Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10]([C:12]1[CH:13]=[C:14]([NH2:27])[CH:15]=[C:16]3[O:20][C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18][C:17]=13)=[O:11])[CH2:2]2.N1C=CC=CC=1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>C(Cl)Cl>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10]([C:12]1[CH:13]=[C:14]([NH:27][C:34](=[O:36])[CH3:35])[CH:15]=[C:16]3[O:20][C:19]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[N:18][C:17]=13)=[O:11])[CH2:2]2
Reactant: Nc1cc(C(=O)NC2CN3CCC2CC3)c2nc(-c3ccccc3)oc2c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1cc(C(=O)NC2CN3CCC2CC3)c2nc(-c3ccccc3)oc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.7 %

Procedure:
To a solution of N-(1-azabicyclo[2.2.2]oct-3-yl)-6-amino-2-phenylbenzoxazole-4-carboxamide (35 mg, 0.09 mmol) in methylene chloride (1 mL) was added pyridine (11 μL, 0.14 mmol) and acetic anhydride (11 μL, 0.10 mmol) at 0° C. and stirred for 30 min, then allowed to warm to room temperature for 1 h. The reaction mixture was quenched with saturated solution of sodium bicarbonate and concentrated under reduced pressure. The crude was purified by semi-preparative HPLC to afford N-(1-azabicyclo[2.2.2]oct-3-yl)-6-acetylamino-2-phenylbenzoxazole-4-carboxamide (13 mg, 44%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.58 (d, J=7.4 Hz, 1H), 8.73 (d, J=1.9 Hz, 1H), 8.20 (d, J=6.8 Hz, 1H), 8.13 (s, 1H), 7.81 (d, J=1.7 Hz, 1H), 7.55-7.50 (m, 4H), 4.35-4.27 (m, 1H), 3.57-3.48 (m, 1H), 3.16-3.03 (m, 2H), 2.97-2.82 (m, 2H), 2.27 (s, 3H), 2.17-2.05 (m, 2H), 1.85-1.60 (m, 3H); MS (ESI+) m/z 405 (M+H); HPLC>99% (AUC), tR=23.81 min.
Reaction SMILES: ClC1C(OC)=NN=NC=1OC.[NH2:12][C:13]1[NH:14][C:15](=[O:33])[C:16]2[CH:21]([CH2:22][CH2:23][C:24]3[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=3)[CH2:20][NH:19][C:17]=2[N:18]=1.CN1CCOCC1.Cl.[CH2:42]([O:44][C:45](=[O:55])[C@H:46]([CH2:48][CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])[NH2:47])[CH3:43]>CN(C)C=O>[CH2:42]([O:44][C:45](=[O:55])[C@H:46]([CH2:48][CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])[NH:47][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][C:24]([CH2:23][CH2:22][CH:21]2[C:16]3[C:15](=[O:33])[NH:14][C:13]([NH2:12])=[N:18][C:17]=3[NH:19][CH2:20]2)=[CH:25][CH:26]=1)[CH3:43]
Reactant: Nc1nc2c(c(=O)[nH]1)C(CCc1ccc(C(=O)O)cc1)CN2
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Agent: COc1nnnc(OC)c1Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(CCC2CNc3nc(N)[nH]c(=O)c32)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
1.12 Grams (6.36 mmol) of chlorodimethoxytriazine was added to a solution of 1.91 grams (6.36 mmol) of 4-(2-[2-amino-4,5,6,7-tetrahydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl]ethyl)benzoic acid and 0.63 grams (6.3 mmol) of N-methylmorpholine (NMM) in 20 ml of dimethylformamide (DMF) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. Next, an additional 0.3 grams (2.97 mmol) of NMM and 0.22 grams (1.25 mmol) of chlorodimethoxytriazine was added.to the solution and the mixture stirred for an additional 30 min. Then, 0.64 grams (6.3 mmol) of NMM and 1.52 grams (6.3 mmol) of diethyl-L-glutamate hydrochloride was added to the mixture. After stirring overnight at room temperature, the resulting suspension was mixed with 30 grams of silica gel and dried under vacuum. The residue was added to a column of 70 grams silica gel and eluted with 500 ml of CH2Cl2 -EtOH 90:10 followed by CH2Cl2 -EtOH 80:20. 1.62 Grams (52%) of purified N-[4-[2-(2-amino-4,5,6,7-tetrahydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid diethyl ester was obtained as a colorless powder. Selected data: 1H NMR (DMSO-d6) δ 9.55 (s, 1H), 8.60 (d, J=7.4 Hz, 1 H), 7.73 (d, J=8.3 Hz, 2H) 7.27 (d, J=8.3 Hz, 2H), 6.28 (s, 1H), 6.20 (s, 2H), 4.38 (m, 1H), 4.05 (q, J=7.1 Hz, 2H), 3.99 (q, J=7.1 Hz, 2H), 3.40 (m, 1H), 3.02 (m, 2H), 2.65 (t, J=7.6 Hz, 2H), 2.39 (t, J=7.5 Hz, 2H), 2.00 (m, 3H), 1.54 (m, 1H), 1.13 (t, J=7.1 Hz, 3H), 1.11 (t, J=7.1 Hz, 3H).
Reaction SMILES: Cl[CH:2](Cl)[CH3:3].[F:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:7]=1[N:16]1[C:25]2[C:20](=[CH:21][C:22]([F:27])=[C:23]([F:26])[CH:24]=2)[C:19](=[O:28])[C:18]([C:29]([OH:31])=[O:30])=[CH:17]1.C(Cl)(=O)C(Cl)=O>C(O)C>[F:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:7]=1[N:16]1[C:25]2[C:20](=[CH:21][C:22]([F:27])=[C:23]([F:26])[CH:24]=2)[C:19](=[O:28])[C:18]([C:29]([O:31][CH2:2][CH3:3])=[O:30])=[CH:17]1
Reactant: CC(Cl)Cl
Reactant: O=C(O)c1cn(-c2cc([N+](=O)[O-])c(F)cc2F)c2cc(F)c(F)cc2c1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCO
Product: CCOC(=O)c1cn(-c2cc([N+](=O)[O-])c(F)cc2F)c2cc(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 40 ml of dichloroethane was added 4.2 g of 1-(2,4-difluoro-5-nitrophenyl)-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. With ice cooling, 7 g of oxalyl chloride was added dropwise. After the completion of addition, the solution was stirred for 2 hours at room temperature. Ethanol (15 ml) was added dropwise to the reaction solution, which was stirred overnight at room temperature. The reaction solution was concentrated in vacua, ethanol was added to the residue, and the solid was collected by filtration and washed with diethyl ether to give 3.7 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][NH2:22])[CH2:15][CH2:14]1.C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:22][CH2:21][CH2:20][CH2:19][N:16]3[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: CN1CCN(CCCN)CC1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(CCCNc2ccc3ncc(Br)n3n2)CC1

