Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@H:11]3[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]3)=[N:9][N:10]=2)[CH:7]=1.C=O.[CH3:19]C(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@H:11]3[CH2:16][CH2:15][CH2:14][N:13]([CH3:19])[CH2:12]3)=[N:9][N:10]=2)[CH:7]=1
Reactant: Fc1ccc2nnc([C@H]3CCCNC3)n2c1
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CN1CCC[C@H](c2nnc3ccc(F)cn23)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a yellow solution of Intermediate 88c (220 mg, 1.00 mmol), formaldehyde (37% in water, 0.811 mL, 10.0 mmol) and AcOH (0.057 mL, 1.00 mmol) in DCM-MeOH (5:1, 12 mL) was added NaBH(OAc)3 (424 mg, 2.00 mmol) (CARE: gas evolution) and the solution stirred at RT for 2 h. The solution was concentrated in vacuo to ˜5 mL volume, then applied to an SCX-2 cartridge (10 g) and washed with MeOH (50 mL). The product was eluted with 2M NH3 in MeOH (50 mL); concentration in vacuo gave the title compound as a pale yellow gum, that became a white solid on standing (234 mg, quant.). LCMS (Method 3): Rt 0.45 min, m/z 235 [MH+].
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[F:35][C:36]([F:47])([F:46])[C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1>>[F:31][C:30]([F:32])([F:33])[C:27]1[CH:28]=[CH:29][C:24]([C:12]2[CH:11]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([OH:3])=[O:34])[CH:15]=[C:14]([C:40]3[CH:41]=[CH:42][C:37]([C:36]([F:47])([F:46])[F:35])=[CH:38][CH:39]=3)[CH:13]=2)=[CH:25][CH:26]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccc(C(F)(F)F)cc2)c1

Procedure:
The title compound was prepared from a Suzuki coupling of 4-Methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (intermediate Example 1g) with 4-trifluoromethyl-phenylboronic acid under the conditions described in Example 1; 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.93-1.02 (m, 6H), 1.59 (dt, J=13.39, 6.63 Hz, 1H), 1.79 (ddd, J=13.76, 7.34, 7.03 Hz, 1H), 2.08 (dt, J=13.69, 7.58 Hz, 1H), 3.84 (t, J=7.83 Hz, 1H), 7.26 (s, 2H), 7.58 (d, J=1.47 Hz, 2H), 7.68-7.75 (m, 7H).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].O.[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[CH2:20]([O:11][C:10](=[O:12])[C@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[N:1]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ClCc1ccccc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C(OCc1ccccc1)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 90 °C

Procedure:
A solution containing L-phenylalanine (161 kg, 975 moles), potassium carbonate (445 kg, 3220 moles), water (675 L), ethanol (340 L), and benzyl chloride (415 kg, 3275 moles) was heated to 90±15° C. for 10-24 hours. The reaction mixture was cooled to 60° C. and the lower aqueous layer was removed. Heptane (850 L) and water (385 L) were added to the organics, stirred, and the layers separated. The organics were then washed once with a water/methanol mixture (150 L/150 L). The organics were then stripped to give the desired product as an oil, which was carried on in the next step without purification.
Reaction SMILES: C[O:2][C:3](=[O:40])[C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:12][CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=3)[N:16]([CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:15]=2[CH2:37][CH2:38][NH2:39])[CH3:11])=[CH:6][CH:5]=1.[Cl:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([CH3:48])[C:43]=1[S:49](Cl)(=[O:51])=[O:50]>>[CH:24]([N:16]1[C:17]2[C:22](=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:14]([CH2:13][CH2:12][N:10]([CH3:11])[C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:2])=[O:40])=[CH:9][CH:8]=2)=[C:15]1[CH2:37][CH2:38][NH:39][S:49]([C:43]1[C:44]([CH3:48])=[CH:45][CH:46]=[CH:47][C:42]=1[Cl:41])(=[O:50])=[O:51])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Cc1cccc(Cl)c1S(=O)(=O)Cl
Reactant: COC(=O)c1ccc(N(C)CCc2c(CCN)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Product: Cc1cccc(Cl)c1S(=O)(=O)NCCc1c(CCN(C)c2ccc(C(=O)O)cc2)c2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Yield: 96 %

