Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH2:35][CH2:36][O:37][CH3:38])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(O)(C)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:22]3[C:31]4[C:26](=[CH:27][C:28]([O:34][CH2:35][CH2:36][O:37][CH3:38])=[C:29]([O:32][CH3:33])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OC
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(O)c2)no1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)O
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OC
Temperature: 70 °C
Yield: 68.3 %

Procedure:
According to the procedure described in Example 50, a mixture of 1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea (4.405 g, 16 mmol) from Example 1A, 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline from Example 7A (4.837 g, 18 mmol), and Cs2CO3 (8.145 g, 16 mmol) in isopropanol (80 mL) was heated at 70° C. for 4 hours, to afford 1-(5-tert-butylisoxazol-3-yl)-3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}urea as a solid (5.548 g, 68.3%). 1H NMR (300 MHz, DMSO-d6) δ 9.58 (s, 1H), 9.00 (s, 1H), 8.57 (s, 1H), 7.58 (m, 2H), 7.41 (m, 2H), 7.25 (d, 1H), 6.98 (d, 1H), 6.48 (s, 1H), 4.34 (t, 2H), 3.99 (s, 3H), 3.78 (t, 2H), 3.35 (s, 3H), 1.28 (s, 9H); LC-MS (ESI) m/z 508 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[CH:7]([C:9]1[CH:10]=[C:11]([C:20]([CH3:24])([CH3:23])[C:21]#[N:22])[CH:12]=[C:13]([C:15]([CH3:19])([CH3:18])[C:16]#[N:17])[CH:14]=1)[CH3:8]>>[N:1]1([CH:7]([C:9]2[CH:14]=[C:13]([C:15]([CH3:18])([CH3:19])[C:16]#[N:17])[CH:12]=[C:11]([C:20]([CH3:24])([CH3:23])[C:21]#[N:22])[CH:10]=2)[CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(Cl)c1cc(C(C)(C)C#N)cc(C(C)(C)C#N)c1
Reactant: c1c[nH]cn1
Product: CC(c1cc(C(C)(C)C#N)cc(C(C)(C)C#N)c1)n1ccnc1

Procedure:
The process described in Example 8 was repeated, using imidazole in place of 1,2,4-triazole, and 2,2'-[5-(1-chloroethyl)-1,3-phenylene]di(2-methylpropiononitrile), (obtained as described in the second part of Example 7), as the starting materials, to give 2,2'-[5-(1-[imidazol-1-yl]ethyl)-1,3-phenylene]di(2-methylpropiononitrile), mp. 77°-80°.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=O.[N+]([O-])(O)=O.[F:18][C:19]([F:34])([O:23][C:24]1[CH:25]=[C:26]([NH:30][C:31]([NH2:33])=[NH:32])[CH:27]=[CH:28][CH:29]=1)[CH:20]([F:22])[F:21].[OH-].[Na+]>C(O)C(C)C>[F:18][C:19]([F:34])([O:23][C:24]1[CH:25]=[C:26]([NH:30][C:31]2[N:33]=[C:5]([C:7]3[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][N:32]=2)[CH:27]=[CH:28][CH:29]=1)[CH:20]([F:21])[F:22]
Reactant: N=C(N)Nc1cccc(OC(F)(F)C(F)F)c1
Reactant: CN(C)C=CC(=O)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: CC(C)CO
Product: FC(F)C(F)(F)Oc1cccc(Nc2nccc(-c3ccncc3)n2)c1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
To a solution of 13.2 g (75 mmol) of 3-dimethylamino-1-(4-pyridyl)-2-propen-1-one [described in EP-A-0 233 461] in 500 ml of isobutanol are added 23.6 g (75 mmol) of 3-(1,1,2,2-tetrafluoroethoxy)phenylguanidine nitrate. Following the addition of 4 g (100 mmol) of sodium hydroxide, the reaction mixture is stirred for 3 hours at 110° C. The suspension is concentrated under reduced pressure, the residue is dissolved in 500 ml of methylene chloride/tetrahydrofuran (1:1), and the solution is extracted with 300 ml of water. The organic phase is dried over sodium sulfate and concentrated on a rotovap. Recrystallisation from diethyl ether/tetrahydrofuran gives N-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-4-(4-pyridyl)-2-pyrimidine-amine; Rf =0.9 (methylene chloride:methanol =9:1), FAB-MS: 365 (M+ +1), m.p. 191°-192°.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1/[CH:12]=[CH:13]/[C:14]([OH:16])=O)(=[O:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH2:38]([O:45][CH2:46][C@@H:47]1[CH2:52][N:51]([CH2:53][C:54]2[CH:59]=[CH:58][C:57]([F:60])=[CH:56][CH:55]=2)[C@@H:50]([CH3:61])[CH2:49][NH:48]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C1COCC1>[CH2:38]([O:45][CH2:46][C@@H:47]1[CH2:52][N:51]([CH2:53][C:54]2[CH:55]=[CH:56][C:57]([F:60])=[CH:58][CH:59]=2)[C@@H:50]([CH3:61])[CH2:49][N:48]1[C:14](=[O:16])/[CH:13]=[CH:12]/[C:6]1[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:5]=1[NH:4][C:1](=[O:3])[CH3:2])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: C[C@H]1CN[C@H](COCc2ccccc2)CN1Cc1ccc(F)cc1
Reactant: CC(=O)Nc1cc(Cl)ccc1/C=C/C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(Cl)ccc1/C=C/C(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 28 h
Yield: 46.7 %

