95° C. for 20 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 49 mg (56%) of the title compound as an orange crystalline solid.
Reaction SMILES: [CH3:1][C@@H:2]1[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[C:10]([CH2:13][NH:14][CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])[CH:11]=[CH:12][C:4]=2[O:3]1.[C:22](OC(OC(OC(C)(C)C)=O)=O)(C)([CH3:24])[CH3:23].C(N(CC)CC)C>ClCCl>[CH3:1][C@@H:2]1[O:3][C:4]2[CH:12]=[C:11]3[C:10](=[CH:9][C:5]=2[NH:6][C:7]1=[O:8])[C@H:13]([NH:14][CH2:15][CH2:16][CH2:17][C:18]([F:19])([F:21])[F:20])[CH2:24][CH2:22][CH2:23]3
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: C[C@H]1Oc2ccc(CNCCCC(F)(F)F)cc2NC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1Oc2cc3c(cc2NC1=O)[C@H](NCCCC(F)(F)F)CCC3
Yield: 105.5 %

Procedure:
608 mg (2.014 mmol) of (2R)-methyl-3-oxo-6-(4,4,4-trifluorobutylamino-methyl)-3,4-dihydro-2H-1,4-benzoxazine is stirred with 439.9 mg (2.014 mmol) of di-tert-butyldicarbonate and 303 mg (2.995 mmol) of triethylamine in 15 ml of dichloromethane for four hours at room temperature. The batch is spun in until a dry state is reached, and the residue is put on a column on silica gel (mobile solvent: ethyl acetate/hexane). 727.6 mg (99%) of the desired compound is isolated.
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl[CH2:7][C:8]1[C:9]([CH3:14])=[N:10][O:11][C:12]=1[CH3:13].[NH2:15][CH2:16][CH2:17][C:18]1[CH:33]=[CH:32][C:21]([O:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([NH2:29])=[O:28])=[CH:25][N:24]=2)=[CH:20][CH:19]=1.[OH-].[Na+]>CN(C)C=O>[CH3:14][C:9]1[C:8]([CH2:7][NH:15][CH2:16][CH2:17][C:18]2[CH:33]=[CH:32][C:21]([O:22][C:23]3[CH:31]=[CH:30][C:26]([C:27]([NH2:29])=[O:28])=[CH:25][N:24]=3)=[CH:20][CH:19]=2)=[C:12]([CH3:13])[O:11][N:10]=1
Reactant: NCCc1ccc(Oc2ccc(C(N)=O)cn2)cc1
Reactant: Cc1noc(C)c1CCl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1noc(C)c1CNCCc1ccc(Oc2ccc(C(N)=O)cn2)cc1
Temperature: 25 °C
Yield: 59 %

Procedure:
Add sodium bicarbonate (0.0481 g, 0.573 mmol) to a stirred solution of 4-(chloromethyl)-3,5-dimethylisoxazole (0.054 mL, 0.435 mmol), and 6-[4-(2-amino-ethyl)-phenoxy]-nicotinamide (0.1004 g, 0.390 mmol), in dimethylformamide (4 mL). Heat the reaction to reflux under nitrogen for 4 h. Cool to room temperature, pour the reaction mixture into 1 N sodium hydroxide (50 mL), extract with diethyl ether (3×50 mL), dry the extracts over magnesium sulfate, filter, and concentrate on a rotary evaporator to give the crude product. The crude product is purified by flash chromatography on silica gel eluting with 0.8% concentrated ammonium hydroxide/8% ethanol/chloroform to yield 0.0843 g (59%) of 6-(4-{2-[(3,5-dimethyl-isoxazol-4-ylmethyl)-amino]-ethyl}-phenoxy)-nicotinamide: mass spectrum (ion spray): m/z=367.1 (M+1); 1H NMR (CDCl3): 8.57 (dd, 1H), 8.16 (dd, 1H), 7.26-7.22 (m, 4H), 7.09-7.05 (m, 2H), 6.96 (d, 1H), 3.54 (s, 2H), 2.88-2.79 (m, 4H), 2.33 (s, 3H), 2.20 (s, 3H), 1.50 (br s, 1H).
Reaction SMILES: CC(C)=O.[CH3:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][N:13]=[C:14]2[N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:9][CH:8]=1.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>C(N(CC)CC)C>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:20]2[CH2:21][CH2:22][N:17]([C:14]3[C:15]4[C:10](=[CH:9][CH:8]=[C:7]([O:6][CH3:5])[CH:16]=4)[CH:11]=[CH:12][N:13]=3)[CH2:18][CH2:19]2)=[CH:26][CH:25]=1
Reactant: COc1ccc2ccnc(N3CCNCC3)c2c1
Reactant: Fc1ccc(CBr)cc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc2ccnc(N3CCN(Cc4ccc(F)cc4)CC3)c2c1
Yield: 72 %

