Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C:10]#[N:11])[CH:5]=[N:6][CH:7]=1.[CH2:12]([Mg]Br)[CH3:13].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C:10]2([NH2:11])[CH2:13][CH2:12]2)[CH:5]=[N:6][CH:7]=1
Reactant: N#CCOc1cncc(Br)c1
Reactant: CC[Mg]Br
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Solvent: C1CCOC1
Product: NC1(COc2cncc(Br)c2)CC1
Yield: 19 %

Procedure:
A dry, 10 mL round bottom flask was charged with 2-(5-bromopyridin-3-yloxy)acetonitrile (0.0996 g, 0.47 mmol), 3 mL dry THF, and a stirbar. The flask was fitted with an inert atmosphere inlet, and swept with Ar for several minutes. The solution was treated with titanium isopropoxide (0.15 ml, 0.51 mmol). To the stirring solution was added ethylmagnesium bromide 1.0 m solution in the (0.94 ml, 0.94 mmol) via a syringe pump over 30 minutes. The reaction was stirred at room temperature for 24 h after which time 1 mL of saturated Rochelle's salt was added, followed by 5 mL dry THF. The slurry was stirred/sonicated over the course of 1 h. The solution was then applied to 20 g of SiO2 wet packed with THF. The Silica was eluted with 75 mL dry THF, and the eluent was concentrated in vacuo. The crude was purified using a 19×150 mm Waters Xterra Prep C18 OBD column (100 Å pore diameter, 5 μm particle size, spherical shape, PN 186002381; Gradient: 0→5 min@20 mL/min, 10% B; 5.0→35 min@20 mL/min, linear gradient to 40% B; 35→45@20 mL/min, isocratic at 40% B, 45→55 min@20 mL/min, step to 100% B; 55→60 min@20 mL/min, step to 10% B; 60 min end; A=10.7 mM NH4HCO3 in water, pH adjusted to 8.6 with concentrated NH4OH; B acetonitrile). A band that eluted from 16.1 to 18.3 minutes was isolated. The solvent was removed in vacuo to afford 1-((5-bromopyridin-3-yloxy)methyl)cyclopropanamine (0.0214 g, 19% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 0.64-0.67 (m, 2H) 0.77-0.81 (m, 2H) 1.78 (br. s., 2H) 3.88 (s, 2H) 7.37 (dd, J=2.54, 1.86 Hz, 1H) 8.26 (d, J=2.54 Hz, 1H) 8.29 (d, J=1.86 Hz, 1H). 13C NMR (101 MHz, chloroform-d) δ ppm 12.89 (s, 2 C) 33.49 (s, 1 C) 77.00 (s, 1 C) 120.35 (s, 1 C) 124.03 (s, 1 C) 136.43 (s, 1 C) 143.07 (s, 1 C) 155.53 (s, 1 C). HPLC-MS: retention time=0.87 min (>99%@215 nm; >99% @254 nm; m/z=242.9, calculated for C9H1179BrN2O+H+=243.0; m/z=244.9, calculated for C9H1181BrN2O+H+=245.0).
Reaction SMILES: C(O)=O.[C:4]1([C:13]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=1.[C:22](=[O:29])([O:26]CC)[O:23][CH2:24][CH3:25].C[O-].[Na+].C(O)(=O)C>O>[C:22](=[O:26])([O:23][CH2:24][CH3:25])[O:29][C:4]1([CH:13]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: C1=C(C2=CCCCCCCC2)CCCCCCC1
Reactant: CCOC(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: O=CO
Solvent: CC(=O)O
Product: CCOC(=O)OC1(C2CCCCCCCC2)CCCCCCCC1
Reaction time: 1.25 h

