Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH3:2].[OH:9]O.C=O>C(O)(=O)C>[CH2:1]([C:3]1[CH:8]=[CH:7][N+:6]([O-:9])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccncc1
Reactant: OO
Agent: C=O
Solvent: CC(=O)O
Product: CCc1cc[n+]([O-])cc1
Reaction time: 4 h
Yield: 83 %

Procedure:
A solution of 4-ethylpyridine (10.7 g, 0.10 mol) in 35 ml of acetic acid heated at 95-100° C. is treated dropwise over a 18 min period with 30% hydrogen peroxide (28 ml). After 4 h, the excess hydrogen peroxide is decomposed by the portionwise addition of paraformaldehyde (10.0 g) at the previously maintained temperature until a negative starch iodide test is obtained. The reaction mixture is cooled and concentrated at reduced pressure. The residue is chromatographed with 325 g of silica gel packed and eluted initially with acetone-chloroform-methanol (3:6.7:0.3) and thereafter with an increasing methanol gradient to obtain 10.55 g (83%) of 4-Ethylpyridine-1-oxide.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[H-].[Na+].[N+:17]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1)([O-:19])=[O:18]>C1COCC1>[CH2:7]([O:6][P:4]([CH:9]([CH2:24][C:23]1[CH:26]=[CH:27][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc([N+](=O)[O-])cc1)P(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.2 %

Procedure:
Ethyl 2-(diethoxyphosphoryl)acetate (5.0 ml, 25.2 mmol) was added to a suspension of sodium hydride (60% in mineral oil, 1.10 g, 27.6 mmol) in THF (40 ml) at 0°. After 30 min at room temperature, a solution of 4-nitrobenzylbromide (5.42 g, 25.2 mmol) in THF (40 ml) was added over 30 min. The reaction mixture was stirred for 2 h at room temperature, quenched with water and partitioned between Et2O and water. The aqueous phase was extracted with Et2O and the combined organic layers washed with brine, dried (MgSO4) and evaporated in vacuo. Column chromatography (silica; MeOH/DCM, 1:49) gave the title compound as a pale yellow oil (2.01 g): δH (CDCl3) 8.13 (2H, d, J 8.8 Hz), 7.37 (2H, d, J 8.8 Hz), 4.23-4.06 (6H, m), 3.37-3.20 (3H, m), 1.35 (6H, t, J 7.1 Hz), 1.16 (3H, t, J 7.1 Hz): m/z (El+, 70V) 360.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]#[N:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:13]([O:15][C:16](=[O:25])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[CH3:14].C(OC(=O)C=C(C1C=CC=C2C=1C(C#N)=CN2)C1C=CC=CC=1)C>>[CH2:13]([O:15][C:16](=[O:25])[CH:17]=[C:18]([C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]#[N:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[CH3:14]
Reactant: N#Cc1c[nH]c2cc(Br)ccc12
Reactant: CCOC(=O)C=Cc1ccccn1
Agent: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Product: CCOC(=O)C=C(c1ccc2c(C#N)c[nH]c2c1)c1ccccn1

Procedure:
3-(3-Cyano-1H-indol-6-yl)-3-pyridin-2-yl-acrylic acid ethyl ester CLXX was prepared from 6-bromo-1H-indole-3-carbonitrile (CLI) and 3-pyridin-2-yl-acrylic acid ethyl ester using the procedure described for preparation of 3-(3-Cyano-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester LVIII (Example 14).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Br:17])[CH:15]=3)[C:10]([C:18]([OH:20])=O)=[N:9]2)[CH:5]=[CH:4][N:3]=1.S(Cl)(Cl)=O.Cl.[NH:26]1[CH2:29][CH:28]([OH:30])[CH2:27]1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Br:17])[CH:15]=3)[C:10]([C:18]([N:26]3[CH2:29][CH:28]([OH:30])[CH2:27]3)=[O:20])=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: OC1CNC1
Reactant: Nc1nccc(-n2nc(C(=O)O)c3ccc(Br)cc32)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Nc1nccc(-n2nc(C(=O)N3CC(O)C3)c3ccc(Br)cc32)n1
Temperature: 40 °C
Reaction time: 8 h
Yield: 49.1 %

