Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8].[C:22]([Si:26]([O:39][CH2:40][CH2:41]I)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:25])([CH3:24])[CH3:23].O>CN(C=O)C>[C:22]([Si:26]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[O:39][CH2:40][CH2:41][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][OH:1])[S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8])([CH3:23])([CH3:24])[CH3:25]
Reactant: O=S(=O)(NCCCCO)c1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)[Si](OCCI)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](OCCN(CCCCO)S(=O)(=O)c1ccc(-c2ccccc2)cc1)(c1ccccc1)c1ccccc1

Procedure:
Biphenyl-4-sulfonic acid-(4-hydroxybutyl)-amide (1 g) and tert-butyl-(2-iodo-ethoxy) diphenyl silane (2 g) were heated in DMF (30 mL) for 3 hours at 60° C. The resultant mixture was poured into water and extracted with dichloromethane. Evaporation and column chromatography (petrol/ethyl acetate) gave the title compound as an amorphous solid. δC (CDCl3, 62.9 MHz): 19.2, 25.1, 26.8, 29.5, 49.3, 49.8, 62.4, 62.9, 127.3, 127.6, 127.7, 127.8, 128.5, 129.1, 129.9, 133.2, 135.6, 138.4, 139.4 and 145.3.
Reaction SMILES: Cl[C:2]1([C:27]([F:30])([F:29])[F:28])[CH2:11][C:10]2[C:5](=[CH:6][C:7]([N:13]3[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]3=[O:25])=[C:8]([F:12])[CH:9]=2)[NH:4][C:3]1=[O:26].C(N(CC)CC)C>O1CCCC1>[F:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N:13]1[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]1=[O:25])[NH:4][C:3](=[O:26])[C:2]([C:27]([F:30])([F:28])[F:29])=[CH:11]2
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc3c(cc2F)CC(Cl)(C(F)(F)F)C(=O)N3)c1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc3[nH]c(=O)c(C(F)(F)F)cc3cc2F)c1=O
Yield: 47.3 %

Procedure:
This compound was prepared in a manner analogous to that of Step H of Example 1, using 3.2 grams (0.007 mole) of 3-(3-chloro-6-fluoro-3,4-dihydro-3-trifluoromethylquinolin-2-on-7-yl)-1-methyl -6-trifluoromethyluracil and 3.2 grams (0.031 mole) of triethylamine in 100 mL of tetrahydrofuran. The product was recrystallized from ethanol, yielding 1.4 grams of 3-(6-fluoro-3-trifluoromethylquinolin-2-on-7-yl)-1-methyl-6-trifluoromethyluracil. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH2:4]Cl.[CH3:13][O-:14].[Na+].CCCCCC.C1C=CC=CC=1>CO>[CH3:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH2:4][O:14][CH3:13]
Reactant: C[O-]
Reactant: Cc1ccc([N+](=O)[O-])cc1CCl
Agent: [Na+]
Solvent: CCCCCC
Solvent: c1ccccc1
Solvent: CO
Product: COCc1cc([N+](=O)[O-])ccc1C
Yield: 72.7 %

Procedure:
2-Methyl-5-nitrobenzyl chloride (16.2 g) was dissolved in methanol (180 ml) and then sodium methoxide (5.4 g) was added and the mixture refluxed. The reaction was followed by tlc (75/25 v/v, hexane/benzene) and additional quantities of sodium methoxide added and heating continued until the reaction was complete. Finally, the mixture was cooled and filtered. The filtrate was concentrated in vacuo and the residue taken up in methylene chloride, washed with water, then the organic layer was separated and dried over magnesium sulfate. Removal of the drying agent by filtration and concentration of the filtrate in vacuo left 15.8 g, which was recrystallized from 150 ml of hexane to give 11.5 g of white solid with m.p. 45°-49° C. Another run gave a solid which after recrystallization from hexane gave a solid with m.p. 50°-52° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[C:10]1[N:15]=[C:14]([NH:16][C:17]2[CH:18]=[N:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[C:13]([F:24])=[CH:12][N:11]=1>>[Cl:23][C:20]1[N:19]=[CH:18][C:17]([NH:16][C:14]2[C:13]([F:24])=[CH:12][N:11]=[C:10]([NH:5][C:4]3[CH:6]=[CH:7][CH:8]=[C:2]([OH:1])[CH:3]=3)[N:15]=2)=[CH:22][CH:21]=1
Reactant: Nc1cccc(O)c1
Reactant: Fc1cnc(Cl)nc1Nc1ccc(Cl)nc1
Product: Oc1cccc(Nc2ncc(F)c(Nc3ccc(Cl)nc3)n2)c1