Procedure:
(E)-3-(2-Acetylamino-4-chloro-phenyl)-acrylic acid (168 mg, 0.7 mmol), EDCI (269 mg, 1.4 mmol); HOBT (190 mg, 1.4 mmol) and 230 mg (0.7 mmol) (2S,5S)-5-Benzyloxymethyl-1-(4-fluorobenzyl)-2-methyl-piperazine (prepared as outlined in example 47) were dissolved in 10 ml THF and stirred for 28 hours at room temperature. This mixture was then extracted 3 times with water and once with saturated sodium chloride solution. The title compound was purified by chromatography (SiO2, ethyl acetate/MeOH/NH3conc. 90/10/1) and was isolated as a pale solid (180 mg, 47%)
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:19]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:19]
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Reactant: O=C(CBr)C1CCCCC1
Product: CCOC(=O)n1c(C(=O)C2CCCCC2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-[(ethoxycarbonyl)amino]benzonitrile (Example 1, step 1) and 2-bromoacetylcyclohexane (Lotfield, Schaad, J. Am. Chem. Soc., 1954, 76, 35).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:20])[N:4]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[NH2:8].[F:21][C:22]([F:35])([F:34])[O:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31](O)=[O:32])[CH:27]=[CH:28][CH:29]=1.CCN=C=NCCCN(C)C>C(O)C.O>[NH2:8][C:7]1[N:6]([CH3:9])[C:5](=[O:10])[N:4]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:3](=[O:20])[C:2]=1[NH:1][C:31](=[O:32])[CH2:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([O:23][C:22]([F:34])([F:21])[F:35])[CH:25]=1
Reactant: O=C(O)Cc1cccc(OC(F)(F)F)c1
Reactant: COc1ccc(Cn2c(=O)c(N)c(N)n(C)c2=O)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: CCO
Product: COc1ccc(Cn2c(=O)c(NC(=O)Cc3cccc(OC(F)(F)F)c3)c(N)n(C)c2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.8 %

