Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:33])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[O:9][C:10]2[CH:16]=[C:15]([CH2:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C@H:27]([CH3:32])[CH2:28][C:29]([OH:31])=[O:30])=[CH:23][CH:22]=3)=[O:19])[CH:14]=[CH:13][C:11]=2[N:12]=1.F[P-](F)(F)(F)(F)F.[N:41]1([O:50]C(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[OH2:9].[OH2:50].[C:1]1([CH3:33])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[NH:41][C:10]2[CH:16]=[C:15]([CH2:17][C:18]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([C@H:27]([CH3:32])[CH2:28][C:29]([OH:31])=[O:30])=[CH:25][CH:26]=3)=[O:19])[CH:14]=[CH:13][C:11]=2[N:12]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1ccccc1Nc1nc2ccc(CC(=O)Nc3ccc([C@H](C)CC(=O)O)cc3)cc2o1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1Nc1nc2ccc(CC(=O)Nc3ccc([C@H](C)CC(=O)O)cc3)cc2[nH]1
Product: O
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.5 %

Procedure:
A solution of 2-(2-o-tolylamino)benzimidazole-5-acetic acid hydrochloride (200 mg, Reference Example 7), ethyl (R)-3-(4-aminophenyl)butanoate (147 mg, Reference Example 1) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (300 mg) in dimethylformamide (5 mL) was treated with diisopropylethylamine (470 mg). After stirring at room temperature for 2 hours the reaction mixture was partitioned between ethyl acetate and dilute aqueous acetic acid. The layers were separated and the organic layer was washed with 5% aqueous sodium bicarbonate solution, then dried, and then evaporated. The yellow semi-solid residue (120 mg) was dissolved in ethanol (5 mL) and the solution was treated with aqueous lithium hydroxide solution (2 mL, 2M). After standing at room temperature for 2 hours the mixture was acidified by addition of dilute acetic acid. The resulting white solid was collected by filtration, and sucked dry in the filter funnel to give the title compound (42 mg) as a white amorphous solid. LC-MS: RT=2.29 minutes (100% by ELSD); MS (ES+), 443 (MH+).
Reaction SMILES: CN(C)[CH2:3][C:4]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[NH:6][CH:5]=1.O.[C-:15]#[N:16].[Na+]>C1COCC1>[NH:6]1[C:7]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[C:4]([CH2:3][C:15]#[N:16])=[CH:5]1
Reactant: [C-]#N
Reactant: CN(C)Cc1c[nH]c2cccnc12
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#CCc1c[nH]c2cccnc12
Yield: 68 %