Procedure:
In like manner to the preparation of N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine, the reaction of 3-hydroxyaniline with 2-chloro-N4-(6-chloropyridin-3-yl)-5-fluoro-4-pyrimidineamine gave N4-(6-chloropyridin-3-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 10.10 (bs, 1H), 9.64 (bs, 1H), 8.85 (m, 1H), 8.30 (m, 2H), 8.22 (d, 1H, J=4.2 Hz), 7.43 (d, 1H, J=8.7 Hz), 7.01 (m, 3H), 6.42 (bd, 1H, J=8.4 Hz); LCMS: purity: 93%; MS (m/e): 332 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]2[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH:13]=2)=[C:8]2[C:3]=1[C:4](=[O:24])[C:5]([CH3:23])=[CH:6][NH:7]2>CCO.[Pd]>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]([C@@H:12]2[CH2:13][CH2:14][C@H:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH2:17]2)=[C:8]2[C:3]=1[C:4](=[O:24])[C:5]([CH3:23])=[CH:6][NH:7]2
Reactant: CCOC(=O)C1CC=C(c2ccc(N)c3c(=O)c(C)c[nH]c23)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@H]1CC[C@@H](c2ccc(N)c3c(=O)c(C)c[nH]c32)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of ethyl 4-(5-amino-3-methyl-4-oxo-1,4-dihydroquinolin-8-yl)cyclohex-3-ene-1-carboxylate (Compound 304C, 0.270 g, 0.83 mmol) and palladium 10% wt on activated carbon (88.0 mg, 0.083 mmol) in EtOH (2.17 mL) was evacuated and purged with hydrogen (3×) and subsequently stirred under one atmosphere of hydrogen at rt for 16 hrs. The reaction mixture was filtered and the filtrate was concentrated in vacuo to an orange oil. The product was purified by mass directed purification which resolved the cis and trans isomers. Compound 304A, the trans isomer eluted first: 1H NMR (400 MHz, MeOD) δ ppm 1.27 (t, J=7.07 Hz, 3H) 1.53-1.73 (m, 4H) 1.79 (d, J=4.29 Hz, 2H) 2.02 (d, J=0.76 Hz, 3H) 2.26 (d, J=13.14 Hz, 2H) 2.70-2.82 (m, 2H) 4.17 (q, J=7.07 Hz, 2H) 6.38 (d, J=8.34 Hz, 1H) 7.12 (d, J=8.34 Hz, 1H) 7.63 (s, 1H). MS (ES+): m/z 329.16/329.36 (100/70) [MH+]. HPLC: tR=1.28 min (Micromass TOF: polar—3 min). Compound 304B, the cis isomer eluted after: 1H NMR (400 MHz, CDCl3) δ ppm 1.25 (t, J=7.07 Hz, 3H) 1.54 (br. s., 1H) 1.70 (d, J=12.63 Hz, 1H) 1.87 (br. s., 1H) 2.02 (d, J=0.51 Hz, 1H) 2.07 (br. s., 1H) 2.35-2.45 (m, 1H) 2.69-2.81 (m, 1H) 4.12 (q, J=7.07 Hz, 1H) 6.39 (d, J=8.34 Hz, 1H) 7.20 (d, J=8.34 Hz, 1H) 7.64 (d, J=0.76 Hz, 1H). MS (ES+): m/z 329.14/329.35 (100/70) [MH+]. HPLC: tR=1.30 min (Micromass TOF: polar—3 min).
Reaction SMILES: [Cl:1][C:2]1[C:19]([Cl:20])=[CH:18][C:5]2[NH:6][C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].[CH3:23][O:24][C:25](=[O:34])[C:26]1[CH:31]=[CH:30][C:29]([CH2:32]Br)=[CH:28][CH:27]=1.C(Cl)Cl>CN(C=O)C.[Cl-].[Na+].O.CCOC(C)=O>[Cl:20][C:19]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:32][C:29]3[CH:30]=[CH:31][C:26]([C:25]([O:24][CH3:23])=[O:34])=[CH:27][CH:28]=3)[C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=3)=[N:6][C:5]=2[CH:18]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: COc1ccc(Nc2nc3cc(Cl)c(Cl)cc3[nH]2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(Cn2c(Nc3ccc(OC)cc3)nc3cc(Cl)c(Cl)cc32)cc1
Reaction time: 2 h

