Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([NH:9][OH:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:11](=O)(O)[O-:12].[K+].C(OCC(F)(F)F)=O>C(OC)(C)(C)C>[CH2:2]([N:9]([OH:10])[CH:11]=[O:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C([O-])O
Reactant: ONCc1ccccc1
Agent: Cl
Agent: O=COCC(F)(F)F
Agent: [K+]
Solvent: COC(C)(C)C
Product: O=CN(O)Cc1ccccc1
Yield: 96 %

Procedure:
A suspension of N-benzyl-N-hydroxylamine hydrochloride (1.0 g, 6.26 mmol; Aldrich Chemical Company, Milwaukee, Wis.) in methyl tert-butyl ether (10 mL) was vigorously stirred 10% potassium bicarbonate solution and separated into an aqueous fraction and an organic fraction. The organic fraction was treated with the 2,2,2-trifluoroethyl formate reagent (92% (w/w), 4.35 g, 31.3 mmol, 5 equiv), and heated at reflux for 6 hours. The mixture was washed sequentially with water, 15% potassium bicarbonate, and 15% brine, then concentrated to provide 0.90 g (96%) of the desired product as a mixture of rotamers. 1H NMR (300 MHz, CDCl3) δ 8.28, 7.86 (2s, 1H total), 7.35-7.15 (m, 5H total), 7.10, 6.90 (2 br s, 1H total), 4.64, 4.56 (2s, 2H total).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:15]2[CH2:24][C:23]([CH3:26])([CH3:25])[C:22]3[C:17](=[C:18]([C:27]([O:29]C)=[O:28])[CH:19]=[CH:20][CH:21]=3)[CH2:16]2)=[N:6][C:7]=1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[Li+].[OH-].Cl>O1CCCC1.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:15]2[CH2:24][C:23]([CH3:26])([CH3:25])[C:22]3[C:17](=[C:18]([C:27]([OH:29])=[O:28])[CH:19]=[CH:20][CH:21]=3)[CH2:16]2)=[N:6][C:7]=1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: COC(=O)c1cccc2c1CN(c1ccc(Br)c(C(=O)OC(C)(C)C)n1)CC2(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1nc(N2Cc3c(C(=O)O)cccc3C(C)(C)C2)ccc1Br
Reaction time: 8 h

Procedure:
To an ambient solution of EXAMPLE 14A (245 mg) in tetrahydrofuran (2.1 mL) was added a solution of LiOH (30.9 mg) in water (0.52 mL). The reaction was stirred overnight, diluted with 2 mL water and 2 mL ethyl acetate, and acidified to pH ˜3 with 10% aqueous HCl solution. The layers were separated, and the aqueous layer was extracted with additional ethyl acetate (2×8 mL). The combined organic layers were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH:30]2[CH2:32][O:31]2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].[H-].[Na+]>>[C:16]([O:20][C:21]([N:23]1[CH2:24][CH2:25][N:26]([CH2:29][CH:30]([OH:31])[CH2:32][N:6]2[C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:14][C:13]=3[C:12]3[C:7]2=[CH:8][CH:9]=[C:10]([Br:15])[CH:11]=3)[CH2:27][CH2:28]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: Brc1ccc2[nH]c3ccc(Br)cc3c2c1
Reactant: CC(C)(C)OC(=O)N1CCN(CC2CO2)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCN(CC(O)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)CC1
Yield: 72 %

Procedure:
The same method as employed in the preparation of Example 1 but starting from 3,6-dibromo-9H-carbazole, (±)-4-oxiranylmethyl-piperazine-1-carboxylic acid tert-butyl ester and sodium hydride gives after flash chromatography the title compound as a white foam in a 72% yield. M.p: 90-95° C.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:21])[C:7]([CH3:9])([CH3:8])[O:6][B:5]([C:10]2[CH:11]=[N:12][N:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH:14]=2)[O:4]1.BrCCO[Si]([C:29](C)([CH3:31])[CH3:30])(C)C.CCN(C(C)C)C(C)C.[I-].[K+]>CN(C=O)C>[CH3:30][CH:29]([N:18]1[CH2:19][CH2:20][CH:15]([N:13]2[CH:14]=[C:10]([B:5]3[O:6][C:7]([CH3:8])([CH3:9])[C:3]([CH3:21])([CH3:2])[O:4]3)[CH:11]=[N:12]2)[CH2:16][CH2:17]1)[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CC1(C)OB(c2cnn(C3CCNCC3)c2)OC1(C)C
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Temperature: 50 °C