Procedure:
Into a 1 liter reaction vessel equipped with stirrer, thermometer and addition funnel are placed 339 grams (2.04 moles) of bicyclononenyl formate produced according to Example I containing compounds having the structures: ##STR175## 531 grams (4.5 moles) diethyl carbonate; and 31 grams (0.14 moles) of an aqueous 25% solution of sodium methoxide. The resulting mixture is stirred for a period of 1.25 hours. At the end of the 1.25 hour period, 30 grams (0.5 moles) of acetic acid and 2 liters of water is added to the reaction mass with stirring. The reaction mass is then washed with one 2 liter portion of saturated aqueous sodium chloride. The organic phase is then distilled on a 2" splash column yielding the following fractions:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[O:8][C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:6][C:5]2=[C:15]([C:17]([OH:19])=O)[CH:16]=1.[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1>>[CH3:27][N:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:17]([C:15]2[CH:16]=[C:2]([Cl:1])[CH:3]=[C:4]3[O:8][C:7]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)=[N:6][C:5]=23)=[O:19])[CH2:22][CH2:23]1
Reactant: O=C(O)c1cc(Cl)cc2oc(-c3ccccc3)nc12
Reactant: CN1CCC(N)CC1
Product: CN1CCC(NC(=O)c2cc(Cl)cc3oc(-c4ccccc4)nc23)CC1
Yield: 46 %

Procedure:
This material was prepared from 6-chloro-2-phenyl-benzoxazole-4-carboxylic acid and 4-amino-1-methylpiperdine using the method outlined in Step C of Example 7. This compound was obtained in 46% yield as a tan solid: mp 170-172° C.; 1H NMR (300 MHz, CDCl3) δ 9.14 (d, J=7.8 Hz, 1H), 8.23 (dd, J=6.6, 1.5 Hz, 2H), 8.18 (d, J=1.5 Hz, 1H), 7.71 (d, J=2.1 Hz, 1H), 7.65-7.54 (m, 3H), 4.19-4.13 (m, 1H), 2.87 (d, J=1.5 Hz, 2H), 2.37 (s, 3H), 2.32-2.26 (m, 2H), 2.17-2.13 (m, 2H), 1.84-1.72 (m, 2H); MS (ESI) m/z 370 [M+H]+
Reaction SMILES: [C:1]([C:3]1[CH:36]=[CH:35][C:6]2[N:7]([C:28](=[O:34])[CH2:29][S:30]([CH3:33])(=[O:32])=[O:31])[C@@H:8]([CH3:27])[C@H:9]([NH:13][C:14](=[O:26])[C@@H:15]([N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH3:16])[C:10](=[O:12])[NH:11][C:5]=2[CH:4]=1)#[N:2].[Br:37][C:38]1[CH:47]=[CH:46][CH:45]=[C:44]2[C:39]=1[CH:40]=[CH:41][C:42]([O:50][CH3:51])=[C:43]2[CH2:48]Cl.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+]>CN(C=O)C.CCOC(C)=O>[Br:37][C:38]1[CH:47]=[CH:46][CH:45]=[C:44]2[C:39]=1[CH:40]=[CH:41][C:42]([O:50][CH3:51])=[C:43]2[CH2:48][N:11]1[C:10](=[O:12])[C@@H:9]([NH:13][C:14](=[O:26])[C@@H:15]([N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])[CH3:16])[C@H:8]([CH3:27])[N:7]([C:28](=[O:34])[CH2:29][S:30]([CH3:33])(=[O:32])=[O:31])[C:6]2[CH:35]=[CH:36][C:3]([C:1]#[N:2])=[CH:4][C:5]1=2
Reactant: C[C@@H](C(=O)N[C@@H]1C(=O)Nc2cc(C#N)ccc2N(C(=O)CS(C)(=O)=O)[C@H]1C)N(C)C(=O)OC(C)(C)C
Reactant: COc1ccc2c(Br)cccc2c1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2c(Br)cccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)N(C(=O)CS(C)(=O)=O)c2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 38.8 %

