Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:37])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[C:24](C(C)(C)C)=[C:25]([CH:29]=[CH:30][CH:31]=5)[C:26]([O-:28])=[O:27])[C:20]([CH3:36])=[CH:19][CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.O.Cl>CC#N>[F:37][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=5)[C:26]([OH:28])=[O:27])[C:20]([CH3:36])=[CH:19][CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1cccc(C(=O)[O-])c1C(C)(C)C
Agent: Cl
Solvent: O
Solvent: CC#N
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1cccc(C(=O)O)c1
Temperature: 45 °C
Reaction time: 36 h

Procedure:
To a slurry of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate (1.0 eq) in MeCN (3.0 vol) was added water (0.83 vol) followed by concentrated aqueous HCl (0.83 vol). The mixture was heated to 45±5° C. After stirring for 24 to 48 h, the reaction was complete, and the mixture was allowed to cool to ambient. Water (1.33 vol) was added and the mixture stirred. The solid was collected by filtration, washed with water (2×0.3 vol), and partially dried on the filter under vacuum. The solid was dried to a constant weight (<1% difference) in a vacuum oven at 60° C. with a slight N2 bleed to afford 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid.HCl as an off-white solid.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH2:9]1)C1C=CC=CC=1>[Pd].C(O)C>[NH:8]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH2:9]1
Reactant: COC(=O)CC1CCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CC1CCNC1

Procedure:
The above prepared methyl 1-benzyl-3-pyrrolidineacetate hexamate was reduced in three portions, using 3.9 g. of 10% palladium on carbon in 200 ml. of absolute ethanol, for one hour at 50° C. The reaction mixture was filtered and concentrated to give methyl 3-pyrrolidineacetate hexamate, m.p. 68.5°-69.5° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH3:10])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].C([Li])CCC.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH2:29][CH:28]3[CH2:30][CH:25]([CH2:26][CH2:27]3)[C:24]=2[CH:31]=[CH:32][CH:33]=[O:34])=[CH:19][CH:18]=1>C1COCC1.CCCCC>[F:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH2:29][CH:28]3[CH2:30][CH:25]([CH2:26][CH2:27]3)[C:24]=2/[CH:31]=[CH:32]/[CH:33]([OH:34])[CH2:7][C:5](=[O:6])[CH2:4][C:3]([O:9][CH3:10])=[O:8])=[CH:21][CH:22]=1
Reactant: COC(=O)CC(C)=O
Reactant: O=CC=CC1=C(c2ccc(F)cc2)CC2CCC1C2
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCC
Product: COC(=O)CC(=O)CC(O)/C=C/C1=C(c2ccc(F)cc2)CC2CCC1C2
Reaction time: 0.5 h

Procedure:
To a 0°-5° C. suspension of pentane-washed sodium hydride (0.43 g, 10.6 mmoles) in 10 ml anhydrous THF was added dropwise methyl acetoacetate. The solution was stirred for 30 minutes and n-butyl lithium (5.8 ml of a 1.6M solution in hexanes, 9.31 mmoles) was added dropwise. The solution was stirred for 20 minutes and a solution of 3-[3-(4-fluorophenyl)bicyclo [3.2.1]oct-2-en-2-yl]propenal (2.50 g, 9.75 mmoles) in 15 ml anhydrous THF was added. The resulting solution was stirred for 60 minutes and quenched with ether and aqueous HCl. The organic layer was washed with water and brine and dried (MgSO4). Removal of the volatiles in vacuo provided 3.3 g of the solid product which was used without further purification.
Reaction SMILES: N[C:2]([C@:4]1([CH3:30])[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[N:5]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:3].[OH:31][Li].O>CO>[CH3:27][C:26]([O:25][C:23]([N:5]1[C@@H:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[CH2:7][CH2:8][C@@:4]1([CH3:30])[C:2]([OH:31])=[O:3])=[O:24])([CH3:29])[CH3:28]
Reactant: [Li]O
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2ccc(OCc3ccccc3)cc2)CC[C@@]1(C)C(N)=O
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@@H](c2ccc(OCc3ccccc3)cc2)CC[C@@]1(C)C(=O)O
Yield: 93.4 %