Procedure:
A stirred solution of dimethyl-(1H-pyrrolo[3,2-b]pyridin-3-yl)methylamine (0.828 g, 4.73 mmol) in dry THF (20 mL) under nitrogen is treated with a solution of (CH3O)2SO2 (0.49 mL) in THF, heated at reflux temperature for 0.5 h, cooled in an ice bath, and decanted. The gummy residue is washed with ether, treated with water (15 mL) and NaCN (0.39 g, 6.2 mmol), heated at reflux temperature for 0.75 h, cooled and extracted with 4:1 CH2Cl2:ethanol. The combined extracts are dried over MgSO4 and concentrated in vacuo. The resultant residue is chromatographed (silica gel, ethyl acetate as eluent) to afford the title compound as a white solid, 0.51 g (68% yield), mp 201-202° C., identified by NMR and mass spectral analyses.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:35][CH2:36][CH2:37][CH2:38][CH:39]([OH:44])[CH2:40][CH2:41][CH2:42][CH3:43].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:24](=[O:26])[O:44][CH:39]([CH2:40][CH2:41][CH2:42][CH3:43])[CH2:38][CH2:37][CH2:36][CH3:35])=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCCCC(O)CCCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(CCCC)OC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Yield: 2.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 5-nonanol (38 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (2 mg, yield 2%).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][CH:12]=[C:13]2[N+:16]([O-:18])=[O:17])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:20]O.[OH-].[K+].O>CCO.CO>[NH2:20][C:10]1[C:9]2[C:14](=[CH:15][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:7][CH:8]=2)[C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1
Reactant: CC(C)(C)Oc1ccc2cccc([N+](=O)[O-])c2c1
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Solvent: O
Product: CC(C)(C)Oc1ccc2c(N)ccc([N+](=O)[O-])c2c1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 7-tert-butoxy-1-nitronaphthalene, as described above in Step D, (3.35 g, 13.7 mmol) and hydroxylamine hydrochloride (5.94 g, 85.5 mmol) in 95% EtOH (140 mL) at 60° C. was added KOH (11.9 g, 212 mmol) in MeOH (75 mL), dropwise over 30 min. The reaction mixture was stirred at 60° C. for 6 hours, then poured into H2O (200 mL) and extracted with CH2Cl2 (3×300 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with a gradient of hexane—20% to 40% EtOAc to yield the titled product.
Reaction SMILES: [C:1]([N:4]1[CH:9]([CH2:10]OCC2C=CC=CC=2)[CH2:8][N:7]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:6](=[O:27])[CH2:5]1)(=[O:3])[CH3:2].[S:28]1(=[O:35])(=[O:34])[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]1.C(C=P(CCCC)(CCCC)CCCC)#N>C(O)C.C1C=CC=CC=1.[Pd]>[C:1]([N:4]1[CH:9]([CH2:10][N:29]2[CH2:30][CH2:31][CH2:32][CH2:33][S:28]2(=[O:35])=[O:34])[CH2:8][N:7]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[C:6](=[O:27])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=S1(=O)CCCCN1
Reactant: CC(=O)N1CC(=O)N(Cc2ccc(F)cc2)CC1COCc1ccccc1
Agent: [Pd]
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: c1ccccc1
Solvent: CCO
Product: CC(=O)N1CC(=O)N(Cc2ccc(F)cc2)CC1CN1CCCCS1(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-acetyl-5-[(benzyloxy)methyl]-1-(4-fluorobenzyl)piperazin-2-one (6.5 g) and 20% Pd/C (1.4 g) in ethanol (175 mL) was shaken under an atmosphere of hydrogen (60 psi) at room temperature overnight. The product mixture was filtered through a pad of Celite, and concentrated under vacuum. Residual ethanol was removed by co-evaporation with toluene under vacuum (3×). The resultant alcohol was used without further purification. A mixture of the alcohol (1.0 g, 3.57 mmol), 1,2-thiazinane 1,1-dioxide (0.73, 5.4 mmol), and cyanomethylenetri-n-butylphosphorane (1.3 g, 5.4 mmol; [157141-27-0]) in benzene (20 mL) was purged with nitrogen and heated in a sealed tube at 100° C. overnight. The reaction mixture was concentrated under vacuum, and the residue was subjected to column chromatography on silica gel eluting with a mixture of 5% methanol in ethyl acetate. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[N:24]([C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]([CH3:34])[CH:28]=1)=[C:25]=[O:26]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[N:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]([CH3:34])[CH:28]=3)[C:25]2=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Reactant: Cc1ccc(N=C=O)cc1C
Product: COc1cccc2c1ncc1c(=O)n(-c3ccc(C)c(C)c3)c(=O)n(C3CCCC3)c12
Yield: 79.7 %

Procedure:
1-Cyclopentyl-3-(3,4-dimethyl-phenyl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (106 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.32 mmol) and 1-isocyanato-3,4-dimethyl-benzene (0.48 mmol) following general procedure C. LCMS: m/z 416 [M+1]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]1[C:20]([OH:21])=[C:19]([O:22][CH3:23])[C:18]([O:24][CH3:25])=[CH:17][C:16]=1[CH3:26])=O.Cl(O)(=O)(=O)=O.[C:32](O)(=[O:34])[CH3:33]>[C].[Pd]>[C:32]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:15]1[C:20]([OH:21])=[C:19]([O:22][CH3:23])[C:18]([O:24][CH3:25])=[CH:17][C:16]=1[CH3:26])(=[O:34])[CH3:33]
Reactant: CC(=O)O
Reactant: COc1cc(C)c(C(=O)CCCCCCCCCCCO)c(O)c1OC
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Product: COc1cc(C)c(CCCCCCCCCCCCOC(C)=O)c(O)c1OC

