Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1(CC2N3C=C(C)C=CC3=NC=2C2C=CC(C)=CC=2)C=CN=C1.Cl.Cl[CH2:26][C:27]1[N:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]2=[N:29][C:28]=1[C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1.[CH3:43][C:44]1[CH:48]=[C:47]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[NH:46][N:45]=1>>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([C:28]2[N:29]=[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]3[C:27]=2[CH2:26][N:45]2[C:44]([CH3:43])=[CH:48][C:47]([C:49]([O:51][CH2:52][CH3:53])=[O:50])=[N:46]2)=[CH:37][CH:38]=1
Reactant: ClCc1c(-c2ccc(Cl)cc2)nc2ccccn12
Reactant: CCOC(=O)c1cc(C)n[nH]1
Agent: Cc1ccc(-c2nc3ccc(C)cn3c2Cn2ccnc2)cc1
Agent: Cl
Product: CCOC(=O)c1cc(C)n(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)n1

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 1 from 3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochloride and ethyl 3-methyl-1H-pyrazole-5-carboxylate. The regioisomers were separated by silica gel chromatography. Compound 28: M/e+ 395 for C21H20ClN4O2 (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.24 (d, J=6.9 Hz, 1H), 7.82 (d, J=8.4 Hz, 2H), 7.61 (d, J=8.8 Hz, 1H), 7.36 (d, J=8.4 Hz, 2H), 7.17 (td, J=6.6, 1.1 Hz, 1H), 6.78 (td, J=6.6, 1.1 Hz, 1H), 6.50 (s, 1H), 6.01 (s, 2H), 4.30 (q, J=7.3 Hz, 2H), 2.26 (s, 3H), 1.30 (q, J=7.3 Hz, 3H) ppm; Compound 29: M/e+ 395 for C21H20ClN4O2 (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.47 (d, J=6.6 Hz, 1H), 7.64 (d, J=8.4 Hz, 2H), 7.63 (m, 1H), 7.48 (d, J=8.4 Hz, 2H), 7.24 (t, J=6.6 Hz, 1H), 6.84 (t, J=6.6 Hz, 1H), 6.44 (s, 1H), 5.84 (s, 2H), 4.36 (q, J=7.3 Hz, 2H), 1.73 (s, 3H), 1.37 (t, J=3H) ppm.
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[CH:20]1([NH:23][C:24](=[O:41])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27](B3OC(C)(C)C(C)(C)O3)[CH:26]=2)[CH2:22][CH2:21]1>>[CH:20]1([NH:23][C:24]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([C:2]3[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=4)=[O:7])=[CH:4][N:3]=3)[CH:26]=2)=[O:41])[CH2:21][CH2:22]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1cccc(CNC(=O)c2ccc(Cl)nc2)c1
Product: COc1cccc(CNC(=O)c2ccc(-c3cc(C(=O)NC4CC4)ccc3C)nc2)c1

Procedure:
6-[5-Cyclopropylcarbamoyl-2-methyl-phenyl]-N-(3-methoxybenzyl)-nicotinamide was prepared from 6-chloro-N-(3-methoxybenzyl)nicotinamide (intermediate 3) and N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 8) using General Method B. LCMS: retention time 2.94 min, MH+ 416. NMR: δH [2H6]-DMSO 9.29,(1H, t), 9.15,(1H, s), 8.48,(1H, d), 8.35,(1H, d), 7.89,(1H, s), 7.81,(1H, d), 7.72,(1H, d), 7.41,(1H, d), 7.26,(1H, t), 6.93,(2H, m), 6.84,(1H, s), 4.51,(2H, d), 3.75,(3H, s), 2.86,(1H, m), 2.38,(3H, s), 0.69,(2H, m), 0.57,(2H, m).
