Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.Cl.[C:13]1([C:19]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:27]3[CH:23]([CH2:24][NH:25][CH2:26]3)[C:22](=[O:28])[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([N:25]2[CH2:24][CH:23]3[CH:27]([C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:20][CH2:21][C:22]3=[O:28])[CH2:26]2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Reactant: O=C(O)Cc1ccc(F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3ccc(F)cc3)CC12
Reaction time: 1 h
Yield: 66.8 %

Procedure:
N,N'-Carbonyldiimidazole (1.13 g) is added to a solution of 2-(4-fluorophenyl)acetic acid (1.08 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 1 hour at +5° C. and a solution of 7,7-diphenyl-4-perhydroisoindolone hydrochloride (2.3 g) and triethylamine (0.98 cc) in dichloromethane (40 cc) is then added. The reaction mixture is stirred for 1 hour at +5° C. and then for 16 hours at 20° C. The reaction mixture is washed with distilled water (3×50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized form acetonitrile (5 cc). The crystals are drained, washed with isopropyl ether (10 cc) and dried. (3aRS,7aRS)-2-[(4-fluorophenyl)acetyl]-7,7-diphenyl-4-perhydroisoindolone (2 g) melting at 210° C. is obtained.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:22][CH3:23])[CH2:4][NH:5][C:6](=[O:21])[C@H:7]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH2:8][C:9]#[CH:10].[F:24][C:25]([F:44])([F:43])C1C=C(S(N[C@H](CC#C)C(O)=O)(=O)=O)C=CC=1>>[CH3:23][O:22][CH:3]([O:2][CH3:1])[CH2:4][NH:5][C:6](=[O:21])[C@H:7]([NH:11][S:12]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([C:25]([F:44])([F:43])[F:24])[CH:20]=1)(=[O:14])=[O:13])[CH2:8][C:9]#[CH:10]
Reactant: C#CC[C@@H](NS(=O)(=O)c1ccccc1)C(=O)NCC(OC)OC
Reactant: C#CC[C@@H](NS(=O)(=O)c1cccc(C(F)(F)F)c1)C(=O)O
Product: C#CC[C@@H](NS(=O)(=O)c1cccc(C(F)(F)F)c1)C(=O)NCC(OC)OC

Procedure:
Using the same procedure describe for the synthesis of 39, (R)-2-(3-trifluoromethylbenzenesulfonamido)pent-4-ynoic acid afforded the title compound. 1H NMR (300 MHz, CDCl3): δ 2.05 (s, 1H), 2.65 (m, 2H), 2.85 (s, 3H), 2.96 (s, 3H), 3.35 (m, 2H), 3.96 (t, 6.3 Hz, 1H), 4.32 (t, 5.4 Hz, 1H), 6.86 (t, 5.4 Hz, 1H), 7.68 (t, 7.8 Hz, 1H), 7.82 (d, 7.8 Hz, 1H), 7.97 (s5; 1H), 8.03 (d, 7.8 Hz, 1H), 8.11 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Br)([O-:3])=[O:2].[O:12]([S:14]([CH3:16])=[O:15])[Na]>CCO>[CH3:16][S:14]([CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:15])=[O:12]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: CS(=O)O[Na]
Solvent: CCO
Product: CS(=O)(=O)Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 77.3 %

Procedure:
To a mixture of 3-nitrobenzyl bromide (1 g, 4.63 mmol) in EtOH (12 mL) was added NaOSOCH3 (0.61 g, 5.09 mmol). After heating at reflux for 2 h, the mixture was cooled to room temperature, and the precipitates were collected by filtration to give 1-(methylsulfonylmethyl)-3-nitrobenzene (0.77 g).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([NH:8][NH2:9])=[O:7])([O-:3])=[O:2].Cl[C:15](OC(Cl)(Cl)Cl)=[O:16]>O1CCOCC1>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]1[O:7][C:15](=[O:16])[NH:9][N:8]=1)([O-:3])=[O:2]
Reactant: NNC(=O)c1ccccc1[N+](=O)[O-]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: O=c1[nH]nc(-c2ccccc2[N+](=O)[O-])o1
Yield: 86.3 %