Procedure:
A solution of 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-piperidine hydrochloride (500 mg, 1.59 mmol) in DMF (15.0 mL) was charged with (2-bromoethoxy)-tert-butyldimethylsilane (0.376 mL, 1.75 mmol), DIPEA (0.694 mL, 3.99 mmol) and potassium iodide (26 mg, 0.16 mmol) and was heated at 50° C. for 16 h. The DMF was then concentrated in vacuo. The product was purified by flash chromatography (0 to 15% MeOH:EtOAc) to afford the title compound. 1H NMR (400 MHz, CD3OD): δ 7.90 (s, 1H), 7.69 (s, 1H), 4.31 (td, J=7.71, 15.41 Hz, 1H), 3.88 (t, J=5.68 Hz, 2H), 3.28 (br s, 2H), 3.00 (s, 3H), 2.86 (s, 3H), 2.76-2.84 (m, 2H), 2.51-2.67 (m, 2H), 2.10-2.19 (m, 4H), 1.31 (s, 12H), 0.91-0.94 (m, 9H); MS (ESI): 436.28 [M+H]+; HPLC tR=1.26 min (TOF polar—3 min).
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH:10]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][C:5]2[CH:22]=[CH:23][CH:24]=[CH:25][C:4]=2[CH2:3]1.[Br:26][CH:27]([CH2:31][CH2:32][CH2:33][CH2:34][N:35]1[C:39](=[O:40])[C:38]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:37]2[C:36]1=[O:45])[C:28](O)=[O:29].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>ClCCl>[C:14]([O:13][C:11](=[O:12])[CH:10]([N:7]1[C:8](=[O:9])[CH:2]([NH:1][C:28](=[O:29])[CH:27]([Br:26])[CH2:31][CH2:32][CH2:33][CH2:34][N:35]2[C:39](=[O:40])[C:38]3=[CH:41][CH:42]=[CH:43][CH:44]=[C:37]3[C:36]2=[O:45])[CH2:3][C:4]2[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=2[CH2:6]1)[CH2:18][CH:19]([CH3:21])[CH3:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)CC(C(=O)OC(C)(C)C)N1Cc2ccccc2CC(N)C1=O
Reactant: O=C(O)C(Br)CCCCN1C(=O)c2ccccc2C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)CC(C(=O)OC(C)(C)C)N1Cc2ccccc2CC(NC(=O)C(Br)CCCCN2C(=O)c3ccccc3C2=O)C1=O
Reaction time: 17 h

Procedure:
Combine 2-(4-amino-3-oxo-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-4-methyl-valeric acid, tert-butyl ester (0.34 mmol), 2-bromo-6-phthalimidohexanoic acid (0.189 g, 0.56 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.106 g, 0.55 mmol), and 1-hydroxybenztriazole hydrate ((75 mg, 0.56 mmol) in dicloromethane (8 mL). After 17 hours, evapoarte in vacuo to give a residue, partition the residue between ethyl aceate and an aqueous 5% sulfuric acid solution (about 20 mL). Separate the layers, extract the organic layer with a saturate aqueiosu sodium bicarbonate solution and then brine, dry over Na2SO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: Cl.NC(N)=N.C[O-].[Na+].C1(C)C=CC=CC=1.[Cl:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[C:24](=C(OCC)CF)[C:25]#[N:26]>CO>[Cl:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:24][C:25]#[N:26]
Reactant: CCOC(CF)=C(C#N)c1cccc(Cl)c1Cl
Agent: C[O-]
Agent: Cl
Agent: N=C(N)N
Solvent: CO
Solvent: Cc1ccccc1
Product: N#CCc1cccc(Cl)c1Cl
Yield: 38 %