Procedure:
To a rt solution of tert-butyl(S)-1-((2S,3S)-7-cyano-2-methyl-1-(2-(methylsulfonyl)acetyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (122 mg, 234 μmol) in DMF (585 μl) was added 5-bromo-1-(chloromethyl)-2-methoxynaphthalene (80.2 mg, 281 μmol), cesium carbonate (99.1 mg, 304 μmol), and sodium iodide (45.6 mg, 304 μmol). The reaction was stirred at rt for 1.5 h, then diluted with EtOAc, washed with H2O and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(S)-1-((2S,3S)-5-((5-bromo-2-methoxynaphthalen-1-yl)methyl)-7-cyano-2-methyl-1-(2-(methylsulfonyl)acetyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (70 mg, 39% yield) as a white solid. MS m/z 792/794 (MNa)+.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[C:16]1([CH3:25])[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.[F-].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1(C)C=CC=CC=1>[CH3:25][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccc(Br)cc1
Reactant: Cc1ccccc1B(O)O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [F-]
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1ccc(C(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
A 4 ml vial was charged with 4-bromobenzophenone (268 mg, 1.03 mmol), o-tolylboronic acid (152 mg, 1.12 mmol), KF (116 mg, 2.00 mmol), Pd(dba)2 (5.8 mg, 1 mol %), and Ph5FcP(t-Bu)2 (7.1 mg, 2 mol %). Anhydrous toluene (2 ml) was added to the mixture, and the vial was sealed with a cap containing PTFE septum and removed from the drybox. The reaction solution was stirred at room temperature for 18 h. After the starting aryl halide was consumed, the reaction solution was directly absorbed onto silica gel and the coupling product was isolated by eluting with hexane/ethyl acetate to give 275 mg (98%) of 4-(2-methylphenyl)benzophenone as a solid:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=[C:4]2[CH:3]=1.[C:14](=[O:21])([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[NH2:15].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH:11]([C:9]1[N:10]=[C:4]2[CH:3]=[C:2]([NH:15][C:14](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=[CH:6][N:5]2[N:8]=1)([CH3:13])[CH3:12]
Reactant: CC(C)c1nc2cc(Br)ccn2n1
Reactant: CC(C)(C)OC(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)c1nc2cc(NC(=O)OC(C)(C)C)ccn2n1
Yield: 93.4 %

Procedure:
To an argon purged solution of 7-bromo-2-isopropyl-[1,2,4]triazolo[1,5-a]pyridine (378 mg, 1.57 mmol) in dioxane (10 ml) are added tert-butyl carbamate (221 mg, 1.89 mmol), cesium carbonate (718 mg, 2.2 mmol), tris(dibenzylideneacetone)dipalladium(0) (28.8 mg, 31.5 μmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (36.4 mg, 63.0 μmol). The resulting mixture is refluxed for 2.5 days (weekend) under argon atmosphere. The crude material is loaded on silicagel and purified by flash chromatography on a 20 g silica column using heptane/ethyl acetate 20-70% as eluent affording tert-butyl 2-isopropyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamate (405 mg, 93.1%) as a light yellow solid. Mp.: 215-8° C. MS: m/z=277.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:18])[N:13]([CH:15]([CH3:17])[CH3:16])[N:14]=2)=[N:6][C:7]=1Br.[CH3:25][S-:26].[Na+].O>CN1CCN(C)C1=O>[NH2:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:18])[N:13]([CH:15]([CH3:17])[CH3:16])[N:14]=2)=[N:6][C:7]=1[S:26][CH3:25]
Reactant: C[S-]
Reactant: CC(C)n1nc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=O
Agent: [Na+]
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: CSc1nc(-c2ccc(=O)n(C(C)C)n2)c(-c2ccccc2)nc1N
Temperature: 102.5 °C
Yield: 41.6 %

Procedure:
A mixture of 6-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (11.35 g) and sodium thiomethoxide (4.12 g) in 1,3-dimethyl-2-imidazolidinone (17 ml) was heated at 100-105° C. for one hour. The mixture was poured into water (170 ml). The precipitate was collected by filtration, dissolved in CHCl3, dried over MgSO4, concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (50:50 v/v) to give 6-[5-amino-6-(methylthio)-3-phenyl-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone as a solid (4.32 g).
Reaction SMILES: C=[C:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:4]2[CH:16]=[CH:17][CH:18]=[N:19][C:3]1=2.BrC1C(N(CCCC=C)C(=O)[O:29]C(C)(C)C)=CC=CN=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])=O.[K+]>CN(C=O)C.O.[Cl-].C([N+](CC)(CC)CC)C.CCOC(C)=O.C([O-])(O)=O.[Na+].CC([O-])=O.CC([O-])=O.[Pd+2]>[O:29]=[C:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:4]2[CH:16]=[CH:17][CH:18]=[N:19][C:3]1=2
Reactant: C=CCCCN(C(=O)OC(C)(C)C)c1cccnc1Br
Reactant: C=C1CCCN(C(=O)OC(C)(C)C)c2cccnc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[N+](CC)(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(=O)c2ncccc21
Temperature: 110 °C
Reaction time: 16 h