Procedure:
A solution of 1,1-dimethylethyl (2S,5R)-2-(aminocarbonyl)-2-methyl-5-{4-[(phenylmethyl)oxy]phenyl}-1-pyrrolidinecarboxylate (D7, 0.977 g, 2.29 mmol) and LiOH.H2O (192 mg, 4.59 mmol, dissolved in 7 ml H2O) in methanol (7 ml) was heated in a microwave synthesizer for 1 hour at 100° C. After evaporation of methanol, the aqueous phase was acidified to pH 3 with 1M HCl and extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered and evaporated affording the title compound (white solid, 880 mg, 93%); R (cyclohexane:ethyl acetate=6:4): 0.24; Rt (HPLC): 6.07 min. MS: (ES/−) m/z: 410 [M−H]; C24H29NO5 requires 411; 1H NMR (500 MHz, DMSO-d6) δ(ppm): 12.92-12.23 (br. s, 1H); 7.48-7.40 (m, 4H); 7.40-7.33 (m, 2H); 7.31 (t, 1H); 6.92 (t, 2H); 5.08 and 5.06 (s, s, 2H); 4.85 and 4.76 (d, d, 1H); 2.48-2.34 (m, 1H); 2.19-2.05 (m, 1H); 1.81-1.72 (m, 1H); 1.64-1.57 (m, 1H); 1.46 and 1.43 (s, s, 3H); 1.32 and 1.03 (s, s, 9H).
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[CH3:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[C:11]([C:19]1[CH:20]=[N:21][C:22]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[N:23][CH:24]=1)[NH:12][C:13]2=[O:18].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH:1]1([C:4]([N:28]2[CH2:27][CH2:26][N:25]([C:22]3[N:23]=[CH:24][C:19]([C:11]4[NH:12][C:13](=[O:18])[C:14]5[C:9]([CH:10]=4)=[C:8]([CH3:7])[CH:17]=[CH:16][CH:15]=5)=[CH:20][N:21]=3)[CH2:30][CH2:29]2)=[O:5])[CH2:3][CH2:2]1
Reactant: Cc1cccc2c(=O)[nH]c(-c3cnc(N4CCNCC4)nc3)cc12
Reactant: O=C(Cl)C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cccc2c(=O)[nH]c(-c3cnc(N4CCN(C(=O)C5CC5)CC4)nc3)cc12
Reaction time: 0.17 h
Yield: 44.4 %

Procedure:
Cyclopropylcarbonyl chloride (9 μL, 2.28 mmol) was added to a stirred solution of 5-methyl-3-(2-piperazin-1-yl-pyrimidin-5-yl)-2H-isoquinolin-1-one (36 mg, 0.11 mmol) and N,N-diisopropylethylamine (23 μL, 0.132 mmol) in CH2Cl2 (2 mL) at −20° C. and allowed to stir for 10 min. The reaction mixture was concentrated in vacuo. The crude residue was purified by reverse phase preparative HPLC-MS to afford 3-[2-(4-cyclopropanecarbonyl-piperazin-1-yl)-pyrimidin-5-yl]-5-methyl-2H-isoquinolin-1-one as a white solid (19 mg, 45%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])(C)(C)C.[NH2:31][CH2:32][CH:33]([C:35]1[CH:36]=[C:37]([OH:41])[CH:38]=[CH:39][CH:40]=1)[OH:34]>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:31][CH2:32][CH:33]([OH:34])[C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([OH:41])[CH:36]=3)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: NCC(O)c1cccc(O)c1
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Product: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCC(O)c3cccc(O)c3)n2)c1

