Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]([C:19]1[CH:23]=[C:22]([NH2:24])[N:21]([C:25]2[CH:34]=[CH:33][CH:32]=[C:31]3[C:26]=2[CH:27]=[CH:28][CH:29]=[N:30]3)[N:20]=1)([F:18])[CH3:17].[OH-].[Li+].[OH-].[Na+].Cl>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:24][C:22]2[N:21]([C:25]3[CH:34]=[CH:33][CH:32]=[C:31]4[C:26]=3[CH:27]=[CH:28][CH:29]=[N:30]4)[N:20]=[C:19]([C:16]([F:18])([F:15])[CH3:17])[CH:23]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(F)(F)c1cc(N)n(-c2cccc3ncccc23)n1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: [Li+]
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(C(C)(F)F)nn2-c2cccc3ncccc23)cc1
Temperature: 85 °C
Yield: 53.1 %

Procedure:
A mixture of 4-t-butylbenzene-1-sulfonyl chloride (0.080 g, 0.34 mmol), 3-(1,1-difluoroethyl)-1-(quinolin-5-yl)-1H-pyrazol-5-amine (0.045 g, 0.16 mmol), and DMAP (0.020 g, 0.16 mmol) in pyridine (1 mL) was heated at 85° C. for 5 h with stirring. After cooling to room temperature, 1 M aqueous lithium hydroxide (1 mL) and 1 M aqueous sodium hydroxide (1 mL) were added to the reaction mixture. The resulting mixture was heated at 75° C. for 1.5 h. After cooling to room temperature, the reaction mixture was neutralized with 1 N aqueous hydrochloric acid. The aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with aqueous saturated sodium bicarbonate, dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by reverse phase HPLC(C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.040 g, 0.085 mmol, 53%). 1H NMR (400 MHz, CD3OD) δ 10.70 (s, 1H), 8.88 (dd, J=1.6, 4.4 Hz, 1H), 8.14 (dd, J=1.2, 8.4 Hz, 1H), 7.77 (dd, J=7.2, 8.8 Hz, 1H), 7.64-7.61 (m, 2H), 7.52-7.42 (m, 5H), 7.31 (dd, J=1.2, 7.2 Hz, 1H), 1.96 (t, J=15.4 Hz, 3H), 1.35 (s, 9H); MS: (ES) m/z calculated for C24H25F2N4O2S [M+H]+ 471.2. found 471.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[C@H:7]([NH:14][CH2:15][CH2:16][CH2:17][C:18](O)=[O:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C>N1C=CC=CC=1.CN(C)C=O.CCOC(C)=O>[O:19]=[C:18]1[CH2:17][CH2:16][CH2:15][N:14]1[C@H:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:21]
Reactant: CC(C)(C)OC(=O)[C@H](NCCCC(=O)O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@@H](c1ccccc1)N1CCCC1=O
Yield: 86.1 %

Procedure:
The product of example 128B (307 mg, 1.05 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (602 mg, 3.14 mmol) in pyridine (5 mL) and dimethylformamide (5 mL) was stirred at ambient temperature for 16 hours. The mixture was diluted with EtOAc and washed with H2O and brine. The organic was dried (MgSO4), filtered and concentrated. Purification by chromatography (silica gel, 60% EtOAc in Hexanes) afforded 249 mg (86%) of the title compound. MS (ESI) m/z 276 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:13]1[CH:17]=[C:16]([CH2:18][N:19]2[C:23](=[O:24])[N:22]([CH2:25][C@H:26]([OH:31])[C:27]([F:30])([F:29])[F:28])[C:21]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)=[N:20]2)[N:15]=[N:14]1)[C:9](OC)=[O:10].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1COCC1>[Cl:38][C:35]1[CH:34]=[CH:33][C:32]([C:21]2[N:22]([CH2:25][C@H:26]([OH:31])[C:27]([F:28])([F:29])[F:30])[C:23](=[O:24])[N:19]([CH2:18][C:16]3[N:15]=[N:14][N:13]([CH:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[CH2:9][OH:10])[CH:17]=3)[N:20]=2)=[CH:37][CH:36]=1
Reactant: COC(=O)C(c1ccccc1Cl)n1cc(Cn2nc(-c3ccc(Cl)cc3)n(C[C@H](O)C(F)(F)F)c2=O)nn1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: O=c1n(Cc2cn(C(CO)c3ccccc3Cl)nn2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