Procedure:
To the title compound of Example 19, Step A (1.3 mmol, 407 mg) in DMF (5 mL) was added NaH (1.6 mmol, 62 mg of 60% suspension in mineral oil). After 10 min methyl-4-(bromomethyl)benzoate (1.3 mmol, 304 mg) was added and the reaction mixture was allowed to stand at ambient temperature for 2 h. Aqueous workup with CH2Cl2/saturated NaHCO3 and brine, followed by flash chromatography on silica eluting with 40%, 50% and 60% EtOAc in hexanes afforded the product as a tan solid. LC-MS (ESI, Method B): 1.93 min, m/z 456.1 (M+1).
Reaction SMILES: [CH2:1]([S:3]([CH2:6][C:7]1[C:16](C(OC)=O)=[N+:15]([O-:21])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N+:8]=1[O-:22])(=[O:5])=[O:4])[CH3:2]>[OH-].[Na+]>[CH2:1]([S:3]([CH2:6][C:7]1[CH:16]=[N+:15]([O-:21])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N+:8]=1[O-:22])(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)Cc1c(C(=O)OC)[n+]([O-])c2ccccc2[n+]1[O-]
Agent: [Na+]
Agent: [OH-]
Product: CCS(=O)(=O)Cc1c[n+]([O-])c2ccccc2[n+]1[O-]
Temperature: 120 °C
Yield: 95 %

Procedure:
A slurry of 2-ethylsulfonylmethyl-3-carbomethoxyquinoxaline-1,4-dioxide (28.2 g., 0.087 m) and 0.5 N sodium hydroxide (280 ml.) was stirred at room temperature for 30 minutes. It was then filtered and the filtrate acidified to pH 3 with 6N hydrochloric acid. The resulting slurry was heated in an oil bath (bath temperature 120°C.) for 30 minutes. It was removed from the oil bath, allowed to cool to room temperature and the solid filtered off: 22.2 g. (95 percent yield); m.p. 216°C.
Reaction SMILES: [CH3:1][N:2]([CH3:35])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH:19]=3)[C:14]([OH:29])=[C:13]([C:30](OC)=[O:31])[C:12]2=[O:34])=[CH:7][CH:6]=1)=[O:4].[NH2:36][CH2:37][CH2:38][NH:39][C:40](=[O:42])[CH3:41]>CO>[C:40]([NH:39][CH2:38][CH2:37][NH:36][C:30]([C:13]1[C:12](=[O:34])[N:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([N:2]([CH3:35])[CH3:1])=[O:4])=[CH:6][CH:7]=2)[C:20]2[C:15]([C:14]=1[OH:29])=[N:16][CH:17]=[C:18]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[CH:19]=2)=[O:31])(=[O:42])[CH3:41]
Reactant: COC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(C(=O)N(C)C)cc2)c1=O
Reactant: CC(=O)NCCN
Solvent: CO
Product: CC(=O)NCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(C(=O)N(C)C)cc2)c1=O
Yield: 53.5 %