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and 3-(4-methylpiperazin-1-yl)propan-1-amine according to general procedure 1 providing the intermediate (200 mg, 85%) as a clear oil: Rf=0.25 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CD3OD) δ 7.54 (d, J=9.6 Hz, 1H), 7.39 (s, 1H), 6.67 (d, J=9.7 Hz, 1H), 3.42 (t, J=7.0 Hz, 2H), 2.53-2.50 (m, 10H), 2.29 (s, 3H), 1.91 (quin, J=6.6 Hz, 2H)
Reaction SMILES: [NH:1]([C:23]([O:25][CH:26]1[CH2:31][C:30]([CH3:33])([CH3:32])[N:29]([O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[C:28]([CH3:42])([CH3:41])[CH2:27]1)=[O:24])[NH:2][C:3]([O:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]([CH3:22])([CH3:21])[CH2:7]1)=[O:4].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>>[N:2]([C:3]([O:5][CH:6]1[CH2:7][C:8]([CH3:22])([CH3:21])[N:9]([O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:10]([CH3:13])([CH3:12])[CH2:11]1)=[O:4])=[N:1][C:23]([O:25][CH:26]1[CH2:27][C:28]([CH3:41])([CH3:42])[N:29]([O:34][CH:35]2[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]2)[C:30]([CH3:32])([CH3:33])[CH2:31]1)=[O:24]
Reactant: CC1(C)CC(OC(=O)NNC(=O)OC2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)CC(C)(C)N1OC1CCCCC1
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Product: CC1(C)CC(OC(=O)N=NC(=O)OC2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)CC(C)(C)N1OC1CCCCC1
Yield: 84.7 %