Procedure:
To guanidine hydrochloride (25.4 kg, 266 mole) in methanol (60 liters) was added 30% w/w sodium methoxide in methanol solution (49.2 kg, 273.3 mole). The suspension was heated to 55° C.±2° C. The toluene solution of 2-(2,3-dichlorophenyl)-3-ethoxy-4-fluoro-2-butenenitrile was added over a period of 45 minutes and the resultant mixture was boiled under reflux for 4 hours, cooled then quenched into water (230 liters). The solid precipitate was washed with 5 portions of methanol (25 liters) to yield the racemate as an off white solid (26.3 kg, 38% yield from 2,3-dichlorophenylacetonitrile).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([C:18]2[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=2[F:25])[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:36]2[CH:41]=[CH:40][C:39]([N:42]3[CH2:47][CH2:46][O:45][CH2:44][C:43]3=[O:48])=[CH:38][CH:37]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[F:24][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([F:25])[C:18]=1[N:9]1[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([O:16][CH3:17])[C:11]=2[C:7]([C:36]2[CH:37]=[CH:38][C:39]([N:42]3[CH2:47][CH2:46][O:45][CH2:44][C:43]3=[O:48])=[CH:40][CH:41]=2)=[N:8]1
Reactant: CC1(C)OB(c2ccc(N3CCOCC3=O)cc2)OC1(C)C
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2-c1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1nccc2c1c(-c1ccc(N3CCOCC3=O)cc1)nn2-c1c(F)cccc1F
Temperature: 120 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
To a mixture of 1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (150 mg) obtained in Step C of Example 35, 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholin-3-one (145 mg) and sodium carbonate (78 mg) in DME/water (1.5 mL/0.070 mL) was added dichloro(1,1′-bis(diphenylphosphino)ferrocene)palladium(II) (21 mg) under nitrogen atmosphere. The reaction mixture was stirred under microwave irradiation at 120° C. for 1 hr. The insoluble substance was removed by the filtration, the filtrate was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by thin layer silica gel chromatography (ethyl acetate/petroleum ether) to give the title compound (143 mg).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C:4]([CH:11]([CH3:13])[CH3:12])([C:7]([O:9]C)=[O:8])[CH2:3]1>O1CCOCC1.Cl>[O:1]=[C:2]1[CH2:6][CH2:5][C:4]([CH:11]([CH3:13])[CH3:12])([C:7]([OH:9])=[O:8])[CH2:3]1
Reactant: COC(=O)C1(C(C)C)CCC(=O)C1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)C1(C(=O)O)CCC(=O)C1
Temperature: 0 °C

Procedure:
A solution of methyl 3-oxo-1-isopropylcyclopentanecarboxylate (27 g, 146.6 mmol) in dioxane (300 mL) and conc HCl (100 mL) was heated to reflux overnight. The crude product was extracted into diethyl ether (4×200 mL) and the combined organic extracts were washed with an aqueous solution of sodium hydroxide (5N, 2×150 mL). The combined aqueous extracts were cooled to 0° C. and acidified with conc HCl. The product was extracted with ether (3×200 mL), dried with magnesium sulfate and the solvent was evaporated in vacuo. The weight of the product was 20 g (98%). 1H NMR (500 MHz, CDCl3): 2.81 (d, J=8.54 Hz, 1H), 2.48 (m, 1H), 2.32 (m, 2H), 2.15 (d, J=18.53 Hz, 1H), 2.08 (m, 1H), 1.95 (m, 1H), 1.03 (d, J=6.86 Hz, 3H), 0.96 (d, J=6.87 Hz, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:15]=[C:14]([CH2:16][OH:17])[CH:13]=[CH:12][C:4]=1[O:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]([C:3]1[CH:15]=[C:14]([CH:16]=[O:17])[CH:13]=[CH:12][C:4]=1[O:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2]
Reactant: CCOC(=O)COc1ccc(CO)cc1CC
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)COc1ccc(C=O)cc1CC
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.4 %

