Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:9]=2[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.[CH2:25]=O>C(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH3:25])[CH2:15][CH2:14]3)[C:9]=2[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2[nH]nc(N3CCNCC3)c2-c2ccncc2)cc1
Reactant: C=O
Solvent: O=CO
Product: CN1CCN(c2n[nH]c(-c3ccc(Cl)cc3)c2-c2ccncc2)CC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
The compound of Example A-170 was also synthesized in the following manner. 1-[5-(4-Chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]piperazine (12.2 g, 36 mmol, prepared as set forth in Example A-169), 88% formic acid (20 mL), and formaldehyde (37% formalin solution; 44 g, 540 mmol) were combined and stirred at 60° C. for 16 hours under a nitrogen atmosphere. Excess solvent was removed on the rotary evaporator and the residue was dissolved in water (150 mL). The pH was adjusted to 8-9 by addition of solid sodium bicarbonate. The resulting precipitate was filtered and air dried. It was then treated with hot methanol (400 mL), filtered and blown down to a volume of 75 mL, cooled and filtered. After drying in a vacuum oven at 80° C. overnight, there was obtained 8.75 g (68%) of 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-methylpiperazine, m. p. 262-264° C. Anal. Calc'd. for C19H20N5Cl: C, 64.49; H, 5.70; N, 19.79. Found: C, 64.04; H, 5.68; N, 19.63.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)=[CH:4][C:3]=1[N+:14]([O-:16])=O.O.[NH2:18][NH2:19].[ClH:20]>C(O)C>[ClH:20].[N:9]1([CH2:8][C:5]2[CH:6]=[CH:7][C:2]3[N:19]=[N:18][N:14]([OH:16])[C:3]=3[CH:4]=2)[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: O=[N+]([O-])c1cc(Cn2ccnc2)ccc1F
Reactant: NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: On1nnc2ccc(Cn3ccnc3)cc21
Yield: 54.3 %

Procedure:
A mixture of 6.5 parts of 1-[(4-fluoro-3-nitrophenyl)methyl]-1H-imidazole, 6.01 parts of hydrazine monohydrate and 80 parts of ethanol was stirred and refluxed for 5 hours. After cooling, 12 parts of a hydrochloric acid solution 5N were added. The whole was evaporated. The residue was stirred with 30 parts of water and the precipitated product was filtered off and boiled in 40 parts of 2-propanol. 2-Propanol, saturated with hydrogen chloride, was added. The salt was allowed to crystallize at room temperature. It was filtered off and dried, yielding 4.1 parts (54.3%) of 6-(1H-imidazol-1-ylmethyl)-1H-benzotriazol- 1-ol-monohydrochloride; mp. 207.4° C. (compound 158).
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1.[CH2:10]([O:17][C:18](Cl)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>[OH-].[Na+]>[CH2:10]([O:17][C:18]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)C1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
A solution of isonipecotic acid (12.9 g, 100 mmol) in 2N NaOH (55 mL) was cooled to 0° C. in an ice-bath. Benzylchloroformate (15.7 mL, 110 mmol, 1.1 eq.) and 2N NaOH (55 mL) were then added in about 10 portions, alternatively. The reaction mixture remained distinctly alkaline. The temperature of the reaction mixture was kept between 5 and 10° C. by controlling the rate of addition of reactants (about 45 min). The ice-bath was removed and the mixture was stirred at room temperature for 30 min. TLC showed the reaction was completed. The alkaline solution was extracted with Et2O (4×50 mL). The aqueous layer was acidified using 6N HCl to pH ˜5, extracted with EtOAc (3×100 mL). The combined EtOAc extracts were washed with saturated brine (100 mL), dried over Na2SO4, filtered and concentrated by rotary evaporation to give 1-benzyloxycarbonyl-piperidine-4-carboxylic acid as a white solid (17.3 g, 66 mmol, 66%). 1H NMR (300 MHz, CDCl3): δ 7.35 (m, 5H), 5.14 (s, 2H), 4.12 (m, 2H), 2.97 (t, 2H), 2.53 (m, 1H), 1.95 (m, 2H), 1.68 (m, 2H).