Procedure:
A solution of 2-nitrobenzoylhydrazine (9.05 g, 0.05 mol) in dioxane (30 mL) was slowly added to a solution of trichloromethyl chloroformate (4.6 mL, 0.04 mol) in dioxane (30 mL) at room temperature. On completion of the addition the reaction was heated to reflux for 4 hours. The solvent was evaporated off and the residue re-crystallised from 96%. ethanol (50 mL) to give 7.15 g of the 5-(2-nitrophenyl)-3H-[1,3,4]oxadiazol -2-one. M.p. 157-158° C. A solution of the nitro compound (2 g, 9.7 mmol) in 96% ethanol (25 mL) was hydrogenated over 5% palladium on charcoal to give desired 1.6 g of the desired amine.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:8]([Cl:16])[CH:7]=2)[CH2:2]1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[O:29][C:28]([C:30](OCC)=[O:31])=[N:27][N:26]=2)=[CH:21][CH:20]=1>>[Cl:16][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=1[CH2:12][N:13]([CH3:14])[CH3:15])[O:5][CH:3]1[CH2:4][N:1]([C:30]([C:28]2[O:29][C:25]([C:22]3[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)=[N:26][N:27]=2)=[O:31])[CH2:2]1
Reactant: CN(C)Cc1ccc(OC2CNC2)cc1Cl
Reactant: CCOC(=O)c1nnc(-c2ccc(OC)cc2)o1
Product: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(CN(C)C)c(Cl)c4)C3)o2)cc1
Yield: 81.8 %

Procedure:
Using a similar protocol as described in Example 16 employing 47A (70 mg, 0.29 mmol) and ethyl 5-(4-methoxyphenyl)-1,3,4-oxadiazole-2-carboxylate (75 mg, 0.30 mmol) as starting materials afforded 105 mg (82%) of 47 as a solid. 1H NMR (500 MHz, CDCl3): δ 2.20 (s, 6H), 3.48 (s, 2H), 3.90 (s, 3H), 4.32 (dd, 1H), 4.65 (dd, 1H), 4.74 (dd, 1H), 5.06 (m, 1H), 5.13 (dd, 1H), 6.68 (dd, 1H), 6.80 (d, 1H), 7.02 (d, 2H), 7.35 (d, 1H), 8.10 (d, 2H), MS (APCI+) m/z 443 [M+H]+, LC purity: 91%.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([O:12][CH3:13])[C:10]=2[N:11]=1.[Cl:14][C:15]1[C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][CH:18]=[CH:17][N:16]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[Cl:14][C:15]1[C:20]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]=[CH:7][N:8]=[C:9]([O:12][CH3:13])[C:10]=3[N:11]=2)=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: CC1(C)OB(c2cccnc2Cl)OC1(C)C
Reactant: COc1ncnc2ccc(Cl)nc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ncnc2ccc(-c3cccnc3Cl)nc12
Temperature: 98 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
A reaction flask was charged 6-chloro-4-methoxypyrido[3,2-d]pyrimidine (3.5 g, 17.8 mmol), 2-chloro-3-pyridineboronic acid pinacol ester (4.35 g, 18.2 mmol), Na2CO3 (4.0 g, 38.2 mmol) and 1,4-dioxane (100 mL) and a stir bar. The contents were degassed by vacuum and back filled with argon three times while stirring. Subsequently, Pd(PPh3)3 (0.87 g, 0.75 mmol) was added to the reaction contents, repeated degassing cycles and heated under argon at 98° C. The heating was stopped after overnight, the yellow hot heterogeneous reaction mixture was suction filtered on a Buchner funnel and washed the cake with additional amount of dioxane (30 mL). The pale yellow clear filtrate solution was passed through a pad of Celite® and concentrated the filtrate. The crude pale yellow solid residue was partitioned between CH2Cl2 (150 mL)/water (50 mL). The organic layer was separated, dried over MgSO4, filtered and concentrated. The crude concentrate was stirred in EtOAc (30 mL) and suction filtered. The filter cake was washed further with EtOAc (10 mL) and dried to obtain 1.6 g of 6-(2-chloropyridin-3-yl)-4-methoxypyrido[3,2-d]pyrimidine (purity: 95%) as a white solid. The filtrate was concentrated and purified the concentrate by flash column chromatography (Combiflash® companion System® with RediSep® silica gel column 40 g, 0-30-60% EtOAC/hexanes eluting solvent gradient) to obtain additional 0.65 g of titled compound. 1H NMR (300 MHz, DMSO-d6): δ 8.92 (s, 1H), 8.57 (dd, J=4.8, 2.0 Hz, 1H), 8.45 (d, J=8.7 Hz, 1H), 8.28 (d, J=8.7 Hz, 1H), 8.13 (dd, J=7.6, 2.0 Hz, 1H), 7.63 (dd, J=7.6, 4.8 Hz, 1H), 4.16 (s, 3H).
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[C:11](#[N:20])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[NH2:20][C:11]1[CH2:12][CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([Cl:2])[CH:4]=2)[N:10]=1
Reactant: NNc1cccc(Cl)c1
Reactant: N#CC=Cc1ccccc1
Agent: [Na]
Solvent: CCO
Product: NC1=NN(c2cccc(Cl)c2)C(c2ccccc2)C1
Reaction time: 0.08 h