Procedure:
To a solution of ethyl [2-ethyl-4-(hydroxymethyl)phenoxy]acetate (2.74 g, 11.5 mmol) in chloroform (250 mL) was added manganese dioxide (10 g, 11.5 mmol). The resulting mixture was stirred for 18 h at room temperature. The mixture was filtered through a celite pad and then concentrated in vacuo to afford the title compound as a pale yellow oil (2.7 g).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH3:6][O:7][C:8](=[O:19])[C:9]([C:12]1[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=1)([CH3:11])[CH3:10]>CN(CCN(C)C)C.C1COCC1.CCOCC.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>[CH3:6][O:7][C:8](=[O:19])[C:9]([C:12]1[CH:13]=[CH:14][C:15]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[CH:16][CH:17]=1)([CH3:11])[CH3:10]
Reactant: COC(=O)C(C)(C)c1ccc(Br)cc1
Reactant: c1ccoc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN(C)CCN(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)c1ccc(-c2ccco2)cc1
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 89.8 %

Procedure:
To a cooled (0° C.) solution of furan (5.7 mL, 78 mmol) in TMEDA/THF (81.4 mL, 14/86) is added n-buLi (15 mL, 2.5 M in hexanes). The cold bath is removed and the resulting solution stirred for 45 minutes, then a solution of ZnCl2 in THF added (40 mL, 0.5M). To this solution is added (Ph3P)4Pd (1.0 g, 0.86 mmol) and 2-(4-Bromo-phenyl)-2-methyl-propionic acid methyl ester (4.5 g, 17.5 mmol) (reference example 31 a). The resulting solution is warmed to 60° C. and stirred for 3 hours. The reaction mixture is then cooled, diluted with ether, washed with hydrochloric acid (2M), then brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (eluting with 5% ether in hexanes) to give 3.84 g of the title compound as a solid. 1H NMR (CDCl3) d 1.60 (s, 6H), 3.67 (s, 3H), 6.45 (m, 1H), 6.63 (d, J=3 Hz, 1H), 7.35 (m, 2H), 7.46 (m, 1H), 7.65 (m, 2H). MS (EI) m/z 245 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[S:14]([OH:17])(=[O:16])=[O:15].CO>ClCCl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:14]([OH:17])(=[O:16])=[O:15])=[C:7]([O:11][CH3:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cccc(C(C)(C)C)c1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Solvent: CO
Product: COc1cc(C(C)(C)C)ccc1S(=O)(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 131.1 %

Procedure:
To a cooled (0° C.) solution of 29 (6.19 g; 37.69 mmol) in anhydrous dichloromethane (160 mL) was added chlorosulfonic acid (3.0 mL; 45.22 mmol) dropwise. After addition as complete, the reaction was stirred at 0° C. for an additional 30 minutes, allowed to gradually warm to room temperature and further stirred overnight. The reaction mixture was concentrated under reduced pressure to about 500 mL and washed with aqueous hydrochloric acid (20 nm; 20N). The organic layer was separated and dried over magnesium sulfate which resulted in formation of a white precipitate. Methanol (200 mL) was added to dissolve the precipitate. The organic solution was filtered and concentrated under reduced pressure to yield the title compound as a purple solid (12.07 g).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].O=[C:7]1CCC[N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][CH2:8]1.O>O1CCCC1.CCCCCC>[CH2:4]=[C:3]1[CH2:7][CH2:8][CH2:9][N:10]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:1][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Reactant: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C1CCCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under argon 12.56 g methyltriphenylphosphonium bromide are dissolved in 100 ml of tetrahydrofuran, cooled to −14° C. and within 45 minutes a 2 M solution of 17.58 ml n-butyllithium in hexane is added dropwise. The mixture is stirred for another 1 hour and then a solution of 5 g tert-butyl 4-oxo-azepan-1-carboxylate in 20 ml of tetrahydrofuran is added dropwise. Then the mixture is heated to ambient temperature and stirred for 12 hours. It is then divided between water and hexane and the aqueous phase is extracted twice with hexane. The combined organic phases are washed with saturated aqueous sodium chloride solution and dried on magnesium sulphate. The solvents are eliminated in vacuo and the residue is stirred with petroleum ether/tert.-butyl-methyl-ether. The solid is suction filtered and the mother liquor is evaporated down in vacuo. The residue is chromatographed on silica gel (petroleum ether/ethyl acetate 100:0, then 95:5).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:19](I)=[C:11]2[N:12]=[CH:13][CH:14]=[C:15]([O:16][CH2:17][CH3:18])[N:10]2[N:9]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:19]2[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:9][N:10]3[C:15]([O:16][CH2:17][CH3:18])=[CH:14][CH:13]=[N:12][C:11]=23)=[CH:24][CH:23]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCOc1ccnc2c(I)c(-c3ccccc3Cl)nn12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOc1ccnc2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Temperature: 87 °C
Yield: 29.3 %