Procedure:
The intermediate from Example 147 step 7 was treated with 2-chloro-6-methyl-benzenesulfonyl chloride according to the procedure in Example 87 step 2 to generate the desired product in 96% yield.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([F:22])[CH:21]=1)[C:16](O)=O)#[N:12].N>>[F:22][C:20]1[CH:21]=[C:13]([CH:14]=[C:15]([C:16]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)[CH:19]=1)[C:11]#[N:12]
Reactant: N#Cc1cc(F)cc(C(=O)O)c1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: N#Cc1cc(F)cc(-c2nc(-c3cccnc3)no2)c1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 3-cyano-5-fluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.65 (ddd, J=8.0, 5.1, 0.8 Hz, 1H), 7.95 (ddd, J=8.1, 2.6, 1.6 Hz, 1H), 8.32 (ddd, J=8.7, 2.6, 1.4 Hz, 1H), 8.46 (t, J=1.4 Hz, 1H), 8.58 (ddd, J=8.1, 2.0, 1.8 Hz, 1H), 8.76 (dd, J=5.2, 1.6 Hz, 1H), 9.31 (dd, J=2.0, 0.8 Hz, 1H) ppm; MS (DCI/NH3) m/z 267 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH3:16])[CH3:2].Cl[CH2:22][C:23]1[N:24]=[C:25]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([CH3:36])[CH:30]=2)[O:26][C:27]=1[CH3:28]>>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:22][C:23]1[N:24]=[C:25]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[C:31]([CH3:36])[CH:30]=3)[O:26][C:27]=1[CH3:28])[CH:11]=[C:10]2[CH3:16])[CH3:2]
Reactant: Cc1cc(-c2nc(CCl)c(C)o2)ccc1F
Reactant: CCOC(=O)C(Cc1ccc2[nH]cc(C)c2c1)OCC
Product: CCOC(=O)C(Cc1ccc2c(c1)c(C)cn2Cc1nc(-c2ccc(F)c(C)c2)oc1C)OCC

Procedure:
In analogy to the procedures described in examples 36a) and 36b), rac-2-ethoxy-3-(3-methyl-1H-indol-5-yl)-propionic acid ethyl ester (preparation 4) was reacted with 4-chloromethyl-2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazole to give rac-2-ethoxy-3-{1-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethyl]-3-methyl-1H-indol-5-yl}-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][CH3:19])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)(=[O:23])=[O:22]>>[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([C:2]2[C:3]3[N:4]([N:8]=[C:9]([NH:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[O:18][CH3:19])[N:10]=3)[CH:5]=[CH:6][CH:7]=2)=[CH:26][CH:25]=1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: COc1ccccc1Nc1nc2c(Br)cccn2n1
Product: COc1ccccc1Nc1nc2c(-c3ccc(S(C)(=O)=O)cc3)cccn2n1

Procedure:
[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(2-methoxy-phenyl)-amine was prepared from (8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-(2-methoxy-phenyl)-amine (100.0 mg, 0.3133 mmol) and (4-methylsulfonylphenyl)boronic acid (75.0 mg, 0.375 mmol) in a manner analogous to Step 2c and was isolated as a pale yellow solid (0.097 g, 78%). MP=211-213° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.53-8.49 (m, 1H), 8.38 (dd, J=8.0, 1.3 Hz, 1H), 8.24 (d, J=8.4 Hz, 2H), 8.10 (d, J=8.5 Hz, 2H), 7.66-7.62 (m, 1H), 7.61 (s, 1H), 7.08-6.89 (m, 4H), 3.92 (s, 3H), 3.11 (s, 3H). MS=395 (MH)+.
Reaction SMILES: C([O:5][C:6](=[O:31])[C@@H:7]([N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:16]1=[O:30])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:22]([NH:21][C:17]1[C:16](=[O:30])[N:15]([C@@H:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([OH:31])=[O:5])[CH:20]=[CH:19][CH:18]=1)(=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)n1cccc(NC(=O)c2ccccc2)c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccn([C@@H](Cc2ccccc2)C(=O)O)c1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.8 %