Procedure:
To a solution of 5,6-diamino-3-(4-methoxybenzyl)-1-methylpyrimidine-2,4(1H,3H)-dione (50 mg, 0.181 mmol, intermediate 59) in ethanol (3 ml) was added 2-(3-(trifluoromethoxy)phenyl)acetic acid (40 mg, 0.181 mmol) and EDCI (52 mg, 0.271 mmol) The mixture was stirred at room temperature for 2 h. The reaction was diluted with water, filtered and the solids were rinsed with water. The solid residue was dissolved in ethyl acetate, dried over sodium sulfate, filtered and concentrated to give N-(6-amino-3-(4-methoxybenzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide (70 mg, 80.1%) as light gray solid. LCMS retention time 1.239 min; LCMS MH+ 479.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C([Li])CCC.[CH3:17][C:18]1[C:19](=O)[CH2:20][CH:21]([CH3:24])[C:22]=1[CH3:23].Cl.N>O1CCCC1>[CH3:17][C:18]1[C:22]([CH3:23])=[C:21]([CH3:24])[CH2:20][C:19]=1[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: CC1=C(C)C(C)CC1=O
Reactant: Brc1cccc2cccnc12
Agent: Cl
Agent: N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1=C(C)C(C)=C(c2cccc3cccnc23)C1
Temperature: -80 °C
Reaction time: 0.25 h
Yield: 42.8 %

Procedure:
A solution of 8.3 g (40 mmol) of 8-bromoquinoline in 100 ml of tetrahydrofuran was cooled to −80° C. and 16 ml of n-butyllithium (2.5 M in hexane, 40 mmol) were subsequently added dropwise. After the addition was complete, the mixture was stirred for a further 15 minutes at −80° C. and 4.96 g (40 mmol) of 2,3,4-trimethylcyclopent-2-enone were then added. The mixture was allowed to come to room temperature and was then refluxed for 30 minutes. After cooling to room temperature, the reaction mixture was admixed with ice water and 10 ml of concentrated hydrochloric acid and stirred for 30 minutes. A dilute aqueous ammonia solution was then added until a pH of 12 had been reached. The aqueous phase was then separated off from the organic phase and the aqueous phase was extracted twice with diethyl ether. The organic phases were combined, dried over magnesium sulfate, filtered and the solvent was distilled off. Distillation at 117-132° C. and 2×10−2 mbar gave 4.02 g (17.1 mmol, 43%) of 2,3,4-trimethyl-1-(8-quinolyl)cyclopentadiene.
Reaction SMILES: [C:1]([C:4]([CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].[O:22]([CH2:29][CH2:30][CH2:31]Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[C:1]([C:4]([CH:17]1[CH2:21][CH2:20][N:19]([CH2:31][CH2:30][CH2:29][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCNC1
Reactant: BrCCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCN(CCCOc2ccccc2)C1

Procedure:
A mixture containing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (0.3 g--see Preparation B), 3-phenoxypropylbromide (0.24 g), anhydrous potassium carbonate (0.4 g) and acetonitrile (10 ml) was heated under reflux for 5 hours. On cooling to room temperature water (40 ml) was added and the resulting mixture extracted with dichloromethane (3×50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 7%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless foam, yield, 0.23 g.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([OH:17])[CH2:14][CH2:13][C@H:12]1[C:18]([O:20][CH3:21])=[O:19])=[O:10])[C:2]1C=CC=C[CH:3]=1.ClC(OCC=C)=O.C(N(CC)CC)C.C(OCC)(=O)C>CO.[C].[Pd]>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([OH:17])[CH2:14][CH2:13][C@H:12]1[C:18]([O:20][CH3:21])=[O:19])=[O:10])[CH:2]=[CH2:3]
Reactant: COC(=O)[C@@H]1CC[C@@H](O)CN1C(=O)OCc1ccccc1
Agent: [Pd]
Agent: C=CCOC(=O)Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=CCOC(=O)N1C[C@H](O)CC[C@H]1C(=O)OC
Reaction time: 2 h
Yield: 55.9 %