Procedure:
To a mixture of 2-(2-chlorophenyl)-7-ethoxy-3-iodopyrazolo[1,5-a]pyrimidine (1–11A-1a; 6.76 g, 16.9 mmol), 4-chlorophenylboronic acid (4.07 g, 26.0 mmol), powdered K2CO3 (4.7 g, 34 mmol) and (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II), dichloromethane complex (0.69 g, 0.85 mmol) was added degassed dimethoxyethane (136 ml) and water (34 ml). The reaction was heated at 87° C. for 1.5 hours, cooled, and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with 1 M aqueous NaOH, 1 M aqueous HCl, and brine. Suspended solids were collected by filtration (3.0 g). The solvent was removed, in vacuo, and the residue was triturated from ethanol to give additional solids (1.9 g). The combined solids were purified by silica gel chromatography using 9:1 methylene chloride/ hexanes as eluant to afford 11A-1 (4.45 g, 68%) as an off-white solid: +ESI MS (M+1) 384.3; 1H NMR (400 MHz, CD3OD) δ 8.51 (d, J=5.0 Hz, 1H), 7.53–7.40 (m, 6H), 7.24 (d, J=8.7 Hz, 2H), 6.66 (d, J=5.0 Hz, 1H), 4.59 (q, J=7.1 Hz, 2H), 1.60 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=O)[CH2:10][NH:9][C:8](=O)[C:7]=2[CH:15]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][CH2:11][CH2:10][NH:9][CH2:8][C:7]=2[CH:15]=1
Reactant: COc1ccc2c(c1)C(=O)NCC(=O)N2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CNCCN2
Temperature: 74 °C
Reaction time: 24 h
Yield: 71.1 %

Procedure:
To a solution of 7-methoxy-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione (3.1 g, 15 mmol) in THF (26 mL), was added lithium aluminum hydride (1M solution in THF, 68 mL, 68 mmol) by dropwise addition over 20 minutes. The reaction was heated to 74° C. and held for 24 hours. After 24 hours, the reaction was quenched with water, 15% NaOH and another portion of water. The reaction mixture was then diluted with ethyl acetate and sodium sulfate was added. The reaction mixture was then stirred for 1 hour, after which it was filtered through a bed of celite, with subsequent washing of the bed with ethyl acetate. The solvent was removed from the filtrate to give the crude desired product. Further purification (1% ammonia in 2M solution of ethanol/ethyl acetate, then 3%, then 5%) yielded 1.9 g of the desired product as orange crystals (71%).
Reaction SMILES: C([O:8][C:9]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[S:11][CH:10]=1)C1C=CC=CC=1.ClC(Cl)(Cl)Cl.I[Si](C)(C)C>O>[OH:8][C:9]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[S:11][CH:10]=1
Reactant: FC(F)(F)c1cc(OCc2ccccc2)cs1
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: Oc1csc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 66 %

Procedure:
A mixture of 1G (7.75 g) and tetrachloromethane (50 ml) was treated with iodotrimethylsilane (12.30 ml) and heated to 60° C. for 12 hours. The reaction mixture was stirred at room temperature for 12 hours. Water (50 ml) was added and the resulting reaction mixture was extracted with dichloromethane three times. The combined organic phases were washed with water and dried. The crude reaction mixture was eluted through hexane (100 g/silica gel) to remove benzyliodide and then with diethyl ether. The etheral phases were concentrated and distilled in vacuo to give the product (3.33 g, 74%) having a boiling point of 65°-66° C. at 4 mm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]#[N:11].Br[CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1.CS(C)=O.[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)[C:10]#[N:11]
Reactant: COc1ccccc1CC#N
Reactant: BrCC1CCCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccccc1C(C#N)CC1CCCCO1
Reaction time: 2 h
Yield: 82 %