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]([O:14][C:15]2[CH:24]=[N:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:25])[CH:21]=3)[N:16]=2)[CH:11]=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6](O)=[O:7].S(Cl)([Cl:28])=O>>[F:1][C:2]1[CH:13]=[C:12]([O:14][C:15]2[CH:24]=[N:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:25])[CH:21]=3)[N:16]=2)[CH:11]=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6]([Cl:28])=[O:7]
Reactant: CC(Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1F)C(=O)O
Reactant: O=S(Cl)Cl
Product: CC(Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1F)C(=O)Cl
Reaction time: 5 h

Procedure:
2-[2-Fluoro-4-(6-chloroquinoxalin-2-yloxy)phenoxy]-propionic acid (1.73 g; 4.77 mmole) was treated with thionyl chloride and the mixture was heated under reflux with stirring for a period of 5 hours. The excess thionyl chloride was removed by distillation under reduced pressure to give 2-[2-fluoro-4-(6-chloroquinoxalin-2-yloxy)phenoxy]-propionyl chloride as a straw coloured oil.
Reaction SMILES: [CH:1](=O)[CH3:2].[C:4]([O:8][C:9]([NH:11][CH:12]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:13]1[CH2:16][NH:15][CH2:14]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>C(O)C.[Pd]>[C:21]([O:20][C:18]([NH:17][CH:12]([NH:11][C:9]([O:8][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:10])[CH:13]1[CH2:14][N:15]([CH2:1][CH3:2])[CH2:16]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC=O
Reactant: CC(C)(C)OC(=O)NC(NC(=O)OC(C)(C)C)C1CNC1
Agent: [Pd]
Solvent: CCO
Product: CCN1CC(C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
A mixture of acetaldehyde (1.5 g) and 3-[bis-(tert-butoxycarbonyl-amino)methyl]azetidine (Intermediate 151, 1.0 g) in ethanol (20 mL) was stirred at room temperature for 30 minutes and then 10% palladium on carbon (0.3 g) was added. The mixture was stirred under an atmosphere of hydrogen overnight. The solid was filtered off and the filtrate was evaporated to dryness. The residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM (10%) to give 3-[bis-(tert-butoxycarbonylamino)methyl]-1-ethylazetidine (0.83 g) as a colourless liquid, which was used without further characterization.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:5][C:3]=1[NH2:4].C(Cl)(=O)[C:17](Cl)=[O:18].Cl>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:5][C:3]=1[N:4]=[C:17]=[O:18]
Reactant: Nc1cc(OC2CCCC2)c(Cl)cc1F
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C=Nc1cc(OC2CCCC2)c(Cl)cc1F
Temperature: 25 °C
Yield: 86 %

Procedure:
A solution of 2-fluoro-4-chloro-5-cyclopentyloxyaniline (1.0 g, 5 mmol) in toluene (50 mL) was added dropwise to a solution of oxalyl chloride (2.0 g, 10 mmol) in toluene (20 mL) with stirring. The reaction mixture was stirred at room temperature for 1 hour and then heated to reflux for 4 hours until HCl evolution ceased. The mixture was cooled down to room temperature and the solvents were removed at reduced pressure to give 1.1 g of 2-fluoro-4-chloro-5-cylcopentyloxyphenyl isocyanate as an oily product. This was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1.[OH-].[Na+].I[CH2:33][CH:34]([OH:37])[CH2:35][OH:36].CCOCC>O>[F:1][C:2]([F:28])([F:29])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([O:25][CH2:33][CH:34]([OH:37])[CH2:35][OH:36])=[O:24])=[CH:21][CH:20]=1
Reactant: OCC(O)CI
Reactant: O=C(O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: O=C(OCC(O)CO)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 7.34 g. of 4-[15-(trifluoromethyl)pentadecylamino]benzoic acid, 4.80 g. of 25% aqueous sodium hydroxide, and 12.6 g. of 3-iodo-1,2-propanediol in 50 ml. of hexamethylphoshoramide is stirred for 24 hours at ambient temperature, diluted with 100 ml. of ether and stirred for 5 days at ambient temperature. The mixture is treated with water and extracted with ether. The dried extracts are evaporated to yield the product as a white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:20]([CH:21](O)[CH3:22])=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][N:17]=2)[N:12]=1)(=[O:4])=[O:3].