Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:10][C:11]([C:13]1[C:14](=[O:34])[N:15]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][C:19]([Cl:24])=[CH:18][N:17]=2)=O)C>C1(C)C(C)=CC=CC=1>[CH:1]1([NH:7][C:11]([C:13]2[C:14](=[O:34])[N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[C:16]3[C:21]([C:22]=2[OH:23])=[CH:20][C:19]([Cl:24])=[CH:18][N:17]=3)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: CCOC(=O)c1c(O)c2cc(Cl)cnc2n(Cc2ccc(OC)cc2)c1=O
Solvent: Cc1ccccc1C
Product: COc1ccc(Cn2c(=O)c(C(=O)NC3CCCCC3)c(O)c3cc(Cl)cnc32)cc1
Temperature: 140 °C
Yield: 89.3 %

Procedure:
Cyclohexylamine (6.15 mL, 53.70 mmol) was added to a stirred solution of 6-chloro-4-hydroxy-1-(4-methoxy-benzyl)-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (75) (10.44 g, 26.85 mmol) in xylene and heated at 140° C. for 3 h. The solution was cooled and the solvent was evaporated under vacuum. The residue was suspended in water and extracted by dichloromethane. The combined organic phase was washed by water and brine, then dried over Na2SO4 and evaporated to yield 10.6 g (89%) of 6-chloro-4-hydroxy-1-(4-methoxy-benzyl)-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid cyclohexylamide (93) as white solids. MP: 193° C.; 1H-NMR (CDCl3): δ 1.24-1.99 (m, 10H), 3.47 (s, 3H), 3.93 (m, 1H), 5.59 (s, 2H), 6.78 (m, 2H), 7.37 (m, 2H), 8.39 (d, J=2.4 Hz, 1H), 8.60 (d, J=2.4 Hz, 1H), 10.15 (s, 1H); EIMS m/z 442 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:21])[CH2:10][O:11][C:12]1[CH:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[NH:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([N:14]1[C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:12]([O:11][CH2:10][C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH3:21])=[N:13]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(OC[C@H](C)NC(=O)OC(C)(C)C)n[nH]1
Product: COC(=O)c1cc(OC[C@H](C)NC(=O)OC(C)(C)C)nn1Cc1ccccc1

Procedure:
Using methyl 3-({(2S)-2-[(tert-butoxycarbonyl)amino]propyl}oxy)-1H-pyrazole-5-carboxylate and (bromomethyl)benzene, and in the same manner as in Example 1, step A (reaction temperature was room temperature), the title compound was obtained.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[N:19]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[N:27]=[C:28]([CH3:41])[N:29]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[C:34]([F:40])[CH:33]=4)[CH:30]=3)[CH2:21][C:20]2=[O:42])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CO.CCOC(C)=O.[Pd]>[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[N:19]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[N:27]=[C:28]([CH3:41])[N:29]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[C:34]([F:40])[CH:33]=4)[CH:30]=3)[CH2:21][C:20]2=[O:42])=[CH:11][CH:10]=1
Reactant: Cc1nc(CN2CCN(c3cccc4ccc(OCc5ccccc5)cc34)C(=O)C2)cn1Cc1ccc(C#N)c(F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1nc(CN2CCN(c3cccc4ccc(O)cc34)C(=O)C2)cn1Cc1ccc(C#N)c(F)c1
Reaction time: 16 h

