Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Li+].[CH3:3][O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:16]=[C:15]([C:17]([NH:19][C:20]3[C:29]([CH3:30])=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][C:21]=3[CH3:31])=[O:18])[C:14]([CH3:32])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.O.CO>C1COCC1>[CH3:3][O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:16]=[C:15]([C:17]([NH:19][C:20]3[C:21]([CH3:31])=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:28][C:29]=3[CH3:30])=[O:18])[C:14]([CH3:32])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1
Reactant: COC(=O)c1cc(C)c(NC(=O)c2nc(N3CCC(OC)CC3)ccc2C)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COC1CCN(c2ccc(C)c(C(=O)Nc3c(C)cc(C(=O)O)cc3C)n2)CC1
Reaction time: 2 h
Yield: 88.4 %

Procedure:
Lithium hydroxide (LiOH.H2O, 0.026 g, 0.62 mmol) is added to a stirred solution of methyl 4-[[6-(4-methoxy-1-piperidyl)-3-methyl-pyridine-2-carbonyl]amino]-3,5-dimethyl-benzoate (0.129 g, 0.313 mmol) in THF:H2O:MeOH (0.7 ml:0.3 ml:0.7 ml). After 2 hours at 50° C., the organic solvent is removed under reduced pressure and the residue is diluted with water, acidified to pH 6 with aqueous 1N HCl, and extracted with ethyl acetate (3×20 ml). The organic layers are combined and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure and the resulting precipitate is triturated with diethyl ether and filtered to afford the title compound as an off-white solid (0.11 g, 88%). Mass spectrum (m/z): 398.2 (M+1).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[C:6]#[N:7].[Cl-].[Li+].CN(C=O)C.Cl>O>[OH:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[C:6]#[N:7]
Reactant: COc1cc(C#N)ccc1O
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(O)c(O)c1
Temperature: 180 °C
Yield: 70.6 %

Procedure:
To a 3-necked 250 mL round bottom flask equipped with a mechanical stirrer and a condenser, 3-methoxy-4-hydroxybenzonitrile (13.4 g, 89.9 mmole), lithium chloride (7.6 g, 179.2 mmole), and N,N′-dimethylformamide (60 mL) were added successively at 25° C., followed by heating in an oil bath at 180° C. for 20 hours. The reaction mixture was allowed to cool to 85° C. Water (285 mL) was then added, and upon cooling to 25° C., treatment with concentrated hydrochloric acid proceed. The resulting mixture was extracted with ethyl acetate (300 mL×2). The extract was concentrated under reduced pressure to give a pale brown solid. Water (430 mL) was added and the mixture was then heated till the mixture became homogeneous. After the reaction mixture was cooled down to approximately 40° C., 3,4-Dihydroxybenzonitrile was precipitated out and the reaction mixture was further cooled to 10° C. so as to ensure complete precipitation. The resulting solid was isolated by filtration and dried under reduced pressure. 3,4-Dihydroxybenzonitrile was obtained as a white solid with a yield of 70.6% and a purity of greater than 99% as indicated by HPLC analysis.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[N:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1)([O-])=O.C([OH:22])C>O=[Pt]=O>[NH2:1][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[N+:10]1([O-:22])[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1
Reactant: CCO
Reactant: O=[N+]([O-])c1ccncc1N1CCc2ccccc2C1
Agent: O=[Pt]=O
Product: Nc1ccncc1[N+]1([O-])CCc2ccccc2C1
Reaction time: 24 h

Procedure:
To a slurry of PtO2 (0.3 g) in 10 ml of ethanolwas added 2-(4-nitro-3-pyridinyl)-1,2,3,4-tetrahydroisoquinoline, N-oxide (5.0 g) in 240 ml of ethanol and this was hydrogenated with a Parr apparatus at room temperature for 24 hours. The mixture was filtered and the filtrate concentrated to yield an oil (5.1 g), which was eluted with 20% methanol/DCM on a silica gel column via HPLC. The desired fractions were concentrated to a solid (2.0 g), m.p. 216°-219° C. (decomp). This solid was recrystallized from acetonitrile to yield a solid, 1.0 g, m.p. 217°-219° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[CH:19][C:18](Br)=[CH:17][N:16]=2)=[C:11]([F:22])[C:10]=1[F:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][N:34]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[CH:19][C:18]([C:36]3[CH:35]=[N:34][C:33]([O:32][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:38][CH:37]=3)=[CH:17][N:16]=2)=[C:11]([F:22])[C:10]=1[F:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1c(OCc2ccccc2)ccc(-c2ncc(Br)cn2)c1F
Reactant: CCCCCCCCOc1ccc(B(O)O)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCOc1ccc(-c2cnc(-c3ccc(OCc4ccccc4)c(F)c3F)nc2)cn1
Yield: 60.7 %