Procedure:
A solution of (S)-2-(3-benzoylamino-2-oxo-2H-pyridin-1-yl)-3-phenyl-propionic acid tert-butyl ester (2.07 g, 4.95 mmol) in dichloromethane (25 mL) was cooled to 0° C. Trifluoroacetic acid (25 ml) was added and the resulting mixture allowed to warm to room temperature and stir for 5 hours. The mixture was then concentrated under reduced pressure and the residue re-dissolved in dichloromethane. This process was repeated several times in order to remove excess trifluoroacetic acid. The resulting solid was slurried in diethyl ether, filtered and washed with more diethyl ether. The solid was then dried to constant weight under vacuum. This gave the title product as a white solid (1.61 g, 90%); 1H NMR (400 MHz, CDCl3) δ 3.48 (1H, dd), 3.65 (1H, dd), 5.32 (1H, m), 6.35 (1H, t), 6.80 (1H, m), 7.08 (2H, d), 7.27-7.35 (3H, m), 7.56-7.65 (3H, m), 7.92 (2H, d), 8.65 (1H, d), 9.18 (1H, br s).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH:22]1[C:26]2=[N:27][CH:28]=[C:29]([NH2:31])[CH:30]=[C:25]2[CH:24]=[CH:23]1.[CH2:32]([N:34]([C:40]1[C:41]([F:50])=[C:42]([C:46]([F:49])=[CH:47][CH:48]=1)[C:43](O)=[O:44])[S:35](=[O:39])(=[O:38])[NH:36][CH3:37])[CH3:33]>CN(C=O)C.CCOC(C)=O>[CH2:32]([N:34]([C:40]1[C:41]([F:50])=[C:42]([C:46]([F:49])=[CH:47][CH:48]=1)[C:43]([NH:31][C:29]1[CH:30]=[C:25]2[CH:24]=[CH:23][NH:22][C:26]2=[N:27][CH:28]=1)=[O:44])[S:35](=[O:38])(=[O:39])[NH:36][CH3:37])[CH3:33]
Reactant: CCN(c1ccc(F)c(C(=O)O)c1F)S(=O)(=O)NC
Reactant: Nc1cnc2[nH]ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(c1ccc(F)c(C(=O)Nc2cnc3[nH]ccc3c2)c1F)S(=O)(=O)NC
Temperature: 25 °C
Reaction time: 16 h
Yield: 7.1 %

Procedure:
HOBt (0.011 g, 0.085 mmol), EDCI (0.036 g, 0.19 mmol), and 1H-pyrrolo[2,3-b]pyridin-5-amine (0.025 g, 0.19 mmol) was added to 3-(N-ethyl-N-methylsulfamoylamino)-2,6-difluorobenzoic acid (0.050 g, 0.17 mmol) in DMF (1 mL). The reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with EtOAc (6 mL) and washed with brine (3×5 mL). The organic layers were dried over sodium sulfate, decanted, and concentrated under reduced pressure. The residue was purified via silica gel chromatography eluting with 5% MeOH-DCM to afford 3-(N-ethyl-N-methylsulfamoylamino)-2,6-difluoro-N-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide (0.005 g, 0.012 mmol, 7.2% yield). m/z (APCI-neg) M−1=408.0.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]([C@H:14](C)[CH2:15][CH3:16])[CH2:6][CH:7](C(O)=O)C(O)=O)=[O:4].C([O-])(=[O:20])C.[Na+].C(OC(=O)C)(=O)C>>[CH3:1][O:2][C:3]([C@@H:5]1[C@H:6]([CH3:7])[CH2:16][C:15](=[O:20])[CH2:14]1)=[O:4]
Reactant: CC[C@@H](C)[C@H](CC(C(=O)O)C(=O)O)C(=O)OC
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COC(=O)[C@H]1CC(=O)C[C@H]1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.5 %

