Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:14]=[CH:15]/[CH2:16][C@@H:17]([C:26]([NH:28][C@H:29]([C:34]([NH:36][C@@H:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:38])=[O:35])[C:30]([CH3:33])([CH3:32])[CH3:31])=[O:27])[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1(C)C=CC=CC=1.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:14][CH2:15][CH2:16][C@@H:17]([C:26]([NH:28][C@H:29]([C:34]([NH:36][C@@H:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:38])=[O:35])[C:30]([CH3:31])([CH3:32])[CH3:33])=[O:27])[CH2:18][C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C[C@@H](NC(=O)[C@@H](NC(=O)[C@H](C/C=C/c1ccc(-c2ccccc2)c(Cl)c1)CC(=O)OC(C)(C)C)C(C)(C)C)c1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CCCc1ccc(-c2ccccc2)c(Cl)c1)CC(=O)OC(C)(C)C)C(C)(C)C)c1ccccc1
Yield: 74.5 %

Procedure:
A mixture of tert-butyl (3R,5E)-6-[3-chloro-(4-phenyl)phenyl]-3-({[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)hex-5-enoate (936 mg, 1.52 mmol) and p-toluenesulphonyl hydrazide (1.41 gm, 7.60 mmol) in toluene (15 mL) was stirred under nitrogen at reflux for 4 h. After being cooled, the mixture was diluted with ether (150 mL), and washed with water (50 mL), 0.5M hydrochloric acid (50 mL) and saturated aqueous sodium chloride (50 mL), dried (MgSO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution with hexane/ethyl acetate) to give tert-butyl (3R)-6-[3-chloro-(4-phenyl)phenyl]-3-({[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino)carbonyl)hexanoate (701 mg, 74%), as a colourless foam.
Reaction SMILES: CS(O[CH2:6][C:7]1[C:8]([C@@H:14]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:15]([CH3:17])[CH3:16])=[N:9][CH:10]=[C:11]([Cl:13])[CH:12]=1)(=O)=O.ClC1C=C(CCl)C([C@@H](NC(=O)OC(C)(C)C)C(C)C)=NC=1.[H-].[Na+]>C1COCC1>[Cl:13][C:11]1[CH:12]=[C:7]2[CH2:6][N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@@H:14]([CH:15]([CH3:17])[CH3:16])[C:8]2=[N:9][CH:10]=1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)c1ncc(Cl)cc1COS(C)(=O)=O
Agent: CC(C)[C@H](NC(=O)OC(C)(C)C)c1ncc(Cl)cc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[C@H]1c2ncc(Cl)cc2CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 85 %

Procedure:
To a solution of (S)-(2-(1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-5-chloropyridin-3-yl)methyl methanesulfonate and tert-butyl(S)-(1-(5-chloro-3-(chloromethyl)pyridin-2-yl)-2-methylpropyl)carbamate (3:1 mixture, 6.39 g, 16.9 mmol) in THF (75 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 811 mg, 20.3 mmol). The mixture was warmed to rt and stirred for 15 h, at which point it was quenched with saturated aqueous ammonium chloride solution (100 mL). The aqueous phase was extracted with ethyl acetate (3×100 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 5% EtOAc in hexanes, gradient to 10%) to give tert-butyl(S)-3-chloro-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (4.31 g, 85% yield over 3 steps) as a yellow oil. LC-MS tR=1.12 min in 1 min chromatography, MS (ESI) m/z 297.3 [M+H]+. 1H NMR (CDCl3, 400 MHz, mixture of rotamers): δ 8.43 (s, 1H), 7.56 (s, 0.6H), 7.50 (s, 0.4H), 4.96 (s, 0.4H), 4.87 (s, 0.6H), 4.86 (d, J=16.0 Hz, 0.6H), 4.74 (d, J=15.6 Hz, 0.4H), 4.52 (d, J=12.0 Hz, 0.4H), 4.49 (d, J=15.2 Hz, 0.6H), 2.60-2.51 (m, 0.4H), 2.40-2.36 (m, 0.6H), 1.49 (s, 9H), 1.08 (d, J=7.2 Hz, 1.2H), 0.99 (d, J=7.2 Hz, 1.8H), 0.78 (d, J=6.8 Hz, 1.8H), 0.72 (d, J=6.8 Hz, 1.2H).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[CH:11]=[C:12]([NH:18][C@H:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[CH3:20])[C:13]([F:17])=[CH:14][C:15]=3[NH2:16])[CH:5]=2)[CH2:3][CH2:2]1.[C:28](O)(=O)C.C(N)=N.C(=O)(O)[O-].[Na+].CCOC(C)=O>CCO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([N:9]3[C:10]4[CH:11]=[C:12]([NH:18][C@H:19]([C:21]5[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=5)[CH3:20])[C:13]([F:17])=[CH:14][C:15]=4[N:16]=[CH:28]3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)O
Reactant: C[C@H](Nc1cc(Nc2cc(C3CC3)[nH]n2)c(N)cc1F)c1ccc(F)cc1
Agent: N=CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: C[C@H](Nc1cc2c(cc1F)ncn2-c1cc(C2CC2)[nH]n1)c1ccc(F)cc1
Yield: 54.9 %