48 mg (0.084 mmol) of the compound from Example 103 were dissolved in 2 ml of THF, and 88 μl (0.088 mmol) of a 1 M solution of lithium aluminum hydride in THF were added at −10° C. After the addition had ended, the mixture was stirred at RT for 1 h. For work-up, 2 ml of saturated aqueous sodium potassium tartrate solution were added at RT, and the mixture was extracted with 5 ml of ethyl acetate. The organic phase was washed once with 5 ml of saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified chromatographically [Method 19]. This gave 8 mg (18% of theory) of the target compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:14]([F:27])[CH:13]=1)=[O:11].[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([Sn](C)(C)C)[CH2:34][CH2:33]2>>[F:27][C:14]1[CH:13]=[C:12]([C:10]([C:3]2[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=2[C:35]2[CH2:34][CH2:33][C:32]3[C:37](=[CH:38][CH:39]=[C:30]([O:29][CH3:28])[CH:31]=3)[CH:36]=2)=[O:11])[CH:17]=[CH:16][C:15]=1[O:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COc1ccc2c(c1)CCC([Sn](C)(C)C)=C2
Reactant: COc1ccc(C(=O)c2ccc(OCCN3CCCCC3)c(F)c2)c(Br)c1
Product: COc1ccc2c(c1)CCC(c1cc(OC)ccc1C(=O)c1ccc(OCCN3CCCCC3)c(F)c1)=C2
Yield: 59.4 %

Procedure:
Synthesized from (2-bromo-4-methoxyphenyl)[3-fluoro-4-(2-piperidin-1-ylethoxy)phenyl]methanone (420 mg) and (6-methoxy-3,4-dihydronaphthalen-2-yl)trimethyltin (352 mg) according to an analogous synthetic method to Example 1, the title compound (295 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]3[C:13](=[C:14]([C:15]4[CH:20]=[CH:19][C:18]([O:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:17][CH:16]=4)[C:4]=2[C:3]=1[CH3:26])[CH:12]=[CH:11][CH:10]=[CH:9]3.S(=O)(=O)(O)O.II.[I:34](O)(=O)=O.S(=O)(O)[O-].[Na+]>O1CCCC1.C(O)(=O)C>[I:34][C:7]1[C:5]2[S:6][C:2]([CH3:1])=[C:3]([CH3:26])[C:4]=2[C:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:17][CH:16]=2)=[C:13]2[C:8]=1[CH:9]=[CH:10][CH:11]=[CH:12]2
Reactant: [O-][I+2]([O-])O
Reactant: Cc1sc2cc3ccccc3c(-c3ccc(OS(C)(=O)=O)cc3)c2c1C
Agent: II
Agent: O=S(=O)(O)O
Agent: O=S([O-])O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1sc2c(I)c3ccccc3c(-c3ccc(OS(C)(=O)=O)cc3)c2c1C
Temperature: 25 °C
Reaction time: 288 h
Yield: 69.9 %

Procedure:
To a solution of methanesulfonic acid 4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenyl ester (3.00 g, 7.84 mmol), in tetrahydrofuran (31.5 mL), 80% aqueous acetic acid (16 mL) and concentrated sulfuric acid (0.87 mL) was added iodine (1.59 g, 6.27 mmol, 0.8 eq) and iodic acid (0.414 g, 2.35 mmol, 0.9 eq) at room temperature. The mixture was stirred at room temperature for 12 days. The reaction mixture was poured into a dilute aqueous solution of sodium bisulfite (200 mL) and the organics were extracted with ether (2×200 mL). The extracts were combined and silica gel was added. The solvents were removed and the adsorbate was flash chromatographed (90/10 petroleum ether/ethyl acetate) without achieving purification. The recovered material was purified by high pressure liquid chromatography which gave recovered starting material (30.5%) and gave the title compound as a white solid (0.835 g, 30%): mp 212-213° C.; NMR (DMSO-d6); δ8.09 (d, J=8 Hz, 1H), 7.64-7.58 (m, 1H), 7.54-7.42 (m, 5H), 7.43 (d, J=8 Hz, 1H), 3.47 (s, 3H, SO3CH3), 2.42 (s, 3H), 1.50 (s, 3); MS(EI): [M+] 508 (100%); Anal. calc. for C21H17IO3S2, C, 49.61; H, 3.37; N, 0.00. Found: C, 49.44; H, 3.52; N, 0.03.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[CH3:10].[CH2:11]([NH2:16])[CH2:12][CH:13]([CH3:15])[CH3:14].[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:16][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:4][C:3]=1[CH3:10]