Procedure:
tert-butyl 9-methylene-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]azepine-5-carboxylate. To a solution of tert-butyl (2-bromopyridin-3-yl)(pent-4-en-1-yl)carbamate (1 eq.) in DMF (0.2 M), PPh3 (0.25 eq.), Pd(OAc)2 (0.1 eq), and KOAc (5 eq.), is added, under an argon atmosphere, tetraethyl ammonium chloride hydrate (2 eq.). The flask is purged with argon for 15 min, and the resulting reaction mixture is stirred at 110° C. for 16 h. The reaction progress is monitored by TLC. The reaction mixture is diluted with EtOAc and saturated NaHCO3 solution. The organic layer is separated, dried over Na2SO4, and concentrated. The product thus obtained is purified by column chromatography to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.C[O:20][CH2:21][CH2:22][NH2:23]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:23][CH2:22][CH2:21][OH:20])=[O:14]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: COCCN
Product: O=C(NCCO)c1ccncc1Nc1ccc(I)cc1F

Procedure:
3-(2-Fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethyl)-isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.45 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.60 mmol of 2-methoxy-ethylamine. LC/MS [3.42 min; 402 (M+1)]
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]1=[O:11].[OH:13][C:14]1([CH2:27][SH:28])[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C(N(CC)CC)C>C(#N)C>[O:11]=[C:2]1[C:1](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([S:28][CH2:27][C:14]2([OH:13])[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:18][CH2:19]2)=[CH:3]1
Reactant: O=C1C=Cc2ccccc2C1=O
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CS)CC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(O)(CSC2=CC(=O)C(=O)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 294.5 %

Procedure:
To a solution of naphthalene-1,2-dione (3.2 g, 2.02 mmol) and tert-butyl 4-hydroxy-4-(mercaptomethyl)piperidine-1-carboxylate (5.0 g, 2.02 mmol) in anhydrous acetonitrile (400 ml) was added triethylamine (2.82 ml, 2.02 mmol). The reaction mixture was allowed to stir for 1 hour at room temperature and the solvents were evaporated under reduced pressure. The crude product was purified by flash column chromatography (SiO2, 40% EtOAc in hexanes to 70% EtOAc in hexanes). Fractions containing the product were concentrated and tritrated with ethyl acetate/ether to afford the desired product as a red solid (2.4 g, 29%). M.p.=156-157° C.; 400 MHz 1H NMR (CDCl3) δ: 8.17-8.12 (m, 1H), 7.87-7.83 (m, 1H), 7.69-7.62 (m, 1H), 7.59-7.52 (m, 1H), 6.49 (s, 1H), 4.0-3.85 (m, 2H), 3.25-3.14 (m, 4H), 1.84-1.78 (m, 2H), 1.76-1.66 (m, 2H), 1.47 (s, 9H); LCMS: 404 [M+H].
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][NH:10][C:9]2[CH:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:8]=2[O:7]1)=[O:5])C.[C:20]([O-])([O-])=O.[K+].[K+].IC.Cl>CN(C=O)C.O>[CH3:20][N:10]1[C:9]2[CH:12]=[C:13]([C:16]([F:17])([F:18])[F:19])[CH:14]=[CH:15][C:8]=2[O:7][CH:6]([C:4]([OH:3])=[O:5])[CH2:11]1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C1CNc2cc(C(F)(F)F)ccc2O1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CN1CC(C(=O)O)Oc2ccc(C(F)(F)F)cc21
Temperature: 150 °C
Yield: 14.4 %

Procedure:
To a solution of 6-trifluoromethyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid ethyl ester (650 mg, 2.4 mmol) in anhydrous DMF (7 mL) was added K2CO3 (816 mg, 5.9 mmol), followed by iodomethane (294 μL, 4.7 mmol). The reaction was heated in the microwave (300 W, 150° C.) for 1 hour. After cooling, the mixture was poured into water (50 mL), acidified with 2N HCl and extracted with EtOAc (3×50 mL). The combined organics were washed with brine (3×50 mL), dried (MgSO4), filtered and concentrated. Flash chromatography (0 to 12% MeOH in DCM) gave the title compound (90 mg, 10%) as a beige solid. m/z=262.1 (M+1), r.t.=3.28 mins. 1H NMR (400 MHz; d6-DMSO) δ 6.93-6.86 (3H, m), 4.85 (1H, s), 3.45-3.36 (2H, m), 2.86 (3H, s).
Reaction SMILES: [CH:1]1([S:4][C:5]2[CH:10]=[CH:9][C:8]([C:11](=[CH:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:32])C=1>>[CH:1]1([S:4]([C:5]2[CH:6]=[CH:7][C:8]([C:11](=[CH:17][CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][CH:10]=2)=[O:32])[CH2:3][CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)C(=CC1CCOCC1)c1ccc(SC2CC2)cc1
Product: CCOC(=O)C(=CC1CCOCC1)c1ccc(S(=O)C2CC2)cc1