Procedure:
The procedure of Example 4 is repeated using 12.2 g of bis(1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-yl) hydrazine-1,2-dicarboxylate and 7.2 g of iodobenzene diacetate to afford 10.3 g of the title compound; mp 189°-19 1° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][NH:11][CH2:12][C:13]([CH3:36])=[CH:14][CH2:15][C:16]1[C:17]([O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])=[C:18]2[C:22](=[C:23]([CH3:27])[C:24]=1[O:25][CH3:26])[CH2:21][O:20][C:19]2=[O:28])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[CH:37](=O)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>CN(C=O)C>[CH2:1]([O:3][P:4]([CH2:9][CH2:10][N:11]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:12][C:13]([CH3:36])=[CH:14][CH2:15][C:16]1[C:17]([O:29][CH2:30][CH2:31][Si:32]([CH3:33])([CH3:34])[CH3:35])=[C:18]2[C:22](=[C:23]([CH3:27])[C:24]=1[O:25][CH3:26])[CH2:21][O:20][C:19]2=[O:28])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(CCNCC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)OCC
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCOP(=O)(CCN(CC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)Cc1ccccc1)OCC
Yield: 43.2 %

Procedure:
A solution of (2-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-ethyl)-phosphonic acid diethyl ester (30 mg, 0.055 mmol), benzaldehyde (5.6 μL, 0.055 mmol), and sodium triacetoxyborohydride (23 mg, 0.11 mmol) was stirred with acetic acid (15.7 μL, 0.28 mmol) in DMF (0.5 mL) at room temperature over night. The reaction was quenched with a 10% aqueous Na2CO3 solution and the product was extracted with EtOAc. The organic layer was dried and concentrated under reduced pressure. The product was purified purified by RP HPLC using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 15 mg of the product (43%) as a clear gel. 1H NMR (300 MHz, CDCl3) δ 0.02 (s, 9H), 1.18-1.25 (m, 2H), 1.24 (t, 6H, J=7 Hz), 1.86 (s, 3H), 1.88-2.02 (m, 2H), 2.16 (s, 3H), 2.65-2.74 (m, 2H), 3.93 (s, 2H), 3.46 (br d, 4H, J=7 Hz), 3.76 (s, 3H), 4.00 (pent, 4H, J=7 Hz), 4.25-4.34 (m, 2H), 5.11 (s, 2H), 5.34-5.43 (m, 1H), 7.18-7.33 (m, 5H) ppm; 31P (121.4 MHz, CDCl3) δ 30.9 ppm; MS (m/z) 632.4 [M+H]+, 654.3 [M+Na]+.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])=[CH:4][CH:3]=1.[CH3:16]N(C=O)C.C(=O)([O-])[O-].[K+].[K+].CI>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][CH3:16])=[CH:14][CH:15]=1
Reactant: Oc1ccccc1Cc1ccc(F)cc1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Product: COc1ccccc1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
A mixture of 2-(4-fluorobenzyl)phenol (4.51 gm, 22.41 mmol), DMF (60 mL), potassium carbonate (7.78 gm, 56.02 mmol) and methyl iodine (1.67 mL, 26.81 mmol) was stirred at rt for 16 h. The reaction was poured into 150 mL ethyl acetate, filtered, washed 3× with 50 mL H20, 1× with 100 m]L brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford 2-(4-fluorobenzyl)anisole (4.27 gm, 88%); 1H NMR (200 MHz, DMSO-d6): δ 7.11(m, 7H), 3.88(s, 2H), 3.76(s, 3H); TLC conditions: Uniplate silica gel, 250 microns; methylene chloride-hexanes (1:1); Rf=0.64.
Reaction SMILES: [C:1]([C:4]1[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([O:14][CH3:15])=[CH:7][C:5]=1[NH2:6])(=[O:3])[CH3:2].[CH:16]1([C:19](Cl)=[O:20])[CH2:18][CH2:17]1.C1(C2NC3C(C(=O)C=2)=CC(OC)=C(OC)C=3)CC1>C(N(CC)CC)C>[CH:16]1([C:19]([NH:6][C:5]2[CH:7]=[C:8]([O:14][CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[CH:10][C:4]=2[C:1](=[O:3])[CH3:2])=[O:20])[CH2:18][CH2:17]1
Reactant: CCOc1cc(C(C)=O)c(N)cc1OC
Reactant: O=C(Cl)C1CC1
Agent: COc1cc2[nH]c(C3CC3)cc(=O)c2cc1OC
Solvent: CCN(CC)CC
Product: CCOc1cc(C(C)=O)c(NC(=O)C2CC2)cc1OC