Procedure:
To a solution of the benzyl ether from Step B (240 mg, 0.43 mmol) in 4 mL of 1:1 MeOH/EtOAc was added 10% palladium on carbon (240 mg). The solution was stirred under a balloon atmosphere of hydrogen at room temperature. After 16 hours, the solution was filtered through celite. Concentration in vacuo provided the titled which was used in the next reaction without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@@H:10]1[CH2:25][N:14]2[C:15]3[CH:16]=[C:17]([C:22]([OH:24])=O)[CH:18]=[CH:19][C:20]=3[CH:21]=[C:13]2[C:12](=[O:26])[NH:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=[N:42][C:37]2[CH:38]=[CH:39][CH:40]=[N:41][C:36]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.NC1C=NC=CC=1>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C@@H:10]1[CH2:25][N:14]2[C:15]3[CH:16]=[C:17]([C:22](=[O:24])[NH:42][C:37]4[CH:36]=[N:41][CH:40]=[CH:39][CH:38]=4)[CH:18]=[CH:19][C:20]=3[CH:21]=[C:13]2[C:12](=[O:26])[NH:11]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)NC[C@@H]1Cn2c(cc3ccc(C(=O)O)cc32)C(=O)N1
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1cccnc1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC[C@@H]1Cn2c(cc3ccc(C(=O)Nc4cccnc4)cc32)C(=O)N1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 64 %

Procedure:
To a solution of the above carboxylic acid (94 mg, 0.262 mmol) in 2 mL of DMF (2 mL) was added HATU (104.5 mg, 0.275 mmol), HOAt (18.6 mg, 0.137 mmol) and N,N′-diisopropylethylamine (96 uL, 0.55 mmol). After 15 min, 3-amino-pyridine (26 mg, 0.275 mmol) in 1 mL of DMF was added. The reaction mixture was warmed at 80° C. for 8 h. The reaction was concentrated and extracted with EtOAc several times. The combined organic extracts were washed with brine, dried over MgSO4 and concentrated. Purification by silica gel chromatography gave 73 mg of [(R)-1-oxo-7-(pyridin-3-ylcarbamoyl)-1,2,3,4-tetrahydro-pyrazino[1,2-a]indol-3-ylmethyl]-carbamic acid tert-butyl ester, yield 64%. The product was characterized by 1H NMR and mass spectroscopy. ESI-MS m/z 436.48 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[Br:9]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1>[Br:9][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1
Reactant: Cc1cccc(F)n1
Reactant: O=C1CCC(=O)N1Br
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cccc(CBr)n1
Reaction time: 18 h
Yield: 36.8 %

Procedure:
Combine 2-methyl-6-fluoro-pyridine (19.6 g, 176 mmol), 1,1′-azobis-(cyclohexane-carbonitrile) (0.431 g, 1.77 mmol), and freshly recystallized N-bromo-succinimide (32.96 g, 185 mmol) in carbon tetrachloride (200 mL) and stir in a 1000 mL flask while radiating with UV light for 18 h. Allow to cool, then filter to remove succinimide and wash with dilute Na2S2O3 solution. Dry over Na2SO4, filter and evaporate to give an amber oil. Purify by silica gel chromatography, eluting with 0-30% EtOAc/hexanes to obtain 12.3 g (37%) of a clear oil. MS 100% (m/e) 190 (EI); 1H NMR (DMSO, 400 MHz): δ 8.03-7.95 (m, 1H), 8.03-7.95 (m, 1H), 7.48 (dd, 1H, J=7.5, 2.6 Hz), 7.11 (dd, 1H, J=7.9, 2.6 Hz), 4.63 (s, 2H).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.C(N(CC)C(C)C)(C)C.[CH3:30][O:31][CH2:32][CH2:33][NH:34][CH2:35][C:36]1[CH:48]=[CH:47][C:39]([O:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[C:38]([CH3:49])[CH:37]=1>C(Cl)Cl>[CH3:30][O:31][CH2:32][CH2:33][N:34]([CH2:35][C:36]1[CH:48]=[CH:47][C:39]([O:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[C:38]([CH3:49])[CH:37]=1)[C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1
Reactant: CCOC(=O)COc1ccc(CNCCOC)cc1C
Reactant: CS(=O)(=O)c1nccc(-c2ccc(C(F)(F)F)cc2)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)COc1ccc(CN(CCOC)c2nccc(-c3ccc(C(F)(F)F)cc3)n2)cc1C
Temperature: 100 °C
Yield: 24.1 %