Reaction SMILES: CC(C[AlH]CC(C)C)C.[S:10]1[C:18]2[CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][C:13]=2[CH:12]=[C:11]1[C:26](OC)=[O:27].CO.[Cl-].[Na+]>C1(C)C=CC=CC=1>[OH:27][CH2:26][C:11]1[S:10][C:18]2[CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][C:13]=2[CH:12]=1
Reactant: COC(=O)c1cc2c(s1)CCN(C(=O)OC(C)(C)C)C2
Agent: CC(C)C[AlH]CC(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2sc(CO)cc2C1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
DIBAL-H (11.1 mmol) was added to a −78° C. cold solution of 5-tert-butyl 2-methyl 6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxylate (1.5 g, 5.3 mmol) in dry toluene (30 ml). The reaction mixture obtained was stirred at −78° C. for 1.5 hours. The course of the reaction was monitored by thin layer chromatography. Methanol (12 ml) was then added to the reaction mixture, the mixture was warmed slowly to 25° C. and thereafter saturated sodium chloride solution was added. The reaction mixture was filtered over Celite and the filter cake was washed with ethyl acetate. The organic phases were concentrated under reduced pressure. The crude product obtained in this way was employed in the next stage without further purification. The crude yield was 1.4 g.
Reaction SMILES: [CH2:1]1[CH2:5][C:4]2([CH2:12][C:10](=[O:11])[O:9][C:7](=[O:8])[CH2:6]2)[CH2:3][CH2:2]1.BrBr.[OH-:15].[Na+]>>[O:8]=[C:7]1[CH2:6][C:4]2([CH2:3][CH2:2][CH2:1][CH2:5]2)[CH:12]([C:10]([OH:9])=[O:11])[O:15]1
Reactant: [OH-]
Reactant: O=C1CC2(CCCC2)CC(=O)O1
Agent: BrBr
Agent: [Na+]
Product: O=C1CC2(CCCC2)C(C(=O)O)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3,3-Tetramethylene glutaric anhydride (5 g, 30 mmol) was heated to 105° C. and irradiated with a sun lamp while bromine (2 ml, 38.7 mmol) was added dropwise. After the bromine color dispersed, the reaction was cooled to room temperature and 2.4M NaOH (50 ml) was added and the mixture was heated to reflux for 2 hours. The solution was cooled to room temperature and the pH was adjusted to pH 2 and stirred in a ice water bath for 0.5 hour. The precipitate (unreacted 3,3-tetrametylene glutaric acid) was filtered and discarded. The filtrate was extracted three times with ethyl acetate and the combined organics were washed with brine and dried over MgSO4. Evaporation yielded the title acid as a colorless oil, 5 g, 90%. NMR (CDCl3, 300 MHz) δ 7.95 (broad s, OH), 4.65 (s, 1, methine), 2.61 and 2.35 (ab, 2, methylene), 1.9-1.45 (m, 8, tertramethylene).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:20]([O:24][C:25](=[O:35])[NH:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]=O)=[CH:29][CH:28]=1)([CH3:23])([CH3:22])[CH3:21]>C(O)(=O)C.ClCCl>[F:19][C:16]([F:17])([F:18])[C:13]1[N:11]2[N:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:33][C:30]4[CH:29]=[CH:28][C:27]([NH:26][C:25](=[O:35])[O:24][C:20]([CH3:22])([CH3:21])[CH3:23])=[CH:32][CH:31]=4)[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C=O)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)Nc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Reaction time: 96 h
Yield: 52.1 %

Procedure:
A solution of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (0.079 g, 0.29 mmol) in a mixture of acetic acid and dichloromethane (1:9; 3 mL) was added to a mixture of (polystyrylmethyl)trimethylammonium cyanoborohydride (4.1 mmol/g, 0.097 g, 0.4 mmol) and N-(4-formylphenyl)carbamic acid tert-butyl ester (0.088.4 g, 0.4 mmol). The reaction mixture was shaken for 4 days and then filtered. The filtrate was evaporated and the and the involatile residue was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 21 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents to give tert-butyl 4-((4-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperazin-1-yl)methyl)phenylcarbamate (0.0722 g, 52%) as a white solid, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9](OCC)(=[O:15])[C:10](OCC)=[O:11]>>[NH:8]1[C:10](=[O:11])[C:9](=[O:15])[NH:1][C:2]2[N:3]=[CH:4][CH:5]=[CH:6][C:7]1=2