Procedure:
The reaction of 35 mmol of 2-(4-benzyloxy-2,3-difluorophenyl)-5-bromopyrimidine, 44 mmol of 2-octyloxypyridine-5-boronic acid, 70 mmol of sodium carbonate and 0.4 mmol of tetakis(triphenylphosphine)palladium(0) in 120 ml of toluene, 60 ml of ethanol and 60 ml of water is carried out analogously to the procedure indicated for Example 1a). Corresponding chromatographic purification and recrystallization from ethyl acetate gives 10.7 g (61%) of colorless crystals, m.p. 120° C., cl.p. 182-183° C.
Reaction SMILES: [N:1]1([CH:6]2[CH2:15][CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)/[C:7]/2=[N:16]\[OH:17])[CH:5]=[CH:4][N:3]=[CH:2]1.CCCCC.[H-].[Na+].[CH2:25]([O:27][C:28](=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32]Br)[CH3:26]>CN(C=O)C>[CH2:25]([O:27][C:28](=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32][O:17]/[N:16]=[C:7]1/[CH:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:15][CH2:14][C:13]2[C:8]/1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:26]
Reactant: CCOC(=O)CCCCBr
Reactant: O/N=C1\c2ccccc2CCC1n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCC
Product: CCOC(=O)CCCCO/N=C1\c2ccccc2CCC1n1ccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(+-)-(E)-2-(1H-imidazol-1-yl)-1,2,3,4-tetrahydronaphtalen-1-one oxime (500 mg; 2.2 mmoles) dissolved in dry DMF (27 ml) is added, under dry nitrogen atmosphere, to a pentane-washed sodium hydride suspension (160 mg NaH 55%; 3.6 mmoles), in dry DMF (10 ml). The resulting reaction mixture is stirred at r.t. for 2 hours. Then ethyl-5-bromopentanoate (0.530 ml; 3.3 mmoles) is added at r.t. and the reaction mixture is stirred at r.t. for 3 hrs., the solvent evaporated in vacuo, and the residue carefully taken up with ice-cooled water and extracted with ethyl acetate. The collected organic phases are dried over Na2SO4 and evaporated to give an oily crude material which is chromatographed over silica gel. By eluting with CH2Cl2 /MeOH (95:5), the pure title compound is obtained as a slight yellow oil (250 mg). 1H-NMR (200MH2, CDCl3) ppm.
Reaction SMILES: [Br:1][CH2:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:10][OH:11]>[O-2].[O-2].[Mn+4].ClCCl>[Br:1][CH2:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:10]=[O:11]
Reactant: OCc1cccc(Cl)c1CBr
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1cccc(Cl)c1CBr
Reaction time: 8 h
Yield: 66.2 %