[C:24]1(=[O:34])[NH:28][C:27](=[O:29])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12.N(C(OC(C)C)=O)=NC(OC(C)C)=O.O>C1COCC1>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:20]([CH:21]([N:28]2[C:24](=[O:34])[C:25]3[C:26](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:27]2=[O:29])[CH3:22])=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][N:17]=2)[N:12]=1)(=[O:3])=[O:4]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(O)c1cc2ncccc2nc1-c1ccccc1S(C)(=O)=O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(c1cc2ncccc2nc1-c1ccccc1S(C)(=O)=O)N1C(=O)c2ccccc2C1=O
Reaction time: 0.17 h

Procedure:
To a mixture of crude of 1-(2-(2-(methylsulfonyl)phenyl)-1,5-naphthyridin-3-yl)ethanol (700 mg, 2.13 mmol) and phthalimide (627 mg, 4.26 mmol) in THF (21 mL) was added triphenylphosphene (1.12 g, 4.26 mmol) at 0° C. The reaction mixture was stirred for 10 min at same temperature. Diisopropyl azodicarboxylate (0.9 mL, 4.26 mmol) was added to mixture at 0° C. The reaction mixture was stirred for overnight at 0° C. Water was added to reaction mixture and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo to give 2-(1-(2-(2-(methylsulfonyl)phenyl)-1,5-naphthyridin-3-yl)ethyl)isoindoline-1,3-dione: LC-MS (ESI) m/z 458.1 [M+H]+. It was carried on crude for next step.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[O:15][C:14]2[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:13]=2[NH:12][C:11]1=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>C1(C)C=CC=CC=1>[Si:1]([O:8][CH2:9][C:10]1([CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[O:15][C:14]2[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:13]=2[NH:12][C:11]1=[S:42])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC1(CO[Si](C)(C)C(C)(C)C)Oc2ccc([N+](=O)[O-])cc2NC1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OCC1(CO[Si](C)(C)C(C)(C)C)Oc2ccc([N+](=O)[O-])cc2NC1=S
Yield: 57.1 %

Procedure:
2,2-Bis(((tert-butyldimethylsilyl)oxy)methyl)-6-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (7.8 g) and Lawesson's reagent (7.8 g, 1.2 eq.) were suspended in toluene (100 ml). The reaction mixture was refluxed for four hours. The mixture was then evaporated. The residue was purified by Combiflash chromatography (EtOAc in hexanes=0-80%) to give 2,2-bis(((tert-butyldimethylsilyl)oxy)methyl)-6-nitro-2H-benzo[b][1,4]oxazine-3(4H)-thione (4.6 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:23][CH2:24][CH:25]=[CH2:26].O>O1CCCC1>[CH2:10]([O:9][C:7](=[O:8])[C:6]([CH2:4][CH2:3][CH:2]=[CH2:6])([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:23][CH2:24][CH:25]=[CH2:26])[CH3:11]
Reactant: CCOC(=O)Cc1cccs1
Reactant: C=CCCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCCC(CCC=C)(C(=O)OCC)c1cccs1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Ethyl 2-(thiophen-2-yl)acetate (2.35 g) was dissolved in tetrahydrofuran (30 mL) and cooled to −78° C. Lithium bis(trimethylsilyl)amide (2.31 g) in THF (1M solution, 13.8 mL) was added and the solution was stirred for 30 minutes. 4-Bromo-but-1-ene (1.4 mL) was added and the reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was re-cooled to −78° C. and lithium bis(trimethylsilyl)amide (2.31 g) in THF (1M solution, 13.8 mL) was added and the solution was stirred for 30 minutes. 4-Bromo-but-1-ene (1.4 mL) was added and the reaction mixture was allowed to warm to room temperature and stand overnight. HPLC-MS analysis indicated that the reaction was incomplete so the reaction was again cooled to −78° C. and further aliquots of lithium bis(trimethylsilyl)amide (1M solution, 10 mL) and 4-bromo-but-1-ene (1.0 mL) were added following the procedure outlined above. After stirring for a further 2 hours, water (30 mL) was added and the reaction was extracted with diethyl ether (2×60 mL). The combined organic extracts were dried (MgSO4) and evaporated. The resulting oil was purified by column chromatography on silica eluting with ethyl acetate/isohexane (1/99) afford the sub-titled compound (3.18 g).