Reactant: CC(C)CCN
Reactant: Cc1cc(C=O)ccc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(CNCCC(C)C)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
4-bromo-3-methyl-benzaldehyde (2a: 10.20 g, 51.2 mmol) was dissolved in methanol (150 ml) before adding isoamyl amine (6.75 g, 77 mmol). After stirring overnight at room temperature, sodium borohydride (5.9 g, 154 mmol) was added. After stirring for 1 hour at room temperature, the reaction was quenched using concentrated (37%) hydrochloric acid and the volatiles were removed with a rotary evaporator under reduced pressure. The resulting residue was made basic with a 2 N aqueous sodium hydroxide solution and extracted twice with ethyl acetate. The combined organics were washed with a saturated aqueous sodium bicarbonate solution and dried over sodium sulfate, filtered and concentrated under reduced pressure to provide 13.7 g of the title compound (I-2b).
Reaction SMILES: [CH:1](=[C:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)/C=C\C(OCC)=O>[C].[Pd].C1(C)C=CC=CC=1>[CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCCC1=Cc1ccccc1
Agent: [Pd]
Agent: CCOC(=O)/C=C\C(=O)OCC
Solvent: Cc1ccccc1
Product: Oc1ccccc1Cc1ccccc1
Temperature: 185 °C
Reaction time: 3 h
Yield: 58.1 %

Procedure:
In a 100-ml, four-necked flask equipped with a magnetic stirrer, a reflux condenser and a thermometer were placed 18.6 g (0.1 mole) of the 2-benzylidenecyclohexanone produced in Example 1 and 51.7 g (0.3 mole) of diethyl maleate in this order. The flask inside was purged with nitrogen. Thereto was added 1.9 g (10 wt. %, 0.89 mmole as palladium) of 5% palladium carbon (a product of Wako Pure Chemical Industries, Ltd.). The system was made vacuum using an aspirator and then returned to ordinary pressure using nitrogen; this operation was repeated three times. Then, the system was stirred at 185° C. for 3 hours and cooled to room temperature. 100 ml of toluene was added to the system. Filtration was conducted to remove the palladium carbon. The filtrate was extracted with 100 ml of a 10% aqueous sodium hydroxide solution, and this operation was repeated four times. The aqueous layer was washed with 30 ml of toluene. To the resulting aqueous layer was added 35% hydrochloric acid until the aqueous layer became acidic, after which the aqueous layer was extracted with 100 ml of toluene. The toluene layer was washed with water and a saturated aqueous sodium chloride solution in this order. The toluene layer was dried over anhydrous sodium sulfate and then subjected to vacuum distillation to remove toluene, to obtain 10.7 g of an oil. This oil was subjected to Kugel Rohr distillation to obtain 9.0 of a colorless oil. Yield: 49% The purity of the intended product in the oil was >99.9% as measured by gas chromatography.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]Br)=[CH:20][CH:19]=2)=[O:17])[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:31]3[CH2:32][CH2:33][CH:28]([OH:27])[CH2:29][CH2:30]3)=[CH:20][CH:19]=2)=[O:17])[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CBr)cc1
Reactant: OC1CCNCC1
Solvent: CN(C)C=O
Product: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CN2CCC(O)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 400 mg (0.97 mmol) 4-benzyloxy-1-[2-(4-bromomethyl-phenyl)-2-oxo-ethyl]-1H-pyridin-2-one (preparation 15c) in 5.0 mL of DMF is added 393 mg (3.88 mmol) 4-hydroxypiperidine. The reaction mixture is stirred 1 h at RT and is directly purified by HPLC (Waters Symmetry, C18; water (0.1% formic acid)/acetonitrile (0.1% formic acid) 95:5 to 0:100).