Procedure:
Dichloromethane (15 ml) and manganese dioxide (1.69 g, 19.4 mmol) were added to [2-(bromomethyl)-3-chlorophenyl]methanol obtained in Example 10d (440 mg, 1.87 mmol), followed by stirring at mom temperature overnight. Manganese dioxide (1.2 g, 13.8 mmol) was further added, followed by heating with stirring at 40° C. for 2.5 hours. The reaction mixture was filtered through Celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (silica gel, elution solvent: heptane/ethyl acetate=99/1->90/10) to give the title compound (289 mg, yield 66.2%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]1([N:16]=[C:17]=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl.Cl.[N:21]1[C:29]2[CH2:28][CH2:27][NH:26][CH2:25][C:24]=2[S:23][C:22]=1[NH:30][C:31]([NH2:33])=[NH:32].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:10]1([NH:16][C:17]([N:26]2[CH2:27][CH2:28][C:29]3[N:21]=[C:22]([NH:30][C:31]([NH2:33])=[NH:32])[S:23][C:24]=3[CH2:25]2)=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N=C(N)Nc1nc2c(s1)CNCC2
Reactant: O=C=Nc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N=C(N)Nc1nc2c(s1)CN(C(=O)Nc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Diisopropylethylamine (0.2 mmol) and, after 5 min, phenyl isocyanate (0.11 mmol) are added to a suspension of N-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine-2-yl)-guanidine dihydrochloride (0.1 mmol) in dimethylformamide (0.5 ml). The reaction mixture is stirred for another 3 hours at room temperature. Then saturated aqueous sodium carbonate solution is added and extraction is carried out with ethyl acetate. The pure title compound is obtained after drying of the combined organic phases over sodium sulphate and removal of the solvent in a vacuum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[CH2:6][OH:7].[CH3:14][S:15]([N:18]([CH2:37][CH2:38][Cl:39])[N:19]([S:33]([CH3:36])(=[O:35])=[O:34])[C:20](OCC1C=CC=CC=1[N+]([O-])=O)=[O:21])(=[O:17])=[O:16]>>[CH3:14][S:15]([N:18]([CH2:37][CH2:38][Cl:39])[N:19]([S:33]([CH3:36])(=[O:34])=[O:35])[C:20]([O:7][CH2:6][C:5]1[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:21])(=[O:16])=[O:17]
Reactant: COc1cc(CO)ccc1[N+](=O)[O-]
Reactant: CS(=O)(=O)N(CCCl)N(C(=O)OCc1ccccc1[N+](=O)[O-])S(C)(=O)=O
Product: COc1cc(COC(=O)N(N(CCCl)S(C)(=O)=O)S(C)(=O)=O)ccc1[N+](=O)[O-]

Procedure:
1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)-2-[(3-methoxy-4-nitrobenzyloxy)carbonyl]hydrazine (compound 13d) was prepared from 3-methoxy-4-nitrobenzyl alcohol using a procedure similar to that described for compound 13a. The Mp was determined to be about 56-57° C., and the yield was about 29.4% by weight after recrystallization from ethanol. 1H NMR (acetone d6): δ 7.8, 7.5 and 7.2 (3H, 2d, s, aromatic H), 5.8 (2H, d, ArCH2), 3.6-4.1 (4H, m, CH2CH2Cl), 4.0 (3H, S, OCH3), 3.6 and 3.3 (6H, 2s, 2 CH3SO2).
Reaction SMILES: C([O:8][CH2:9][C@H:10]([OH:17])[CH2:11][C:12]1[NH:13][CH:14]=[CH:15][N:16]=1)C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[NH:13]1[CH:14]=[CH:15][N:16]=[C:12]1[CH2:11][C@@H:10]([OH:17])[CH2:9][OH:8]
Reactant: O[C@@H](COCc1ccccc1)Cc1ncc[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: OC[C@H](O)Cc1ncc[nH]1
Yield: 97.9 %

Procedure:
To a solution of (2R)-1-(benzyloxy)-3-(1H-imidazol-2-yl)-2-propanol (424 mg) in methanol (10 ml), 10% palladium carbon (50% hydrated, 85 mg) was added, followed by stirring at 50-60° C. in a hydrogen atmosphere for 2 days. The catalyst was filtered off; the filtrate was concentrated to yield the titled compound (254 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]([CH3:16])([CH3:15])[CH2:11][C:12]([OH:14])=O)=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.Cl[Sn](Cl)(Cl)Cl>C1C=CC=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][CH:8]=1)[S:9][C:10]([CH3:16])([CH3:15])[CH2:11][C:12]2=[O:14]
Reactant: COc1ccc(SC(C)(C)CC(=O)O)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Solvent: ClCCl
Product: COc1ccc2c(c1)C(=O)CC(C)(C)S2
Yield: 78.3 %

