Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[O:7][CH:6]=[CH:5][C@H:4]([O:8][C:9]([CH3:11])=[O:10])[C@H:3]1[O:12][C:13]([CH3:15])=[O:14].[OH2:16].[Br-].[Li+].O>C(#N)C>[C:9]([O:8][C@@H:4]1[C@@H:3]([O:12][C:13](=[O:14])[CH3:15])[C@H:2]([CH3:1])[O:7][CH:6]([OH:16])[CH2:5]1)(=[O:10])[CH3:11]
Reactant: CC(=O)O[C@H]1[C@H](C)OC=C[C@@H]1OC(C)=O
Reactant: O
Agent: [Br-]
Agent: [Li+]
Solvent: CC#N
Product: CC(=O)O[C@H]1[C@H](C)OC(O)C[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69.2 %

Procedure:
To a solution of 3,4-di-O-acetyl-L-rhamnal (5.0 g) and lithium bromide hydrate (5.0 g) in acetonitrile (150 ml), activated resin prepared as in Example 1 (3.0 g) and water (6 ml) were added and stirred at room temperature for 15 min. The product was isolated as described for Example 1. Purification by chromatography on a column of Silica Gel using ethyl acetate-hexane 3:8) as eluant gave the title compound (3.75 g). α:β=2:1. [α]D20 =-96.8°±2° (c 0 96. CHCl3). 1H NMR δ: 5.36 (H-1α), 5.33 (m, H-3α), 4.98 (m, H-3β), 4.90 (dd, H-1β), 4.75 (t, H-4), 4.12 (m, H-5α), 3.54 (m, H-5β), 2.39 and 2.26 (m, H-2eq), 1.77 and 1.66 (m, H-2ax), 1.23 and 1.17 (d, CH3). MS (calc. mass=232). Obs. m/e 231.13, 215.12, 155.09 (100 %).
Reaction SMILES: C1(OP(Cl)(OC2C=CC=CC=2)=O)C=CC=CC=1.[O:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH:20]=[C:19]1[C:27]([OH:29])=O.C(N(CC)CC)C.[NH2:37][C@H:38]1[CH:43]2[CH2:44][CH2:45][N:40]([CH2:41][CH2:42]2)[C@@H:39]1[CH2:46][C:47]1[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=1.C1(C)C=CC(C([C@@](C(O)=O)(O)[C@@](C(C2C=CC(C)=CC=2)=O)(O)C(O)=O)=O)=CC=1.[OH-].[Na+]>ClCCl>[N:49]1[CH:50]=[CH:51][CH:52]=[C:47]([CH2:46][CH:39]2[CH:38]([NH:37][C:27]([C:19]3[O:18][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[CH:20]=3)=[O:29])[CH:43]3[CH2:42][CH2:41][N:40]2[CH2:45][CH2:44]3)[CH:48]=1
Reactant: N[C@H]1C2CCN(CC2)[C@@H]1Cc1cccnc1
Reactant: O=C(O)c1cc2ccccc2o1
Agent: Cc1ccc(C(=O)[C@](O)(C(=O)O)[C@@](O)(C(=O)O)C(=O)c2ccc(C)cc2)cc1
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1C2CCN(CC2)C1Cc1cccnc1)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 49.6 %