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[OH2:7].[C:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C:15](=[CH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][CH3:27])=[CH:22][CH:21]=1)[C:14]([CH3:28])=[C:13]2[CH2:29][C:30]([OH:32])=[O:31])#[N:9].CO>CC(C)=O>[C:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C:15](=[CH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:27])=[O:7])=[CH:22][CH:21]=1)[C:14]([CH3:28])=[C:13]2[CH2:29][C:30]([OH:32])=[O:31])#[N:9]
Reactant: O
Reactant: CSc1ccc(C=C2C(C)=C(CC(=O)O)c3cc(C#N)ccc32)cc1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(C)=O
Solvent: CO
Product: CC1=C(CC(=O)O)c2cc(C#N)ccc2C1=Cc1ccc(S(C)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of sodium periodate (0.214 g.) (0.001 mole) in 3 ml. of water is added dropwise to 5-cyano-2-methyl-1-(p-methylthiobenzylidene)-3-indenylacetic acid (0.001 mole) in 25 ml. methanol and enough acetone to cause solution. This solution is stirred overnight at room temperature and filtered. The filtrate is evaporated at 30° to a small volume which causes the product to precipitate. The suspension is diluted with several volumes of water, cooled and collected. The product is dried in vacuo over potassium hydroxide pellets and then in a vacuum oven at 70° to give 5-cyano-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indenylacetic acid, m.p. 160°-155° in from ethyl acetate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:24]=[C:23]([C:25](=[O:30])[NH:26][CH2:27][CH2:28][OH:29])[CH:22]=[CH:21][C:20]=4[Cl:31])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:32]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>N1C=CC=CC=1>[C:33]([O:29][CH2:28][CH2:27][NH:26][C:25](=[O:30])[C:23]1[CH:22]=[CH:21][C:20]([Cl:31])=[C:19]([N:17]([CH3:18])[C:15]([C:13]2[S:12][C:11]3[C:5]4[CH:4]=[CH:3][C:2]([Br:1])=[CH:32][C:6]=4[O:7][CH2:8][CH2:9][C:10]=3[CH:14]=2)=[O:16])[CH:24]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1cc(C(=O)NCCO)ccc1Cl
Solvent: c1ccncc1
Product: CC(=O)OCCNC(=O)c1ccc(Cl)c(N(C)C(=O)c2cc3c(s2)-c2ccc(Br)cc2OCC3)c1
Temperature: 0 °C
Yield: 83.5 %

Procedure:
8-Bromo-N-(2-chloro-5-(2-hydroxyethylcarbamoyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (0.5 g, 0.933 mmol) was dissolved in 5 mL of pyridine. The mixture was stirred at 0° C. and acetic anhydride (0.2 g, 2 eq) was added dropwise. It was stirred at room temperature for overnight. The mixture was poured into ice water and the mixture was extracted by DCM. The combined organics were dried and evaporated in vacuum to afford the acetylated product, 2-(3-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-4-chlorobenzamido)ethyl acetate (0.45 g, yield: 83%). LC-MS: (ESI, m/z)=577 [M+H]+
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Cl:11][S:12](O)(=[O:14])=[O:13].S(=O)(=O)(O)N.S(Cl)(Cl)=O>>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:12]([Cl:11])(=[O:14])=[O:13])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=S(=O)(O)Cl
Reactant: CC(=O)Nc1ccccc1
Agent: NS(=O)(=O)O
Solvent: O=S(Cl)Cl
Product: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
135.2 g (1.0 mol) of acetanilide are added in portions to 349.5 g (3.0 mol) of chlorosulfonic acid and 2 g of sulfamic acid such that the temperature remains at 40° C. The mixture is then heated to 60° C. and stirred at this temperature for 60 minutes, then 142.8 g (1.2 mol) of thionyl chloride are added dropwise over the course of 2 hours and the mixture is stirred until evolution of gas has ended. For working up, the mixture is dripped into ice water, and the precipitated crystals are filtered off with suction and washed with water. 394.9 g of 4-acetamidobenzenesulfonyl chloride (water content: 41.7%; chloride content: 58.1%), corresponding to 230.2 g (98.5%) calculated as dry material, having a melting point of 139° C. are obtained.