Procedure:
A mixture of (S)-N3-(5-cyclopropyl-1H-pyrazol-3-yl)-6-fluoro-N1-[1-(4-fluorophenyl)ethyl]benzene-1,3,4-triamine (Method 73; 0.302 g, 0.816 mmol) and formamidine acetate (0.170 g, 1.63 mmol) in EtOH (10 ml) was heated at reflux for 1 hr. After cooling, the reaction mixture was treated with saturated sodium bicarbonate solution (5 ml) and EtOAc (15 ml). The organic layer was separated, washed with brine (3 ml), and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane:EtOAc=1:1) to give the title compound as an off-white solid (0.170 g, 55%). NMR (400 MHz) 12.69 (s, 1H), 8.27 (s, 1H), 7.47 (m, 2H), 7.39 (d, J=12.0 Hz, 1H), 7.12 (t, J=9.0 Hz, 2H), 6.96 (d, J=8.0 Hz, 1H), 6.07 (s, 1H), 5.90 (d, J=4.8 Hz, 1H), 4.56 (m, 1H), 1.96 (m, 1H), 1.51 (d, J=6.8 Hz, 3H), 1.02 (m, 2H), 0.76 (m, 2H). MS: Calcd.: 379; Found: [M+H]+ 380.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[C:6][C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1)([CH3:4])[CH3:3].Br[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[O:25][C:24]([CH3:30])([CH3:29])[CH2:23][C:22]2([CH3:32])[CH3:31]>>[CH3:29][C:24]1([CH3:30])[CH2:23][C:22]([CH3:32])([CH3:31])[C:21]2[C:26](=[CH:27][CH:28]=[C:19](/[C:5](/[Si:2]([CH3:3])([CH3:4])[CH3:1])=[CH:6]/[C:7]3[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=3)[CH:20]=2)[O:25]1
Reactant: CCOC(=O)c1ccc(C#C[Si](C)(C)C)cc1
Reactant: CC1(C)CC(C)(C)c2cc(Br)ccc2O1
Product: CCOC(=O)c1ccc(/C=C(/c2ccc3c(c2)C(C)(C)CC(C)(C)O3)[Si](C)(C)C)cc1

Procedure:
Following General Procedure A, ethyl 4-[(trimethylsilyl)ethynyl]benzoate (Compound 9, 0.51 g, 2.0 mmol) and 6-bromo-2,2,4,4-tetramethylchroman (0.57 g, 2.25 mmol) were coupled to give the title compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11](Cl)(=[O:13])=[O:12])[CH:4]=[CH:3][CH:2]=1.[CH2:15]([O:17][C:18]([C:20]1([NH2:29])[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1)=[O:19])[CH3:16].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:15]([O:17][C:18]([C:20]1([NH:29][S:11]([C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[N:1]=[CH:2][CH:3]=[CH:4]3)(=[O:13])=[O:12])[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1)=[O:19])[CH3:16]
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1(NS(=O)(=O)c2cccc3cccnc23)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.1 %