Procedure:
Diphenylchlorophosphate (96 pL, 124 mg, 0.46 mmol) was added drop-wise to a solution of the benzofuran-2-carboxylic acid (75 mg, 0.46 mmol) and triethylamine (64 μL, 46 mg, 0.46 mmol) in dry dichloromethane (1 mL). After stirring at ambient temperature for 45 min, a solution of (2R,3S)-3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane (0.10 g, 0.46 mmol) (that derived from the di-p-toluoyl-L-tartaric acid salt) and triethylamine (64 μL, 46 mg, 0.46 mmol) in dry dichloromethane (1 mL) was added. The reaction mixture was stirred overnight at ambient temperature, and then treated with 10% sodium hydroxide (1 mL). The biphasic mixture was separated, and the organic layer and a chloroform extract (2 mL) of the aqueous layer was concentrated by rotary evaporation. The residue was dissolved in methanol and purified by HPLC on a C18 silica gel column, using an acetonitrile/water gradient, containing 0.05% trifluoroacetic acid, as eluent. Concentration of selected fractions, partitioning of the resulting residue between chloroform and saturated aqueous sodium bicarbonate, and evaporation of the chloroform gave 82.5 mg (50% yield) of a white powder. The NMR spectrum was identical to that obtained for the 2S,3R isomer.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6](O)[C:7]3[S:13][CH2:12][CH2:11][CH2:10][C:8]=3[N:9]=2)[CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:17])=O>>[CH:1]1([C:4]2[N:5]=[C:6]([Cl:17])[C:7]3[S:13][CH2:12][CH2:11][CH2:10][C:8]=3[N:9]=2)[CH2:3][CH2:2]1
Reactant: Oc1nc(C2CC2)nc2c1SCCC2
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nc(C2CC2)nc2c1SCCC2

Procedure:
A stirred solution of product from Step A (17 g) in phosphorus oxychloride (160 ml) was heated at reflux for 1 hour. Two-thirds of the phosphorus oxychloride was distilled from the reaction mixture and the residue poured into ice water to give 12.1 g of title compound which was dried and used in Step C without further purification or characterization.
Reaction SMILES: [Na].Cl.[C:3]([NH2:9])(=[NH:8])[CH2:4][CH2:5][CH2:6][CH3:7].[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]=[C:18]=[O:19]>CC(C)=O>[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][C:18]([NH:8][C:3](=[NH:9])[CH2:4][CH2:5][CH2:6][CH3:7])=[O:19]
Reactant: O=C=Nc1ccccc1Cl
Reactant: CCCCC(=N)N
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Product: CCCCC(=N)NC(=O)Nc1ccccc1Cl

Procedure:
Following a procedure similar to that described in Example 1 but using 2.3 g. sodium in 250 ml. dry acetone, 13.6 g. valeramidine hydrochloride, and 15.3 g. 2-chlorophenyl isocyanate in 100 ml. dry acetone, there was obtained after recrystallization from isopropyl alcohol-ether 15.4 g. of the hydrochloride of 1-(2-chloropheyl)-3-(pentanimidoyl)yrea; m.p. 132°-134°C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:20]([C:21](=O)[CH:22]=[CH:23]N(C)C)=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]1[CH:44]=[CH:43][C:33]([CH2:34][O:35][CH2:36][CH2:37][CH2:38][NH:39][C:40]([NH2:42])=[NH:41])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:20]([C:21]3[CH:22]=[CH:23][N:42]=[C:40]([NH:39][CH2:38][CH2:37][CH2:36][O:35][CH2:34][C:33]4[CH:32]=[CH:31][C:30]([O:29][CH3:28])=[CH:44][CH:43]=4)[N:41]=3)=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:17])([F:19])[F:18])=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(COCCCNC(=N)N)cc1
Reactant: CN(C)C=CC(=O)c1c(-c2ccc(F)cc2)nn2cc(C(F)(F)F)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COCCCNc2nccc(-c3c(-c4ccc(F)cc4)nn4cc(C(F)(F)F)ccc34)n2)cc1
Temperature: 25 °C