Procedure:
2-Acetyl-4-ethoxy-5-methoxyaniline (490 mg), triethylamine (1.0 ml) and cyclopropylcarbonyl chloride (0.25 ml) were reacted in the same manner as in the preparation of compound 95 to give N-cyclopropylcarbonyl-2-acetyl-4-ethoxy-5-methoxyaniline (420 mg). This compound (380 mg) and potassium t-butoxide (770 mg) were reacted in the same manner as in the preparation of compound 95 to obtain 2-cyclopropyl-6-ethoxy-7-methoxy-4(1H)-quinolone (compound 119, 80 mg).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C@H:8]([C@H:23]([CH3:27])[CH2:24][CH2:25][CH3:26])[C:9](N1[C@H](C2C=CC=CC=2)COC1=O)=[O:10].O>C1COCC1>[CH3:7][C@H:8]([C@H:23]([CH3:27])[CH2:24][CH2:25][CH3:26])[CH2:9][OH:10]
Reactant: CCC[C@@H](C)[C@@H](C)C(=O)N1C(=O)OC[C@H]1c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCC[C@@H](C)[C@@H](C)CO
Reaction time: 3 h
Yield: 100 %

Procedure:
A 1M THF solution of LAH (95.9 mL, 95.9 mmol) was added to (R)-3-((2R,3R)-2,3-dimethyl-hexanoyl)-4-phenyl-oxazolidin-2-one in THF (300 mL) under nitrogen at −78° C. and stirred for 3 hours at that temperature. Water was added dropwise to quench the excess LAH and the solution was poured into a mixture of ice and ether. The mixture was extracted into ether, washed with water and dried over MgSO4. The solution was concentrated followed by the addition of excess hexane. The resulting white precipitate was filtered and washed with haxane. The filtrate was concentrated to afford the titled compound (5.05 g, 100% yield) as an oil: 1H NMR (400 MHz, CDCl3) δ ppm 0.9 (m, 9H) 1.0 (d, J=6.8 Hz, 1H) 1.1 (m, 1H) 1.2 (m, 3H) 1.6 (m, 2H) 3.4 (m, 1H) 3.6 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][C:4]=1[CH3:15])#[N:2].F[B-](F)(F)F.[CH3:21][O+](C)C.[OH-].[Na+]>C(Cl)Cl>[C:1]([C:3]1[C:4]([CH3:15])=[CH:5][C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:7][C:8]=1[O:9][CH3:21])#[N:2]
Reactant: C[O+](C)C
Reactant: CCOC(=O)c1cc(C)c(C#N)c(=O)[nH]1
Agent: F[B-](F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOC(=O)c1cc(C)c(C#N)c(OC)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 52.9 %

Procedure:
To a stirred suspension of ethyl 5-cyano-4-methyl-6-oxo-1,6-dihydropyridine-2-carboxylate (2.0 g, 9.70 mmol) in CH2Cl2 (25 mL) was added trimethyloxonium tetrafluoroborate (2.0 g, 13.52 mmol). The reaction was rinsed down with CH2Cl2 and stirred at RT for 24 h. (The reaction eventually cleared up.) To the reaction was added 1 N NaOH (75 mL). After stirring for 10 minutes the mixture was poured into a separatory funnel. The CH2Cl2 phase was removed, dried (Na2SO4), filtered and concentrated under vacuum. Purification by silica gel chromatography (Analogix SF25-40 g, 50 to 100% CH2Cl2 in hexanes) gave the product ethyl 5-cyano-6-methoxy-4-methylpicolinate (1.13 g, 5.13 mmol, 52.9% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.75 (s, 1H), 4.37 (q, J=7.1 Hz, 2H), 4.03 (s, 3H), 2.55 (s, 3H), 1.33 (t, J=7.2 Hz, 3H). MS (ES)+ m/e 221.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][C:6]([CH2:7][N:8]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:22][C:23]4[CH:24]=[CH:25][C:26]([NH:29]C(=O)OC(C)(C)C)=[N:27][CH:28]=4)=[N:18][CH:19]=[CH:20][CH:21]=3)[N:10]=2)=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:22][C:23]4[CH:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=4)=[N:18][CH:19]=[CH:20][CH:21]=3)[N:10]=2)=[CH:46][CH:47]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3ccc(NC(=O)OC(C)(C)C)nc3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3ccc(N)nc3)n2)cc1
Yield: 95.2 %