Procedure:
To a solution of 1-(2-aminopyrimidin-4-yl)-6-bromoindazole-3-carboxylic acid (0.38 g, 1.12 mmol)) in DCM (5 mL), was added thionyl chloride (0.49 ml, 6.74 mmol) followed by a drop of DMF. The mixture was stirred at 40° C. overnight. The reaction mixture was concentrated in vacuo and DCM added and the concentration repeated (×2). The acid chloride intermediate was suspended in DCM (10 ml), azetidin-3-ol hydrochloride (491.82 mg, 4.49 mmol) followed by DIPEA (0.86 ml, 4.94 mmol). The reaction was stirred at RT for 0.5 hr and then concentrated in vacuo. The residue was diluted with more DCM and water and the organics extracted (2×20 ml DCM). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo to give the title intermediate (214 mg, LC-MS purity=63%); LC-MS: m/z=+388.95/390.80 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]=[N:2]1.FC(F)(F)O[C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[O:17])=[CH:11][CH:10]=1.C(OCC)C>C(#N)C.C(N(CC)CC)C>[N:2]1([C:16]([NH:15][C:12]2[CH:13]=[CH:14][CH:9]=[CH:10][CH:11]=2)=[O:17])[CH2:3][CH2:4][CH:5]=[N:1]1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Reactant: C1=NNCC1
Solvent: CC#N
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)N1CCC=N1
Reaction time: 2 h

Procedure:
2.76 g (0,008 mol) of 3-(4'-chlorophenyl)-4-(4"-methyl-3"-trifluoromethyl-Δ2" -1",2",4"-triazolin-5"-on-1"-yl)-4,5-dihydropyrazole are dissolved in 20 ml of acetonitrile (anhydrous) at 60° C. until a clear solution has formed, this solution is treated with 1.7 g of 4-trifluoromethoxy-phenyl isocyanate, and 2drops of triethylamine are added. The mixture is subsequently allowed to stand for 2 hours at room temperature. The solvent is subsequently stripped off in vacuo, the residue is treated with 20 ml of diethyl ether and, after 2 hours, the precipitate which has formed is filtered off with suction. 2.0 g (45.6% of theory) of N-(4-trifluormethoxy)-3-(4'-chlorophenyl)-4-(4"-methyl-3"-trifluoromethyl-Δ2" -1",2",4,"-triazolin-5"-on-1"-yl)-4,5-dihydro-1-pyrazole-carboxanilide having a melting point of 241° C. are obtained.
Reaction SMILES: OS(O)(=O)=O.[Cl:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.[N+:16]([O-])([OH:18])=[O:17]>O>[Cl:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[N+:16]([O-:18])=[O:17]
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
To a 5-liter, 3-necked, round-bottom flask, equipped with a stirrer and thermometer, is added 2.0 liters of concentrated H2SO4 and 800 g of powdered (about 1-2 microns) p-chlorobenzoic acid. The mixture is stirred and cooled to 0° C. in an oil bath. To the cooled mixture is added 432 ml of 71 weight percent nitric acid in water solution dropwise. The nitric acid solution is added at a rate slow enough to maintain the temperature lower than about 30° C. Upon completion of adding nitric acid, the temperature is raised to 37° C. over 3 hours. The reaction mixture is then cooled to 15° C. To the cooled mixture is added 0.75 liter of room temperature water at a rate so as to keep the reaction temperature below about 40° C. The product is isolated by filtration using fritted glass funnel and washed with 1.5 liters of room temperature water. The washed product is air-dried until a constant weight is observed to yield 1.0174 kg of 4-chloro-3-nitrobenzoic acid, which has a melting point of 178° C.-179.5° C. This is a yield of 99 mole percent. This material can be used without further purification.
Reaction SMILES: [I:1][C:2]1[CH:7]=[N:6][NH:5][C:4](=[O:8])[CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:20]1[CH:25]=[CH:24][CH2:23][CH2:22][CH2:21]1>O1CCCC1>[I:1][C:2]1[CH:7]=[N:6][N:5]([CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][O:20]2)[C:4](=[O:8])[CH:3]=1
Reactant: O=c1cc(I)cn[nH]1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: O=c1cc(I)cnn1C1CCCCO1
Temperature: 25 °C
Reaction time: 48 h
Yield: 22.9 %