Procedure:
A mixture of 2-(4-fluorophenyl)-3-(3-(dimethylamino)-2-propenoyl)-6-trifluoromethyl-pyrazolo[1,5-a]pyridine (Example 65f. 2.0 g, 5.3 mmol), N-(3-(4-methoxybenzyloxy)propyl)-guanidine (2.7 g, 7.95 mmol), and potassium carbonate (2.2 g, 15.9 mmol) was stirred in N,N-dimethylformamide (20 mL) in a 100° C. oil bath for 18 h. The mixture was cooled to room temperature, water (200 mL) was added the mixture was extracted with chloroform. The chloroform extracts were dried over anhydrous MgSO4, filtered, and the solvent was evaporated. The crude material was purified by chromatography on silica gel using 30% EtOAc/hexanes as eluent to afford the title compound as a white solid, 2.1 g (72%). 1H NMR (acetone-d6) δ 9.18 (s, 1H), 8.67 (d, 1H, J=9.4 Hz), 8.15 (d, 1H, J=5.1 Hz), 7.77 (m, 2H), 7.56 (d, 1H, J=9.2 Hz), 7.34 (m, 4H), 6.90 (d, 2H, J=8.6 Hz), 6.50 (s, 1H), 6.38 (d, 1H, J=5.1 Hz), 4.49 (s, 2H), 3.80 (s, 3H), 3.63 (m, 4H), 1.98 (m, 2H). MS (+ve ion electrospray) 551 (30), (M+).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([O:20][CH3:21])=[C:18](Cl)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[Br:23][C:24]1[N:29]=[C:28]([CH3:30])[C:27]([NH2:31])=[CH:26][CH:25]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.[Li]N([Si](C)(C)C)[Si](C)(C)C>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([O:20][CH3:21])=[C:18]([NH:31][C:27]3[C:28]([CH3:30])=[N:29][C:24]([Br:23])=[CH:25][CH:26]=3)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: COc1c(Cl)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Reactant: Cc1nc(Br)ccc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: C1COCCO1
Product: COc1c(Nc2ccc(Br)nc2C)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Reaction time: 4.5 h
Yield: 43.5 %

Procedure:
A mixture of 4-(6-chloro-5-methoxy-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester (3.3 g, 10.0 mmol), 6-bromo-2-methyl-pyridin-3-ylamine (1.88 g, 10.0 mmol), palladium acetate (118 mg, 0.53 mmol), 2-(di-t-butylphosphino) biphenyl (157 mg, 0.53 mmol) and LiN(TMS)2 (1M in THF, 15 mL, 15 mmol) in 75 mL of dioxane was stirred under reflux. After 4.5 h, more palladium acetate (111 mg, 0.50 mmol) was added and mixture was stirred under reflux for another hour and then at room temperature for 3 days. The mixture was concentrated and residue was extracted with brine and AcOEt. Organic phases were dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (hexane/AcOEt 2:1→1:1) to give 4-[6-(6-bromo-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester as a solid (2.09 g, 44%). 1HNMR (CDCl3, 400 MHz) a 1.27-1.28 (d, 6H), 1.84-1.87 (m, 2H), 2.02-2.08 (m, 2H), 2.58 (s, 3H), 3.40-3.47 (m, 2H), 3.73 (s, 3H), 3.77-3.82 (m, 2H), 4.93-4.97 (m, 1H), 5.41-5.43 (m, 1H), 7.44-7.46 (m, 1H), 7.91-7.93 (m, 1H), 8.24 (s, 1H), 8.70 (s br, 1H). Exact mass calculated for C20H26BrN5O4 479.12. found 482.0 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:10][C:9]2=[O:23])=[CH:4][C:3]=1[NH:24][CH3:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:50][C@H:51]1[CH2:53][C@H:52]1[C:54](O)=O.C(N(CC)C(C)C)(C)C.[Cl-].[Cl-].[Ca+2]>CN(C=O)C>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][O:14][C:11]2[CH:12]=[CH:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]4[N:1]=[C:54]([CH:52]5[CH2:53][CH:51]5[F:50])[N:24]([CH3:25])[C:3]=4[CH:4]=3)[C:9](=[O:23])[CH:10]=2)=[CH:21][CH:20]=1
Reactant: CNc1cc(-n2ccc(OCc3ccc(Cl)cc3)cc2=O)ccc1N
Reactant: O=C(O)[C@@H]1C[C@@H]1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Ca+2]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1c(C2CC2F)nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc21
Temperature: 90 °C
Reaction time: 1 h
Yield: 15.8 %