Procedure:
Intermediate 4 was coupled with 3-(2-Amino-1-hydroxy-ethyl)-phenol following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 472. 1H NMR (Varian 300 MHz, CDCl3—CD3OD, shifts relative to the solvent peak at 7.24 ppm) δ 8.1 (m, 2H) 7.9 (m, 1H) 7.6 (m, 1H) 7.5 (m, 1H) 7.3 (m, 1H) 7.0 (m, 1H) 6.8 (m, 2H) 6.6 (m, 1H) 4.8 (m, 1H) 4.4 (s, 2H) 3.8 (m, 2H) 3.3 (m, 2H) 2.9 (s, 3H) 2.7 (m, 2H) 1.7 (m, 2H).
Reaction SMILES: [CH3:1]I.[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][OH:11])[C:5]=1[OH:12]>>[F:3][C:4]1[C:5]([O:12][CH3:1])=[C:6]([CH2:10][OH:11])[CH:7]=[CH:8][CH:9]=1
Reactant: OCc1cccc(F)c1O
Reactant: CI
Product: COc1c(F)cccc1CO

Procedure:
In an analogous manner to that described in (α) 2-fluoro-6-hydroxymethyl-phenol was alkylated with methyliodide to yield (3-fluoro-2-methoxy-phenyl)-methanol as a white solid; MS: 142 (M)+.
Reaction SMILES: [N:1]([C:4]1[CH:16]=[CH:15][C:7]([C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].O=[C:18]([CH2:25][CH2:26][CH3:27])[CH2:19][C:20]([O:22]CC)=[O:21].[O-]CC.[Na+].O>C(O)C>[CH2:11]([NH:10][C:8]([C:7]1[CH:6]=[CH:5][C:4]([N:1]2[C:18]([CH2:25][CH2:26][CH3:27])=[C:19]([C:20]([OH:22])=[O:21])[N:3]=[N:2]2)=[CH:16][CH:15]=1)=[O:9])[CH2:12][CH2:13][CH3:14]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: CCCCNC(=O)c1ccc(N=[N+]=[N-])cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CCC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
4-Azido-N-butylbenzamide (2.3 g) obtained in Example 56a) and ethyl 3-oxohexanoate (1.06 ml, 6.33 mmol, 1.25 eq.) were dissolved in ethanol (20 ml), sodium ethoxide (479 mg, 6.33 mmol, 1.25 eq.) was added, and the mixture was stirred at room temperature for 30 min, and then at 60° C. for 14 hr. Water (20 ml) was added to the reaction mixture, ethanol was evaporated, and the residue was diluted with 2% aqueous sodium carbonate solution (20 ml) and washed with ethyl acetate-hexane (2:1, 50 ml). The organic layer was extracted with 2% aqueous sodium carbonate solution (20 ml). The aqueous layers were combined, washed with ethyl acetate-hexane (1:1, 30 ml), acidified with 6N hydrochloric acid and stood still at 0° C. The precipitate was collected by filtration, washed with ice-cold water and dried to give the title compound as a pale-yellow powder (1.62 g, 4.91 mmol, 97.1%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([NH2:17])=[N:13][NH:14]3)=[CH:10][CH:9]=2)[CH:5]=[C:4](S(C)(=O)=O)[N:3]=1.[C:22]1([CH2:28][CH2:29][CH2:30][NH2:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>>[NH2:17][C:12]1[C:11]2[C:15](=[CH:16][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:31][CH2:30][CH2:29][CH2:28][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:5]=3)=[CH:9][CH:10]=2)[NH:14][N:13]=1
Reactant: NCCCc1ccccc1
Reactant: CS(=O)(=O)c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(NCCCc2ccccc2)cc(-c2ccc3c(N)n[nH]c3c2)n1
Temperature: 140 °C
Yield: 15.3 %