Procedure:
To a solution of 3-(4-methoxy-phenylsulfanyl)-3-methyl-butyric acid (20.0 g, 83.2 mmol) in 250 mL of benzene at room temperature was added a solution of oxalyl chloride (15.84 g, 124.8 mmol) in 10 mL of benzene over 30 minutes. After 4 hours the solution was washed with ice cold 5% aqueous NaOH (CAUTION: a large volume of gas is released during this procedure), followed by ice cold H2O, and finally saturated aqueous NaCl. The solution was dried (Na2SO4) and concentrated under reduced pressure to give a clear yellow oil. This material was used without further purification in the next step. 1H NMR (300 MHz, CDCl3) δ: 7.45 (2H, d, J=8.8 Hz), 6.90 (2H, d, J=8.8 Hz), 3.84 (3H, s), 3.12 (2H, s), 1.41 (6H, s). Step 3: To a solution of the acyl chloride product of Step 2 (21.5 g, 83.2 mmol) in 250 mL of CH2Cl2 at 0° C. was added dropwise a solution of SnCl4 (21.7 g, 83.2 mmol) in 30 mL of CH2Cl2. After 2 hours the reaction was quenched by slow addition of 150 mL H2O. The organic layer was washed with 1M aqueous HCl, 5% aqueous NaOH, H2O, and finally saturated aqueous NaCl before being dried over MgSO4. Concentration under reduced pressure and vacuum distillation of the residual oil (Bulb-to-bulb, 125-135° C., 5 mm/Hg) afforded 14.48 g (78%) of 6-methoxy-2,2-dimethyl-thiochroman4-one as a pale-yellow oil. 1H NMR (300 MHz, CDCl3) δ: 7.62 (1H, d, J=2.9 Hz), 7.14 (1H, d, J=8.6 Hz), 7.03 (1H, dd, J=2.8 Hz), 3.83 (3H, s), 2.87 (2H, s), 1.46 (6H, s).
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([NH:12][C:13](=[O:15])[CH3:14])=[C:6]([C:16](=O)[C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[CH:19][CH:18]=2)[CH:5]=1>C(O)C>[Br:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([NH:12][C:13](=[O:15])[CH3:14])=[C:6]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH3:24])=[CH:21][CH:22]=2)[CH:5]=1
Reactant: CCc1ccc(C(=O)c2cc(Br)c(OC)cc2NC(C)=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCc1ccc(Cc2cc(Br)c(OC)cc2NC(C)=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium borohydride (0.17 g) is added portionwise to an ice-cold suspension of N-[4-bromo-2-(4-ethyl-benzoyl)-5-methoxy-phenyl]-acetamide (3.25 g) in ethanol (50 mL). The cooling bath is removed and the solution is stirred at ambient temperature for 2 h. Then, 1 M aqueous NaOH solution (8.5 mL) is added and the resulting solution is concentrated under reduced pressure. Water is added to the residue and the resulting mixture is extracted with ethyl acetate. The combined organic extracts are washed with brine, dried (Na2SO4) and concentrated. The residue is taken up in trifluoroacetic acid (20 mL) and triethylsilane (4.3 mL) is added. The solution is stirred at ambient temperature overnight and then poured on crushed ice. The resultant mixture is extracted twice with ethyl acetate. The combined extracts are washed with brine, dried (sodium sulphate) and concentrated under reduced pressure. The residue is treated with methanol and the precipitate formed is separated. The precipitate is then washed with diisopropylether and dried to give the desired product.
Reaction SMILES: [CH:1]1[C:13]2N[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CN1C2C=CC=CC=2[C:21]2[C:16]1=[CH:17]C=CC=2>>[C:6]1([CH2:5][CH2:4][CH2:3][C:2]2[CH:1]=[CH:13][CH:21]=[CH:16][CH:17]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: Cn1c2ccccc2c2ccccc21
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Product: c1ccc(CCCc2ccccc2)cc1
Yield: 68 %

Procedure:
The procedure of Example 3 was followed except that the carbazole was replaced by 71 mg of N-methylcarbazole, whereupon 57 mg of 1,3-diphenylpropane (yield 68%) was isolated.
Reaction SMILES: C(ON([C@H]1CN[C@H](C(N)=O)C(C)=C1)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)C=C.[CH2:28]([O:31][N:32]([C@H:45]1[CH2:50][N:49](C(OC(C)(C)C)=O)[C@H:48]([C:58](=[O:60])[NH2:59])[C:47]([CH:61]([CH3:63])[CH3:62])=[CH:46]1)[S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[N+:42]([O-:44])=[O:43])(=[O:35])=[O:34])[CH:29]=[CH2:30]>>[CH2:28]([O:31][N:32]([C@H:45]1[CH2:50][NH:49][C@H:48]([C:58]([NH2:59])=[O:60])[C:47]([CH:61]([CH3:63])[CH3:62])=[CH:46]1)[S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[N+:42]([O-:44])=[O:43])(=[O:35])=[O:34])[CH:29]=[CH2:30]
Reactant: C=CCON([C@@H]1C=C(C(C)C)[C@@H](C(N)=O)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: C=CCON([C@@H]1C=C(C)[C@@H](C(N)=O)NC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: C=CCON([C@@H]1C=C(C(C)C)[C@@H](C(N)=O)NC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 75.4 %