Reaction SMILES: [CH2:1]([O:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]2[C:14](=[O:31])[C:15]3[C:20]([NH:21][C:22]=2[CH:23]=1)=[CH:19][C:18]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[CH:17][C:16]=3[OH:30])=[O:9])[CH2:2]CCCC.[CH3:32][N:33](C)[CH2:34]CO>CCCCCC>[CH3:32][N:33]([CH3:34])[CH2:2][CH2:1][O:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]2[C:14](=[O:31])[C:15]3[C:20]([NH:21][C:22]=2[CH:23]=1)=[CH:19][C:18]([N:24]1[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1)=[CH:17][C:16]=3[OH:30])=[O:9]
Reactant: CN(C)CCO
Reactant: CCCCCCOC(=O)c1ccc2c(=O)c3c(O)cc(N4CCOCC4)cc3[nH]c2c1
Solvent: CCCCCC
Product: CN(C)CCOC(=O)c1ccc2c(=O)c3c(O)cc(N4CCOCC4)cc3[nH]c2c1
Yield: 27 %

Procedure:
8-Hydroxy-6-morpholin-4-yl-9-oxo-9,10-dihydro-acridine-3-carboxylic acid hexyl ester in. N,N-dimethylethanolamine (2 mL) was heated at 13.0° C. in sealed tube for 12 hours. Hexane (5 mL) was added, and a dark solid formed. The suspension was filtered and the remaining solid triturated with acetone. All residues were dissolved in MeOH and concentrated. The concentrate was purified via flash chromatography (CH2Cl2 to MeOH/CH2Cl2, 5:95) to yield an orange solid (10 mg, 27%). 1H NMR (CDCl3, 400 MHz) δ: 13.82 (s, 1H), 11.84 (s, 1H), 8.19 (d, 1H), 8.04 (s, 1H), 7.66 (d, 1H), 6.24 (s, 1H), 6.16 (s, 1H), 4.41 (t, 2H), 3.74-3.64 (m, 4H), 3.33-3.22 (m, 4H), 2.64 (t, 2H), 2.48 (s, 6H) LRMS (APCI, positive): Da/e 412.1 (m+1).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][CH:14]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1N)[CH2:13][CH2:12]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.N1(CCOC2C=CC(C(Cl)=O)=CC=2)CCCCCC1.[N:48]1([CH2:55][CH2:56][O:57][C:58]2[CH:91]=[CH:90][C:61]([CH2:62][NH:63][C:64]3C=C(OC)C=C[C:65]=3C3CCC4C(=CC=C(O[Si](C(C)(C)C)(C)C)C=4)C3)=[CH:60][CH:59]=2)[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1>>[N:48]1([CH2:55][CH2:56][O:57][C:58]2[CH:59]=[CH:60][C:61]([CH2:62][NH:63][CH2:64][CH2:65][C:20]3[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:19]=3[CH:14]3[CH2:13][CH2:12][C:11]4[C:16](=[CH:17][CH:18]=[C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[CH:10]=4)[CH2:15]3)=[CH:90][CH:91]=2)[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54]1
Reactant: COc1ccc(C2CCc3cc(O[Si](C)(C)C(C)(C)C)ccc3C2)c(N)c1
Reactant: COc1ccc(C2CCc3cc(O[Si](C)(C)C(C)(C)C)ccc3C2)c(NCc2ccc(OCCN3CCCCCC3)cc2)c1
Agent: Cl
Agent: O=C(Cl)c1ccc(OCCN2CCCCCC2)cc1
Product: COc1ccc(C2CCc3cc(O[Si](C)(C)C(C)(C)C)ccc3C2)c(CCNCc2ccc(OCCN3CCCCCC3)cc2)c1

Procedure:
Synthesized from 2-[6-(tert-butyldimethylsilyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl]-5-methoxyphenylamine and 4-(2-azepan-1-ylethoxy)benzoyl chloride hydrochloride according to an analogous synthetic method to Example 152, [4-(2-azepan-1-ylethoxy)benzyl]{2-[6-(tert-butyldimethylsilyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl]-5-methoxyphenyl}amine (448 mg) was used according to an analogous synthetic method to Example 36 to provide [4-(2-azepan-1-ylethoxy)benzyl]{2-[6-(tert-butyldimethylsilyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl]-5-methoxyphenyl}ethylamine (392 mg). This compound (390 mg) was used according to an analogous synthetic method to Example 325 described below to provide the title compound (254 mg).