Procedure:
A mixture of 6-[2-amino-6-(methylsulfonyl)-4-pyrimidinyl]-1H-indazol-3-amine (500 mg, 1.64 mmol), (3-phenylpropyl)amine (500 mg, 3.70 mmol), and Hunig's base (2 mL) in 1-1-methyl-2-pyrrolidinone (NMP) (3 mL) was heated for 4 hours at 140° C. in a BiotageInitiator® microwave synthesizer. Upon cooling, the mixture was decanted to remove the solids, and the resulting solution was concentrated to dryness. The crude material was purified by RPHPLC (gradient: 10% CH3CN/H2O to 30% CH3CN/H2O) to afford the title compound (90 mg) as a yellow solid. LC-MS (ES) m/z=360 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.80-1.87 (m, 2H), 2.64-2.68 (m, 2H), 3.28-3.30 (m, 2H), 5.37 (s, 2H), 5.97 (s, 2H), 6.27 (s, 1H), 6.93 (s, 1H), 7.17-7.31 (m, 5H), 7.40 (d, J=8.4 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.84 (s, 1H), 11.51 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([I:11])=[CH:4][N:3]=1.Cl.[CH2:13]([O:15][C:16](=[O:19])[CH2:17][NH2:18])[CH3:14].C(N(CC)CC)C>C(O)C>[CH2:13]([O:15][C:16](=[O:19])[CH2:17][NH:18][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([I:11])=[CH:4][N:3]=1)[CH3:14]
Reactant: O=[N+]([O-])c1cc(I)cnc1Cl
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)CNc1ncc(I)cc1[N+](=O)[O-]
Yield: 82 %

Procedure:
2-Chloro-5-iodo-3-nitro-pyridine (13 g) was dissolved in ethanol. Glycine ethyl ester HCl was added (5.0 eq) followed by triethylamine (5.0 eq). The reaction mixture was heated to 80° C. for four (4) hours. The reaction mixture was concentrated to dryness and triturated with H2O to give the title compound as a white solid (82-94% yield). M.p. 200° C. (dec), LCMS: m/z=352.08 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.30 (t, J=7.1 Hz, 3H), 4.25 (q, J=7.1 Hz, 2H), 4.33 (d, J=5.6 Hz, 2H), 8.44 (bs, 1H), 8.52 (d, J=2.0 Hz, 1H), 8.69 (d, J=2.0 Hz, 1H).
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH:3]=[CH2:4].Br[CH2:7][CH2:8][CH:9]=[O:10].[OH-].[Na+]>CO>[CH2:1]([NH:5][CH2:7][CH2:8][CH:9]=[O:10])[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCN
Reactant: O=CCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=CCCNCCC=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
But-3-enylamine (1.0 mole), the diethyl acetal of 3-bromopropionaldehyde (1.0 mole) and methanol (100 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux with stirring for a period of about 6 hours. After this time the reaction mixture is cooled to room temperature and sodium hydroxide (20 grams) is added. The reaction mixture is then stirred for an additional period of about 16 hours. The mixture is then filtered and the filtrate is distilled to yield the desired product the diethyl acetal of 3-but-3-enylaminopropionaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.[CH2:11]=O.Cl>[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[CH2:11][O:10][CH2:9][CH2:8]2
Reactant: C=O
Reactant: OCCc1cccc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Clc1ccc2c(c1)CCOC2
Reaction time: 8 h
Yield: 88.6 %

Procedure:
2-(3-Chlorophenyl)ethanol (48.2 g) and paraformaldehyde (10.8 g) were mixed and warmed to 70° on an oil bath. A stream of hydrogen chloride gas was passed vigorously through the suspension for about 7 hr. The reaction mixture was then allowed to stand at room temperature overnight. Aqueous sodium hydroxide solution (100 g/100 ml) was added cautiously to the reaction mixture. After the initial reaction subsided the rest of the alkali solution was run in fast and the resulting mixture was heated at reflux on an oil bath for 2 hr. The reaction mixture was cooled and extracted into ether (3×100 ml). The ether layer was dried (sodium sulphate) and evaporated in vacuo to give the 6-chloroisochroman as an oil (46 g), which was purified by distillation in vacuo (25.1 g, b.pt. 76°-80°/0.6 mmHg), characterised by its nmr spectrum.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH2:4]Br.[C-:12]#[N:13].[K+]>ClCCl.O.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH2:4][C:12]#[N:13]
Reactant: [C-]#N
Reactant: COc1ccc(CBr)c(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CC#N)c(Cl)c1
Yield: 96 %