Reaction SMILES: [C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].ClC(OCC(C)C)=O.CN1CCOCC1.[CH3:34][CH2:35][C@H:36]([NH2:39])[CH2:37][OH:38]>>[C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([NH:39][C@H:36]([CH2:37][OH:38])[CH2:35][CH3:34])=[O:15])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CC[C@H](N)CO
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Product: CC[C@@H](CO)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1

Procedure:
This compound was prepared from 4.99 g (20 mmol) N-carbobenzoxy-L-proline, 2.73 g (20 mmol) isobutyl chloroformate, 2.02 g (20 mmol) N-methylmorpholine, and 1.78 g (20 mmol) d-(+)2-amino-1-butanol, substantially according to the mixed anhydride procedure described in Example 1. Crude product (5.16 g) was recrystallized from a mixture of 60 mL ethyl acetate and 15 mL n-hexane to give 4.18 g (13 mmol, 65%) of colorless, crystalline N-carbobenzoxy-L-prolyl-L-homoalaninol; m.p. 105.4°-106.3°, α25D-69.7 (C=1.04 g/100 mL in acetone). A stereochemical assignment for this product was based upon observed similarity of specific rotation to specific rotations measured for L-L isomers of carbobenzoxy-prolyl-leucinol (Example 1), carbobenzoxy-prolyl-valinol (Example 2) and carbobenzoxy-prolyl-alaninol (Example 5).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[C:22]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][N+:35]([O-])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23].CCN(CC)CC>C(Cl)Cl.[Cl-].[Na+].O>[C:22]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([Br:20])[CH:33]=2)=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: BrBr
Reactant: CC(C)(C)c1ccc(-c2cc[n+]([O-])cc2)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1ccc(-c2ccnc(Br)c2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To triphenylphosphine (Aldrich) (2.4 g, 9.1 mmol) dissolved in 10 mL of CH2Cl2 in a 50-mL round-bottomed flask was added bromine (Aldrich) (0.43 mL, 8.5 mmol). After stirring at 0° C. for 10 min, 4-[4-(tert-butyl)phenyl]pyridine 1-oxide (1.5 g, 6.5 mmol) was added dropwise, followed by Et3N (1.2 mL, 8.5 mmol). The reaction mixture was stirred at 0° C. for 1 h and then at room temperature overnight. Methylene chloride and brine were added, and the aqueous layer was extracted with CH2Cl2. The organic layer was collected and dried over Na2SO4, filtered and concentrated in vacuo. Following purification by silica gel chromatography (10:1 hexane:EtOAc), the title compound was obtained as a pale yellow oil. MS (ESI, pos. ion) m/z: 293 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[N:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:30])[CH2:16][N:17]3[CH2:22][CH2:21][NH:20][CH:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:18]3=[O:29])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C=O.[C:40]([BH3-])#N.[Na+]>CO.C(O)(=O)C.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[N:9]2[CH2:10][CH2:11][N:12]([C:15](=[O:30])[CH2:16][N:17]3[CH2:22][CH2:21][N:20]([CH3:40])[CH:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:18]3=[O:29])[CH2:13][CH2:14]2)=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: O=C(CN1CCNC(c2ccccc2)C1=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN1CCN(CC(=O)N2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)C(=O)C1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(2-{4-[bis(4-fluorophenyl)methyl]piperazin-1-yl}-2-oxoethyl)-3-phenylpiperazin-2-one (Example 103B, 0.1 g, 0.2 mmol) in methanol