Procedure:
To a solution of quinoline-8-sulfonyl chloride (400 mg, 1.76 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (361 mg, 1.76 mmol) in anhydrous DCM (8 mL) is added DIPEA (291 μL, 1.76 mmol). The resulting solution is stirred at RT overnight. The reaction solution is diluted with DCM (40 mL), washed with water (1×5 mL) and brine (2×5 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 5-50% EtOAc in heptane) to give a pure product (35) as white solid (245 mg, 35%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.Cl.[NH2:12][CH2:13][CH:14]1[CH2:16][CH2:15]1.Cl.C(N=C=NCCCN(CC)CC)C.ON1C2C=CC=CC=2N=N1>O.O1CCCC1.C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)=[O:10])[CH:3]=1
Reactant: O=C(O)c1cc(Cl)ccn1
Reactant: NCC1CC1
Agent: CCN=C=NCCCN(CC)CC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCC1CC1)c1cc(Cl)ccn1

Procedure:
4-Chloro-2-carboxypyridine (2.0 g), (aminomethyl)cyclopropane hydrochloride (1.7 g), 1-ethyl-3-(3-diethylaminopropyl)carbodiimide hydrochloride (WSC) (2.9 g), 1-hydroxybenzotriazole (HOBt) (2.3 g), triethylamine (2.1 ml) and tetrahydrofuran (30 ml) were stirred together at room temperature for 2 hours. Water was added, extraction was performed with ethyl acetate, and then silica gel was added to the extract and the solvent was distilled off under reduced pressure. The silica gel was charged into a dry column packed with silica gel and purified by column chromatography (hexane:ethyl acetate=4:1, followed by 2:1) to obtain 1.5 mg of the target substance as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.[CH3:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>>[CH:15]1([C:13]([NH:12][C:7]2[N:8]=[CH:9][C:10]3[C:5]([CH:6]=2)=[CH:4][CH:3]=[C:2]([C:20]2[CH:21]=[C:22]([CH:26]=[CH:27][C:19]=2[CH3:18])[C:23]([OH:25])=[O:24])[CH:11]=3)=[O:14])[CH2:17][CH2:16]1
Reactant: O=C(Nc1cc2ccc(Br)cc2cn1)C1CC1
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(C(=O)O)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 90 °C
Yield: 93 %

Procedure:
A mixture of N-(7-bromoisoquinolin-3-yl)cyclopropanecarboxamide (0.3305 g, 1.135 mmol), 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (0.3782 g, 1.443 mmol), potassium carbonate (0.3196 g, 2.312 mmol), and bis(di-tert-butyl(4-dimethylaminophenyephosphine)dichloropalladium(II) (81.9 mg, 0.116 mmol) in 1,4-dioxane (5.0 mL, 64 mmol) and water (0.5 mL, 30 mmol) was heated at 90° C. for 2 hours. The reaction mixture was cooled to room temperature, acidified with 10% aqueous citric acid, and extracted twice with ethyl acetate. The combined organic extracts were reduced in volume under evaporation and the product collected via filtration as a white precipitate and dried under vacuum to yield 365.5 mg (91%) of 3-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-4-methylbenzoic acid. LCMS (ESI): M+H=347.2; 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 9.19 (s, 1H), 8.50 (s, 1H), 8.04 (s, 1H), 7.93 (d, J=8.6 Hz, 1H), 7.89-7.83 (m, 2H), 7.72 (d, J=8.5 Hz, 1H), 7.45 (d, J=7.7 Hz, 1H), 2.34 (s, 3H), 2.14-2.02 (m, 1H), 0.85 (m, 4H).
Reaction SMILES: [OH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][CH:3]1C(O)=O>N1C2C(=CC=CC=2)C=CC=1>[N:5]1[C:6]2[C:11](=[N:10][CH:9]=[CH:8][CH:7]=2)[C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: O=C(O)C1C=Nc2cccnc2C1O
Solvent: c1ccc2ncccc2c1
Product: Oc1ccnc2cccnc12
Temperature: 200 °C