Procedure:
To a solution of 2.46 g (8.39 mmol) of (2S,5R)-1-benzyloxycarbonyl-5-hydroxy-2-methoxycarbonylpiperidine in 100 ml of methanol was added 500 mg of 5% palladium-carbon, and the mixture was hydrogenated for 2 hours at atmospheric pressure and room temperature. The catalyst was removed by filtration, and the filtrate was concentrated. The residue was dissolved in 20 ml of dichloromethane. To this solution was dropwise added 1.3 ml (9.33 mmol) or triethylamine followed by 0.98 ml (9.24 mmol) of allyl chloroformate. After stirring for 2 hours, 1.3 ml (9.33 mmol) of triethylamine and 0.98 ml (9.24 mmol) of allyl chloroformate were additionally added to the mixtures, which was stirred for 1 hours. To the mixture was added 200 ml of ethyl acetate, the organic layer was washed successively with water, 1N potassium bisulfate, water, saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride. After drying over anhydrous sodium sulfate, the solvent was removed. The residue was purified by silica gel column chromatography (Wakogel®C-300, elution with ethyl acetate - hexane system) to give 1.14 g (yield: 55 %) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[O:24]1[C:29]2=[CH:30][CH:31]=[CH:32][C:33]([C:34](O)=[O:35])=[C:28]2[NH:27][CH2:26][CH2:25]1>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:34]([C:33]2[CH:32]=[CH:31][CH:30]=[C:29]3[O:24][CH2:25][CH2:26][NH:27][C:28]=23)=[O:35])=[O:10])[N:12]=1
Reactant: O=C(O)c1cccc2c1NCCO2
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3c2NCCO3)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 3,4-Dihydro-2H-benzo[1,4]oxazine-5-carboxylic acid. LC-MS (basic): tR=0.94 min; [M+H]+=488.9.
Reaction SMILES: O=C[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].[CH:11]([O:16][CH3:17])([O:14][CH3:15])OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:17][O:16][CH:11]([O:14][CH3:15])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)CCCCC=O
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)CCCCC(OC)OC
Reaction time: 48 h
Yield: 88 %

Procedure:
56 g (0.4 Mole) of cyclohexanone enolacetate in 500 ml of methanol was ozonised in a dry ice-acetone bath until the solution turned blue. 60 ml of dimethyl sulphide was added, and the cooling bath was removed. The temperature rose slowly to 48°, and after it had returned to room temperature, 40 ml of trimethyl orthoformate and 1 ml of acetyl chloride were added. The mixture was then left for 48 h at room temperature. Three identical batches were combined and the solvant was removed in vacuo. The residue was dissolved in ether, washed with brine containing a small amount of NaHCO3, dried (Na2SO4), and distilled to give 193 g of product, b.p. 56°-69°/0.1 Torr. The NMR spectrum indicated the presence of ca. 20% of methyl 6-oxohexanoate. The product was mixed with 100 ml of trimethyl orthoformate, 20 ml of methanol, and 0.5 g of p-toluene sulfonic acid. The mixture was left for 48 h at room temperature, then worked up as above yielding 201 g (88%) of methyl 6,6-dimethoxyhexanoate. b.p. 61°/0.1 Torr.
Reaction SMILES: [C:1]1([C:7]2[CH2:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCCCCC.C([Li])CCC.[C:23]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1.C1COCC1.O>[C:1]1([C:7]2[CH:11]=[CH:10][C:9](=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: C1=CCC(c2ccccc2)=C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: C1=CC(=C(c2ccccc2)c2ccccc2)C=C1c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 2.5 g (17.6 mmol) of phenylcyclopentadiene in 30 ml of toluene was ice cooled, and thereto was dropwise added 13.0 ml (21.1 mmol) of a hexane solution of n-butyllithium. The resulting white slurry was stirred at room temperature for one night. From the slurry, the solvent was filtered off to give a THF solution (brown solution). To the solution, a solution of 3.2 g (17.6 mmol) of benzophenone in 10 ml of THF was added, followed by stirring at room temperature for one night. After addition of water, the mixture was subjected to extraction with diethyl ether and dried over magnesium sulfate. Then, the ether was distilled off to obtain a red viscous liquid. The liquid was purified by a silica gel column to obtain a red solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([C@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([CH2:18][CH2:19][N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:13]1)[CH:7]=[C:6]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:5]2=[O:30].CC1(C)C(C)(C)[O:35][B:34](B2OC(C)(C)C(C)(C)O2)[O:33]1.C(N(CC)CC)C.C([O-])(=O)C.[K+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:21]([N:20]([CH2:23][CH3:24])[CH2:19][CH2:18][N:14]1[CH2:15][CH2:16][CH2:17][CH:12]([N:8]2[C:9]3[N:10]=[CH:11][C:2]([B:34]([OH:35])[OH:33])=[CH:3][C:4]=3[C:5](=[O:30])[C:6]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:7]2)[CH2:13]1)[CH3:22]
Reactant: CCOC(=O)c1cn([C@H]2CCCN(CCN(CC)CC)C2)c2ncc(Br)cc2c1=O
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(C2CCCN(CCN(CC)CC)C2)c2ncc(B(O)O)cc2c1=O
Temperature: 75 °C