Procedure:
Partial oxidation of ethyl 2-(4-cyclopropylsulfanylphenyl)-3-(tetrahydropyran-4-yl)acrylate (see Preparation 22, 3.14 g, 9.44 mmol) with mCPBA, employing the protocol described above in Preparation 18, furnished ethyl 2-(4-cyclopropanesulfinylphenyl)-3-(tetrahydropyran-4-yl)acrylate: m/z (ES+)=349.2 [M+H]+. Saponification of this ester (1.15 g, 3.3 mmol), using the procedure described in Preparation 25, afforded the title compound: m/z (ES+)=641.4 [2M+H]+.
Reaction SMILES: [NH2:1][CH:2]1[C:7]2=[N:8][C:9]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[CH:10][C:11](=[O:12])[N:6]2[CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:26][N:27]1[C:31]2[CH:32]=[CH:33][C:34]([C:36](Cl)=[O:37])=[CH:35][C:30]=2[N:29]=[N:28]1.O>O1CCCC1>[CH3:26][N:27]1[C:31]2[CH:32]=[CH:33][C:34]([C:36]([NH:1][CH:2]3[C:7]4=[N:8][C:9]([C:13]5[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=5)=[CH:10][C:11](=[O:12])[N:6]4[CH2:5][CH2:4][CH2:3]3)=[O:37])=[CH:35][C:30]=2[N:29]=[N:28]1
Reactant: Cn1nnc2cc(C(=O)Cl)ccc21
Reactant: NC1CCCn2c1nc(-c1ccncc1)cc2=O
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Cn1nnc2cc(C(=O)NC3CCCn4c3nc(-c3ccncc3)cc4=O)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.6 %

Procedure:
To a solution of 0.050 g (0.21 mmol) of (+/−)9-amino-2-pyridin -4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one dissolved in 2.2 mL of tetrahydrofuran was added 30 μl (0.25 mmol) of triethylamine and 0.0484 g (0.25 mmol) of 1-methyl-1H-1,2,3-benzotriazole-5-carbonyl chloride. The resulting mixture was stirred at room temperature for 16 h. Water was added and the mixture extracted with ethyl acetate. The extracts were washed with a saturated aqueous solution of ammonium chloride, dried and evaporated. The residue was purified by silica gel chromatography, eluting with dichloromethane/methanol/ammonia in the proportions 95/5/0.5 to give 0.041 g of pure product obtained in the form of free base.
Reaction SMILES: [C:1]([Si:5]([CH3:14])([CH3:13])[O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])([CH3:4])([CH3:3])[CH3:2].[Br-].[K+].Cl[O-].[Na+].C(=O)([O-])[O-].[K+].[K+]>ClCCl.CC1(C)N([O])C(C)(C)CCC1.O>[C:1]([Si:5]([CH3:14])([CH3:13])[O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[O:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCCCCO
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCCCC=O
Temperature: 5 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
To a solution of 5-(tert-butyl-dimethyl-silanyloxy)-pentanol (16.8 mmol, 3.66 g) in dichloromethane (30 mL) were added water (5.6 mL), potassium bromide (1.7 mmol, 202 mg), n-tetrabutylammonium hydrogensulfate (0.84 mmol, 290 mg), and TEMPO (30 mg) at room temperature. The resulting light brown solution was cooled to ˜5° C. and a solution of sodium hypochlorite (19.3 mmol, 30 mL, 5%) was added dropwise at this temperature. After addition of half of the sodium hypochlorite solution, solid potassium carbonate (300 mg) was added to maintain the reaction mixture basic. Then, the remaining sodium hypochlorite solution was added at 5-10° C. By this point, a precipitate had formed and the reaction mixture was stirred for another 1 h at ˜10-15° C. Then, water (100 mL) was added and the resulting solution was extracted into diethyl ether (2×100 mL). The combined organic extracts were washed with brine solution (150 mL) and the organic layer was dried over anhydrous magnesium sulfate. Filtration of the drying agent and the removal of the solvent gave 5-(tert-butyl-dimethyl-silanyloxy)-pentanal (3.32 g, 91%) as a light brown oil: ES(+)-HRMS m/e calculated for C11H24O2Si (M+H)+ 217.1619, found 217.1619.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[CH2:4][N:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]2[C:13]([CH3:23])=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[N:15]=[C:6]12.Br[CH2:30][CH:31]1[CH2:33][CH2:32]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:2]([F:1])[C:3]=1[CH2:4][N:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]2[C:13]([CH3:23])=[C:14]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH2:30][CH:31]4[CH2:33][CH2:32]4)=[CH:20][CH:21]=3)[N:15]=[C:6]12
Reactant: BrCC1CC1
Reactant: Cc1c(-c2ccc(O)cc2)nc2n(Cc3c(F)cccc3F)cc(Br)c(=O)n12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(-c2ccc(OCC3CC3)cc2)nc2n(Cc3c(F)cccc3F)cc(Br)c(=O)n12
Temperature: 60 °C
Reaction time: 4 h
Yield: 82.1 %