Procedure:
4-hydroxy-3,4-dihydro-1,5-naphthyridine-3-carboxylic acid (1.4 g, 7.3 mmol) was dissolved in quinoline (50 ml). The mixture was heated to 200° C. for 2 hours, and then cooled to room temperature. The reaction mixture was filtered to give 1,5-naphthyridin-4-ol.
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:24]=[CH:23][C:11]2[C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21]O)=[CH:15][C:13]=3[O:14][C:10]=2[CH:9]=1.S(Cl)([Cl:27])=O>C1(C)C=CC=CC=1>[Cl:27][CH2:21][CH2:20][O:19][C:16]1[CH:17]=[CH:18][C:12]2[C:11]3[CH:23]=[CH:24][C:8]([Cl:7])=[CH:9][C:10]=3[O:14][C:13]=2[CH:15]=1
Reactant: OCCOc1ccc2c(c1)oc1cc(Cl)ccc12
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: ClCCOc1ccc2c(c1)oc1cc(Cl)ccc12
Temperature: 70 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
11.9 g (0.15 mole) of pyridine were added to a suspension of 26.2 g (0.1 mole) of 2-(7-chlorodibenzofuran-3-oxy)-ethanol in 100 ml of dry toluene, and 17.9 g (0.15 mole) of thionyl chloride were then added dropwise at 3°-15° C. The mixture was stirred for 1 day at 40° C. and for a further 8 hours at 70° C. and cooled, and 150 ml of toluene and 200 ml of ice-water were added. The organic layer was washed with 100 ml of water, 50 ml of hydrochloric acid and 50 ml of 1 N sodium hydroxide solution in succession and finally with 100 ml of water, and was dried and concentrated. The solid residue was stirred with 40 ml of petroleum ether at +3° C. (ice-bath) for 30 minutes, filtered off with suction, washed with a little cold petroleum ether and dried. 22.8 g of 1-chloro-2-(7-chlorodibenzofuran-3-oxy)-ethane were obtained as colorless crystals of melting point 105°-107° C.; yield: 81% of theory.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:3]=1.C([N:14](CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([NH2:14])=[O:11])[CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)Cc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: NC(=O)Cc1cccnc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 156.4 %

Procedure:
A solution of 3-pyridylacetic acid hydrochloride (2.6 g), triethylamine (1.52 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.16 g) and N-hydroxybenzotriazole (2.52 g) in N,N-dimethylformamide (40 ml) was stirred at 0° C. for 15 minutes. (2E,4E)- and (2Z,4E)-4-Methyl-2,4-heptadien-1-ylamine (2.69 g) was added to the solution. The solution was stirred at 0° C. for 2 hours and then at room temperature overnight. The reaction mixture was evaporated in vacuo and the residue was diluted with ethyl acetate and washed with aqueous sodium hydrogen carbonate solution. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (4% methanol-chloroform) to give N-[(2E,4E)- and (2Z,4E)-4-methyl-2,4-heptadien-1-yl]-3-pyridylacetamide (3.19 g) as an oil.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[NH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][C:6]1=[O:14].[C:15](Cl)(=[O:19])[CH2:16][CH2:17][CH3:18]>ClCCCl>[C:15]([C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[NH:5][C:6](=[O:14])[CH2:7]2)(=[O:19])[CH2:16][CH2:17][CH3:18]
Reactant: O=C1Cc2ccccc2N1
Reactant: CCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCCC(=O)c1ccc2c(c1)CC(=O)N2
Temperature: 50 °C
Reaction time: 8 h
Yield: 37.6 %