Reactant: CCOC(=O)C(=O)OCC
Reactant: Nc1cccnc1N
Product: O=c1[nH]c2cccnc2[nH]c1=O
Temperature: 120 °C
Reaction time: 1 h

Procedure:
A stirred suspension of 2,3-diaminopyridine (75 g, 687 mmol) in diethyl oxalate (291 ml, 2131 mmol) under N2 was heated to 120° C. After 1 h, the ethanol was distilled off the reaction mixture and the temperature was elevated to 160° C. for a further 2 hours. The reaction mixture was allowed to cool to RT and diluted with diethyl ether (200 ml). The resulting suspension was stirred for 1 hour and the solid was isolated by filtration and dried in a vacuum oven. The solid was suspended in ethanol (500 ml) and sonicated for 1 hour. The suspension was filtered and dried (vacuum oven overnight) to afford the title compound;
Reaction SMILES: [OH:1][CH2:2][C@H:3]([CH3:16])[CH2:4][C:5](=O)[CH2:6][C@H:7]([CH3:14])[CH2:8][CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12].[OH-].[K+].O.NN>C(O)COCCO>[CH3:16][C@H:3]([CH2:4][CH2:5][CH2:6][C@H:7]([CH3:14])[CH2:8][CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:2][OH:1]
Reactant: CC(C)CCC[C@@H](C)CC(=O)C[C@@H](C)CO
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: CC(C)CCC[C@@H](C)CCC[C@@H](C)CO

Procedure:
A mixture of 3.98 g. (0.0174 mole) of (2R,6R)-1-hydroxy-2,6,10-trimethylundecan-4-one, 108 ml. of diethylene glycol, 25 g. of KOH and 43.5 ml. of hydrazine hydrate was stirred and heated until distillation began. Distillation was then continued until the internal temperature of the reaction mixture reached 195° C. then the mixture was maintained at reflux for 4 hours. After cooling, the resulting mixture was treated with ice and 3 N aqueous HCl and worked-up by ether extraction in the manner of Example 1 giving 2.9 g. of a pale yellow oil. This material was chromatographed on 180 g. of silica gel. Elution with 4:1 parts by volume hexane-ether yielded (2R,6R)-(+)-2,6,10-trimethylundecan-1-ol which was evaporatively distilled affording 2.22 g. of a colorless oil, b.p. 90°-105° C. (bath temperature) (0.2 mm Hg.); [α]25D+9.44° (c 2.04, hexane).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[N:3]=1.[N:17]1([CH2:22][C:23]2[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[N:18]1>>[N:17]1([CH2:22][C:23]2[CH:29]=[CH:28][C:26]([NH:27][C:2]3[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=4)[N:3]=3)=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[N:18]1
Reactant: CCc1cc(Cl)nc(-c2cccc(Cl)c2)n1
Reactant: Nc1ccc(Cn2cccn2)cc1
Product: CCc1cc(Nc2ccc(Cn3cccn3)cc2)nc(-c2cccc(Cl)c2)n1
Yield: 44.1 %

Procedure:
Following General Procedure A1, 4-chloro-2-(3-chlorophenyl)-6-ethylpyrimidine (0.100 g, 0.39 mmol) was reacted with 4-((1H-pyrazol-1-yl)methyl)aniline (0.082 g, 0.47 mmol) to afford the title compound (0.067 g, 67%) as a yellow solid. MW=389.88. 1H NMR (DMSO-d6, 500 MHz) δ 9.64 (s, 1H), 8.35-8.25 (m, 2H), 7.82 (d, J=2.1 Hz, 1H), 7.69 (d, J=8.4 Hz, 2H), 7.59-7.52 (m, 2H), 7.48-7.44 (m, 1H), 7.30-7.23 (m, 2H), 6.00 (s, 1H), 6.27 (t, J=2.1 Hz, 1H), 5.30 (s, 2H), 2.67 (q, J=7.6 Hz, 2H), 1.26 (t, J=7.6 Hz, 3H); APCI MS m/z 390 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([F:25])[C:5]2[N:6]([C:8]([CH2:11][O:12][C:13]3[C:22]4[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=4)[N:16]=[CH:15][CH:14]=3)=[N:9][N:10]=2)[CH:7]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[CH3:60][C:61]1[CH:65]=[C:64]([Sn](C)(C)C)[S:63][N:62]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[F:25][C:4]1[C:5]2[N:6]([C:8]([CH2:11][O:12][C:13]3[C:22]4[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=4)[N:16]=[CH:15][CH:14]=3)=[N:9][N:10]=2)[CH:7]=[C:2]([C:64]2[S:63][N:62]=[C:61]([CH3:60])[CH:65]=2)[CH:3]=1