Procedure:
A mixture of 5-iodo-2H-pyridazin-3-one (8.640 g, 38.92 mmol) in tetrahydrofuran (150 mL) was treated with para-toluenesulfonic acid (1.49 g, 7.86 mmol) and 3,4-dihydro-2H-pyran (8.98 mL, 98.18 mmol). The reaction was stirred at 25° C. for 2 d. After this time, the reaction was filtered. The filtrate was treated with para-toluenesulfonic acid (6 g) and 3,4-dihydro-2H-pyran (9 mL), and the reaction stirred at 25° C. for 6 h. The reaction was concentrated in vacuo, taken up in ethyl acetate (400 mL), washed with a saturated aqueous sodium bicarbonate solution (400 mL), and a saturated aqueous sodium chloride solution. The aqueous layer was extracted with ethyl acetate (300 mL) and was washed with a saturated aqueous sodium chloride solution. The combined organics were dried over sodium sulfate, filtered, rinsed, and concentrated in vacuo. Silica gel column chromatography (AnaLogix, 400 g, 0% to 50% ethyl acetate/hexanes) afforded 5-iodo-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (2.73 g, 23%) as a clear light brown, viscous oil. The material contained an impurity. However, it was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:24][CH:12]2[N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:14](=[O:16])[O:15][CH:11]2[CH:10]([CH3:25])[CH2:9]1.[Br:26][C:27]1[N:32]=[C:31]([C:33](O)=[O:34])[CH:30]=[CH:29][C:28]=1[F:36]>CCOC(C)=O>[Br:26][C:27]1[N:32]=[C:31]([C:33]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[CH:8]2[CH2:24][CH:12]3[N:13]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[C:14](=[O:16])[O:15][CH:11]3[CH:10]([CH3:25])[CH2:9]2)=[O:34])[CH:30]=[CH:29][C:28]=1[F:36]
Reactant: O=C(O)c1ccc(F)c(Br)n1
Reactant: CC1CC(c2ccncc2N)CC2C1OC(=O)N2C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Product: CC1CC(c2ccncc2NC(=O)c2ccc(F)c(Br)n2)CC2C1OC(=O)N2C(=O)OC(C)(C)C

Procedure:
Following Method 9, (+/−)-tert-butyl 5-(3-aminopyridin-4-yl)-7-methyl-2-oxohexahydrobenzo[d]oxazole-3(2H)-carboxylate and 6-bromo-5-fluoropicolinic acid were coupled and following addition of EtOAc and washing with H2O, NaCl(sat.) and drying over MgSO4, (+/−)-tert-butyl 5-(3-(6-bromo-5-fluoropicolinamido)pyridin-4-yl)-7-methyl-2-oxohexahydrobenzo[d]oxazole-3(2H)-carboxylate was obtained. LCMS (m/z): 549.2/551.2 (MN), Rt=0.78 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:18]2[C:17](=[O:19])[CH2:16][C:15]([CH3:21])([CH3:20])[CH2:14][C:13]=2[NH:12][C:11]([CH3:22])=[C:10]1[C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24]>C(Cl)Cl.O=[Mn]=O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[C:18]2[C:17](=[O:19])[CH2:16][C:15]([CH3:20])([CH3:21])[CH2:14][C:13]=2[N:12]=[C:11]([CH3:22])[C:10]=1[C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24]
Reactant: CC1=C(C(=O)OC(C)C)C(c2cccc(Cl)c2Cl)C2=C(CC(C)(C)CC2=O)N1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Cc1nc2c(c(-c3cccc(Cl)c3Cl)c1C(=O)OC(C)C)C(=O)CC(C)(C)C2

Procedure:
1.6 g (3.8 mmol) of the compound from Example V are dissolved in 350 ml of CH2Cl2 and treated with 7.5 g of MnO2. The mixture is kept under reflux for 2 h, solid is filtered off with suction through Celite and the filtrate is concentrated. The residue crystallizes from ether/petroleum ether. 1.1 g (69% of theory) of the title compound are obtained.
Reaction SMILES: [F:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:6][CH:5]=[C:4]([N+:15]([O-])=O)[C:3]=1[NH2:18]>O=[Mn]=O.CCOC(C)=O>[F:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:6][CH:5]=[C:4]([NH2:15])[C:3]=1[NH2:18]
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2F)CC1
Agent: O=[Mn]=O
Solvent: CCOC(C)=O
Product: CN1CCN(c2ccc(N)c(N)c2F)CC1
Temperature: 120 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
A 250 mL reaction tube was charged with benzyl alcohol 1 (1.0 g, 3.6 mmol), MnO2 (4.7 g, 54 mmol) and EtOAc (20 mL). The reaction tube was sealed was heated to 120° C. with stirring for 2 h. The reaction was allowed to cool to rt, then filtered through Celite and washed successively with EtOAc, MeOH, and EtOH. The combine organics were concentrated to give 936 mg (3.4 mmol, 94%) of 2 as an orange solid: 1H NMR (300 MHz, CDCl3) δ 10.01 (s, 1H), 8.64 (d, J=5.5 Hz, 1H), 8.09 (br s, 1H), 7.96 (d, J=2.75 Hz, 1H), 7.37 (d, J=2.48 Hz, 1H), 7.29 (d, J=2.75 Hz, 1H), 7.08 (dd, J=2.47, 5.5 Hz, 1H), 6.94 (d, J=9.35 Hz, 1H), 3.08 (d, J=5.23 Hz, 3H).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6]CC)=O)#[N:2].[Cl:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH2:12][NH2:13]>C(O)C>[Cl:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH2:12][NH:13][C:4](=[O:6])[CH2:3][C:1]#[N:2]
Reactant: NCc1ccccc1Cl
Reactant: CCOC(=O)CC#N
Solvent: CCO
Product: N#CCC(=O)NCc1ccccc1Cl
Reaction time: 8 h
Yield: 38 %