Procedure:
To 15 g of aluminum chloride suspended in 30 ml of 1,2-dichloroethane in an ice bath was added 7.5 g of 2-oxindole and then 12 g of butyryl chloride. The resulting suspension was stirred at 50° C. overnight. The mixture was poured into ice water and extracted 3 times with ethyl acetate. The combined ethyl acetate layers were washed with brine, dried over sodium sulfate, and concentrated to dryness to give a brown solid. The solid was chromatographed on silica gel (50% ethyl acetate in hexane) to give 4.3 g (38%) of 5-butanoyl-2-oxindole as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39](=[O:41])[CH3:40])=[CH:35][CH:34]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:39]([C:36]1[CH:37]=[CH:38][C:33]([NH:32][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[NH:10]2)=[O:29])=[CH:34][CH:35]=1)(=[O:41])[CH3:40]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CC(=O)c1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1ccc(NC(=O)C2NC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)cc1
Yield: 27.4 %

Procedure:
In a manner similar to the method described in Examples 1e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (0.35 g, 0.75 mmol) was reacted with 1-(4-amino-phenyl)-ethanone (Aldrich) (0.12 g, 0.9 mmol), HATU (0.5 g, 1.3 mmol) and iPr2NEt (0.33 mL, 2.6 mmol) in CH2Cl2 at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-acetyl-phenyl)-amide as a white solid (0.12 g, 27%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[F:30][C:31]1[CH:32]=[C:33](O)[CH:34]=[CH:35][CH:36]=1>>[F:30][C:31]1[CH:36]=[C:35]([CH:34]=[CH:33][CH:32]=1)[O:29][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(F)cc3)CC2)c1
Reactant: Oc1cccc(F)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3cccc(F)c3)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 3-fluorophenol: ESMS m/e: 492.9 (M+H)+.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][NH:2]1.Br[CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>>[O:11]=[C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][N:2]1[CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1
Reactant: O=c1[nH]ncc2ccccc12
Reactant: O=Cc1ccc(OCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=Cc1ccc(OCCn2ncc3ccccc3c2=O)cc1
Yield: 43.4 %

Procedure:
##STR31## The title compound (700 mg, 44%) was prepared from 1(2H)-phthalazinone (800 mg, 5.48 mmol) (Ref: Chemistry of Heterocyclic Compounds; Condensed Pyridazines including Cinnolines and Phthalazines, edited by R. N. Castle; John Wiley and Sons, 27, (1973) 375-441), 4-[2-bromoethoxy]benzaldehyde (1.25 g, 5.48 mmol) and K2CO3 (1.5 g, 10.96 mmol) by a similar procedure to that described in preparation 2, mp: 104-106° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[CH3:27][NH:28][CH3:29]>C(O)C>[CH3:27][N:28]([CH3:29])[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: CNC
Solvent: CCO
Product: Cc1cc(C)c(CNC(=O)c2cc(N(C)C)nc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described in example 21 from 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (23 mg, 0.062 mmol), ethanol (0.7 mL), and dimethylamine (0.461 mL, 0.923 mmol). The product was dried in vacuum oven at 50° C. for 5 hr and collected as 0.016 g (67%). LCMS E-S (M+H)=383.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44 (d, J=6.57 Hz, 6 H), 2.05-2.25 (m, 6 H), 3.14 (s, 6 H), 4.34 (d, J=4.80 Hz, 2 H), 4.99 (dt, J=13.39, 6.69 Hz, 1 H), 5.89 (s, 1 H), 6.94 (s, 1 H), 7.96 (s, 1 H), 8.64 (t, J=4.93 Hz, 1 H), 11.56 (br. s., 1 H).
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[CH:3]=1.[ClH:10].N([O-])=O.[Na+].[Cl-].[Na+]>O>[Cl:8][C:6]1[CH:7]=[C:2]([Cl:10])[CH:3]=[C:4]([Cl:9])[N:5]=1
Reactant: Cl
Reactant: Nc1cc(Cl)nc(Cl)c1
Agent: O=N[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: Clc1cc(Cl)nc(Cl)c1