Procedure:
212 g (purity 82%) of 2-chloro-4-methoxybenzyl bromide in 900 ml of dichloromethane are reacted in the course of 4 h at 40° C. with 176 g of potassium cyanide in 675 ml of water and 15.5 g of tetrabutylammonium hydrogen sulfate. After working-up, 157 g of brownish oil are obtained (purity 79%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:12][C:13]([N:15]1[CH2:20][CH2:19][C:18]([CH2:22][CH3:23])([CH3:21])[CH2:17][CH2:16]1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1>>[CH2:22]([C:18]1([CH3:21])[CH2:19][CH2:20][N:15]([C:13](=[O:14])[CH2:12][N:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3](=[O:4])[CH2:2][NH:1][C:32]([NH:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([CH3:24])[CH:26]=2)=[O:33])[CH2:16][CH2:17]1)[CH3:23]
Reactant: Cc1cccc(N=C=O)c1
Reactant: CCC1(C)CCN(C(=O)CN(C(=O)CN)c2ccccc2)CC1
Product: CCC1(C)CCN(C(=O)CN(C(=O)CNC(=O)Nc2cccc(C)c2)c2ccccc2)CC1
Yield: 21.1 %

Procedure:
The procedure is analogous to that described in Example 1, but 1.7 g of 2-amino-N-[2-(4-ethyl-4-methylpiperidino)-2-oxoethyl]-N-phenylacetamide and 0.7 g of 3-methylphenyl isocyanate are used as the starting material. After recrystallization from ethyl acetate, 0.5 g of N-[2-(4-ethyl-4-methylpiperidino)-2-oxoethyl]-2-[3-(3-methylphenyl)ureido]-N-phenylacetamide melting at 204° C is obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[O:10]=[CH:11][C:12]1[CH:20]=[CH:19][C:17](O)=[C:14](OC)[CH:13]=1>>[N:4]1([CH2:3][CH2:2][O:1][C:17]2[CH:19]=[CH:20][C:12]([CH:11]=[O:10])=[CH:13][CH:14]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: COc1cc(C=O)ccc1O
Reactant: OCCN1CCOCC1
Product: O=Cc1ccc(OCCN2CCOCC2)cc1

Procedure:
4-[2-(4-Morpholinyl)-ethoxy]-benzaldehyde was prepared from N-(2-hydroxyethyl)morpholine (Aldrich) and vanillin (Aldrich) by method H above.
Reaction SMILES: [CH3:1][C:2]([C@@:4]1([OH:29])[CH2:27][C@H:26]([OH:28])[C:7]2=[C:8]([OH:25])[C:9]3[C:21](=[O:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][C:19]=4[O:23][CH3:24])[C:13](=[O:14])[C:10]=3[C:11]([OH:12])=[C:6]2[CH2:5]1)=[O:3].BrBr.[OH-:32].[Na+]>C(Cl)(Cl)Cl>[CH3:24][O:23][C:19]1[C:20]2[C:21]([C:9]3[C:8]([OH:25])=[C:7]4[C:6]([CH2:5][C@@:4]([OH:29])([C:2]([CH2:1][OH:32])=[O:3])[CH2:27][C@@H:26]4[OH:28])=[C:11]([OH:12])[C:10]=3[C:13](=[O:14])[C:15]=2[CH:16]=[CH:17][CH:18]=1)=[O:22]
Reactant: [OH-]
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(C)=O)C[C@@H]3O
Agent: BrBr
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)CO)C[C@@H]3O
Reaction time: 16 h
Yield: 86.9 %