Procedure:
A solution of 80.5 g. (0.71 mole) of ethyl cyanoacetate and 100 g. (0.71 mole) of 2-chlorobenzylamine in 200 ml. of absolute ethanol heated at reflux for 2 hours and then allowed to stand at ambient temperature overnight. The solvent is removed in vacuo and the residue is recrystallized from ether/pentane to give 56 g. (38% yield) of the desired product as a near white solid, m.p. 102°-4° C.; ν3300 (NH), 2270 (CN), and 1650 cm.-1 (C= O); δ 8.7 (broad, 1H, NH), 7.35 (broad s, 4H, aromatic protons), 4.40 (d, 2H, benzyl methylene) and 3.7 (broad s, 2H, CH2CO).
Reaction SMILES: [NH2:1][CH:2]([CH3:22])[C:3]([NH:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH2:20][CH3:21])[C:12]3[C:17]([C:18]=2[CH:19]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:4].[C:23]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32](O)=[O:33])=[CH:27][CH:26]=1)#[N:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>CN(C=O)C>[C:23]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([NH:1][C@H:2]([C:3]([NH:5][CH2:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH2:20][CH3:21])[C:12]4[C:17]([C:18]=3[CH:19]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)=[O:4])[CH3:22])=[O:33])=[CH:27][CH:26]=1)#[N:24]
Reactant: CCn1c2ccccc2c2cc(CNC(=O)C(C)N)ccc21
Reactant: N#Cc1ccc(CC(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCn1c2ccccc2c2cc(CNC(=O)[C@H](C)NC(=O)Cc3ccc(C#N)cc3)ccc21
Yield: 14 %

Procedure:
A solution of the compound obtained in Step 2 (242 mg, 0.82 mmol), 2-(4-cyanophenyl)acetic acid (198 mg, 1.23 mmol), HATU (468 mg, 1.23 mmol) and TEA (0.343 mL, 2.46 mmol) in DMF (3 mL) was stirred at room temperature for 16 hr. To the reaction solution was added dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: ethyl acetate) to give the title compound (50.3 mg, 0.115 mmol, 14%) as a white powder.
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.[C:12]1(/[C:18](/[C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[I-].[Na+].C([BH3-])#N.[Na+]>CN(C)P(N(C)C)(N(C)C)=O.O>[C:12]1(/[C:18](/[C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: OCCCCC/C=C(\c1ccccc1)c1cccnc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH3-]C#N
Agent: [I-]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCC/C=C(\c1ccccc1)c1cccnc1
Reaction time: 0.17 h
Yield: 74.4 %

Procedure:
p-Toluenesulfonate of (E)-7-phenyl-7-(3-pyridyl)-6-hepten-1-ol (0.45 g, 1.07 mmoles) was dissolved in hexamethylphosphoramide (2 ml), and sodium iodide (0.2 g, 1.3 mmoles) was added to the solution. The mixture was stirred for 10 minutes. To the mixture was added sodium cyanoborohydride (0.1 g, 16 mmoles) and the resulting mixture was stirred at 100° C. for an hour. The reaction mixture was then cooled and water (10 ml) was added followed by extraction of the product with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography using isopropyl ether-ethyl acetate (4:1) as the eluent to give (E)-1-phenyl-1-(3-pyridyl)-1-heptene (0.2 g, 75%) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:8]([OH:10])[CH3:9])[CH:7]=1.[NH2:13][C:14]1[C:19](Br)=[N:18][C:17]([Br:21])=[CH:16][N:15]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+]>O1CCCC1>[Br:21][C:17]1[N:18]=[C:19]([O:10][CH:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:11][CH3:12])[CH3:9])[C:14]([NH2:13])=[N:15][CH:16]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: COc1ccc(F)cc1C(C)O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)Oc1nc(Br)cnc1N
Temperature: 66 °C
Yield: 52.5 %