Procedure:
A mixture of 1-(4-amino-3-(methylamino)phenyl)-4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (200 mg), HATU (224 mg), cis-2-fluoro-cyclopropanecarboxylic acid (100 mg), N,N-diisopropylethylamine (288 μl) and DMF (4 ml) was stirred at room temperature under a dry atmosphere (CaCl2 tube) for 1 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was dissolved in AcOH (4.0 ml) and stirred at 90° C. for 1 h. After AcOH was evaporated, the residue was purified by NH silica gel column chromatography (hexane/EtOAc). The resulting solid was recrystallized from EtOH to give the title compound (37.6 mg) as an off-white solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][C@H:9]3[NH:20][CH2:19][CH2:18][C@@:15]4([C:16]=2[CH:17]=1)[C@H:10]3[C@@H:11]([CH3:22])[CH2:12][C:13](=[O:21])[CH2:14]4.C([O-])(O)=O.[Na+].[CH:28]1([CH2:31]Br)[CH2:30][CH2:29]1.[NH4+].[OH-]>CN(C=O)C.O>[CH:28]1([CH2:31][N:20]2[CH2:19][CH2:18][C@@:15]34[C:16]5[CH:17]=[C:4]([O:3][CH3:2])[CH:5]=[CH:6][C:7]=5[CH2:8][C@@H:9]2[C@@H:10]3[C@@H:11]([CH3:22])[CH2:12][C:13](=[O:21])[CH2:14]4)[CH2:30][CH2:29]1
Reactant: BrCC1CC1
Reactant: COc1ccc2c(c1)[C@]13CCN[C@H](C2)[C@@H]1[C@@H](C)CC(=O)C3
Agent: Cl
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)[C@]13CCN(CC4CC4)[C@H](C2)[C@@H]1[C@@H](C)CC(=O)C3
Temperature: 100 °C
Yield: 72 %

Procedure:
To a suspension of 3-methoxy-8β-methylmorphinan-6-one hydrochloride (prepared in Part C) in DMF (1 g/10 ml) was added NaHCO3 (2.2 equivalents [eq]) and cyclopropylmethyl bromide (1.5 eq). The mixture was heated under an argon atmosphere at 100° C. for 16 hours, then cooled. The mixture was filtered and the filtrate was evaporated in high vacuum to yield a residue. The residue was dissolved in water, adjusted to about pH 11 with concentrated NH4OH and extracted with three portions of benzene. The organic phase was dried, filtered and evaporated to a residue. The residue was chromatographed over silica Gel G using 15:1 (V/V) chloroform:methanol as the eluant. Pure chromatographic fractions were combined and the product crystallized as the free base, mp 114°-115° C., in 72% yield.
Reaction SMILES: [Br:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].[CH3:14][Mg+].[Br-]>C1COCC1>[Br:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH:6]([OH:7])[CH3:14])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COc1cc(C=O)cc(OC)c1Br
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cc(C(C)O)cc(OC)c1Br
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
An oven-dried flask under argon was charged with 4-bromo-3,5-dimethoxybenzaldehyde (10.08 g, 41.1 mmol) and anhydrous THF (70 mL). The mixture was cooled over a −78° C. bath then a solution of MeMgBr (3.0 M in diethyl ether, 17.8 mL, 53.4 mmol) was added dropwise from an addition funnel over a period of 45 min. After stirring for 20 min, the mixture was allowed to warm to room temperature and stirred for 19 hours. After quenching with a solution of aqueous NH4Cl, it was diluted with H2O and EtOAc then cooled over an ice bath. After the mixture was cooled, the layers were separated. The organics were washed with H2O and brine then dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in dichloromethane and concentrated in vacuo again to give 1-(4-bromo-3,5-dimethoxyphenyl)ethanol as a white solid (10.8 g, quantitiative yield). The product was used without further purification.
Reaction SMILES: [CH3:1][Si:2]([CH3:5])([CH3:4])[OH:3]>C(OCC)C>[CH3:1][Si:2]([O:3][Si:2]([CH3:5])([CH3:4])[CH3:1])([CH3:5])[CH3:4]
Reactant: C[Si](C)(C)O
Solvent: CCOCC
Product: C[Si](C)(C)O[Si](C)(C)C