Procedure:
A 0.6 g. amount of sodium metal is dissolved in 100 ml. of absolute ethanol, then 14.76 g. of m-chlorophenylhydrazine is added followed in 5 minutes by 12.92 g. of cinnamonitrile. The reaction mixture is refluxed for 6 hours, then cooled in an ice-bath. The precipitate formed is collected by filtration, then is dissolved in dichloromethane. This solution is passed through a short column of a hydrous magnesium silicate. The effluent is heated to reflux on a steam bath and hexane is added until a precipitate occurs. The product is collected, then is recrystallized from dichloromethane-hexane to give 7.55 g. of the product of the Example as salmon colored needles, m.p. 164°-165° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH:13]1[O:18][CH2:17][CH2:16][CH2:15][O:14]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.C(#N)C>[O:14]1[CH2:15][CH2:16][CH2:17][O:18][CH:13]1[CH2:12][CH2:11][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: BrCCC1OCCCO1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=Cc1ccc(OCCC2OCCCO2)cc1
Yield: 100.2 %

Procedure:
In a 500 ml flask, 120 ml of acetonitrile, 13.8 g of 4-hydroxybenzaldehyde, 21.1 g of 2-(2-bromoethyl)-1,3-dioxane, 1.8 g of potassium iodide, and 35.8 g of potassium carbonate were placed and then, reacted at 80° C. for 5 hrs. Thereafter, 200 ml of ethyl acetate was added to the reaction mixture and washed once with a saturated aqueous potassium carbonate solution, distilled water, and saturated saline. The washed organic phase was dried over anhydrous magnesium sulfate and removed solvent, to give 25.6 g of 4-(2-[1,3]-dioxane-2-yl-ethoxy)benzaldehyde.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[N:11]=[N:10]2)[CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[S:20][C:21]([C:27]2[C:32]([F:33])=[CH:31][C:30]([C:34]([OH:37])([CH3:36])[CH3:35])=[CH:29][C:28]=2[F:38])=[CH:22][C:23]=1[C:24]([NH2:26])=[O:25]>>[NH2:26][C:24]([C:23]1[CH:22]=[C:21]([C:27]2[C:32]([F:33])=[CH:31][C:30]([C:34]([OH:37])([CH3:36])[CH3:35])=[CH:29][C:28]=2[F:38])[S:20][C:19]=1[NH:18][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[N:11]=[N:10]2)[CH:5]=[CH:4][CH:3]=1)=[O:25]
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: COC(=O)c1cn(Cc2cccc(Br)n2)nn1
Product: COC(=O)c1cn(Cc2cccc(Nc3sc(-c4c(F)cc(C(C)(C)O)cc4F)cc3C(N)=O)n2)nn1