Procedure:
To a solution of 6-(12-hydroxy-1-oxododecyl)-2,3-dimethoxy-5-methylphenol (6.4 g) in acetic acid (150 ml) are added 5% palladium-carbon (50% hydrous) (1.1 g) and 70% perchloric acid (0.1 ml) and the mixture is subjected to the catalytic reduction at atmospheric temperature and pressure. After the absorption of hydrogen has been completed, the catalyst is filtered off and the filtrate is concentrated under reduced pressure. The residue is extracted with dichloromethane and the dichloromethane layer is washed with a 5% aqueous solution of sodium hydrogen carbonate and dried over anhydrous magnesium sulfate. The solvent is distilled off to give 6-(12-acetoxydodecyl)-2,3-dimethoxy-5-methylphenol (6.8 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]([CH2:13][CH:14]=O)[C:4](=[O:16])[CH:3]=1.[C:17]([O:21][C:22](=[O:41])[N:23]([CH2:30][C:31]1[CH:40]=[CH:39][C:34]2[O:35][CH2:36][CH2:37][O:38][C:33]=2[CH:32]=1)[CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[C:17]([O:21][C:22](=[O:41])[N:23]([CH2:30][C:31]1[CH:40]=[CH:39][C:34]2[O:35][CH2:36][CH2:37][O:38][C:33]=2[CH:32]=1)[CH:24]1[CH2:29][CH2:28][N:27]([CH2:14][CH2:13][N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=3)[C:2]([Cl:1])=[CH:3][C:4]2=[O:16])[CH2:26][CH2:25]1)([CH3:20])([CH3:18])[CH3:19]
Reactant: O=CCn1c(=O)cc(Cl)c2ccc(F)cc21
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cc(Cl)c3ccc(F)cc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.9 %

Procedure:
To 20 mL of a chloroform solution containing 0.71 g of (4-chloro-7-fluoro-2-oxoquinolin-1(2H)-yl)acetaldehyde, 1.03 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate and 0.18 g of acetic acid were added, and stirred at room temperature for 1 hour. To the reaction mixture, 0.99 g of sodium triacetoxyborohydride was added, and stirred for 1 hour. Aqueous saturated sodium hydrogen carbonate solution was added, and the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; ethyl acetate:hexane=4:1], to give 0.76 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(4-chloro-7-fluoro-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][CH:16]1[CH2:21][CH2:20][CH:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:18][CH2:17]1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([O:43][CH3:44])[C:29]=1[OH:45]>>[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][CH:16]2[CH2:21][CH2:20][CH:19]([N:22]([CH2:23][CH3:24])[CH2:25][CH3:26])[CH2:18][CH2:17]2)[CH:31]=[C:30]([O:43][CH3:44])[C:29]=1[OH:45]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Reactant: CCN(CC)C1CCC(Nc2c(C(C)=O)cnc3ccc(Br)cc23)CC1
Product: CCN(CC)C1CCC(Nc2c(C(C)=O)cnc3ccc(-c4cc(Cl)c(O)c(OC)c4)cc23)CC1
Yield: 43.3 %

Procedure:
Following general procedure D, 1-{6-bromo-4-[4-(diethylamino)cyclohexylamino]quinolin-3-yl}ethanone (42 mg, 0.100 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (57 mg, 0.200 mmol) to afford the desired product (21.5 mg, 43%) as an orange solid: 1H NMR (500 MHz, CD3OD) δ 8.93 (s, 1H), 8.32 (d, J=1.8 Hz, 1H), 8.03 (dd, J=8.7, 1.9 Hz, 1H), 7.90 (d, J=8.7 Hz, 1H), 7.29 (d, J=2.1 Hz, 1H), 7.22 (d, J=2.1 Hz, 1H), 4.26 (s, 1H), 3.99 (s, 3H), 3.08 (q, J=7.2 Hz, 4H), 2.69 (s, 3H), 2.44 (s, 2H), 2.14 (s, 2H), 1.79-1.64 (m, 4H), 1.29 (t, J=7.2 Hz, 6H); ESI MS m/z 496 [C28H34ClN3O3+H]+; HPLC>99% (AUC), tR=10.50 min.
Reaction SMILES: [CH2:1]1[CH:13]2[N:4]([CH2:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:12]2=[O:14])[C:3](=O)[CH2:2]1.Cl.[NH2:17][OH:18].O.O.O.C([O-])(=O)C.[Na+]>C(O)C.O>[CH2:1]1[CH:13]2[N:4]([CH2:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:12]2=[O:14])[C:3](=[N:17][OH:18])[CH2:2]1
Reactant: NO
Reactant: O=C1c2ccccc2CN2C(=O)CCC12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C1c2ccccc2CN2C(=NO)CCC12
Reaction time: 8 h
Yield: 81.9 %