Procedure:
In a similar manner to that described in example 196, from from methyl 1-{4-[(dimethylamino)carbonyl]phenyl}-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (8 mg, 0.0168 mmol), N-(2-aminoethyl)acetamide (10 mg, 0.098 mmol) and methanol (2 mL), was prepared N-[2-(acetylamino)ethyl]-1-{4-[(dimethylamino)carbonyl]phenyl}-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (4.9 mg, 54% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.14 (m, 1 H), 8.52 (s, 1 H), 7.65 (d, J=8.4 Hz, 2 H), 7.27 (d, J=8.4 Hz, 2 H), 7.02-6.98 (m, 2 H), 6.95-6.90 (m, 2 H), 6.79 (s, 1 H), 6.03 (br s, 1 H), 3.94 (s, 2 H), 3.57-3.54 (m, 2 H), 3.47-3.42 (m, 2 H), 3.16 (s, 3 H), 3.04 (s, 3 H), 1.95 (s, 3 H); MS m/z 546 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH2:17][CH2:18][CH3:19])=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH2:15])[N:9]=2)[CH:7]=1.NC1N=[C:25](C2C=C(Br)C=CC=2O)[CH:24]=[C:23](Cl)N=1.C(O)CCCCC>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH2:17][CH2:18][CH2:19][CH2:23][CH2:24][CH3:25])=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH2:15])[N:9]=2)[CH:7]=1
Reactant: CCCOc1ccc(Br)cc1-c1cc(Cl)nc(N)n1
Reactant: Nc1nc(Cl)cc(-c2cc(Br)ccc2O)n1
Solvent: CCCCCCO
Product: CCCCCCOc1ccc(Br)cc1-c1cc(Cl)nc(N)n1
Yield: 47 %

Procedure:
Following the method described in Example 135 for the synthesis of 4-(5-bromo-2-propoxy-phenyl)-6-chloro-pyrimidin-2-ylamine, 2-(2-amino-6-chloro-pyrimidin-4-yl)-4-bromo-phenol and hexan-1-ol provided 4-(5-bromo-2-hexyloxy-phenyl)-6-chloro-pyrimidin-2-ylamine (47% yield).
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]([CH2:14][CH2:15][CH:16]=[C:17]([CH3:29])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:28])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])=[CH:11][CH2:12][OH:13].[OH-].[K+]>CCCCCC>[CH2:1]([O:13][CH2:12][CH:11]=[C:10]([CH3:9])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:29])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:28])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCO
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCC
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCOCc1ccccc1
Reaction time: 2 h
Yield: 61 %

Procedure:
To 100 ml of benzyl chloride were added 15 g of 3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraen-1-ol and 6.0 g of finely divided potassium hydroxide, and the resulting mixture was refluxed under stirring for 2 hours. The mixture was cooled and then to the mixture was added 1 liter of hexane. The hexane solution was then washed with water and concentrated. The concentrate was purified over a silica gel column to give 12 g of 1-benzyloxy-3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraene (yield 61%).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH3:10][C:11]([CH3:54])([CH2:52][CH3:53])[CH2:12][C:13]1[N:14]=[C:15]([CH2:37][CH:38]([C:40]2[CH:45]=[CH:44][C:43]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=3)=[CH:42][CH:41]=2)O)[N:16]([C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:10][C:11]([CH3:54])([CH2:52][CH3:53])[CH2:12][C:13]1[N:14]=[C:15]([CH2:37][CH:38]([C:40]2[CH:45]=[CH:44][C:43]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=3)=[CH:42][CH:41]=2)[F:7])[N:16]([C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=1
Reactant: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(O)c2ccc(-c3ccccn3)cc2)n1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(F)c2ccc(-c3ccccn3)cc2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Diethylaminosulfur trifluoride (0.1 mL, 0.78 mmol) was added to a 0° C. solution of 2-[4-(2,2-dimethylbutyl)-1-trityl-1H-imidazol-2-yl]-1-(4-pyridin-2-ylphenyl)ethanol (385 mg, 0.65 mmol) in methylene chloride (10 mL). After stirring at 0° C. for 30 min then warming to ambient temperature then letting sit at −20° C. overnight, triethylamine (1 mL) was added. After stirring for a further 5 min, the reaction mixture was concentrated in vacuo. Chromatography over silica eluting with 0-40% ethyl acetate/hexane afforded 2-(4-{2-[4-(2,2-dimethylbutyl)-1-trityl-1H-imidazol-2-yl]-1-fluoroethyl}phenyl)pyridine.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[CH:5][CH:4]=1)=O.[CH3:19][C:20]([CH3:25])([CH3:24])[CH2:21][CH2:22][NH2:23].[BH4-].[Na+]>CO>[CH3:19][C:20]([CH3:25])([CH3:24])[CH2:21][CH2:22][NH:23][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)CCN
Reactant: NC(=O)c1cnc(Oc2ccc(C=O)cc2)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)CCNCc1ccc(Oc2cnc(C(N)=O)cn2)cc1
Reaction time: 8 h
Yield: 33.9 %