Procedure:
A mixture of 2-(methylsulfonyl)-4-[4-(trifluoromethyl)phenyl]pyrimidine (0.2 g, 0.66 mmol), N,N-diisopropylethylamine (0.11 mL, 0.66 mmol) and ethyl (4-{[(2-methoxyethyl)amino]methyl}-2-methylphenoxy)acetate (0.28 g. 0.99 mmol) was heated at 100° C. in a sealed reactivial for 20 h. The reaction mixture was then allowed to come to room temperature, and the residue dissolved in CH2Cl2 (30 mL), the organic extract was washed water (20 mL) and passed through a hydrophobic frit before concentrating in vacuo. Purification by Biotage™ chromatography (Silica, 90 g) eluting 1:9 EtOAc:cyclohexane afforded the title compound as a pale yellow oil (0.08 g).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)=[O:12])[N:7]([C:27]2[CH:32]=[CH:31][C:30]([NH:33]C(=O)CC(C)(C)C(O)=O)=[CH:29][CH:28]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]>C1COCC1>[NH2:33][C:30]1[CH:31]=[CH:32][C:27]([N:7]2[C:8]([NH:10][C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]4[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=4)=[CH:16][CH:15]=3)=[O:12])=[CH:9][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6]2)=[CH:28][CH:29]=1
Reactant: CC(C)(CC(=O)Nc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccncc3)cc2)cc1)C(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccncc3)cc2)n(-c2ccc(N)cc2)n1
Temperature: 25 °C
Yield: 54.8 %

Procedure:
A solution of N-[4-(3-tert-butyl-5-{3-[4-(pyridin-4-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-phenyl]-2,2-dimethyl-succinamic acid (190 mg, 0.33 mmol) in 3 mL THF was treated with borane-methylsulfide complex (2M, 1.0 mL, 2.0 mmol, 6 eq). The reaction mixture was heated at reflux under nitrogen for 4 h. The reaction mixture was then cooled to room temperature, slowly quenched by the addition of 0.6 mL EtOH and 2 mL 2N HCl. The reaction mixture was heated again at reflux for 1 hr, then cooled to room temperature, basified by the addition of 1N NaOH, extracted with DCM, and concentrated at reduced pressure. The crude residue was purified by MPLC (eluting with 2% to 6% MeOH in DCM) to afford 80 mg of semi-pure 1-[2-(4-amino-phenyl)-5-tert-butyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yloxy)-phenyl]-urea. Preparative HPLC purification using 5-80% H2O in acetonitrile (containing 0.5% TFA) afforded 33 mg (18%) of the desired product. 1H-NMR (DMSO-d6) δ 9.14 (s, 1H), 8.40 (dd, J=1.6 & 4.8 Hz, 2H), 8.17 (s, 1H), 7.47 (d, J=8.9 Hz, 2H), 7.11 (d, J=8.6 Hz, 2H), 7.07 (d, J=9 Hz, 2H), 6.85 (dd, J=1.5 & 4.9 Hz, 2H), 6.62 (d, J=8.9 Hz, 2H), 6.28 (s, 1H), 5.83 (t, J=5.2 Hz, 1H), 4.58 (t, J=5.2 Hz, 1H), 3.14 (d, J=5.4 Hz, 2H), 3.06-3.01 (m, 2H), 1.52-1.48 (m, 2H), 1.25 (s, 9H), 0.87 (s, 6H); MS LC-MS [M+H]+=543.2, RT=2.31 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][C:11](=[C:14]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[C:15]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9]2)=[C:4]([F:29])[CH:3]=1.[CH2:30]([CH:32]([CH2:36][CH3:37])[C:33](Cl)=[O:34])[CH3:31]>ClCCCl>[CH2:18]([N:17]([CH2:20][CH3:21])[C:15]([C:14]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1)=[C:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:33](=[O:34])[CH:32]([CH2:36][CH3:37])[CH2:30][CH3:31])=[CH:3][C:4]=2[F:29])[CH2:9][CH2:10]1)=[O:16])[CH3:19]
Reactant: CCN(CC)C(=O)C(=C1CCN(c2ccc(N)cc2F)CC1)c1cccc(F)c1
Reactant: CCC(CC)C(=O)Cl
Solvent: ClCCCl
Product: CCC(CC)C(=O)Nc1ccc(N2CCC(=C(C(=O)N(CC)CC)c3cccc(F)c3)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.9 %