Reaction SMILES: [NH:1]1[C:8](=[O:9])[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[NH2:10][C:11](N)=[O:12].O>CN1CCCC1=O>[OH:3][C:2]1[N:4]=[C:5]([OH:6])[C:7]([C:11]([NH2:10])=[O:12])=[C:8]([OH:9])[N:1]=1
Reactant: O=C1CC(=O)NC(=O)N1
Reactant: NC(N)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: NC(=O)c1c(O)nc(O)nc1O
Yield: 96.5 %

Procedure:
A mixture of 128 grams of barbituric acid and 120 grams of urea in 200 ml of 1-methyl-2-pyrrolidone was heated at 145° for 15 minutes. Hot water was then added to the reaction mixture; a white solid precipitated and was collected by filtration. The precipitate was washed with hot dimethylformamide and dried to give 165 grams of 2,4,6-trihydroxy-5-pyrimidinecarboxamide; mp, >270°. The mass spectrum of the product was consistent with the assigned structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][N:9]=[CH:10]2)=[CH:5][C:4]=1F.C(OC(=O)[NH:20][C@H:21]1[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23][CH2:22]1)(C)(C)C>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][N:9]=[CH:10]2)=[CH:5][C:4]=1[O:27][C@@H:24]1[CH2:25][CH2:26][C@H:21]([NH2:20])[CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)CC1
Reactant: COc1cc2cnccc2cc1F
Product: COc1cc2cnccc2cc1O[C@H]1CC[C@@H](N)CC1

Procedure:
Starting from 7-methoxy-6-fluoro-isoquinoline (7) and cis-(4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester the title compound was prepared as trifluoroacetate by the method described for trans-[4-(5-chloro-isoquinolin-6-yloxy)-cyclohexyl]-carbamic acid tert-butyl ester (10) followed by deprotection using 4M hydrochloric acid in isopropanol and purification via preparative HPLC. Rt=0.62 min (Method #2). Detected mass: 273.19 (M+H+).
Reaction SMILES: [NH+]12CC[NH+](CC1)CC2.[F:9][B-:10]([F:13])([F:12])[F:11].F[B-](F)(F)F.[CH2:19]([C:21]1([CH2:34][CH3:35])[CH2:26][N+:25]2(P(O)(O)=O)[CH2:27][CH2:28][N+:22]1(F)[CH2:23][CH2:24]2)[CH3:20].[P:36](Cl)([O:41]CC)([O:38]CC)=[O:37].F[B-](F)(F)F.[Na+]>C1COCC1.C(#N)C>[F:9][B-:10]([F:13])([F:12])[F:11].[CH2:34]([C:21]1([CH2:19][CH3:20])[CH2:26][N:25]2[CH2:27][CH2:28][N+:22]1([P:36]([OH:38])([OH:41])=[O:37])[CH2:23][CH2:24]2)[CH3:35]
Reactant: CCC1(CC)C[N+]2(P(=O)(O)O)CC[N+]1(F)CC2
Reactant: CCOP(=O)(Cl)OCC
Agent: C1C[NH+]2CC[NH+]1CC2
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: CCC1(CC)CN2CC[N+]1(P(=O)(O)O)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diethyl 1-Fluoro-4-phosphono-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) 1,4-Diazoniabicyclo[2.2.2]octane (11 g, 10 mmol) in THF (100 mL) is reacted with diethyl chlorophosphate (17.3 g, 10 mmol) until the reaction is complete by TLC. The reaction is evaporated, diluted with acetonitrile (100 mL) and sodium tetrafluoroborate (40 g, 20 mmol) added. The solution is stirred overnight at room temperature and then filtered to remove all undissolved salts. The filtrate is evaporated to afford diethyl- 1-phosphono-4-aza-1-azoniabicyclo[2.2.2]octane tetrafluoroborate.