Procedure:
3.8 g of (3S, 4R)-3-methoxycarbonyl-4-methylhexane dicarboxylic acid and 1.1 g of sodium acetate were added to 18 ml of acetic anhydride, and the mixture was refluxed for one hour. The reaction mixture was cooled down to room temperature, and then allowed to stand for one hour at 5° C. The resulting precipitate was filtered off, and the filtrate was concentrated. To the residue was added ethyl acetate, and after the insoluble material was filtered off, the filtrate was concentrated. The residue was purified by distillation under a reduced pressure, and thus 2.23 g of the titled compound was obtained.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:7]=O)([OH:3])=[O:2].[CH3:13][C:14](=[O:19])[CH2:15][C:16](=[O:18])[CH3:17].Cl>O1CCCC1>[C:1]([C:4]1[CH:5]=[C:6]([CH:7]=[C:15]([C:14](=[O:19])[CH3:13])[C:16](=[O:18])[CH3:17])[CH:9]=[CH:10][C:11]=1[OH:12])([OH:3])=[O:2]
Reactant: CC(=O)CC(C)=O
Reactant: O=Cc1ccc(O)c(C(=O)O)c1
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)C(=Cc1ccc(O)c(C(=O)O)c1)C(C)=O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture containing 2 g 3-carboxy-4-hydroxybenzaldehyde, 4 ml 2,4-pentanedione and 20 ml tetrahydrofuran was saturated with hydrogen chloride gas. The solution was stirred for 2.0 h at 50° C. and evaporated to dryness in vacuo. The residue was crystallized from ethyl ether, mp. 112°-114° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]2[CH2:18][C@H:17]([OH:19])[C@H:16]([OH:20])[CH2:15]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][C:22]1(C)[C@]2(CS(O)(=O)=O)C(C[C@H:23]1CC2)=O.COC(OC)(C)C.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]2[CH2:15][C@H:16]3[O:20][C:22]([CH3:23])([CH3:21])[O:19][C@H:17]3[CH2:18]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O[C@@H]1CN(c2cccc(Cc3ccccc3)n2)C[C@@H]1O
Reactant: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)OC
Product: CC1(C)O[C@H]2CN(c3cccc(Cc4ccccc4)n3)C[C@H]2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 2.5 g of 2-benzyl-6-(cis-3,4-dihydroxypyrrolidine-1-yl)pyridine, 2.3 g of dl-10-camphorsulfonic acid, 20 ml of 2,2-dimethoxypropane and 5.0 ml of N,N-dimethylformamide was stirred at room temperature overnight. Aqueous saturated sodium bicarbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with water and brine, and the solvent was removed. Then, the residue was subjected to filtration through silica gel and eluted with ethyl acetate, to give 2.87 g of the target compound.
Reaction SMILES: Cl[CH:2]=[C:3]([Cl:7])[C:4](=[O:6])[CH3:5].[C:8]([SH:12])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C>C(OCC)C>[Cl:7][C:3]([C:4](=[O:6])[CH3:5])=[CH:2][S:12][C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(=O)C(Cl)=CCl
Reactant: CC(C)(C)S
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(=O)C(Cl)=CSC(C)(C)C
Temperature: 5 °C
Reaction time: 18 h
Yield: 60.7 %

Procedure:
To a mixture of 20.85 g (0.15 mole) 1,2-dichloro-1-buten-3-one and 13.53 g (0.15 mole) t-butylmercaptan in 300 ml ethyl ether, cooled to 5° C. is added dropwise 15.18 g (0.15 mole) triethylamine in 50 ml ether. After stirring at room temperature for 18 hours the mixture is heated at reflux for 2 days. The resulting mixture is washed with water, brine and the organic layer dried over magnesium sulfate. Evaporation of ether affords a brown oil which is distilled in vacuo to yield 17.56 g of product as a light yellow liquid, B.P. 75° (0.1 mm) which crystallized upon standing, M.P. 73° C. Mass spectrum (m/e) 192 (molecular ion), 138, 136.
Reaction SMILES: [OH-].[Na+].[C:3]1([C:9]2[CH:14]=[C:13]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:16])[CH:12]=[CH:11][C:10]=2[OH:23])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S([O-])(O)(=O)=O.[C:29]1([C:35]2[CH:40]=[CH:39][C:38]([N+:41]#[N:42])=[C:37]([N+:43]([O-:45])=[O:44])[CH:36]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1(C)C(C)=CC=CC=1>CO>[OH:23][C:10]1[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:14][C:13]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:16])[CH3:17])=[CH:12][C:11]=1[N:42]=[N:41][C:38]1[CH:39]=[CH:40][C:35]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:36][C:37]=1[N+:43]([O-:45])=[O:44]
Reactant: N#[N+]c1ccc(-c2ccccc2)cc1[N+](=O)[O-]
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)c(-c2ccccc2)c1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1C
Product: CC(C)(C)CC(C)(C)c1cc(N=Nc2ccc(-c3ccccc3)cc2[N+](=O)[O-])c(O)c(-c2ccccc2)c1
Reaction time: 2 h
Yield: 25.8 %