Procedure:
To a solution of 1-(5-fluoro-2-methoxy-phenyl)-ethanol (33.6 g, 197 mmol, 1.5 eq.) in tetrahydrofuran (140 mL) was added 2-amino-3,5-dibromo-pyrazine (39.9 g, 158 mmol) followed by a solution of sodium hexamethyldisilazide (1M in tetrahydrofuran, 200 mL, 1.5 eq.). This mixture was then heated to 66° C. for 4 hr before cooling and evaporating under reduced pressure. The residue was purified by chromatography on silica gel (100 g) eluting with tert-butyl methyl ether to give an orange solid after evaporating under reduced pressure. This solid was slurried in ice cold methanol and filtered to give the title compound as a beige solid (28.4 g, 42%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:10]([N:12]1[CH2:16][CH:15]([OH:17])[CH2:14][CH:13]1[C:18]([NH:20][C:21]1([C:26]([OH:28])=[O:27])[CH2:23][CH:22]1[CH2:24][CH3:25])=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].Cl[C:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[C:42]([O:50][CH2:51][CH3:52])[N:41]=1.Cl>CS(C)=O>[C:1]([O:5][C:6]([NH:8][CH:9]([C:29]([CH3:31])([CH3:30])[CH3:32])[C:10]([N:12]1[CH2:16][CH:15]([O:17][C:40]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH:43]=[C:42]([O:50][CH2:51][CH3:52])[N:41]=2)[CH2:14][CH:13]1[C:18]([NH:20][C:21]1([C:26]([OH:28])=[O:27])[CH2:23][CH:22]1[CH2:24][CH3:25])=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc2ccccc2c(Cl)n1
Reactant: CCC1CC1(NC(=O)C1CC(O)CN1C(=O)C(NC(=O)OC(C)(C)C)C(C)(C)C)C(=O)O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: CCOc1cc2ccccc2c(OC2CC(C(=O)NC3(C(=O)O)CC3CC)N(C(=O)C(NC(=O)OC(C)(C)C)C(C)(C)C)C2)n1
Yield: 42 %