Procedure:
To a mixture of 2-[1-(4-amino-2-fluoro-phenyl)-piperidin-4-ylidene]-N,N-diethyl-2-(3-fluoro-phenyl)-acetamide (0.33 mmol) and TEA (2.0 mmol) in DCE (10 mL) was added 2-ethylbutyryl chloride (1 mmol) dropwise. The mixture was stirred at rt for 16 h, then was washed with H2O (10 mL). The organic layer was concentrated and the residue was purified by PTLC to provide the title compound (54 mg, 33%). MS (ESI): mass calcd. for C29H37F2N3O2, 497.29. m/z found, 498.4 [M+H]+. 1H NMR (CDCl3): 7.58-7.53 (m, 1H), 7.47 (NH, 1H), 7.37-7.32 (m, 1H), 7.18-7.06 (m, 3H), 7.04-6.97 (m, 1H), 6.92-6.85 (m, 1H), 3.50-3.00 (m, 6H), 2.62-2.52 (m, 4H), 2.10-2.02 (m, 1H), 1.79-1.67 (m, 4H), 1.62-1.52 (m, 2H), 1.16 (t, J=7.1, 3H), 1.00-0.87 (m, 9H).
Reaction SMILES: Cl.[CH2:2]([CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19](=[NH:21])[NH2:20])[CH:16]=2)[CH2:11]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH3:22][O-:23].[Na+].CO.S(=O)(=O)(O)O>O>[CH2:2]([CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19]3[N:20]=[CH:18][C:17]([C:12]4[CH:13]=[CH:14][C:22]([OH:23])=[CH:10][CH:11]=4)=[CH:16][N:21]=3)[CH:16]=2)[CH2:11]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCC1Cc2ccc(C(=N)N)cc2C1
Reactant: C[O-]
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCCCCCC1Cc2ccc(-c3ncc(-c4ccc(O)cc4)cn3)cc2C1
Temperature: 0 °C
Yield: 151.1 %

Procedure:
1.00 g (3.24 mM) of 2-octyl-5-amidinoindan hydrochloride, 0.70 g (13.7 mM) of sodium methylate, 1.04 g (3.26 mM) of 3-dimethylamino-2-(4-hydroxyphenyl)-N,N-dimethylpropene-(2)-ammonium perchlorate and 20 ml of methanol were placed in a 50 ml-round bottomed flask and heat-refluxed for 14.5 hours under stirring. After the reaction, an appropriate amount of water was poured into the reaction mixture and 0.66 ml of concentrated sulfuric acid was further added thereto under cooling with ice water, followed by stirring. The resultant insoluble matter was recovered by filtration, followed by washing with water and drying with anhydrous sodium sulfate. The resultant insoluble was purified by silica gel column chromatography (eluent: toluene) and recrystallized from a mixture solvent (acetone/methanol) to obtain 0.98 g of 2-octyl-5-[5-(4-hydroxyphenyl)pyrimidine-2-yl]indan (Yield: 75.6%).
Reaction SMILES: [H][H].[CH3:3][O:4][C:5]([C:7]1[N:8]=[C:9]([NH:12][C:13](=[O:40])[C@@H:14]([N:22]2[C:26](=[O:27])[C@H:25]([CH2:28][C:29]3C=CC4C(=CC=CC=4)[CH:30]=3)[NH:24][C:23]2=[O:39])[CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[S:10][CH:11]=1)=[O:6]>>[CH3:3][O:4][C:5]([C:7]1[N:8]=[C:9]([NH:12][C:13](=[O:40])[C@@H:14]([N:22]2[C:26](=[O:27])[C@@H:25]([CH2:28][CH2:29][CH3:30])[NH:24][C:23]2=[O:39])[CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[S:10][CH:11]=1)=[O:6]
Reactant: COC(=O)c1csc(NC(=O)[C@H](CC2CCCCC2)N2C(=O)N[C@@H](Cc3ccc4ccccc4c3)C2=O)n1
Reactant: [H][H]
Product: CCC[C@H]1NC(=O)N([C@@H](CC2CCCCC2)C(=O)Nc2nc(C(=O)OC)cs2)C1=O