Procedure:
To a solution of the compound obtained in Example 23 (0.25 g, 0.56 mmol) in DMF (30 ml) is added (bromomethyl)cyclopropane (0.114 g, 0.84 mmol), K2CO3 (0.116 g, 0.84 rmnol) and KI (0.047 g, 0.28 mmol). The residual reaction mixture is stirred at 60° C. for 4 hours. To this mixture is added (bromomethyl)cyclopropane (0.14 g, 1.0 mmol). It is stirred at this temperature for 21 hours and is evaporated under reduced pressure to afford the residue, which is partitioned between chloroform (100 ml) and aqueous saturated NaHCO3 solution (30 ml). The aqueous layer is extracted with chloroform (30 ml). The combined organic extract is dried over Na2SO4 and concentrated under reduced pressure to give the residue, which is chromatographed on silica gel to afford white crystals (0.23 g, 82%).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([C:22](O)=[O:23])[C@@H:18]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C@@H:17]2[C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.ClC(OCC(C)C)=O.C(N(CC)CC)C>C1COCC1>[F:37][C:2]([F:1])([F:38])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][OH:23])[C@@H:18]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C@@H:17]2[C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CCOC(=O)[C@H]1[C@H](c2ccc(F)cc2)[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC[C@@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1[C@@H](CO)CC[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
To a solution of intermediate carboxylic acid (2.7 g, 4.91 mmol) from Step A in 60 mL THF was added isobutyl chloroformate (0.96 mL, 7.32 mmol) and triethyl amine (1.23 mL, 8.84 mmol). The mixture was stirred at 0° C. for 0.5 hr then at room temperature for 0.5 hr. The white precipitate was filtered and the solid was washed with dry THF. The filtrate was added to a suspension of 1 g NaBH4 in 3 mL water at 0° C. The resulting mixture was stirred at room temperature for 16 hr, quenched with 2 N aq. HCl (20 mL), then diluted with ethyl acetate (50 mL). The organic layer was separated and the aqueous was extracted with ethyl acetate (2×60 mL). The combined organic extract was washed with brine, dried over MgSO4, filtered and the solvent was removed under vacuum. The residue was purified by column chromatography (2:1 hexane:ethyl acetate) to give the title compound (1.8 g). 1H-NMR (CDCl3) δ: 7.71 (1H, s), 7.20 (2H, s), 7.00 (2H, m), 6.85 (2H, m), 4.45 (1H, q, J=6.4 Hz), 3.83 (2H, m), 3.55 (2H, m), 3.35 (1H, m), 2.93 (1H, t, J=11.0 Hz), 2.47 (1H, t, J=11.0Hz), 2.37 (1H, s), 2.33 (1H, m), 1.97 (2H, m), 1.62-1.50 (2H, m), 1.20 (1H, m), 1.33 (3H, d, J=6.4 Hz), 0.90 (3H, t, J=7.1 Hz).