Procedure:
Place 5-(4-formylphenoxy)pyrazine-2-carboxamide (Example 437, Part B) (0.150 g, 0.617 mmol), 3,3-dimethylbutylamine (0.0624 g, 0.617 mmol) and 3 Å molecular sieves in a vial. Add methanol (3.1 mL), cap and stir overnight. Add NaBH4 (in excess over two portions) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 5 g ISCO®0 pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 10 g ISCO® column with 2.0 M NH3 in methanol, ethyl acetate and hexanes. After concentrating, take the product up in dichloromethane (25 mL) and wash with 1.0 N NaOH solution (2×10 mL). Dry the organic layer over Na2SO4, filter and concentrate to give the title compound (0.0687 g, 33.8%): MS ES+ 329.1 (M+H)+, base peak 228.0 (M-C6H15N)+; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95% over 19 min], tR=9.2 min, 100% purity.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:20]C)[C:10](=[O:19])[N:11]([CH3:18])[C:12]=2[CH2:16][CH3:17])[C:7]1=[O:22].Br>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:20])[C:10](=[O:19])[N:11]([CH3:18])[C:12]=2[CH2:16][CH3:17])[C:7]1=[O:22]
Reactant: CCc1c2c(c(OC)c(=O)n1C)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Agent: Br
Solvent: CC(=O)O
Product: CCc1c2c(c(O)c(=O)n1C)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2

Procedure:
A solution of 2-(3-chloro-4-fluorobenzyl)-5-ethyl-8-methoxy-6-methyl-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione (55 mg, 0.15 mmol) and 33% HBr in acetic acid (5 mL) in acetic acid (10 mL) was stirred at room temperature overnight. The product mixture was concentrated under vacuum. The residue was subjected to preparative reverse phase HPLC purification. Collection and lyophilization of appropriate fractions provide the titled compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:17]2[CH2:22][C@H:21]([CH3:23])[O:20][C@H:19]([CH3:24])[CH2:18]2)=[C:4]([CH:9]=[C:10]([C:13](=[N:15][OH:16])[CH3:14])[C:11]=1F)[C:5]([O:7]C)=[O:6].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[C:11]2[O:16][N:15]=[C:13]([CH3:14])[C:10]=2[CH:9]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[N:17]1[CH2:22][C@H:21]([CH3:23])[O:20][C@H:19]([CH3:24])[CH2:18]1
Reactant: COC(=O)c1cc(C(C)=NO)c(F)c(Cl)c1N1C[C@@H](C)O[C@@H](C)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1noc2c(Cl)c(N3C[C@@H](C)O[C@@H](C)C3)c(C(=O)O)cc12
Temperature: 130 °C