Procedure:
Daunomycinone (IX) (10 mg, 0.025 mmole) was placed in CHCl3 (1 ml). Br2 (13.5 mg) in CHCl3 (0.25 ml) was added and the solution stirred at 23° for 16 hrs. The solvent was removed and the residue was dissolved in 80% aq acetone (5 ml). NaOH (1.1 mg. 0.028 mmole) was added and the blue solution was refluxed for 5 min when the red color returned. The solution was concentrated to approximately 2 ml, diluted with water (10 ml) and extracted with 50% CHCl3 /MeOH (3 × 10 ml). The extracts were combined, dried and evaporated. The residue was crystallized from CHCl3 -MeOH/pet. ether (30°-60°) to afford 9.0 mg (87%) of (XI): irnujol 2.85 (OH), 5.75 (C = O), 615, 628 μ (chelated quinone); pmr 100 MHz CDCl3 δ 2.0-2.5 (m, 2H, 8-H2), 2.8-3.2 (m, 2H, 10-H2), 3.43 (m, 1H, 9-OH), 4.09 (s, 3H, OMe), 4.70 (d, 2H, J = 16Hz, 14-H2), 5.34 (m, 1H, ∥1/2 = 8Hz, 7-H), 7.38 (dd, 1H, J = 8Hz and J = 1Hz, 3-H), 7.76 (t, 1H, J = 8Hz, 2-H), 8.00 (dd, 1H, J = 8Hz and J = 1Hz, 1-H), 13.24 (s, 1H, 6-OH), 13.99 (s, 1H, 11-OH).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH:4]=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[CH3:13].[BH4-].[Na+]>CO.O>[Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[CH3:13]
Reactant: Cc1c(Cl)cccc1N=Cc1ccccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1c(Cl)cccc1NCc1ccccc1Cl
Reaction time: 0.25 h

Procedure:
A suspension of N-(o-chlorobenzylidene)-2-methyl-3-chloroaniline (0.038 mole) is brought to reflux in 100 cc of absolute methanol. An equivalent of sodium borohydride (1.5 g.) is added in portions and refluxing is continued for 15 mins. The reaction mixture is cooled and diluted with an equal volume of cold water to precipitate a solid. This material is collected, washed with H2O and air dried. Recrystallization from ethanol gives N-(o-Chlorobenzyl)-2-methyl-3-chloroaniline. m.p. 63°-66° C.
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[N:9][N:10]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:11]=2[CH:12]([CH3:14])[CH3:13])[C:3]1=[O:22].[F:23][C:24]([F:31])([F:30])[C:25]1[N:26]=[CH:27][NH:28][CH:29]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:21][C:18]1[CH:19]=[CH:20][C:15]([N:10]2[C:11]([CH:12]([CH3:14])[CH3:13])=[C:7]([N:4]3[CH2:5][CH2:6][CH:2]([N:28]4[CH:29]=[C:25]([C:24]([F:31])([F:30])[F:23])[N:26]=[CH:27]4)[C:3]3=[O:22])[CH:8]=[N:9]2)=[CH:16][CH:17]=1
Reactant: FC(F)(F)c1c[nH]cn1
Reactant: CC(C)c1c(N2CCC(Br)C2=O)cnn1-c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1c(N2CCC(n3cnc(C(F)(F)F)c3)C2=O)cnn1-c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
A mixture of 3-bromo-1-[1-(4-fluorophenyl)-5-isopropyl-pyrazol-4-yl]pyrrolidin-2-one (0.020 g, 0.055 mmol), 4-(trifluoromethyl)-1H-imidazole (0.024 g, 0.17 mmol) and K2CO3 (0.030 g, 0.22 mmol) in DMF (0.6 mL) was stirred at 60° C. for 1 hr. The mixture was then cooled to room temperature, quenched with water (30 mL) and extracted with EtOAc (50 mL). The organic layer was separated, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to yield the title compound (0.022 g, TFA salt, 75%); 1H NMR (TFA salt) (400 MHz, CDCl3) δ 7.98 (s, 1H), 7.59 (s, 1H), 7.51 (s, 1H), 7.39 (dd, J=8.4, 4.8 Hz, 2H), 7.20 (dd, J=8.6, 8.6 Hz, 2H), 5.06 (dd, J=10.8, 8.8 Hz, 1H), 3.90 (m, 1H), 3.83 (m, 1H), 2.98 (m, 2H), 2.54 (m, 1H), 1.21 (d, J=7.2 Hz, 3H), 1.20 (d, J=7.2 Hz, 3H); MS: (ES) m/z calculated for C20H19F4N5O (free form) [M+H]+ 422.1. found 422.1.
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH2:8][C:5]([CH2:10][NH:11][C:12]3[N:17]=[C:16]([N:18]4[C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[N:20]=[C:19]4[CH:27]([F:29])[F:28])[CH:15]=[C:14]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[N:13]=3)([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.C(N(CC)C(C)C)(C)C.[CH3:45][C:46]1([CH3:49])[CH2:48][O:47]1>C(O)C>[F:29][CH:27]([F:28])[C:19]1[N:18]([C:16]2[CH:15]=[C:14]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[N:13]=[C:12]([NH:11][CH2:10][C:5]34[CH2:6][CH2:7][C:2]([NH:1][CH2:45][C:46]([CH3:49])([OH:47])[CH3:48])([CH2:9][CH2:8]3)[CH2:3][CH2:4]4)[N:17]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=1
Reactant: CC1(C)CO1
Reactant: NC12CCC(CNc3nc(N4CCOCC4)cc(-n4c(C(F)F)nc5ccccc54)n3)(CC1)CC2
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(O)CNC12CCC(CNc3nc(N4CCOCC4)cc(-n4c(C(F)F)nc5ccccc54)n3)(CC1)CC2
Temperature: 140 °C
Reaction time: 1 h