Procedure:
To a solution of sodium hydroxide (12 g, 0.3 mol) and 2-phenyl-4-tert-octylphenol (14.1 g, 0.05 mol) in 150 mL of methanol maintained at 0–5° C. is added portionwise over 1.25 hours 4-phenyl-2-nitrobenzenediazonium hydrogen sulfate (30.6 g, 0.065 mol), prepared in (C) above. The reaction mixture is stirred for two hours at 0–5° C. Xylene (200 mL) is added to the reaction mixture. The organic phase is separated and extracted with water (4×200 mL). The organic phase is filtered and the solvent removed by distillation under an atmosphere of nitrogen. The residue is purified by flash chromatography (90:10 heptane:ethyl acetate eluent) to give 6.56 g of the title compound as a viscous dark red liquid.
Reaction SMILES: [F:1][CH2:2][CH2:3][OH:4].[CH3:5][C:6]1([CH3:28])[C@@H:8](/[CH:9]=[CH:10]\[C:11](=O)[O:12]C(C)(C)C)[C@H:7]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>C(Cl)(Cl)Cl>[CH3:5][C:6]1([CH3:28])[C@@H:8](/[CH:9]=[CH:10]\[C:11](=[O:12])[O:4][CH2:3][CH2:2][F:1])[C@H:7]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]
Reactant: CC(C)(C)OC(=O)/C=C\[C@H]1[C@@H](C(=O)OCc2ccccc2)C1(C)C
Reactant: OCCF
Solvent: ClC(Cl)Cl
Product: CC1(C)[C@H](C(=O)OCc2ccccc2)[C@@H]1/C=C\C(=O)OCCF

Procedure:
Using the procedure of Example 48, 2-fluoro-ethanol and the product of Step A were reacted to obtain benzyl (1R,cis,Z) 2,2-dimethyl-3-[3-oxo-3-(2-fluoroethoxy)-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+53° (c=0.5% in chloroform).
Reaction SMILES: Cl.[F:2][C:3]([F:18])([F:17])[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=2)=[CH:7][CH:6]=1.Br[CH2:20][CH2:21][O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1>>[O:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH:23]1[O:22][CH2:21][CH2:20][N:14]1[CH2:13][CH:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][C:3]([F:2])([F:17])[F:18])=[CH:6][CH:7]=2)[CH2:16][CH2:15]1
Reactant: FC(F)(F)Oc1ccc(C2=CCNCC2)cc1
Reactant: BrCCOC1CCCCO1
Agent: Cl
Product: FC(F)(F)Oc1ccc(C2=CCN(CCOC3CCCCO3)CC2)cc1
Yield: 47.1 %

Procedure:
Using 4-(4-trifluoromethoxyphenyl)-1,2,3,6-tetrahydropyridine monohydrochloride (680 mg, 2.43 mmol) and 2-(2-bromoethoxy)tetrahydropyran (610 mg, 2.92 mmol), 1-[2-(tetrahydropyran-2-yloxy)ethyl]-4-(4-trifluoromethoxyphenyl)-1,2,3,6-tetrahydropyridine (425 mg, yield 47%) as a pale brown oil was prepared in the same manner as described in Reference Example 15.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([O:11][CH3:12])[CH:5]=1)=[O:3].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]([O:11][CH3:12])[CH:5]=1)=[O:3]
Reactant: COc1cc(C(C)=O)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(C)=O)ccc1OCc1ccccc1
Yield: 98.5 %