Procedure:
1-{[1-(2-tert-Butoxycarbonylamino-3,3-dimethylbutyryl)-4-hydroxypyrrolidine-2-carbonyl]-amino}-2-ethyl-cyclopropanecarboxylic acid (See Example 33), 0.21 g, 0.46 mmol) was diluted in DMSO (4 mL) and treated with potassium tert-butoxide (0.26 g, 2.3 mmol) at rt for 30 min. 1-Chloro-3-ethoxyisoquinoline (0.100 g, 0.48 mmol) was added and the solution allowed to age overnight. Icewater was added, followed by 1M HCl until the solution reaches pH 3. Extraction with EtOAc was followed by washing of the combined organics with brine and drying over anhydrous Na2SO4 prior to concentration in vacuo. The resulting residue was purified by preparatory HPLC to produce 0.127 g (42%) of 1-{[1-(2-tert-Butoxycarbonylamino-3,3-dimethyl-butyryl)-4-(3-ethoxy-isoquinolin-1-yloxy)-pyrrolidine-2-carbonyl]-amino-}2-ethyl-cyclopropanecarboxylic acid as a white solid. LCMS found 626.90 [M+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][CH:7]=1.C([Li])CCC.[C:19](=[O:21])=[O:20].CO>O1CCCC1>[F:1][C:2]1[C:3]([C:19]([OH:21])=[O:20])=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: O=C=O
Reactant: Fc1ccc(-c2ccccc2)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc(-c2ccccc2)ncc1F
Temperature: -45 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To a solution of 5-fluoro-2-phenylpyridine (760.0 mg, 4.39 mmol) in tetrahydrofuran (15.0 ml) was added n-butyllithium (2.11 ml, 2.50 M in THF, 5.27 mmol) at −45° C. The mixture was stirred for 1 h at −45° C., then poured into THF containing dry ice Stirred for 1 h, then MeOH (2 ml) was added. The solution was concentrated, and purified on Flashmaster II to get 560 mg (58%) of 5-fluoro-2-phenylisonicotinic acid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[NH:10][C:11]([NH:13][C:14](=[NH:17])[NH:15][CH3:16])=[O:12].[CH3:18]C#N.COC(OC)N(C)C>C(NC(N)=O)(=N)N>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[N:10]1[CH:16]=[N:15][C:14]([NH:17][CH3:18])=[N:13][C:11]1=[O:12]
Reactant: CC#N
Reactant: CNC(=N)NC(=O)Nc1c(Cl)cccc1Cl
Agent: COC(OC)N(C)C
Agent: Cl
Agent: N=C(N)NC(N)=O
Product: CNc1ncn(-c2c(Cl)cccc2Cl)c(=O)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a magnetically stirred suspension of 11.88 g. (40 mmol) of 1-(2',6'-dichlorophenyl)-3-methylamidinourea hydrochloride in 30 ml. of CH3CN is added 9.52 g. (80 mmol) of N,N-dimethylformamide dimethylacetal in 20 ml. of CH3CN. The solid material begins to dissolve immediately but in a few minutes, before the starting material amidinourea has dissolved, another fine particle white solid begins to precipitate out. The reaction mixture is stirred at ambient temperature for 1 hour then heated to reflux for 2 hours. After 2 hours the reaction mixture is allowed to come to ambient temperature and the white solid precipitate filtered out to yield the desired product, melting point 270° C.; TLC (EtoAc 9:1); one major spot, one minor spot at origin. A small sample recrystallized from CH3OH/EtoAc gave 1 spot on TLC. (9.6 g. 89%). The product is recrystallized from MeOH to yield 1-(2',6'-dichlorophenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:22]([CH:24]1[C:28]2[S:29][CH:30]=[CH:31][C:27]=2[C:26](=O)[O:25]1)C.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:26]1[O:25][CH:24]([CH3:22])[C:28]2[S:29][CH:30]=[CH:31][C:27]1=2
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: CCC1OC(=O)c2ccsc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1OC(=C2C(=O)Nc3ccc(F)cc32)c2ccsc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (453 mg, 3.0 mmol.) in THF (3 mL) is cooled to 0° C. under an Argon atmosphere and treated with a solution of lithium bis(trimethylsilyl)amide (6.0 mL of a 1 M solution in THF, 6.0 mmol) dropwise. The resulting solution is stirred at 0° C. for 10 min and warmed to room temperature. A solution of 6-ethyl-6H-thieno[2,3-c]furan-4-one, (310 mg, 2.0 mmol) in THF (5 mL) is added dropwise to the reaction mixture. The resulting solution is stirred for 4 h. The reaction mixture is poured into aqueous 10% HCl solution (50 mL). The resulting mixture is heated to 90° C. for 45 min and stirred at room temperature for 36 h. The precipitate which formed is collected by filtration and dried. The solid obtained is purified by chromatography (silica gel, ethyl acetate/hexanes) to give the title compound as a yellow solid.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][S:11](Cl)(=[O:13])=[O:12].[NH2:15][C:16]1[N:21]=[C:20]([CH2:22][OH:23])[CH:19]=[CH:18][N:17]=1>O1CCCC1.C(OCC)(=O)C>[NH2:15][C:16]1[N:21]=[C:20]([CH2:22][O:23][S:11]([CH3:10])(=[O:13])=[O:12])[CH:19]=[CH:18][N:17]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1nccc(CO)n1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CS(=O)(=O)OCc1ccnc(N)n1
Temperature: 25 °C
Reaction time: 7 h
Yield: 53 %

Procedure:
N,N-Diisopropylethylamine (490 μL, 2.9 mmol) and methanesulfonyl chloride (110 μL, 1.5 mmol) were added to a suspension of 2-amino-4-hydroxymethylpyrimidine (170 mg, 1.3 mmol, Reference Compound No. 4-1) in anhydrous tetrahydrofuran (5.0 mL) under ice-cooling, and the mixture was stirred for 7 hours at room temperature. The reaction mixture was diluted with ethyl acetate (300 mL), washed with water (300 mL), and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the precipitated solid was filtered off with ethyl acetate, and dried under reduced pressure to give 140 mg of the title Reference Compound as a white solid (Yield: 53%).