Procedure:
(2S,5R)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-3-isopropyl-1,2,5,6-tetrahydropyridine-2-carboxamide (160 mg, 86%) was prepared a similar manner as described in Intermediate 84 as a beige solid, using (2S,5R)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-carbamoyl-3-isopropyl-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 94, 260 mg, 0.5 mmol) as a starting material.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:50][C:51]1[CH:52]=[C:53]([C:67]([C:72]2[CH:77]=[CH:76][C:75](/[CH:78]=[CH:79]/[C:80]([CH2:84][CH3:85])([OH:83])[CH2:81][CH3:82])=[C:74]([CH3:86])[CH:73]=2)([CH2:70][CH3:71])[CH2:68][CH3:69])[CH:54]=[C:55]([CH3:66])[C:56]=1B1OC(C)(C)C(C)(C)O1.[Cl-].[NH4+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:56]2[C:55]([CH3:66])=[CH:54][C:53]([C:67]([CH2:68][CH3:69])([C:72]3[CH:77]=[CH:76][C:75](/[CH:78]=[CH:79]/[C:80]([CH2:84][CH3:85])([OH:83])[CH2:81][CH3:82])=[C:74]([CH3:86])[CH:73]=3)[CH2:70][CH3:71])=[CH:52][C:51]=2[CH3:50])=[CH:7][CH:6]=1
Reactant: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2cc(C)c(B3OC(C)(C)C(C)(C)O3)c(C)c2)cc1C)CC
Reactant: COC(=O)Cc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2cc(C)c(-c3ccc(CC(=O)OC)cc3)c(C)c2)cc1C)CC
Temperature: 100 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
(4-Bromo-phenyl)acetic acid methyl ester (Tetrahedron Letters 44 (2003) 331-334; 34 mg, 0.149 mmol), palladium acetate (2.2 mg, 0.010 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (8.2 mg, 0.020 mmol), potassium phosphate (63 mg, 0.297 mmol) and water (0.2 mL) were added to a solution of (E)-1-(4-{1-[3,5-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-3-ethyl-1-penten-3-ol (Example 38-(6); 50 mg, 0.099 mmol) in toluene (2 mL). After replacement with nitrogen, the mixture was stirred at 100° C. for one hour. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1) to give the target compound as a colorless oil (31.8 mg, 61%).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][C:9]([CH3:14])([CH3:13])[C:10](O)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].ClC(OCC(C)C)=O.C([N:27](CC)CC)C.N>ClCCl.CO>[N+:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][C:9]([CH3:14])([CH3:13])[C:10]([NH2:27])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCN(CC)CC
Reactant: CC(C)(Oc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: ClCCl
Solvent: CO
Product: CC(C)(Oc1ccc([N+](=O)[O-])cc1)C(N)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(4-nitrophenoxy)isobutyric acid (50) (5 g), isobutyl chloroformate (4.36 mL) and triethylamine (8 mL) in dichloromethane (20 mL) was stirred at room temperature for 1 hour. Then 2.0 M ammonia in methanol (20 mL) was added to the solution. The resulting solution was stirred at room temperature for 2 hours and then solvent was removed under reduced pressure. The mixture was purified by recrystallization from EtOAc and hexanes to give 2-(4-nitrophenoxy)-2-methylpropanamide (51).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:11]([O:13][C:14](=[O:28])[CH:15]([C:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:16][C:17](=O)[CH3:18])[CH3:12].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:11]([O:13][C:14]([C:15]1[CH:16]=[C:17]([CH3:18])[N:8]([C:7]2[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C:20]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:28])[CH3:12]
Reactant: CCOC(=O)C(CC(C)=O)C(=O)c1ccccc1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)c1cc(C)n(-c2ccc([N+](=O)[O-])cc2)c1-c1ccccc1