Procedure:
This reaction proceeds slowly without diethylether but reacts faster at reflux temperatures. Trimethylsilanol is condensed during the HMDS distillation step to give HMDSO, which reacts as shown above.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][NH:19][C@@H:18]([CH3:22])[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C@@H:18]([CH3:22])[CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: Clc1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(Cl)cc1
Temperature: 110 °C
Yield: 50.8 %

Procedure:
To a mixture of 4-chlorobromobenzene (1.05 g, 5.5 mmol) and 3-(S)-Methyl-piperazine-1-carboxylic acid tert-butyl ester (1 g, 5 mmol) in toluene (30 mL) was added tris(dibenzylideneacetone)dipalladium(0) (0.057 g, 0.063 mmol), BINAP (0.12 g, 0.19 mmol) and sodium-t-butoxide (2.02 g, 21 mmol). The resulting mixture was heated 110° C. for 20 h. The solvent was evaporated and the residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine and dried over magnesium sulfate. Column chromatography (10% ethyl acetate/hexane) provided 0.79 g (51%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:12]([NH:13][CH3:14])[CH2:11][N:10]([C:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:23]([C:25]4([CH3:28])[CH2:27][CH2:26]4)=[O:24])[CH2:19][CH2:18]3)=[O:16])[CH2:9]2)=[CH:4][CH:3]=1.Cl[C:30]([O:32][CH2:33][CH:34]([CH3:36])[CH3:35])=[O:31]>>[CH2:33]([O:32][C:30](=[O:31])[N:13]([C@H:12]1[C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:9][N:10]([C:15]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([C:25]3([CH3:28])[CH2:27][CH2:26]3)=[O:24])[CH2:19][CH2:18]2)=[O:16])[CH2:11]1)[CH3:14])[CH:34]([CH3:36])[CH3:35]
Reactant: CN[C@@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@H]1c1ccc(Cl)cc1
Reactant: CC(C)COC(=O)Cl
Product: CC(C)COC(=O)N(C)[C@@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 136, the title compound {(3S,4R)-4-(4-chloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid isobutyl ester was prepared from [(3R,4S)-3-(4-chloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone instead of 4-[(3R,4S)-3-(4-chloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carbonitrile using isobutyl chloroformate instead of ethyl chloroformate and was obtained as a colorless foam. MS m/e: 504.2 [M]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:11]=[C:10]([CH2:12][CH3:13])[N:9]([C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)[N:8]=2)[CH:2]=1.[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]1[C:31](O)=[O:32].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:12]([C:10]1[N:9]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:31]([C:23]3[N:22]([CH3:21])[C:30]4[C:25]([CH:24]=3)=[CH:26][CH:27]=[CH:28][CH:29]=4)=[O:32])=[CH:18][CH:19]=2)[N:8]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:11]=1)[CH3:13]
Reactant: CCc1cc(-c2cccnc2)nn1-c1ccc(N)cc1
Reactant: Cn1c(C(=O)O)cc2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(-c2cccnc2)nn1-c1ccc(NC(=O)c2cc3ccccc3n2C)cc1
Reaction time: 18 h