Procedure:
N-[(4-Aminobicyclo[2.2.2]oct-1-yl)methyl]-4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)pyrimidin-2-amine (150 mg) was dissolved in ethanol (3 mL), and N,N-diisopropyl ethylamine (81 μL) and 2,2-dimethyloxirane (36 μL) were added thereto, followed by stirring at 120° C. for 1 hour and at 140° C. for 1 hour using a microwave reactor. The reaction solution was concentrated and the residue was purified by amino silica gel column chromatography (hexane:ethyl acetate=20:80, and subsequently chloroform:methanol=98:2) to obtain 1-({4-[({4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)pyrimidin-2-yl}amino)methyl]bicyclo[2.2.2]oct-1-yl}amino)-2-methylpropan-2-ol (148 mg) as a white amorphous substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=2)OCCC#N)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:25]([NH2:28])(=O)[CH3:26].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:24]=[CH:23][C:22]([CH2:26][CH2:25][NH2:28])=[CH:16][CH:15]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: N#CCCOc1cccc(CCNS(=O)(=O)c2ccc(Cl)cc2)c1
Reactant: CC(N)=O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1
Product: NCCc1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 110 °C
Yield: 63 %

Procedure:
1-[3-[2-(4-chlorophenylsulphonylamino)-ethyl]-phenoxy]-2-cyanoethane, m.p. 90°-93° C. which can be prepared by heating to 110° C. for 5 hours s mixture of 3-[2-[4-chlorophenylsulphonylamino)-ethyl]-phenoxy]-acetamide (1 mol), P2O5 (2 mol) and toluene. Yield 63% of theory; m.p. 94° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6](C1C=CC=CC=1)[C:5]2(OCC)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.N[OH:30]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N+:6]([O-:30])=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC1(c2ccccc2)c2cc(Cl)ccc2NC(=O)N1c1ccccc1
Reactant: NO
Agent: Cl
Product: O=c1[nH]c2ccc(Cl)cc2c(-c2ccccc2)[n+]1[O-]
Yield: 71.8 %

Procedure:
A mixture of 3.51 g (0.0093 mole) of 6-chloro-4-ethoxy-3,4-dihydro-3,4-diphenyl-2(1H)-quinazolinone and 2.09 g (0.03 mole) of hydroxylamine hydrochloride in 50 ml alcohol was refluxed for 4 days, and then cooled. The solid that formed was collected on a filter, washed with ethanol, and dried in air to give 1.82 g (72%) of 6-chloro-4-phenyl-2(1H)-quinazolinone 3-oxide as yellow crystals, mp 267°-269°.