Procedure:
p-Nitroaniline (10 mmol, 1.4 g), 2-benzoyl-4-oxo-pentanoic acid ethyl ester (10 mmol, 2.5 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The reaction mixture was filtered and the solids washed with ethanol. The collected material was determined to be the named product (m.p. 190° C.-192° C.).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C:15]1[CH:16]=[N:17][C:18]2[C:23]([CH:24]=1)=[N:22][C:21]([O:25][CH3:26])=[CH:20][CH:19]=2)(C)(C)C>ClCCl>[NH2:14][C:15]1[CH:16]=[N:17][C:18]2[C:23]([CH:24]=1)=[N:22][C:21]([O:25][CH3:26])=[CH:20][CH:19]=2
Reactant: COc1ccc2ncc(NC(=O)OC(C)(C)C)cc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2ncc(N)cc2n1
Temperature: 25 °C
Reaction time: 19 h
Yield: 21.1 %

Procedure:
Trifluoroacetic acid (101 mL, 1.32 mol, 20.85 eq) is added to a stirred solution of (6-methoxy-[1,5]naphthyridine-3-yl)-carbamic acid tert-butyl ester (18.2 g, 66.11 mmol, 1.0 eq) in dichloromethane (500 mL). After 19 hours stirring at room temperature, the solution is evaporated to dryness, 6N sodium hydroxide aqueous solution is added to adjust pH to 9˜10 and a lot of solid precipitated. The mixture is extracted with dichloromethane (200 mL) and the residue is extracted with ethyl acetate (3×250 mL). Evaporation of the dichloromethane phase gives 2.44 g of product with 83% purity, which is then purified by column chromatography (silica gel, eluent: dichloromethane:petroleum ether:ethyl acetate, 25:25:2, v/v/v) to afford 6-methoxy-[1,5]naphthyridin-3-ylamino as a light yellow solid (1.95 g with 98% purity). Evaporation of the ethyl acetate phase yields additional 9.88 g of light yellow product with 99% purity. Total: 11.83 g (98% yield).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([O:10][C:11]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1[NH2:13])=[N:5]2.C(N(CC)CC)C.[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([O:10][C:11]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1[NH:13][C:32]([NH:31][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:33])=[N:5]2
Reactant: Nc1ccccc1Oc1ccc2nccn2n1
Reactant: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)Nc1ccccc1Oc1ccc2nccn2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.5 %

Procedure:
To a solution of 2-(imidazo[1,2-b]pyridazin-6-yloxy)aniline (90 mg, 0.40 mmol) and triethylamine (0.011 mL, 0.08 mmol) in tetrahydrofuran (20 mL) was added phenyl isocyanate (0.061 mL, 0.56 mmol), and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from methanol to give the title compound (99 mg, 0.29 mmol, yield 72%) as a white powder.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.F[C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][N:16]=1.CCN(C(C)C)C(C)C.C(O)CC>CCOC(C)=O>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([NH:1][C@@H:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)=[N:16][CH:17]=1)#[N:22]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: N#Cc1ccc(F)nc1
Solvent: CCOC(C)=O
Solvent: CCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC[C@@H](Nc2ccc(C#N)cn2)C1
Temperature: 150 °C
Yield: 89.6 %

Procedure:
A heavy-walled, screw-cap glass tube was charged with (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate (3.30 g, 17.7 mmol), 2-fluoro-5-cyanopyridine (1.63 g, 13.2 mmol), i-Pr2NEt (6.3 mL, 35.5 mmol) and n-PrOH (3 mL). The mixture was heated at 150° C. in an oil bath for 2 h. The mixture was diluted with EtOAc (180 mL), washed with 1% aq HCl (3×40 mL), satd aq NaHCO3 (40 mL) and brine (40 mL), and dried over Na2SO4. Removal of the solvent left an oil (3.28 g) which was purified by chromatography on a 40-g silica gel cartridge eluted with a 0-100% EtOAc in hexanes gradient to afford (R)-tert-butyl 3-(5-cyanopyridin-2-ylamino)pyrrolidine-1-carboxylate (3.41 g, 88% based on 2-fluoro-5-cyanopyridine). LC-MS Method 1 tR=1.57 min, m/z=289.