Procedure:
To a solution of methyl 3-chloro-2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-4-fluoro-5-[N-hydroxyethanimidoyl]benzoate (Intermediate 171, 700 mg, 1.94 mmol) in DMF (4 mL) was added Cs2CO3 (1.9 g, 5.84 mmol) and the mixture was heated to 130° C. for 14 hours. The reaction mixture was cooled to room temperature and filtered through a celite bed. The solvent was removed under vacuum and the residue was purified by silica gel chromatography column using ethyl acetate-pet. ether gradient to obtain product. Yield: 250 mg, (41%).
Reaction SMILES: C(OC([C:6]1[S:10][N:9]=[C:8]([C:11]2[C:19]3[C:14](=[C:15]([O:20][CH3:21])[CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:12]=2)[N:7]=1)=O)C.C[Mg]Br.[CH2:32]([O:34]CC)[CH3:33]>>[CH:23]1([CH2:22][N:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])[C:11]([C:8]3[N:7]=[C:6]([C:32](=[O:34])[CH3:33])[S:10][N:9]=3)=[CH:12]2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CCOC(=O)c1nc(-c2cn(CC3CCCCC3)c3c(OC)cccc23)ns1
Reactant: CCOCC
Agent: C[Mg]Br
Product: COc1cccc2c(-c3nsc(C(C)=O)n3)cn(CC3CCCCC3)c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a cooled solution (dry-ice acetone bath) of 3-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-[1,2,4]thiadiazole-5-carboxylic acid ethyl ester (500 mg, 1.3 mmol) in diethyl ether (50 ml) was added methyl magnesium bromide solution (0.52 ml, 3M in diethyl ether, 1.56 mmol) and the reaction stirred for 15 minutes, a further portion of methyl magnesium bromide solution (0.25 ml, 3M in diethyl ether, 0.75 mmol) was then added and the reaction mixture stirred for 5 minutes. The reaction was then quenched with saturated aqueous ammonium chloride (5 ml) and the reaction allowed to warm to room temperature. The reaction mixture was poured into a separating funnel and the organics washed with water (20 ml). The aqueous layer was then backwashed with diethyl ether (20 ml). The combined organic layers were dried over magnesium sulfate, filtered and the solvent removed in vacuo. The resulting residue was purified by flash column chromatography to give 1-[3-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-[1,2,4]thiadiazol-5-yl]-ethanone (170 mg, 0.46 mmol) as a yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[C:14]([O:18][C:19](=[O:23])[CH2:20][CH2:21][NH2:22])([CH3:17])([CH3:16])[CH3:15].C(N(CC)CC)C.[BH4-].[Na+]>CO.O>[C:14]([O:18][C:19](=[O:23])[CH2:20][CH2:21][NH:22][CH2:9][C:8]1[CH:11]=[CH:12][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: CC(C)(C)OC(=O)CCN
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)CCNCc1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
3.24 g (20 mmol) of 4-tert-butyl benzaldehyde, 3.63 g (20 mmol) of beta-alanine tert-butylester hydrochloride and 2.22 g (22 mmol) of triethyl amine were dissolved in 20 ml methanol and stirred at rt for 1 h. 1.11 g (30 mmol) of sodium borohydride were added in portions under nitrogen and the reaction mixture was stirred for 2 h at rt after complete addition. Water was added and the solvent was evaporated. The residue was extracted twice with diethyl ether. The combined organic layers were washed twice with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography (silica gel, diethyl ether) to yield 4.62 g (79%) product as a colorless oil. 1H NMR (DMSO-d6, 300 MHz): δ 7.34 (d, 2H), 7.25 (d, 2H), 3.76 (s, 2H), 2.86 (t, 2H), 2.45 (t, 2H), 1.44 (s, 9H), 1.31 (s, 9H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:32]([NH:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:33])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CCCCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: O=C=Nc1ccccc1
Product: CCCCCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)Nc1ccccc1
Yield: 26.9 %

Procedure:
Using the general method of Example 149, 1-(4-aminobutyl)-2-pentyl-1H-imidazo[4,5-c]quinolin-4-amine (800 mg, 2.5 mmol) was reacted with phenyl isocyanate (0.26 mL, 2.5 mmol) to provide 299 mg of N-[4-(4-amino-2-pentyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-phenylurea as an off white solid, m.p. 159.0-160.4° C. Analysis: Calculated for C26H32N6O2.1.0 H2O: % C, 67.51; % H, 7.41; % N, 18.17. Found: % C, 67.73; % H, 7.33; % N, 17.97.