Reactant: COc1ccc2c(OCc3nnc4c(F)cc(Cl)cn34)ccnc2c1
Reactant: Cc1cc([Sn](C)(C)C)sn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: COc1ccc2c(OCc3nnc4c(F)cc(-c5cc(C)ns5)cn34)ccnc2c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
Dioxane (3.6 mL) was added to 4-((6-chloro-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)-7-methoxyquinoline (175 mg, 488 μmol), X-Phos (32.6 mg, 68.3 μmol), 3-methyl-5-(trimethylstannyl)isothiazole (153 mg, 585 μmol), palladium acetate (7.67 mg, 34.1 μmol). The flask was purged with argon and sealed. The reaction mixture was stirred at 80° C. for 2d. More X-Phos (32.6 mg, 68.3 μmol), palladium acetate (7.67 mg, 34.1 μmol) and 3-methyl-5-(trimethylstannyl)isothiazole (153 mg, 585 μmol) were added and stirring was continued at 80° C. overnight. The reaction mixture was cooled at RT, concentrated in vacuo and purified by MPLC(CH2Cl2/MeOH: 100/0 to 90/10). Further purification by MPLC (ISCO, EtOAc/MeOH:9/1, isocratic) afforded the title compound (105 mg, 51% yield). MS m/z=422.0 [M+H]+. Calc'd for C21H16FN5O2S: 421.46
Reaction SMILES: [OH:1][CH:2]1[CH:9]2[CH:5]3[O:6][C:7]([O:12][CH2:13][C:14]45[CH:25]6[CH2:26][C:21]([CH:33]=[O:34])([C:22]4([C:30]([OH:32])=[O:31])[C:23]([CH:27]([CH3:29])[CH3:28])=[CH:24]6)[CH:20]4[CH:16]([CH:17]([CH3:35])[CH2:18][CH2:19]4)[CH2:15]5)([CH:10]([OH:11])[CH:3]1[O:4]3)[O:8]2.[C:36]1(=[O:42])[O:41][C:39](=[O:40])[CH2:38][CH2:37]1>N1C=CC=CC=1>[C:39]([CH2:38][CH2:37][C:36]([O:1][CH:2]1[CH:9]2[CH:5]3[O:6][C:7]([O:12][CH2:13][C:14]45[CH:25]6[CH2:26][C:21]([CH:33]=[O:34])([C:22]4([C:30]([OH:32])=[O:31])[C:23]([CH:27]([CH3:29])[CH3:28])=[CH:24]6)[CH:20]4[CH:16]([CH:17]([CH3:35])[CH2:18][CH2:19]4)[CH2:15]5)([CH:10]([OH:11])[CH:3]1[O:4]3)[O:8]2)=[O:42])([OH:41])=[O:40]
Reactant: CC(C)C1=CC2CC3(C=O)C4CCC(C)C4CC2(COC24OC5OC(C(O)C5O2)C4O)C13C(=O)O
Reactant: O=C1CCC(=O)O1
Solvent: c1ccncc1
Product: CC(C)C1=CC2CC3(C=O)C4CCC(C)C4CC2(COC24OC5OC(C(OC(=O)CCC(=O)O)C5O2)C4O)C13C(=O)O
Reaction time: 52 h
Yield: 16.6 %

Procedure:
20 mg of compound (2) was dissolved in 1.0 ml of pyridine and stirred together with 16.4 mg of succinic anhydride at room temperature. After 52 hours, 8.2 mg of succinic anhydride was added, and the reaction was conducted for another 20 hours. The reaction solution was concentrated in vacuo and subjected to reversed phase chromatography (Capcell Pak C18 UG-120, Shiseido, 2.0φ×25 cm, 0.05% trifluoroacetic acid-acetonitrile [6:4], flow rate 10.0 ml/min, detection 210 nm) for purification, and the desired fraction was recovered. The recovered fraction was poured into 100 ml of 0.1 M sodium phosphate buffer pH 5.5 and extracted with 100 ml of ethyl acetate. The ethyl acetate extract was concentrated in vacuo to give 4.0 mg of compound (20).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH:10]=[C:9](I)[CH:8]=[C:7]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]2=[O:23])[CH2:3][CH2:2]1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C(O)C.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>[CH:1]1([CH2:4][N:5]2[CH:10]=[C:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:8]=[C:7]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]2=[O:23])[CH2:3][CH2:2]1
Reactant: O=C(Nc1cc(I)cn(CC2CC2)c1=O)OCc1ccccc1