Procedure:
To a flask was added 20 g. (0.1346 mole) of (2-methoxyphenyl)acetonitrile, 25 g. (0.1346 mole) of 2-(bromomethyl)tetrahydro-2H-pyran, and 200 ml. of DMSO. The mixture was stirred for five minutes at room temperature and to the resultant solution was added 22 g. (0.2692 mole) of 50% aqueous sodium hydroxide over 30 minutes with the reaction temperature being allowed to exotherm to 60° C. The reaction was stirred an additional two hours, then cooled, water added and the organic material extracted with ether. The combined ether extracts were then washed with water, dried, filtered, and the ether distilled. The organic residue wss fractionally distilled to obtain 27 g. (82% yield) of the 2-(2-methoxyphenyl)-3-(tetrahydropyran-2-yl)propionitrile boiling 145°-160° C. at 5 mm of Hg.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([NH2:6])=[N:2]1.[CH2:7]([O:10][CH:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1)[CH:8]=[CH2:9].C([BH3-])#N.[Na+].O>C(O)(=O)C>[CH2:7]([O:10][CH:11]1[CH2:16][CH2:15][CH:14]([NH:6][C:3]2[NH:4][CH:5]=[N:1][N:2]=2)[CH2:13][CH2:12]1)[CH:8]=[CH2:9]
Reactant: C=CCOC1CCC(=O)CC1
Reactant: Nc1nc[nH]n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: C=CCOC1CCC(Nc2nnc[nH]2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.4 %

Procedure:
To a solution (100 mL) of 1H-1,2,4-triazol-3-amine (2.4 g) and 4-(prop-2-en-1-yloxy)cyclohexanone (5.3 g) in acetic acid was added sodium cyanoborohydride (9.1 g), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The obtained residue was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with a mixed solvent of ethyl acetate and isopropyl alcohol (3:1). The obtained extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (3.2 g, 50%).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N-]>ClCCl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:16]
Reactant: OCc1ccccc1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93.2 %

Procedure:
To a solution of benzyl alcohol (1.04 mL, 10.0 mmol) in dichloromethane (30 mL) is added rhodium (II) acetate dimer (40 mg) followed by ethyl diazoacetate (1.14 g, 10.0 mmol). The reaction mixture is stirred at RT for 20 min. The reaction mixture is rotary evaporated, and the residue is vacuum distilled at 110° C. to give 1.81 g of the product 390. 1H NMR (CDCl3) δ 7.4-7.26 (m, 5H), 4.65 (s, 2H), 4.23 (q, 2H), 4.10 (s, 2H), 1.30 (t, 3H).
Reaction SMILES: I[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][C:9]=3[O:8][CH2:7][CH2:6][N:5]2[CH:19]=1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.C(#N)C>C(=O)([O-])[O-].[Na+].[Na+].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>[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[C:26]([C:2]2[N:3]=[C:4]3[C:10]4[CH:11]=[CH:12][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][C:9]=4[O:8][CH2:7][CH2:6][N:5]3[CH:19]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc2c(c1)OCCn1cc(I)nc1-2
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: CC#N
Product: COC(=O)c1ccc2c(c1)OCCn1cc(-c3cccc(C(F)(F)F)c3)nc1-2
Yield: 40.5 %

Procedure:
Methyl 2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate (80 mg, 1 eq), 3-(trifluoromethyl)phenylboronic acid (76 mg, 1.75 eq), and tetrakis(triphenylphosphine)palladium (10 mg, 0.05 eq), in 1.0 M aqueous sodium carbonate (1.0 mL) and acetonitrile (1.0 mL) were heated to 140° C. for 10 min in a sealed microwave reactor. The crude reaction mixture was concentrated and purified using reverse phase HPLC to yield 299 (34 mg). ESI-MS: 389.1 (M)+