Procedure:
The starting material, 4-benzyloxy-3-methoxyacetophenone, was obtained by heating a solution of 4-hydroxy-3-methoxyacetophenone (20 g, 0.12 mol), benzyl bromide (15.7 ml, 0.13 mol) and potassium carbonate (49.8 g, 0.36 mol) in DMF (400 ml) at 40° C. overnight. After cooling, the mixture was diluted with water, acidified to approximately pH3 and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and the solvent evaporated. The residue was purified by flash chromatography using petroleum ether/ethyl acetate (8/2 followed by 65/35) as eluent to give 4-benzyloxy-3-methoxyacetophenone (30.3 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:11](I)=[CH:10][N:9]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[CH2:24]([N:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][CH2:34][C:35]#[CH:36])[CH2:28][CH2:27]1)[CH3:25]>>[Cl:1][C:2]1[C:3]2[C:11]([C:36]#[C:35][CH2:34][CH2:33][CH2:32][N:29]3[CH2:28][CH2:27][N:26]([CH2:24][CH3:25])[CH2:31][CH2:30]3)=[CH:10][N:9]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: C#CCCCN1CCN(CC)CC1
Reactant: COc1c(C)cnc(Cn2cc(I)c3c(Cl)nc(N)nc32)c1C
Product: CCN1CCN(CCCC#Cc2cn(Cc3ncc(C)c(OC)c3C)c3nc(N)nc(Cl)c23)CC1

Procedure:
Sonogashira coupling of 4-chloro-5-iodo-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo [2,3-d]pyrimidin-2-amine with 1-ethyl-4-(pent-4-ynyl)piperazine, according to the general procedure A gave the title compound, as a solid. Mp=142.3-144.1° C. HPLC Rt=4.11 min.
Reaction SMILES: P(Br)(Br)[Br:2].[O:5]1[CH2:10][CH:9]=[C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](=[O:21])[O:13][C:12]=2[CH:22](O)[CH3:23])[CH2:7][CH2:6]1>C(Cl)Cl>[Br:2][CH:22]([C:12]1[O:13][C:14](=[O:21])[C:15]2[C:20]([C:11]=1[C:8]1[CH2:7][CH2:6][O:5][CH2:10][CH:9]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:23]
Reactant: BrP(Br)Br
Reactant: CC(O)c1oc(=O)c2ccccc2c1C1=CCOCC1
Solvent: ClCCl
Product: CC(Br)c1oc(=O)c2ccccc2c1C1=CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.7 %

Procedure:
1 M PBr3 in DCM (1.43 mL, 1.43 mmol) was added to 4-(3,6-dihydro-2H-pyran-4-yl)-3-(1-hydroxyethyl)-1H-isochromen-1-one (intermediate B18, 130 mg, 0.477 mmol) in DCM (2 mL) and stirred for 2 hrs at RT, then the reaction mixture was adsorbed on silica pad and straightforward purified on Biotage silica cartridge eluting with a gradient of hexane and AcOEt to give the title compound (94 mg, 58.7%) as an off white solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([NH:12][CH2:13][CH2:14]O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CCOCC>C(Cl)(Cl)Cl>[CH2:5]([NH:12][CH2:13][CH2:14][Cl:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OCCNCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: ClCCNCc1ccccc1

Procedure:
100 ml. of thionyl chloride are added to a stirred solution of 100 g. of 2-benzylaminoethanol in 500 ml. of chloroform over a period of 20 minutes. The mixture is refluxed for 6 hours. 1350 ml. of ether is added to the cooled chloroform solution and the mixture is stored in the refrigerator overnight. The product, N-benzyl-2-chlorethylamine hydrochloride, is filtered off and crystallized from ethanol-ether; yield 130.9 g., m.p. 192°-194°.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([O:24]C(=O)C)=[C:8]2[C:16]([Br:17])=[CH:15][N:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=O)C.[NH2:28][CH2:29][C:30]([OH:32])=[O:31].C[O-].[Na+].CO>>[Br:17][C:16]1[C:8]2[C:9](=[C:10]([C:12]#[N:13])[N:11]=[C:6]([C:4]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:3])[C:7]=2[OH:24])[N:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:15]=1
Reactant: CCOC(=O)c1nc(C#N)c2c(c(Br)cn2-c2ccccc2)c1OC(C)=O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2c(Br)cn(-c3ccccc3)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 4-acetoxy-3-bromo-7-cyano-1-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 428 (M+H)+.