Reaction SMILES: [NH:1]([C:8]1[C:13]([Br:14])=[CH:12][N:11]=[C:10]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH:24]3[O:26][CH2:25]3)=[CH:18][CH:17]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][N:28]([CH3:30])[NH2:29]>C1COCC1>[NH:1]([C:8]1[C:13]([Br:14])=[CH:12][N:11]=[C:10]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH:24]([OH:26])[CH2:25][NH:29][N:28]([CH3:30])[CH3:27])=[CH:20][CH:21]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)N
Reactant: Brc1cnc(Nc2ccc(OCC3CO3)cc2)nc1Nc1ccccc1
Solvent: C1CCOC1
Product: CN(C)NCC(O)COc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1
Temperature: 100 °C
Yield: 73.1 %

Procedure:
4-Anilino-5-bromo-2-[4-(2,3-epoxypropoxy)anilino]pyrimidine (Method 3, 100 mg, 0.24 mmol) was dissolved in THF (1 ml). N,N-Dimethylhydrazine (148 mg, 2.42 mmol) was added and the mixture was heated at 100° C. for 1 hour. Volatile material was removed by evaporation and the residue was triturated with diethyl ether (2 ml) to give the product as a yellow solid (83 mg, 74%). MS (MH+): 473, 475; HPLC (RT): 3.37.
Reaction SMILES: C[O:2][C:3]1[NH:4][C:5]([CH3:33])=[C:6]([C:18]([O:20][C@@H](C)CN(C)CC2C=CC=CC=2)=[O:19])[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:8]=1.N1C=CC=CC=1.C1C([N+]([O-])=O)=CC=C([Cl-][C:50]([O-:52])=[O:51])C=1>ClCCl>[CH3:33][C:5]1[NH:4][C:3](=[O:2])[N:8]([C:50]([OH:52])=[O:51])[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:6]=1[C:18]([OH:20])=[O:19]
Reactant: COC1=NC(c2cccc([N+](=O)[O-])c2)C(C(=O)O[C@@H](C)CN(C)Cc2ccccc2)=C(C)N1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1=C(C(=O)O)C(c2cccc([N+](=O)[O-])c2)N(C(=O)O)C(=O)N1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 1,4-dihydro-2-methoxy-6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, (S)-1-methyl-2-[methyl(phenylmethyl)amino]ethyl ester (2.20 g, 4.87 mmol) and pyridine (2.36 ml, 29.2 mmol) in dichloromethane (20 ml) in an ice bath under argon was treated dropwise, via addition funnel, with a solution of 4-nitrophenylchloroformate (1.08 g, 5.36 mmol) in dichloromethane (20 ml). The reaction was then stirred in the ice bath for 15 minutes and evaporated. The residue was coevaporated with toluene to remove pyridine. The residue was then taken up in tetrahydrofuran (50 ml) and methanol (25 ml) and treated with 3N hydrochloric acid (5.0 ml, pH 1). After stirring at ambient temperature for 1.5 hours, the reaction was quenched by pouring into cold (ice bath) saturated sodium bicarbonate. After evaporating to near dryness, the mixture was extracted with ethyl acetate. The combined organic phase was washed with saturated sodium chloride, dried (potassium carbonate), and evaporated to give 3,4-dihydro-6-methyl-4-(3-nitrophenyl)-2-oxo-3,5-pyrimidinedicarboxylic acid, 5[(S)-1-methyl-2-[methyl(phenylmethyl)methyl)amino)ethyl], 3-(4-nitrophenyl)ester as a brown solid (2.38 g, 83%). TLC (10% acetone/dichloromethane) two major spots, Rf =0.25 and 0.39.