Procedure:
The title compound was prepared as described in Example 1 using methyl 1-[(6-bromopyridin-2-yl)methyl]-1H-1,2,3-triazole-4-carboxylate (357 mg, 1.20 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (375 mg, 1.20 mmol) as starting materials.
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]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])=[CH:20][CH:19]=1.[Cl:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[C:32]([Cl:45])[C:31]=1[OH:46]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])=[CH:22][CH:23]=2)=[CH:3][C:2]([C:34]2[CH:35]=[C:30]([Cl:29])[C:31]([OH:46])=[C:32]([Cl:45])[CH:33]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: CN(C)CCc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cc1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CN(C)CCc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)cc1
Yield: 55.1 %

Procedure:
Following general procedure D, (6-bromo-4-(4-(2-(dimethylamino)ethyl)phenyl amino)quinolin-3-yl)(cyclopropyl)methanone (100 mg, 0.23 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (98 mg, 0.34 mmol) to afford the desired product (66 mg, 55%) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.46 (s, 1H), 8.21 (dd, J=8.8, 1.9 Hz, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.89 (s, 1H), 7.56 (d, J=8.4 Hz, 2H), 7.46 (d, J=8.4 Hz, 2H), 7.23 (s, 2H), 3.40 (m, 2H), 3.22 (m, 2H), 2.98 (s, 6H), 2.90 (m, 1H), 1.22 (m, 4H); ESI MS m/z 520 [C29H27Cl2N3O2+H]+; HPLC 97.6% (AUC), tR=11.15 min.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:36])[N:4]2[C:16](=[CH:17][C:18]=1[CH:19]([O:22][C:23](=[O:35])[C:24]([NH:27]C(OC(C)(C)C)=O)([CH3:26])[CH3:25])[CH2:20][CH3:21])[C:7]1=[N:8][C:9]3[C:14]([CH:15]=[C:6]1[CH2:5]2)=[CH:13][CH:12]=[CH:11][CH:10]=3.C(C(O)=O)(F)(F)F>O>[NH2:27][C:24]([CH3:25])([CH3:26])[C:23]([O:22][CH:19]([C:18]1[CH:17]=[C:16]2[N:4]([CH2:5][C:6]3[C:7]2=[N:8][C:9]2[C:14]([CH:15]=3)=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3](=[O:36])[C:2]=1[CH3:1])[CH2:20][CH3:21])=[O:35]
Reactant: CCC(OC(=O)C(C)(C)NC(=O)OC(C)(C)C)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCC(OC(=O)C(C)(C)N)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2

Procedure:
The title compound was prepared according to the procedure in Example 3B except using (±)-8-methyl-7-[1-[[2-[[(1,1-dimethylethoxy)carbonyl]amino]-2-methyl-1-oxopropyl]oxy]propyl]indolizino[1,2-b]quinolin-9(11H)-one. 1H NMR (DMSO-d6) d 8.67 (s, 1H), 8.11 (m, 2H), 7.84 (m, 1H), 7.70 (m, 1H), 7.21 (s, 1H), 5.85 (dd, J=7.9, 5.8 Hz, 1H), 5.25 (s, 2H), 2.24 (s, 3H), 2.1-1.83 (m, 2H), 1.52 (s, 3H), 1.49 (s, 3H), 0.97 (t, J=7.3 Hz, 3H). Anal. Calcd for C23H25N3O3.CF3CO2H.2 H2O: C, 55.45; H, 5.58; N, 7.76. Found: C, 55.85; H, 5.19; N, 7.83.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](O)=[O:27])=[C:21]([CH3:29])[CH:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:26](=[O:27])[CH2:25][C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][C:21]=2[CH3:29])[CH2:7]1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: Cc1cc(F)ccc1CC(=O)O
Product: Cc1cc(F)ccc1CC(=O)NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 16.5 %

Procedure:
Example 19 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 1 (0.055 g) and (4-fluoro-2-methylphenyl)acetic acid (0.034 g) to give the title compound (0.014 g).
Reaction SMILES: [CH2:1]([NH:15][CH2:16][CH2:17][NH:18][CH2:19][CH2:20][NH2:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH:22]([CH2:24][CH:25]([CH3:30])[C:26](OC)=[O:27])=O>>[CH2:1]([NH:15][CH2:16][CH2:17][N:18]1[C:26](=[O:27])[CH:25]([CH3:30])[CH2:24][CH:22]=[N:21][CH2:20][CH2:19]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][CH3:14]
Reactant: COC(=O)C(C)CC=O
Reactant: CCCCCCCCCCCCCCNCCNCCN
Product: CCCCCCCCCCCCCCNCCN1CCN=CCC(C)C1=O