Procedure:
A DMF (2 mL) solution of 3-(3-pyridyl)-5-ethyl-1-(4′-aminophenyl)pyrazole (264 mg, 1 mmol), N-methylindole-2-carboxylic acid (192.5 mg, 1.1 mmol), PyBOP (570 mg, 1.1 mmol) and N,N-diisopropylethylamine (0.21 mL, 1.2 mmol) was stirred at room temperature. for 18 hr. The reaction mixture was poured into crushed ice, and extracted with methylene chloride (3×50 mL). The combined extracts were washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated. Chromatography of the residue over silica gel (4% methanol/methylene chloride) followed by preparative TLC (silica gel, developer 5% methanol/methylene chloride) gave the title compound as a light, cream colored solid, m.p. 178-179° C. 1H NMR (DMSO-d6) δ 1.2 (3H, t, J=7.5), 2.73 (2H, q, J=7.5 Hz), 4.05 (3H, s), 6.93 (1H, s), 7.16 (1H, t, J=7.5), 7.34 (1H, t, J=7.5), 7.37 (1H, s), 7.44-7.48 (1H, dd, J=3.1 & 4.7 Hz), 7.57-7.61 (3H, m), 7.74 (1H, d, J=7.9 Hz), 7.98 (2H, d, J=8.8 Hz), 8.2-8.22 (1H, m), 8.53-8.54 (1H, m), 9.07 (1H, d, J=1.8 Hz), 10.56 (1H, s).
Reaction SMILES: [K].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)#[N:3].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][Br:11])=[CH:6][CH:5]=1)#[N:3]
Reactant: N#Cc1ccc(O)cc1
Reactant: BrCCCCCBr
Agent: [K]
Product: N#Cc1ccc(OCCCCCBr)cc1

Procedure:
The intermediate 5-(4-cyanophenoxy)pentyl bromide was prepared from the potassium salt of 4-cyanophenol and 1,5-dibromopentane.
Reaction SMILES: [C:1]([C:4]1[CH:28]=[CH:27][C:7]([O:8][CH2:9][CH:10]([OH:26])[CH2:11][S:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22]C)=[O:21])=[C:15]([Cl:24])[C:14]=2[Cl:25])=[C:6]([CH2:29][CH2:30][CH3:31])[C:5]=1[OH:32])(=[O:3])[CH3:2].C(C1C=CC(OCCCSC2C=CC(CC(OC)=O)=C(Cl)C=2Cl)=C(CCC)C=1O)(=O)C>>[C:1]([C:4]1[CH:28]=[CH:27][C:7]([O:8][CH2:9][CH:10]([OH:26])[CH2:11][S:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[C:15]([Cl:24])[C:14]=2[Cl:25])=[C:6]([CH2:29][CH2:30][CH3:31])[C:5]=1[OH:32])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCC(O)CSc2ccc(CC(=O)OC)c(Cl)c2Cl)ccc(C(C)=O)c1O
Agent: CCCc1c(OCCCSc2ccc(CC(=O)OC)c(Cl)c2Cl)ccc(C(C)=O)c1O
Product: CCCc1c(OCC(O)CSc2ccc(CC(=O)O)c(Cl)c2Cl)ccc(C(C)=O)c1O

Procedure:
By following Step H of Example 1, but substituting the product of Step A of this example for the ester of Step G of Example 1, the title compound, mp 151°-153° C., was obtained.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([OH:19])(=O)[CH2:14][C:15]#[C:16][CH3:17].[NH2:20][C:21]1[CH2:27][N:26]=[C:25]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)[C:24]2[CH:35]=[C:36]([CH2:42][CH3:43])[C:37]([S:39][CH2:40][CH3:41])=[CH:38][C:23]=2[N:22]=1>O1CCCC1.CN(C)C=O>[CH2:40]([S:39][C:37]1[C:36]([CH2:42][CH3:43])=[CH:35][C:24]2[C:25]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)=[N:26][CH2:27][C:21]3[N:22]([C:15]([CH2:16][CH3:17])=[CH:14][C:13](=[O:19])[N:20]=3)[C:23]=2[CH:38]=1)[CH3:41]
Reactant: CCSc1cc2c(cc1CC)C(c1ccc(C)cc1)=NCC(N)=N2
Reactant: CC#CCC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCSc1cc2c(cc1CC)C(c1ccc(C)cc1)=NCc1nc(=O)cc(CC)n1-2