Reactant: OB(O)c1ccccc1
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: C1CCOC1
Solvent: CCO
Product: O=C(Nc1cc(-c2ccccc2)cn(CC2CC2)c1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.132 mg, 0.11 mmol) and benzyl 1-(cyclopropylmethyl)-5-iodo-2-oxo-1,2-dihydropyridin-3-ylcarbamate (0.097 mg, 0.229 mmol) in tetrahydrofuran (1 mL) were stirred at room temperature for 30 minutes. A solution of phenylboronic acid in ethanol (1 mL) was then added to the reaction mixture. After 1 h, a 2 M solution of sodium carbonate (1 mL) was added and the reaction was heated to reflux. After 3 h, the mixture was allowed to cool to ambient temperature and extracted with ethyl acetate and water. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by chromatography (silica gel, 5% to 30% ethyl acetate in hexanes gradient elution) gave the title compound (0.061 g). MS 375 (M+1)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23]([OH:25])=O)[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:26][CH2:27][CH2:28][NH:29][CH2:30][CH2:31][OH:32]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:22][C:23]([N:29]([CH2:30][CH2:31][OH:32])[CH2:28][CH2:27][OH:26])=[O:25])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: OCCNCCO
Product: Cc1ccc(N(CC(=O)N(CCO)CCO)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with 2-(2-hydroxy-ethylamino)-ethanol
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][CH3:18])[CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][N:8]=1.C(N(CC)CC)C.[CH3:26][N:27]1[CH:31]=[C:30]([S:32](Cl)(=[O:34])=[O:33])[C:29]([CH3:36])=[N:28]1>ClCCl>[Cl:2][C:3]1[C:4]([N:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][N:17]([CH3:18])[S:32]([C:30]3[C:29]([CH3:36])=[N:28][N:27]([CH3:26])[CH:31]=3)(=[O:34])=[O:33])[CH2:13][CH2:14]2)=[N:5][CH:6]=[CH:7][N:8]=1
Reactant: CNCCN1CCN(c2nccnc2Cl)CC1
Reactant: Cc1nn(C)cc1S(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nn(C)cc1S(=O)(=O)N(C)CCN1CCN(c2nccnc2Cl)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Dissolve [2-(3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)-ethyl]-methyl-amine hydrochloride salt (0.5 g, 1.29 mmol) in dichloromethane (10 ml) and cool in an ice-bath. Add triethylamine (0.90 ml, 6.44 mmol) and then 1,3-dimethylpyrazole-4-sulfonyl chloride (250 mg, 1.29 mmol). Remove the ice-bath and allow to warm to ambient temperature and allow to stir for 2 hr. Wash the organic phase with aqueous sodium bicarbonate, brine and water. Dry over sodium sulfate and concentrate. Purify by chromatography, eluting with 1:2 hexanes:acetone to afford the title preparation (535 mg, 100% yield) as a white foam. MS ES: m/z=414 [M+H]+.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[O:19][C@@H:20]1[C@@H:26]([O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[C@H:25]([O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[C@@H:24]([CH2:41][O:42][CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][O:44]2)[O:23][C:21]1=[O:22]>C(OCC)C.CCCCCC>[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[O:19][C@@H:20]1[C@@H:26]([O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[C@H:25]([O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[C@@H:24]([CH2:41][O:42][CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][O:44]2)[O:23][C:21]1([OH:22])[CH2:1][P:2]([O:5][CH3:6])([O:3][CH3:4])=[O:7]
Reactant: COP(C)(=O)OC