Reaction SMILES: Br[C:2]1([C:8]([OH:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][NH:3]1.C([O-])([O-])=O.[Na+].[Na+].[F:17][C:18]1[CH:23]=[CH:22][C:21](B2OCC(C)(C)CO2)=[CH:20][CH:19]=1.CCO>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:4]2[N:3]=[C:2]([C:8]([OH:10])=[O:9])[CH:7]=[CH:6][CH:5]=2)=[CH:20][CH:19]=1
Reactant: O=C(O)C1(Br)C=CC=CN1
Reactant: CC1(C)COB(c2ccc(F)cc2)OC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: O=C(O)c1cccc(-c2ccc(F)cc2)n1
Temperature: 100 °C
Yield: 46 %

Procedure:
A solution of 2-bromo-picolinic acid (Aldrich, 2.02 g, 10 mmol) in DME containing 4 mL of 10% aq Na2CO3 was purged with Ar gas. To this mixture was added Pd(PPh3)4 followed by 2-(4-fluorophenyl)-5,5-dimethyl-1,3,2-dioxaborinane (Aldrich, 2.40 g, 11.5 mmol) and EtOH (20 mL), and the mixture was purged with Ar gas. The reaction mixture was heated at 100° C. for 2.5 h in a sealed tube. Additional 2-bromo-picolinic acid (900 mg) and Pd(PPh3)4 was added, and after purging with Ar gas it was heated at 100° C. for 4.5 h. Trifluoroacetic acid (20 mL) was added to the reaction and the mixture was concentrated in vacuo. MeOH (150 mL) was added to the residue and the insoluble material was filtered, and the filtrate solution was concentrated in vacuo. Purification of the resulting residue by flash column chromatography on silica gel eluting with EtOAc/MeOH/900:100 followed by EtOAc/MeOH/HOAc/700:1500:50 provided the desired product (1.0 g, 40% based on borinane starting material) as a white solid. 1H NMR (CD3OD) δ 8.01 (d, 1H, J=7.7 Hz), 7.94-7.87 (m, 3H), 7.73 (d, 1H, J=7.7 Hz), 7.13 (t, 2H, J=8.8 Hz); MS (ESI+) m/z 234 (M+H)+.
Reaction SMILES: CO[C:3](=[O:31])[N:4]=[C:5](SC)[C:6](=[N:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=1)[C:7]1[CH:16]=[C:15]([O:17][CH3:18])[C:10]2[O:11][CH2:12][CH2:13][O:14][C:9]=2[C:8]=1[F:19].[CH3:32][O:33][C:34]([C:36]1[S:37][CH:38]=[CH:39][C:40]=1[NH:41][NH2:42])=[O:35].C(N(CC)CC)C>CN(C=O)C>[CH3:32][O:33][C:34]([C:36]1[S:37][CH:38]=[CH:39][C:40]=1[N:41]1[C:3](=[O:31])[NH:4][C:5]([CH:6]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]#[N:28])=[CH:25][CH:26]=2)[C:7]2[CH:16]=[C:15]([O:17][CH3:18])[C:10]3[O:11][CH2:12][CH2:13][O:14][C:9]=3[C:8]=2[F:19])=[N:42]1)=[O:35]
Reactant: COC(=O)c1sccc1NN
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(C#N)cc1)c1cc(OC)c2c(c1F)OCCO2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1sccc1-n1nc(C(Nc2ccc(C#N)cc2)c2cc(OC)c3c(c2F)OCCO3)[nH]c1=O
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a solution of 2 g of [2-(4-cyanophenylimino)-2-(5-fluoro-8-methoxy-2,3-dihydrobenzo[1,4]dioxin-6-yl)-1-methylsulfanylethylidene]carbamic acid methyl ester in 24 ml of DMF there were added 720 mg of 3-hydrazinothiophene-2-carboxylic acid methyl ester and 1.2 ml of triethylamine, and the mixture was stirred overnight at 85° C. under a nitrogen atmosphere.