Procedure:
(S)-ethyl 6-bromo-1-(1-(2-(diethylamino)ethyl)piperidin-3-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (Intermediate 35, 2.7 g, 5.63 mmol) and PdCl2(PPh3)2 (0.395 g, 0.56 mmol) were combined and suspended in 1,4-dioxane (50 mL). The slurry was degassed, purged with nitrogen and then gently warmed to 75° C. for 20 min. 4,4,4′,4′,5,5,5′,5′-Octamethyl-2,2′-bi(1,3,2-dioxaborolane) (4.29 g, 16.90 mmol) was then added in a single portion and the temperature was raised to 100° C. After an hour of heating, triethylamine (0.784 mL, 5.63 mmol) and potassium acetate (1.658 g, 16.90 mmol) were added sequentially. The reaction mixture was stirred at reflux overnight. The reaction mixture was cooled to room temperature and filtered through a celite. Solvent was removed in vacuo and the residue was purified via ISCO DCM/Methanol 0-20% gradient. (S)-8-(1-(2-(diethylamino)ethyl)piperidin-3-yl)-6-(ethoxycarbonyl)-5-oxo-5,8-dihydro-1,8-naphthyridin-3-ylboronic acid (2.0 g, 80%) was recovered as a brown solid.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5].[CH2:9](O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1CCC(N=C=NC2CCCCC2)CC1>>[CH2:9]([CH:3]([CH2:2][C:1]([OH:8])=[O:7])[C:4]([OH:6])=[O:5])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)CCC(=O)O
Reactant: OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: O=C(O)CC(Cc1ccccc1)C(=O)O