was added 30% aqueous formaldehyde solution (0.06 mL, 0.3 mmol) and sodium cyanoborohydride (0.02 g, 0.3 mmol). A few drops of acetic acid were added, and the reaction was stirred at ambient temperature overnight. The reaction mixture was diluted with methylene chloride and washed with aqueous bicarbonate solution. The organic layer was separated, dried over MgSO4, evaporated and chromatographed, eluting with 5% methanol/methylene chloride to yield the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.37-7.42 (m, 2H), 7.26-7.35 (m, 7H), 6.94-7.01 (m, 4H), 4.22 (d, J=15.3 Hz, 1H), 4.21 (s, 1H), 4.09 (d, J=15.5 Hz, 1H), 3.79 (s, 1H), 3.73-3.83 (m, 1H), 3.60 (t, J=4.7 Hz, 2H), 3.34-3.43 (m, 3H), 3.03 (ddd, J=12.0, 4.2, 2.9 Hz, 1H), 2.78 (ddd, J=12.0, 10.7, 3.9 Hz, 1H), 2.29-2.37 (m, 4H), 2.20 (s, 3H); MS (ESI+) m/z 519 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([CH2:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[C:38]([CH2:43][OH:44])[CH:37]=1)[CH2:3][NH:4][CH:5]([CH3:33])[CH2:6][C:7]1[CH:32]=[CH:31][C:10]([O:11][CH2:12][P:13]([CH2:20][CH2:21][CH2:22][O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:19])[O:14]CCCC)=[CH:9][CH:8]=1.[ClH:45]>>[ClH:45].[OH:1][CH:2]([CH2:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[C:38]([CH2:43][OH:44])[CH:37]=1)[CH2:3][NH:4][CH:5]([CH3:33])[CH2:6][C:7]1[CH:32]=[CH:31][C:10]([O:11][CH2:12][P:13]([CH2:20][CH2:21][CH2:22][O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:14])[OH:19])=[CH:9][CH:8]=1
Reactant: CCCCOP(=O)(CCCOCc1ccccc1)COc1ccc(CC(C)NCC(O)COc2ccc(O)c(CO)c2)cc1
Agent: Cl
Product: CC(Cc1ccc(OCP(=O)(O)CCCOCc2ccccc2)cc1)NCC(O)COc1ccc(O)c(CO)c1

Procedure:
The title compound was prepared from (SR)-4-{2-[2-hydroxy-3-(4-hydroxy-3-hydroxymethylphenoxy)propylamino]propyl}phenoxymethyl(3-benzyloxypropyl)phosphinic acid, n-butyl ester according to a modification of the procedure described in Example 5. Acidification to pH 3.5 with 1M hydrochloric acid followed by C18 reverse phase chromatography, eluting with water-methanol (30%) and freeze drying of the resultant foam gave the title compound as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]([C:18](=O)[CH:19]([CH3:21])[CH3:20])=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)=[CH:5][CH:4]=1.Cl.[NH2:24][OH:25].[OH-].[Na+].Cl>CCO.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]([C:18](=[N:24][OH:25])[CH:19]([CH3:21])[CH3:20])=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)=[CH:5][CH:4]=1
Reactant: NO
Reactant: COc1ccc(-c2nn3ccccc3c2C(=O)C(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2nn3ccccc3c2C(=NO)C(C)C)cc1
Temperature: 0 °C
Yield: 50.5 %

Procedure:
To a solution of 4.4 (14.9 mmol) of 1-(2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one in 32 ml of anhydrous EtOH was added 4.15 g of hydroxylamine hydrochloride, followed by a solution of 13.73 g (14.9 mmol) of NaOH in 10 ml water dropwise. The mixture was stirred and refluxed over night. After cooling, the solution was poured into a solution of 6 ml 6N HCl and 100 ml ice water with stirring for 30 minutes. The mixture was extracted with ethyl acetate three times. The organic phase was washed with brine and dried over MgSO4. After evaporation of the solvent under vacuum, 5 g of crude product was obtained. Purification on an aluminum oxide column with hexane-dichloromethane-ethyl acetate as eluant afforded 2.33 g (50.5%) of 1-(2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one oxime. Compound 1022.