Procedure:
In yet another embodiment of Compound A-1b, R3 is naphthyl and R4 is hydrogen. An example of such a compound is (S,S)-2-[[3-cyclohexyl-2-[2,5-dioxo-4-(naphthalen-2-yl)methylimidazolidin-1-yl]propanoyl]amino]thiazole-4-carboxylic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH:19]([CH3:23])[CH2:20][O:21][CH3:22])[C:13]=1[NH2:24].[C:25](OC)(=[O:29])[C:26]([CH3:28])=O>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[C:12]1[C:13]2[N:24]=[C:26]([CH3:28])[C:25](=[O:29])[N:18]([CH:19]([CH3:23])[CH2:20][O:21][CH3:22])[C:14]=2[N:15]=[CH:16][CH:17]=1
Reactant: COCC(C)Nc1nccc(-c2ccc(OC(F)F)cc2Cl)c1N
Reactant: COC(=O)C(C)=O
Product: COCC(C)n1c(=O)c(C)nc2c(-c3ccc(OC(F)F)cc3Cl)ccnc21

Procedure:
4-(2-Chloro-4-difluoromethoxy-phenyl)-N2-(2-methoxy-1-methyl-ethyl)-pyridine-2,3-diamine (0.149 g, 0.42 mmol) and methyl pyruvate (75 μL, 0.83 mmol) were treated substantially as described in Part F of Example 113 to give 8-(2-chloro-4-difluoromethoxy-phenyl)-4-(2-methoxy-1-methyl-ethyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 121a): 1H NMR (300 MHz, CDCl3): δ 8.54–8.53 (d, 1H, J=4.8 Hz), 7.34–7.32 (m, 2H), 7.21–7.13 (m, 2H), 6.85–6.36 (t, 1H, J=73.2 Hz), 4.41–4.37 (m, 1H), 3.82–3.76 (m, 2H), 3.34 (s, 3H), 2.47 (s, 3H), 1.62 (d, 3H, J=6.9 Hz). MS (AP) m/z 410.0 [(M+H)+, 100].
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1.[Cl:16][C:17]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[C:19]([CH3:32])[N:18]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[Cl:16][C:17]1[CH:22]=[C:21]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:20]=[C:19]([CH3:32])[N:18]=1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)n1
Reactant: Nc1nnc(Br)c(-c2ccc(F)cc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(-c2nnc(N)nc2-c2ccc(F)cc2)cc(Cl)n1
Yield: 61 %

Procedure:
6-bromo-5-(4-fluorophenyl)-1,2,4-triazin-3-amine (1 molar eq.), 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-methylpyridine (1 molar eq.) and K2CO3 (1.5 molar eq.) are suspended in a mixture of 1,4-dioxane and water (2:1; 10 mL of solvent per gram of bromotriazine). The resulting mixture is degassed, treated with dichlorobis[di-tert-butyl(4-dimethylaminophenyl)phosphino]palladium(II) (2 mol %) and refluxed until full consumption of bromotriazine is observed by LCMS. The cooled reaction mixture is then diluted with water, extracted with DCM and passed through a phase separator. The organic phase is concentrated under reduced pressure and purified by gradient flash chromatography, eluting with mixtures of ethyl acetate and hexanes to afford 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine (61%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].CC(C)=O>C1CCCCC1>[CH2:16]([O:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]([CH:3]=1)[C:12]([O:14][CH3:15])=[O:13])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCCCC1
Solvent: CC(C)=O
Product: COC(=O)c1cc(OCc2ccccc2)cc(C(=O)OC)c1