Procedure:
A mixture consisting of 2.5 g of 1,10a-dihydropyrrolo[1,2-b]isoquinoline-3,10[2H,5H]-dione in 20 ml of 95% ethanol (EtOH), 1.72 g of hydroxylamine hydrochloride in 10 ml of water and 3.7 g of sodium acetate trihydrate in 10 ml of water was refluxed for 7 hours and thereafter allowed to stand overnight at ambient temperature. The product crystallized from the reaction mixture to give 2.2 g of crystals. Recrystallization from 95% EtOH gave 1.4 g of crystals, m.p. 206°-209° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)=O.[NH2:12][C:13]1[N:18]=[C:17]([NH2:19])[CH:16]=[CH:15][N:14]=1>CC(C)=O>[F:11][C:7]1[CH:6]=[C:5]([C:3]2[N:12]=[C:13]3[N:18]=[C:17]([NH2:19])[CH:16]=[CH:15][N:14]3[CH:2]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CBr)c1cccc(F)c1
Reactant: Nc1ccnc(N)n1
Solvent: CC(C)=O
Product: Nc1ccn2cc(-c3cccc(F)c3)nc2n1

Procedure:
2-Bromo-1-(3-fluorophenyl)ethanone (10.9 g, 50 mmol) was added to a solution of 2,4-diaminopyrimidine (3.70 g, 34 mmol) in acetone (185 ml), and the mixture was heated to reflux for 6 h. The cooled suspension was filtered and the precipitate was washed with acetone (50 ml). The solid was re-suspended in water (35 ml) and NH4OHaq. (25%, 50 ml), then it was collected over a glass fiber paper and the filtrate was washed with H2O (75 ml). After drying under vacuum, the product was obtained (5.56 g, 72%) as a yellow solid.
Reaction SMILES: [CH2:1]([CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]=2)[CH2:7][CH2:6][C:5]1=[O:22])[CH:2]=[CH2:3].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(Cl)(Cl)Cl>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][C:4]1([CH2:1][CH:2]=[CH2:3])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:12]=2)[CH2:7][CH2:6][C:5]1=[O:22])[CH3:29]
Reactant: CCOC(=O)CBr
Reactant: C=CCC1C(=O)CCc2ccc(OCc3ccccc3)cc21
Solvent: ClC(Cl)Cl
Product: C=CCC1(CC(=O)OCC)C(=O)CCc2ccc(OCc3ccccc3)cc21

Procedure:
Crude 1-allyl-7-benzyloxy-3,4-dihydro-2(1H)-naphthalenone (VIIIc), 22.9 g (78.5 mmol) was reacted with ethyl bromoacetate by the method of Example 5 to yield 25.5 g (87%) crude crystalline IXc. Recrystallization from ethanol gave 19.5 g (66%) m.p. 83°-85°. IR (CHCl3) 1725, 1710 cm-1 (ketone and ester); NMR δ, 1.05 and 3.96 (triplet and quartet and OCH2CH3) 4.8-5.8 (m, 5, olefinic and PhCH2O), 5.15 (s, 2, PhCH2O), 6.80-7.55 (m, 8, ArH).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C(N1CCN(C2C=C(N[C:30]([C:32]3[C:33]4[N:34]=[CH:35][CH:36]=[N:37][C:38]=4[C:39]([C:42]4[C:51]5[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=5)[CH:45]=[N:44][CH:43]=4)=[CH:40][CH:41]=3)=[O:31])C=CC=2)CC1)C>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([NH:14][C:30]([C:32]3[C:33]4[N:34]=[CH:35][CH:36]=[N:37][C:38]=4[C:39]([C:42]4[C:51]5[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=5)[CH:45]=[N:44][CH:43]=4)=[CH:40][CH:41]=3)=[O:31])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CCN1CCN(c2cccc(NC(=O)c3ccc(-c4cncc5ccccc45)c4nccnc34)c2)CC1
Reactant: CN1CCN(c2ccc(N)cn2)CC1
Product: CN1CCN(c2ccc(NC(=O)c3ccc(-c4cncc5ccccc45)c4nccnc34)cn2)CC1
Reaction time: 20 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but stirring the reaction mixture for 20 h at it and using 6-(4-methylpiperazin-1-yl)-pyridin-3-ylamine (prepared as described in Example 33 but using N-methyl-piperazine in Step 33.2) and 8-isoquinolin-4-yl-quinoxaline-5-carboxylic acid (Example 52). Title compound: ESI-MS: 476.1 [M+H]+; tR=1.98 min (System 1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]([N:20]3[CH2:25][CH2:24][C:23]4([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=5[CH2:27][O:26]4)[CH2:22][CH2:21]3)=[O:19])=[CH:7][N:8]2[CH2:11][C@H:12]2[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]2)=[CH:4][CH:3]=1.[CH3:34]C(O)=O.[BH3-]C#N.[Na+]>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]([N:20]3[CH2:21][CH2:22][C:23]4([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=5[CH2:27][O:26]4)[CH2:24][CH2:25]3)=[O:19])=[CH:7][N:8]2[CH2:11][C@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([CH3:34])[CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=C(c1cn(C[C@H]2CCCNC2)c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Reactant: CC(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN1CCC[C@H](Cn2cc(C(=O)N3CCC4(CC3)OCc3ccccc34)c3ccc(Cl)cc32)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 1′-({6-chloro-1-[(3S)-piperidin-3-ylmethyl]-1H-indol-3-yl}carbonyl)-3H-spiro[2-benzofuran-1,4′-piperidine] in MeOH was treated with aq. H2CO (1.5 eq), AcOH (1.1 eq) and stirred for 15 min at room temperature, then treated with NaCNBH3 (1.1 eq) and stirred at room temperature for 1 h. Concentration and purification by preparative HPLC the desired product. ES-MS m/e (%): 478.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)=[C:6]([NH2:8])[N:7]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>CN(C)C1C=CN=CC=1.O1CCOCC1>[NH2:8][C:6]1[N:7]=[C:2]([NH:1][C:17]([CH3:18])=[O:19])[N:3]=[N:4][C:5]=1[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nnc(-c2ccc(Cl)c(Cl)c2)c(N)n1
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Product: CC(=O)Nc1nnc(-c2ccc(Cl)c(Cl)c2)c(N)n1