Procedure:
To a mixture composed of 4-amino-2,6-dichloropyridine (5.5 g), cuprous chloride (4.4 g) and concentrated hydrochloric acid (50 ml), sodium nitrite (3.5 g) was added little by little under cooling with ice and sodium chloride. After the resultant mixture was stirred for one hour at the same temperature and for one and a half hour at a room temperature, water was added, and the mixture was extracted with chloroform. After the obtained extract was dried over anhydrous sodium sulfate, solvent was distilled off under reduced pressure to give 2,4,6-trichloropyridine (5.5 g).
Reaction SMILES: [C:1]1([C:11]#[C:12][CH:13]([OH:17])[CH2:14][CH:15]=[CH2:16])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1>C1(C)C=CC=CC=1.[Pt](Cl)Cl>[C:1]1([C:11]23[CH2:16][CH:15]2[CH2:14][C:13](=[O:17])[CH2:12]3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C=CCC(O)C#Cc1cccc2ccccc12
Agent: Cl[Pt]Cl
Solvent: Cc1ccccc1
Product: O=C1CC2CC2(c2cccc3ccccc23)C1
Temperature: 80 °C
Reaction time: 24 h
Yield: 57 %

Procedure:
To a stirred solution of 1-naphthalen-1-yl-hex-5-en-1-yn-3-ol (1.00 g, 4.50 mmol) under an atmosphere of nitrogen in toluene (100 mL) was added platinum chloride (0.06 g, 0.22 mmol, 5 mol %); the resulting black mixture was stirred at 80° C. for 24 hr. TLC indicated that the reaction was complete. The organics were concentrated in vacuo to afford a black residue. The crude material was purified by flash chromatography (SiO2, ethyl acetate:petroleum ether 40-60; 10%:90%) to afford the desired compound as a yellow oil (0.57 g, 57%). 1H NMR (400 MHz, CDCl3) δ ppm 0.73 (1H, t, J 4.0 Hz, CH), 0.82-0.84 (1H, m, CH), 1.17-1.24 (1H, m, CH), 2.47 (1H, d, J 19.0 Hz, CH), 2.75 (2H, d, J 10 Hz, CH)), 2.95-3.09 (1H, m, CH), 7.38-7.51 (4H, m, ArH), 7.73 (1H, d, J 8.0 Hz, ArH), 7.84 (1H, d, J 8.0 Hz, ArH), 8.10 (1H, d, J 8.0 Hz, ArH).
Reaction SMILES: N#N.[Br:3][C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[N:8][CH:9]=1.[CH2:13](O)[CH2:14][OH:15].COC(OC)OC.C([O-])([O-])=O.[Na+].[Na+]>>[Br:3][C:4]1[CH:9]=[N:8][CH:7]=[C:6]([C:10]2([CH3:11])[O:15][CH2:14][CH2:13][O:12]2)[CH:5]=1
Reactant: CC(=O)c1cncc(Br)c1
Reactant: OCCO
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COC(OC)OC
Product: CC1(c2cncc(Br)c2)OCCO1
Temperature: 95 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-(5-bromo-pyridin-3-yl)-ethanone (1800 mg, 9.00 mmol) in ethylene glycol (9.57 mL, 171.69 mmol) was treated with trimethylorthoformate (2.01 mL, 18.34 mmol) followed by LiBF4 (172 mg, 1.80 mmol). The reaction mixture was heated at 95° C. overnight. Sat. aq. Na2CO3 was added and the mixture was extracted twice with ether. The combined organic extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (20:1 hept-EA) gave the title compound as a pale yellow oil. TLC: rf (50:50 hept-EA)=0.57. LC-MS-conditions 02: tR=0.87 min.