Procedure:
A mixture of 156 g (0.743 mole) of dimethyl 5-hydroxyisophthalate, 171 g (1 mole) of benzylbromide and 138 g (1 mole) of K2CO3 in 1 l. of acetone was refluxed for 18 hours. The reaction mixture was evaporated to a residue which was extracted with hot cyclohexane to give the crystalline product in a quantitive yield upon cooling. The analytical sample was obtained by recrystallization from cyclohexane, mp. 94-95° .
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[OH-].[Na+].O.I[CH3:29]>C(Cl)Cl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:29][O:1][C:2]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: CI
Reactant: CCCCCCCCCc1ccc(O)c(C(=O)c2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCc1ccc(OC)c(C(=O)c2ccccc2)c1
Yield: 84.4 %

Procedure:
A sample of 2-hydroxy-5-nonyl benzophenone (25 g, 0.077 mol) was dissolved in 100 mL methylene chloride. To this solution was added a solution of 20 g (0.5 mol) sodium hydroxide in 100 mL deionized water, followed by the addition of 22 g (0.154 mol) iodomethane and 2.5 g (0.006 mol) tetra-n-butylammonium bromide. The entire mixture was agitated with vigorous mechanical stirring for 1.5 hours at 40° C. The reaction mixture was allowed to cool, and the layers separated. The aqueous phase was extracted with 50 mL methylene chloride. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under vacuum. The residual oil was, taken up in petroleum ether, washed with water, dried over magnesium sulfate and again concentrated under vacuum to provide 22 g (85% yield) of 2-methoxy-5-nonyl benzophenone.
Reaction SMILES: Br.Br[CH2:3][CH2:4][C:5]1[C:14](=[O:15])[N:13]2[C:8]([S:9][CH2:10][CH2:11][CH2:12]2)=[N:7][C:6]=1[CH3:16].Br.[C:18]1([C:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[C:18]1([C:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:25]2[CH2:26][CH2:27][N:28]([CH2:3][CH2:4][C:5]3[C:14](=[O:15])[N:13]4[C:8]([S:9][CH2:10][CH2:11][CH2:12]4)=[N:7][C:6]=3[CH3:16])[CH2:29][CH2:30]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: c1ccc(C(=C2CCNCC2)c2ccccc2)cc1
Reactant: Cc1nc2n(c(=O)c1CCBr)CCCS2
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: Cc1nc2n(c(=O)c1CCN1CCC(=C(c3ccccc3)c3ccccc3)CC1)CCCS2
Yield: 60 %