Procedure:
Into 10 ml of acetone, 50 mg of 7-methoxy-1-piperazin-1-ylisoquinoline, 100 mg of 4-fluorobenzyl bromide and 100 mg of triethylamine were added and heated under reflux for 5 hours. Distilling the solvent off under reduced pressure, the residue was purified on silica gel column chromatography (methanol:chloroform=1:19) to provide 52 mg (79%) of 1-[4-(4-fluorobenzyl)piperazin-1-yl]-7-methoxyisoquinoline.
Reaction SMILES: [H-].[Na+].[C:3]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].Cl[C:16]1[CH:17]=[CH:18][C:19]([N+:27]([O-:29])=[O:28])=[C:20]([CH:26]=1)[C:21]([N:23]([CH3:25])[CH3:24])=[O:22].O>CN(C)C=O>[CH3:8][O:7][C:5](=[O:6])[CH:4]([C:16]1[CH:17]=[CH:18][C:19]([N+:27]([O-:29])=[O:28])=[C:20]([C:21](=[O:22])[N:23]([CH3:24])[CH3:25])[CH:26]=1)[C:3]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: COC(=O)CC(=O)OC(C)(C)C
Reactant: CN(C)C(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])c(C(=O)N(C)C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
Sodium hydride (350 mg) was dissolved in dimethylformamide (10 mL)), and the solution was cooled to 0° C. After addition of tert-butyl methyl malonate (1.52 g), the mixture was stirred for one hour, and the 5-chloro-N,N-dimethyl-2-nitrobenzamide (1.0 g) obtained in Example 2a) was added thereto. The mixture was stirred at 70° C. for 4.5 hours and water was added thereto. The resulting solution was concentrated, diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate and purified by column chromatography on silica gel with ethyl acetate:hexane=1:1 to give the title compound (1.29 g).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:42])[C:14]1[CH:19]=[C:18]([C:20]2[CH2:24][CH2:23][CH2:22][C:21]=2[C:25]2[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=2[O:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[CH:17]=[CH:16][C:15]=1[CH3:41])(C)(C)C>ClCCl>[F:40][C:37]1[CH:36]=[CH:35][C:34]([CH2:33][O:32][C:26]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:25]=2[C:21]2[CH2:22][CH2:23][CH2:24][C:20]=2[C:18]2[CH:17]=[CH:16][C:15]([CH3:41])=[C:14]([CH:19]=2)[C:13]([OH:42])=[O:12])=[CH:39][CH:38]=1
Reactant: Cc1ccc(C2=C(c3cc(Cl)ccc3OCc3ccc(F)cc3)CCC2)cc1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C2=C(c3cc(Cl)ccc3OCc3ccc(F)cc3)CCC2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.4 %

Procedure:
Trifluoroacetic acid (1 ml) was added to a solution of 5-[2-(2-(4-fluorobenzyloxy)-5-chlorophenyl)cyclopent-1-enyl]-2-methylbenzoic acid t-butyl ester (60 mg 0.12 mmol) in dichloromethane (5 ml). The reaction mixture was stirred at room temperature for three hours. The solvent was evaporated, and the residue chromatographed (RP silica C18, acetonitrile/water 30:70–100:0) to give the title compound as a colourless solid 17 mg 33%.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[CH3:22][C:23]1[CH:32]=[C:31]([CH2:33][O:34][C:35]2[CH:59]=[CH:58][C:38]([C:39]([NH:41][CH2:42][C:43]3([N:52]4[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]4)[C:48](=[O:49])[NH:47][C:46](=[O:50])[NH:45][C:44]3=[O:51])=[O:40])=[CH:37][CH:36]=2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1>CC(C)=O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[CH:2]([N:55]1[CH2:54][CH2:53][N:52]([C:43]2([CH2:42][NH:41][C:39](=[O:40])[C:38]3[CH:37]=[CH:36][C:35]([O:34][CH2:33][C:31]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:24]=[C:23]([CH3:22])[CH:32]=4)=[CH:59][CH:58]=3)[C:44](=[O:51])[NH:45][C:46](=[O:50])[NH:47][C:48]2=[O:49])[CH2:57][CH2:56]1)([CH3:3])[CH3:9]
Reactant: Cc1cc(COc2ccc(C(=O)NCC3(N4CCNCC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Solvent: CC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(COc2ccc(C(=O)NCC3(N4CCN(C(C)C)CC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Yield: 52.7 %

Procedure:
Following a procedure analogous to that used in reaction (9), the material from example 8 was reacted with acetone for 7 days to provide the title compound (13.7 mg, 52.7%). MS found: (M+H)+=559.6.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:32]=[CH:31][CH:30]=[CH:29][C:18]=1[CH2:19][O:20][C:21]1[CH:22]=C(O)[CH:24]=[C:25]([CH3:27])[CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN1CCOCC1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:16][C:17]1[CH:32]=[CH:31][CH:30]=[CH:29][C:18]=1[CH2:19][O:20][C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)[CH:22]=1
Reactant: Cc1cc(O)cc(OCc2ccccc2Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccccc2Cl)cc(C2CCN(C(=O)OC(C)(C)C)CC2)c1
Reaction time: 8 h
Yield: 70.4 %

Procedure:
To 177 mg (0.823 mmol) of N-tert-butoxycarbonyl-4-piperidinemethanol, as prepared in step f of Example 1, 195 mg (0.785 mmol) of 3-(2-chlorobenzyloxy)-5-methylphenol, as prepared in the preceding step, 262 mg (1.02 mmol) of triphenylphosphine, and 250 μL (2.27 mmol) of N-methylmorpholine in 3 mL of tetrahydrofuran was added 140 μL (0.892 mmol) of diethyl azodicarboxylate. The reaction mixture was stirred overnight, quenched with saturated NaCl (50 mL), and extracted into ethyl acetate (50 mL). The organic extract was dried (MgSO4), and the product was partially purified by flash chromatography (ethyl acetate/hexane (1:4)), to give 230 mg of impure title compound (contaminated with 3-(2-chlorobenzyloxy)-5-methylphenol). This material was used as is in the next reaction.