Procedure:
Into an apparatus similar to that in Example 1, where charged 299.5 g (1 mole) of N-tetradecyldiethylenetriamine and 130.1 g (1 mole) of methyl 3-formyl-2-methylpropionate. At 145° to 150° C., 18 g of water and 32 g of methanol were distilled off to obtain 4-tetradecylaminoethyl-6-methyl-2,3,6,7-tetrahydro-1,4-diazocin-5-one.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8](=[O:11])[NH:7][C:6]1=[O:12].CS(O[CH2:18][C@H:19]1[O:28][C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[O:21][CH2:20]1)(=O)=O>O1CCOCC1>[O:21]1[C:22]2[C:23](=[N:24][CH:25]=[CH:26][CH:27]=2)[O:28][C@@H:19]([CH2:18][NH:1][CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][C:8](=[O:11])[NH:7][C:6]2=[O:12])[CH2:20]1
Reactant: CS(=O)(=O)OC[C@@H]1COc2cccnc2O1
Reactant: NCCCN1CCC(=O)NC1=O
Solvent: C1COCCO1
Product: O=C1CCN(CCCNC[C@H]2COc3cccnc3O2)C(=O)N1
Yield: 16.1 %

Procedure:
A mixture of intermediate (54) (0.058 mol) in dioxane (400 ml) was stirred. A mixture of intermediate (3) (0.029 mol) and CaO (2.4 g) was added. The reaction mixture was stirred at 140° C. for 16 hours. The solvent was evaporated. DCM and water was added to the residue. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was purified by high-performance liquid chromatography over silica gel (eluent:CH2Cl2/(CH3OH/NH3) 90/10). The product fractions were collected and the solvent was evaporated. The residue was dissolved in ethanol and converted into the ethanedioic acid salt (1:1). The formed precipitate was filtered off and dried, yielding 1.5 g of (S)-1-[3-[[(2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl)methyl]amino]propyl]dihydro-2,4(1H,3H)-pyrimidinedione (compound 25), mp.186; [α]D20 =−37.46°, (c=26.56 mg/5 ml DMF).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:34][OH:35])=[C:19]([N:23]3[C:27]4[N:28]=[CH:29][N:30]=[CH:31][C:26]=4[C:25]([C:32]#[N:33])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C([OH:38])C.O>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:34][OH:35])=[C:19]([N:23]3[C:27]4[N:28]=[CH:29][N:30]=[CH:31][C:26]=4[C:25]([C:32]([NH2:33])=[O:38])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCO
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C#N)c5cncnc54)c3CO)ncc2c1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C(N)=O)c5cncnc54)c3CO)ncc2c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
In a 10 mL round-bottomed flask, 7-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (39 mg, 83.2 μmol, Eq: 1.00) and [hydrogen bis(dimethylphosphinito-kP)]platinum (II) (1 mg, 2.33 μmol, Eq: 0.0280) were combined with Ethanol (2 ml) and Water (1 ml) to give a colorless solution. The reaction mixture was heated to 80° C. and stirred for 2 h. The reaction mixture was diluted with DCM. The reaction mixture was filtered through glass fiber paper. HPLC purification done to obtain 7-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid amide (33 mg, 66%, [M+H]+ 487).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:9])=[N:4][CH:5]=[CH:6][C:7]=1Cl.[CH2:10]([CH:15]1[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16]1)[CH2:11][CH:12]([CH3:14])[CH3:13]>>[Cl:1][C:2]1[C:3]([CH3:9])=[N:4][CH:5]=[CH:6][C:7]=1[NH:20][CH:17]1[CH2:18][CH2:19][CH:15]([CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:16]1
Reactant: Cc1nccc(Cl)c1Cl
Reactant: CC(C)CCC1CCC(N)C1
Product: Cc1nccc(NC2CCC(CCC(C)C)C2)c1Cl
Yield: 61 %