Procedure:
A stirring mixture of 5.0 grams (0.020 mole) of 3,5-diamino-6-(3,4-dichlorophenyl)-1,2,4-triazine (Compound 24; disclosed in J. Med. Chem., 1972, Vol. 15, No 8. 859-861), 2.0 grams (0.020 mole) of acetic anhydride and 0.01 gram (catalyst) of 4-dimethylaminopyridine in 40 mL of dioxane is heated at reflux for about two hours. The mixture is cooled and concentrated under reduced pressure to a residue. The residue is purified by column chromatography on silica gel, yielding 5-amino-3-methylcarbonylamino-6-(3,4-dichlorophenyl)-1,2,4-triazine.
Reaction SMILES: [C:1]1([CH3:25])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.Br[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36]CC)=[O:35]>>[O:24]=[C:21]1[N:20]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])[C:10]2=[N:11][C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)=[C:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:25])=[CH:6][CH:5]=3)[N:8]=[C:9]2[CH2:23][CH2:22]1
Reactant: CCOC(=O)CCCCCCCBr
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)NC(=O)CC3)cc1
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(CCCCCCCC(=O)O)C(=O)CC3)cc1

Procedure:
The titled compound was prepared from 2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-6(5H)-one ((prepared according to the preparation procedures disclosed in PCT patent application PCT/EP2011/062028, Example 12.1 step 1) and ethyl 8-bromooctanoate analogously to Example 1.1 steps 1 and 2;
Reaction SMILES: [C:1]([NH:4][CH:5](C(OCC)=O)[C:6]([O:8]CC)=[O:7])(=[O:3])[CH3:2].[H-].[Na+].[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](Br)(Br)[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:21][CH:20]=1.C1(C)C=CC=CC=1>CN1CCCC1=O.O>[C:1]([NH:4][CH:5]([CH:25]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:22]1[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=1)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: Fc1ccc(C(Br)(Br)c2ccc(F)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)NC(C(=O)O)C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
To a solution of diethyl acetamidomalonate (1.09 g, 5 mmol) in N-methyl-2-pyrrolidone (4 mL) was added 55% sodium hydride (219 mg, 5 mmol), and the mixture was stirred at room temperature for 1 hr. Bis(4-fluorophenyl)methylene bromide (990 mg, 4 mmol) was added, and the mixture was stirred at 50° C. for 4 hrs. After completion of the reaction, toluene (20 mL) and water (10 mL) were added to the reaction mixture and the mixture was partitioned. The obtained organic layer was washed twice with water (10 mL) and concentrated. Ethanol (4.5 mL) and 2M aqueous sodium hydroxide solution (5 mL) were added to the concentrated solution, and the mixture was stirred at 90° C. for 16 hrs. The reaction mixture was allowed to cool to 25° C., toluene (8 mL) and water (5 mL) were added, and the mixture was partitioned. The aqueous layer was concentrated to a half volume, and isopropyl acetate (8 mL) and water (10 mL) were added. The mixture was adjusted to pH 1.1 with concentrated hydrochloric acid and partitioned. The organic layer was washed with water (10 mL), concentrated and dried under vacuum to give the title compound (973 mg).