Procedure:
A solution of tert-butyl 5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)pyridin-2-ylamino)pyridin-2-ylcarbamate (0.145 g, 0.228 mmol) and TFA (Aldrich) (1.0 mL, 13 mmol) in DCM (3 mL) was stirred at rt for 1 h. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate (40 mL) and DCM (20 mL). The aqueous phase was extracted with 25% iPrOH in CHCl3+1% NH4OH (2×40 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (25 g, eluent: iPrOH (w/10% NH4OH) in CHCl3 0%-10%) to give N5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)pyridin-2-yl)pyridine-2,5-diamine (0.116 g, 95%) as an orange solid. 1H NMR (300 MHz, CDCl3) δ 11.51 (s, 1H); 8.80 (dd, J=7.67, 1.53 Hz, 1H); 8.18-8.33 (m, 1H); 8.12 (d, J=1.75 Hz, 1H); 7.78 (dd, J=8.70, 2.27 Hz, 1H); 7.19 (t, J=8.84 Hz, 4H); 6.85 (t, J=8.84 Hz, 4H); 6.70 (dd, J=7.67, 4.75 Hz, 1H); 6.50 (d, J=8.77 Hz, 1H); 4.83 (d, J=6.58 Hz, 4H); 4.26 (br. s., 2H); 3.69-3.91 (m, 6H); 2.56 (s, 3H). m/z (ESI, +ve ion) 535.1 (M+H)+.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[N:16]=[N:17][C:18](Cl)=[CH:19][CH:20]=1.C(N(CC)CC)C>C(O)CCC>[Cl:14][C:15]1[N:16]=[N:17][C:18]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1ccc(Cl)nn1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Cl)nn2)CC1
Yield: 64.6 %

Procedure:
A mixture of 13.52 g of tert-butyl 1-piperazinecarboxylate, 10.81 g of 3,6-dichloropyridazine and 20 ml of triethylamine in 100 ml of n-butanol is refluxed for 5 hours. The mixture is concentrated under vacuum and the residue is chromatographed on silica gel, eluting with a DCM/EtOAc mixture (90/10; v/v). 14 g of the expected product are obtained, and are used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:9])[NH:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[F:10][C:11]1[CH:23]=[C:22](I)[CH:21]=[CH:20][C:12]=1[CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+]>[Cu]I.CN(C=O)C>[F:10][C:11]1[CH:23]=[C:22]([N:4]2[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[C:3]2=[O:9])[CH:21]=[CH:20][C:12]=1[CH2:13][N:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1
Reactant: Fc1cc(I)ccc1CN1CCOCC1
Reactant: Cc1c[nH]c(=O)c(C)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c(=O)n(-c2ccc(CN3CCOCC3)c(F)c2)c1
Temperature: 25 °C
Yield: 49.2 %

Procedure:
A mixture of 3,5-dimethylpyridin-2(1H)-one (0.22 g, 1.80 mmol), 4-(2-fluoro-4-iodobenzyl)morpholine (0.58 g, 1.80 mmol), K2CO3 (2.48 g, 18 mmol), CuI (0.02 g, 0.1 mmol) and DMF (3 mL) was refluxed under N2. The reaction process was monitored by TLC. The reaction mixture was cooled to rt and filtered. To the filtrate was added H2O (10 mL) and CH2Cl2 (20 mL). The CH2Cl2 layer was separated, and the aqueous layer was extracted with CH2Cl2 (20 mL×2). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a white solid (0.28 g, 50%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [H-].[Na+].C([C:5](CC)(P(O)(O)=O)[C:6]#[N:7])C.[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][C:22](=O)[CH2:23]2)=[CH:18][CH:17]=1>C(COC)OC>[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][C:22]([CH2:5][C:6]#[N:7])=[CH:23]2)=[CH:18][CH:17]=1
Reactant: COc1ccc2c(c1)CC(=O)CC2
Reactant: CCC(C#N)(CC)P(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc2c(c1)C=C(CC#N)CC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred mixture of 7.1 g. of a 57% mineral oil dispersion of sodium hydride in 400 ml. of dry glyme under nitrogen was added dropwise 28.0 g. of diethyl phosphonoacetonitrile followed by a solution of 25.5 g. of 7-methoxy-2-tetralone in 50 ml. of glyme. After stirring four hours at room temperature the mixture was allowed to stand overnight under nitrogen. The mixture was decanted from an insoluble residue; the supernatant was concentrated in vacuo, and poured into 350 ml. of ice-water. The product was extracted with chloroform and the extracts were washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness to give 29.9 g of 3,4-dihydro-7-methoxy-2-naphthaleneacetonitrile which was converted directly to 7-methoxy-2-naphthaleneacetonitrile as described hereinabove in Example 123.
Reaction SMILES: [CH:1]1([NH:6][CH2:7][C:8]([OH:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>C(#N)C>[CH2:16]([N:6]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)[CH2:7][C:8]([OH:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C(C)(O)CNC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(O)CN(Cc1ccccc1)C1CCCC1
Temperature: 80 °C
Yield: 76.4 %