Reactant: O=C1O[C@H](COC2CCCCO2)[C@@H](OC2CCCCO2)[C@H](OC2CCCCO2)[C@H]1OC1CCCCO1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: COP(=O)(CC1(O)O[C@H](COC2CCCCO2)[C@@H](OC2CCCCO2)[C@H](OC2CCCCO2)[C@H]1OC1CCCCO1)OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of dimethyl methylphosphonate (15.3 ml) in ethyl ether (300 ml) was added dropwise with cooling (-70° to -78° C.) in a stream of argon a solution of n-butyllithium in n-hexane (1.6M solution, 84 ml), and the mixture was stirred for 30 minutes. To the solution was added dropwise with cooling at the same temperature a solution of 2,3,4,6-tetra-O-(tetrahydropyranyl)-D-glucono-1,5-lactone (23.1 g) in ethyl ether (80 ml). The mixture was stirred for one hour, then the cooling bath was removed, and then the mixture was allowed to warm to 0° C. with stirring. The reaction solution was added to an ice-cooled mixture of 10%(W/V) ammonium chloride solution (250 ml) and ethyl ether (120 ml). The ethyl ether layer was separated. The aqueous layer was subjected to extraction with ethyl ether. The organic layers were combined, washed with water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and dried further under reduced pressure to give 3,4,5,7-tetra-O-(tetrahydropyranyl)-1-deoxy-1-(dimethoxyphosphoryl)-D-gluco-2-heptulopyranose (26.6 g).
Reaction SMILES: C[O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][CH2:8][C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[C:16]2[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:15]2=[N:14][C:13]=3[NH2:24])=[C:5]([CH3:27])[CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[NH2:24][C:13]1[C:12]2[N:11]=[CH:10][C:9]([CH2:8][CH2:7][C:6]3[CH:25]=[CH:26][C:3]([OH:2])=[CH:4][C:5]=3[CH3:27])=[CH:18][C:17]=2[C:16]2[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:15]=2[N:14]=1
Reactant: COc1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)c(C)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3C)cc12

Procedure:
To a stirred solution of 2-(4-methoxy-2-methylphenethyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine (Example 49) in methylene chloride (0.2 M) in an ice-water bath was added 1 N solution of BBr3 (2 eq) in CH2Cl2 in a drop-wise fashion. In 30 minutes the reaction was quenched with methanol and was concentrated en vacuo to obtain a crude residue. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-20% methanol in dichloromethane to give 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenol as a white solid. 1H NMR (DMSO-d6): δ 8.99 (s, 1H), 8.75 (d, 1H), 8.60 (d, 1H), 8.27 (d, 1H), 7.28 (s, 1H), 7.09 (dd, 1H), 6.99 (bs, 2H), 6.88 (d, 1H), 6.49 (d, 1H), 6.42 (dd, 1H), 3.02-2.96 (dd, 2H), 2.86-2.81 (dd, 2H), 2.38 (s, 3H), 2.13 (s, 3H). LRMS [M+H]=344.2
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([C@H:13]([O:15][CH3:16])[CH3:14])[CH2:11][O:10][C:9]2=[O:17])[CH:5]=[CH:4][N:3]=1.[F-:18].[K+].CS(C)=O>O>[F:18][C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([C@H:13]([O:15][CH3:16])[CH3:14])[CH2:11][O:10][C:9]2=[O:17])[CH:5]=[CH:4][N:3]=1
Reactant: CO[C@H](C)[C@H]1COC(=O)N1c1ccnc(Cl)n1
Reactant: [F-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CO[C@H](C)[C@H]1COC(=O)N1c1ccnc(F)n1
Temperature: 120 °C
Yield: 87.5 %

Procedure:
To a microwe vial with stir bar was added (R)-3-(2-chloropyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one (145 mg, 0.56 mmol), potassium fluoride (327 mg, 5.63 mmol) and DMSO (4 mL). Vial capped and heated to 120° C. in a sand bath for 3 hr. Reaction mixture was then cooled to room temperature, diluted with water and aqueous mixture extracted with EtOAc. The Organic phases were combined and washed with water, brine, dried (Na2SO4), filtered and concentrated to afford a white crystalline of (R)-3-(2-fluoropyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one (117 mg, 0.49 mmol, 86% yield). LCMS m/z 242.1 (M+H)+, Rt 0.63 min.