Procedure:
Preparation was carried out as in Example 59 from 3,4-dichloro-2-methylpyridine and 3-isoamylcyclopentylamine. Yield: 61%
Reaction SMILES: [C:1]1([C:14](O)=[O:15])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:17][Li].O>O1CCCC1>[C:14]([C:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1)(=[O:15])[CH3:17]
Reactant: [Li]C
Reactant: O=C(O)c1cccc2c1Cc1ccccc1-2
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1cccc2c1Cc1ccccc1-2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 108 g. of 1-fluorenecarboxylic acid in 2 liters of dry tetrahydrofuran cooled to -78° C. by means of an external dry ice/acetone bath were added 2 moles of methyl lithium (6 molar solution in diethyl ether). The reaction was stirred at room temperature for 3 hours and then poured into 3 liters of water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed over silica gel. The appropriate fractions were combined and evaporated to dryness. Recrystallization of the residue from ethyl acetate/hexane gave 1-acetylfluorene, m.p. 84°-87° C.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16]C2C=CC=CC=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[C:42]=3[F:51])[CH:34]=2)([O:31][CH3:32])[O:11][C:10]1([CH2:54][OH:55])CO)C1C=CC=CC=1.F[C:57](F)(F)[C:58](O)=O.C(=O)(O)[O-].[Na+].O>ClCCl>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:58]2[CH:57]=[CH:54][CH:10]=[CH:9][CH:14]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@:12]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[C:42]=4[F:51])[CH:34]=3)[O:11][C@@:10]1([CH2:54][OH:55])[CH2:32][O:31]2)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOc1ccc(Cc2cc([C@]3(OC)OC(CO)(CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)c(F)c1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 102.3 %

Procedure:
To a solution of [(3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl) methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol 23m (3.30 g, 4.26 mmol) in dichloromethane (70 mL) was added trifluoroacetic acid (1.26 mL, 17.03 mmol) at 0° C. The mixture was warmed up to room temperature and stirred for 12 hours. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate to pH 7 and 40 mL of water was added, and then the mixture was partitioned. The aqueous layer was extracted with dichloromethane (20 mL×3). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=10/1 to give the title compound 23n as yellow oil (1.62 g, 50%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ(ppm): 7.36 (m, 13H), 7.20 (m, 3H), 6.92 (m, 2H), 6.66 (m, 1H), 6.53 (m, 1H), 4.88 (m, 3H), 4.78 (d, 1H), 4.31 (m, 2H), 4.06 (m, 5H), 3.98 (d, 1H), 3.89 (d, 1H), 3.83 (d, 1H), 3.72 (m, 3H), 1.45 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[C:16]3[N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[CH:27](=O)[CH2:28][CH3:29].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[C:16]3[N:19]3[CH2:24][CH2:23][N:22]([CH2:27][CH2:28][CH3:29])[CH2:21][CH2:20]3)=[CH:11][CH:10]=2)=[O:7])=[CH:25][CH:26]=1
Reactant: CCC=O
Reactant: O=C(Nc1ccc2cccc(N3CCNCC3)c2c1)c1ccc(Cl)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN1CCN(c2cccc3ccc(NC(=O)c4ccc(Cl)cc4)cc23)CC1

Procedure:
A mixture of 7-(4-chlorobenzamido)-1-(1-piperazinyl)-naphthalene (0.20 g, 0.547 mmol, the product of Example 12), propionaldehyde (0.041 mL, 0.563 mmol) and sodium cyanoborohydride (0.103 g, 1.64 mmol)in methanol (12 mL) and acetic acid (1.2 mL) was stirred at ambient temperature for 20 hours. The solvent was removed at reduced pressure and the residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate. Phases were separated and the organic layer was washed with brine, dried, concentrated onto silica gel and flash chromatographed (1×3 inches). Elution proceeded as follows: ethyl acetate (50 mL) unweighed forrun; ethyl acetate (250 mL) 0.164 g of yellow foam. The foam was triturated with pentane and 0.079 g (28%) of the title compound was collected as a white solid. mp 130°-132° C. Analysis calculated for C24H26ClN3O: C, 70.66; H, 6.42; N, 10.30. Found: C, 70.91; H, 6.66; N, 10.50.