Procedure:
In the manner given in Example 16, carbonyldiimidazole, 3-pentynoic acid and 2-amino-8-ethylthio-7-ethyl-5-(p-methylphenyl)-3H-1,4-benzodiazepine were stirred in tetrahydrofuran-dimethylformamide to give 10-ethylthio 1,9-diethyl-7-(p-methylphenyl)pyrimido[1,2-a][1,4]benzodiazepin-3(5H)-one.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][CH:5]=1.CCN(CC)CC.[O:23]=[C:24]1[NH:33][C:32]2[N:31]=[C:30]([O:34][CH2:35][CH2:36][CH2:37][CH:38]=O)[CH:29]=[CH:28][C:27]=2[CH2:26][CH2:25]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.CCOC(C)=O>[CH3:3][C:4]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:38][CH2:37][CH2:36][CH2:35][O:34][C:30]3[N:31]=[C:32]4[C:27]([CH2:26][CH2:25][C:24](=[O:23])[NH:33]4)=[CH:28][CH:29]=3)[CH2:12][CH2:11]2)[CH:7]=[CH:6][CH:5]=1
Reactant: O=CCCCOc1ccc2c(n1)NC(=O)CC2
Reactant: Cc1cccc(N2CCNCC2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: Cc1cccc(N2CCN(CCCCOc3ccc4c(n3)NC(=O)CC4)CC2)n1
Reaction time: 0.5 h
Yield: 63.2 %

Procedure:
To a suspension of 1-(6-methyl-pyridin-2-yl)-piperazine bishydrochloride (0.77 g, 3.08 mmol) in dichloroethane (10 mL) was added Et3N (1.0 mL, 7.17 mmol) and the mixture was stirred for 30 min. 4-(7-Oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (0.85 g, 3.63 mmol) was added as a solution in dichloroethane (3 mL) and the mixture was stirred at room temperature for 15 min. NaBH(OAc)3 (1.1 g, 5.2 mmol) was added as a solid and the mixture was stirred at room temperature for 3 h. The reaction was poured into EtOAc and washed with saturated NaHCO3 and brine, dried over MgSO4 and concentrated. The residue was partitioned between EtOAc and pH 4.5 aqueous citric acid. The product went into the aqueous layer selectively over the impurities. The aqueous layer was neutralized with solid NaHCO3 to pH 8 and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and concentrated to give the title compound as a sticky foam (0.77 g). The foam was dissolved in Et2O and treated with anhydrous HCl gas to give a white precipitate. The mixture was filtered, washed with Et2O and hexanes, and dried to give a white solid (616 mg). MS: APCI: M+1: 396.1 (Exact Mass: 395.23).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([OH:12])=[N:7][CH:6]=[CH:5]2.Br[CH2:14][CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:14][CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[CH:6]=[CH:5]2
Reactant: CC(CBr)c1ccccc1
Reactant: Oc1nccc2cc(Br)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(Cn1ccc2cc(Br)ccc2c1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 73.1 %

Procedure:
6-Bromo-1-hydroxyisoquinoline (150 mg, 0.67 mmol, 1.0 equiv), tetrabutylammonium bromide (25 mg, 0.07 mmol, 0.1 equiv), and 1-bromo-2-phenylpropane (160 uL, 0.8 mmol, 1.2 equiv) were combined in toluene (10 mL) and treated with 50% aq. NaOH (2 mL), and the resulting mixture was stirred rapidly at ambient temperature for 48 hours, then heated at 60° C. for 24 h. The mixture was diluted with diethyl ether and washed with water and brine. The organic phase was dried over Na2SO4. Concentration and purification of the residue using silica gel flash chromatography (2-12% EtOAc/hex.) gave white crystals of 6-bromo-2-(2-phenylpropyl)-isoquinolin-1-one (169 mg, 0.49 mmol, 74%). This isoquinolinone (169 mg, 0.49 mmol) was converted, via Methods 1 and 2, to compound 5 (65 mg, 43%) which was isolated as white solid. [M−H]−=306.1 m/z. Activity: B