Procedure:
Succinic acid can be protected with benzyl alcohol in the presence of DCC to obtain mono benzyl succinic acid. The product can then be purified via silica gel chromatography. Mono benzyl succinic acid can then be activated with HOSU in the presence of DCC and then coupled to Tris to obtain benzyl-succinate. This compound can then be acylated with lauric acid in the presence of DCC to give a mixture of the title compound. The three compounds can then be separated by silica gel chromatography with elution by organic solvents.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3]1=[O:11].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[CH3:1][N:2]1[C:6]2[C:7]([N+:12]([O-:14])=[O:13])=[N:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3]1=[O:11]
Reactant: Cn1c(=O)[nH]c2ccncc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cn1c(=O)[nH]c2ccnc([N+](=O)[O-])c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
To a solution of 1.73 g (11.6 mmol) of 3-methyl-1,3-dihydroimidazo[4,5-c]pyridin-2-one in 6.3 mL of concentrated sulfuric acid, cooled in an 0° C. ice bath, was slowly added a solution of 1.50 mL (36.0 mmol) of fuming nitric acid in 1.5 mL of concentrated sulfuric acid. The reaction was removed from the ice bath and stirred for 0.5 h at room temperature and then heated at 100° C. for 2 h. The reaction was quenched over 300 mL of ice and solid ammonium carbonate was added to adjust the pH to 9. The resulting slurry was filtered and the collected solids washed with water and dried under high vacuum to give 1.94 g (86%) of the title compound.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH2:9]([C:11]1([CH2:21][C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1)[CH3:10].O>CS(C)=O.C1COCC1>[CH2:9]([C:11]1([CH2:21][C:22]2([C:23]([F:24])([F:26])[F:25])[CH2:4][O:27]2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1)[CH3:10]
Reactant: CCC1(CC(=O)C(F)(F)F)CCCc2ccccc21
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: O
Product: CCC1(CC2(C(F)(F)F)CO2)CCCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of sodium hydride (74 mg of a 60% dispersion in mineral oil, 1.85 mmol) in DMSO (5 ml) was added a solution of trimethylsulphoxonium iodide (610 mg, 2.77 mmol) in DMSO (5 ml). After stirring at room temperature for 30 min a solution of 3-(1-ethyl-1,2,3,4-tetrahydro-1-naphthalenyl)-1,1,1-trifluoro-2-propanone (Intermediate 13) (500 mg, 1.85 mmol) in THF (3 ml) was added and the mixture was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with diethylether. The organic extract was washed repeatedly with water, dried over anhydrous sodium sulphate and evaporated in vacuo to give the title compound as a crude mixture of diastereomers. Extraction of aqueous layer with dichloromethane yielded further title compound as a crude mixture of diastereomers. Combined products were then applied to a 20 g silica SPE cartridge eluting with a 0-10% dichloromethane in cyclohexane gradient for 10 min followed by 10% dichloromethane in cyclohexane for 5 min. This gave, in order of elution, Intermediate 14 (racemic diastereomer 1, 178 mg): and Intermediate 15 (racemic diastereomer 2, 86 mg).
Reaction SMILES: O[C:2]1[C:7]([I:8])=[C:6]([CH3:9])[N:5]=[CH:4][N:3]=1.O=P(Cl)(Cl)[Cl:12]>>[Cl:12][C:2]1[C:7]([I:8])=[C:6]([CH3:9])[N:5]=[CH:4][N:3]=1
Reactant: Cc1ncnc(O)c1I
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ncnc(Cl)c1I
Temperature: 90 °C

Procedure:
A suspension of 90 g (0.38 mol) 4-hydroxy-5-iodo-6-methylpyrimidine in 600 mL POCl3 is heated for 1 h at 90° C. The reaction mixture is concentrated under reduced pressure and the residue is poured into crushed ice. The precipitated solid is collected by filtration and washed with water. After drying, the desired product is obtained as a solid (90 g; 93%).
Reaction SMILES: [C:1]([C:4]1[O:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[Br-].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[S-:63][C:64]#[N:65].[Na+].C(=O)(O)[O-].[Na+]>C(O)C>[O:5]1[CH:6]=[CH:7][CH:8]=[C:4]1[C:1]([CH2:2][S:63][C:64]#[N:65])=[O:3]
Reactant: CC(=O)c1ccco1
Reactant: N#C[S-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Br-]
Solvent: CCO
Product: N#CSCC(=O)c1ccco1
Temperature: 50 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
2-Acetylfuran (10.0 mL, 100 mmol) was dissolved in ethanol (200 mL). To the solution was added N,N,N,N-tetra-n-butylammonium tribromide (50.6 g, 105 mmol), and the mixture was stirred at 50° C. for 1 hour. Sodium thiocyanate (8.91 g, 110 mmol) was added to the reaction mixture, and the mixture was further stirred for 1 hour. A saturated sodium bicarbonate aqueous solution was added to the reaction mixture, and the mixture extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The precipitated crystals were collected by filtration to give a title compound (11.2 g, 67%).