Procedure:
To ethyl 3-(cyclopentylamino)-2-hydroxy-2-methylpropanoate (3.9 g, 18 mmol) in 50 ml of acetonitrile at room temperature, was added benzyl bromide (3.2 ml, 27.2 mmol) dropwise, followed by K2CO3 (7.5 g, 54.3 mmol). The reaction mixture was heated at 80° C. for 18 h. It was then diluted to EtOAc, washed by brine and water. Organic extract dried and concentrated to a residue, which was purified on silica gel column chromatographically (Hex/EtOAc=100:1 to 10:1) to give 4.2 g product (77%). [M+H] calc'd for C18H27NO3, 306; found 306.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]#[C:14][CH3:15])[CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.N[C@H]1C2C(=CC=CC=2)C[C@H]1O>CC(O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([C:13]#[C:14][CH3:15])[CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1
Reactant: CC#CC(CC(=O)O)c1ccc(O)cc1
Agent: N[C@H]1c2ccccc2C[C@H]1O
Solvent: CC(C)O
Product: CC#C[C@@H](CC(=O)O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 5L RB flask was charged with compound 1.3 (66.4 g, 325 mmol) and 2-propanol (1 L) and then heated to 70° C. (1S,2R)-1-amino-2-indanol (46.1 g, 309 mmol) was dissolved in 2-propanol (1 L) with gentle warming. The solution of amine was added to the dissolved carboxylic acid and the resulting solution was allowed to cool to room temperature. After 16 h, the crystals were collected and dried. The salt was re-suspended in 2 L of 2-propanol and dissolved by heating to reflux. After allowing to cool to room temperature, the salt was collected after 16 h. A small sample of the salt was decomposed with aqueous acid and the free carboxylic acid was analyzed by chiral HPLC (Daicel ChiralPAK AD-H column, eluant: 0.1% TFA in 90:10 hexanes:2-propanol) and was found to have 75% ee. The salt was re-suspended in 1.5 L of 2-propanol and dissolved by heating to reflux. After allowing to cool to room temperature, the salt was collected after 16 h. This material was found to have 96% ee by chiral HPLC. This material was suspended in ethyl acetate (300 mL) and water (100 mL). Saturated aqueous KHSO4 (100 mL) was added with vigorous mixing. After two clear layers were obtained, the layers were separated and the aqueous layer extracted with ethyl acetate (100 mL). The combined extracts were washed with saturated brine, dried over MgSO4, filtered, and concentrated to a light yellow oil which crystallized on drying in vacuo. Compound 1.4 was obtained as an off-white solid (23.5 g, 35%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[NH:6].[Cl:11][C:12]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:13]=1[CH:14]=[C:15]([C:18]#[N:19])[C:16]#[N:17]>>[NH2:19][CH2:18][C:15]1[C:16]([NH2:17])=[N:6][C:5]([C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)=[N:7][C:14]=1[C:13]1[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:12]=1[Cl:11]
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Reactant: N=C(N)c1cccc(F)c1
Product: NCc1c(N)nc(-c2cccc(F)c2)nc1-c1ccc(Cl)cc1Cl

Procedure:
The title compound, MS: m/e=362.9 (M+H+), was prepared from 3-fluoro-benzamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.