Procedure:
A mixture of 7.4 parts of 7-(2-bromoethyl)-3,4-dihydro-8-methyl-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one monohydrobromide, 6.6 parts of 4-(diphenylmethylene)piperidine hydrobromide, 12 parts of sodium carbonate and 120 parts of 4-methyl-2-pentanone was stirred and refluxed overnight. The reaction mixture was cooled, water was added and the layers were separated. The organic phase was dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane. The product was filtered off and recrystallized from 2-propanol, yielding 5.5 parts (60%) of 7-[2-[4-(diphenylmethylene)-1-piperidinyl]ethyl]-3,4-dihydro-8-methyl-2H,6H-pyrimido[2,1-b][1,3]-thiazin-6-one; mp. 176.0° C. (compound 104).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[C:12]([O:15][C@@H:16]1[C@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@@H:20]([O:26][C:27](=[O:29])[CH3:28])[C@H:19]([CH3:30])[O:18][C@H:17]1[O:31][C@@H:32]1[C@@H:38]([OH:39])[C@H:37]([CH3:40])[O:36][C@@:34]([C@H:41]2[O:70][C@H:69]([CH2:71][O:72][CH2:73][C:74]3[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=3)[C@@H:60]([O:61][CH2:62][C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[C@H:51]([O:52][CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C@H:42]2[O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([OH:35])[C@@H:33]1[O:80][C:81](=[O:88])[C:82]1[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=1)(=[O:14])[CH3:13].[Cl:89][C:90]([Cl:94])([Cl:93])[C:91]#[N:92]>C(Cl)Cl>[Cl:89][C:90]([Cl:94])([Cl:93])[C:91](=[NH:92])[OH:14].[C:12]([O:15][C@@H:16]1[C@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@@H:20]([O:26][C:27](=[O:29])[CH3:28])[C@H:19]([CH3:30])[O:18][C@H:17]1[O:31][C@@H:32]1[C@@H:38]([OH:39])[C@H:37]([CH3:40])[O:36][C@@:34]([C@H:41]2[O:70][C@H:69]([CH2:71][O:72][CH2:73][C:74]3[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=3)[C@@H:60]([O:61][CH2:62][C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[C@H:51]([O:52][CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C@H:42]2[O:43][CH2:44][C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)([OH:35])[C@@H:33]1[O:80][C:81](=[O:88])[C:82]1[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=1)(=[O:14])[CH3:13]
Reactant: N#CC(Cl)(Cl)Cl
Agent: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](C)O[C@@H](O[C@@H]2[C@@H](O)[C@H](C)O[C@](O)([C@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)[C@@H]2OC(=O)c2ccccc2)[C@@H]1OC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: N=C(O)C(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
DBU (100 μL) was added at 0° C. to a solution of the hemiacetal 522 (3.8 g, 3.58 mmol) in DCM (40 mL) containing trichloroacetonitrile (4 mL). The mixture was stirred for 30 min at 0° C., and volatiles were evaporated. Flash chromatography (solvent B, 7:3+0.2% Et3N) of the crude material gave the donor 505 (3.9 g, 90%) as a while solid; 1H NMR (α anomer): δ 8.75 (s, 1H, NH), 8.13-7.12 (m, 25H, Ph), 6.40 (d, 1H, J1,2=2.4 Hz, H-1C), 5.54 (br s, 1H, H-2B), 5.49 (dd, 1H, J2,3=2.9 Hz, H-2C), 5.26 (d, 1H, J1,2=2.8 Hz, H-1E), 5.20 (dd, 1H, J2,3=J3,4=10.0 Hz, H-3B), 5.17 (br s, 1H, H-1B), 4.96 (dd, 1H, H-4B), 4.99-4.41 (m, 8H, OCH2), 4.34 (m, 1H, H-3C), 4.14-4.02 (m, 3H, H-3E, 5E, 5C), 3.87 (m, 1H, H-4C), 3.78 (dq, 1H, J4,5=9.5, J5,6=6.1 Hz, H-5B), 3.70 (m, 2H, H-6aE, 6bE), 3.65 (dd, 1H, J2,3=3.4, J3,4=9.8 Hz, H-2E), 3.57 (pt, 1H, J2,3=J3,4=9.4 Hz, H-4E), 1.86, 1.83 (2s, 9H, CH3CO), 1.42 (d, 3H, J5,6=6.2 Hz, H-2C), 0.98 (d, 3H, H-6B); 13C NMR (α anomer): δ 170.3, 170.1, 169.9, 166.1 (4C, C═O), 160.7 (C═NH), 139.2-127.8 (Ph), 100.2 (C-1B), 98.1 (C-1E), 94.8 (C-1C), 91.2 (CCl3), 82.4 (C-4C), 82.0 (C-3E), 81.2 (br s, C-2E), 78.5 (br s, C-3C), 78.3 (C-4E), 75.9, 75.4, 74.3, 73.3 (4C, CH2Ph), 71.8 (C-5E), 71.7 (C-2C), 71.3 (C-4B), 70.8 (br s, C-5C), 70.0 (C-2B), 69.3 (C-3B), 69.2 (C-6E), 67.6 (C-5B), 21.3, 21.0, 20.9 (3C, CH3CO), 18.9 (C-6C), 17.1 (C-6B). Anal. Calcd. for C61H66Cl3NO18: C, 60.67; H, 5.51; N, 1.16%. Found: C, 60.53; H, 5.48; N, 1.38%.