Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][NH:5][C:6]([C:8]1[C:9]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][C:20]=2[Cl:26])=[C:10]([Cl:17])[C:11]2[N:12]([CH:14]=[CH:15][N:16]=2)[CH:13]=1)=[O:7].N1C=NN=N1.C(N(C(C)C)[P:36]([O:42]C(C)(C)C)[O:37]C(C)(C)C)(C)C.C([O:54]O)(C)(C)C>CN(C=O)C>[Br:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:9]2[C:8]([C:6]([NH:5][O:4][CH2:3][CH2:2][O:1][P:36](=[O:42])([OH:54])[OH:37])=[O:7])=[CH:13][N:12]3[CH:14]=[CH:15][N:16]=[C:11]3[C:10]=2[Cl:17])=[C:20]([Cl:26])[CH:21]=1
Reactant: CC(C)N(C(C)C)P(OC(C)(C)C)OC(C)(C)C
Reactant: O=C(NOCCO)c1cn2ccnc2c(Cl)c1Nc1ccc(Br)cc1Cl
Reactant: CC(C)(C)OO
Agent: c1nnn[nH]1
Solvent: CN(C)C=O
Product: O=C(NOCCOP(=O)(O)O)c1cn2ccnc2c(Cl)c1Nc1ccc(Br)cc1Cl
Temperature: -78 °C
Reaction time: 3 h

Procedure:
7-(4-bromo-2-chlorophenylamino)-8-chloroimidazo[1,2-a]pyridine-6-carboxylic acid (2-hydroxyethoxy)-amide (33a) (100 mg, 0.234 mmol), tetrazole (23 mg, 0.327 mmol) and di-tert-butyl diisopropylphosphoramidite (0.096 mL, 0.304 mmol) were dissolved/suspended in 30 mL of anhydrous DMF under an atmosphere of dry N2. The reaction mixture was stirred for about 3 hours, after which time the reaction was cooled to −78° C. and tert-butyl hydrogen peroxide (0.100 mL of 70% solution in water) was added. The cooling bath was then taken away and the reaction was slowly warmed up to room temperature and reacted over night. The reaction mixture was then partitioned between a solution of ethyl ether/ethyl acetate (5:1) and saturated aqueous NaHCO3. The organic layer was saved and successively washed with 10% aqueous sodium sulfite, 3 times with water and finally with brine. The resulting organic layer was dried over MgSO4, filtered and concentrated under vacuum. The residue was dissolved in 3 mL of a solution of TFA/DCM (2:1) under an atmosphere of dry N2. The reaction was stirred at room temperature for about 2 hours after which time it was concentrated under vacuum and the resulting residue was stirred in methanol for about 1 hour. The off-white solid was collected via suction filtration, washed with methanol followed by ethyl ether and then air-dried to give the desired compound (74).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](=[O:14])[CH:10]=[C:11]([CH3:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[CH3:8].ClC1C=CC=C(C(OO)=[O:23])C=1.O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([CH:10]2[C:11]([CH3:12])([CH3:13])[O:23]2)=[O:14])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)=CC(=O)c1ccc(C)c(Br)c1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(C(=O)C2OC2(C)C)cc1Br
Temperature: 25 °C
Yield: 100.4 %

Procedure:
To a cooled solution (at 0° C.) of 1-(3-bromo-4-methylphenyl)-3-methylbut-2-en-1-one (1.50 g, 5.92 mmol, 1.0 eq) in DCM (100 mL), m-chloroperbenzoic acid (77%, 4.30 g, 17.78 mmol, 3.0 eq) was added portion wise and then allowed to warm to room temperature. After stirring for 12 h at room temperature water was added to the reaction mixture and the layers were separated. The organic layer was washed with saturated aqueous solution of sodium bicarbonate (3×50 mL) followed by brine (50 mL) and then dried (Na2SO4) and filtered. The filtrate was concentrated under vacuum. The crude product was purified by flash column chromatography (silica gel, 5% ethyl acetate in hexane) to afford 1.60 g of the desired product, as a white solid. 1HNMR (400 MHz, CDCl3) δ 8.13 (d, J=1.5 Hz, 1H), 7.81 (dd, J=1.5, 8.0 Hz, 1H), 7.36 (d, J=8.0 Hz, 1H), 3.99 (s, 1H), 2.47 (s, 3H), 1.58 (s, 3H), 1.23 (s, 3H); ESI-MS (m/z) 269, 271 [(MH)+, Br79,81].
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([O:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])(=[O:14])=[O:13])[CH:7]=[C:8]([CH3:10])[CH:9]=1.Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]#[N:29]>CN(C)C=O>[C:28]([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][O:3][C:4]1[CH:5]=[C:6]([O:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])(=[O:14])=[O:13])[CH:7]=[C:8]([CH3:10])[CH:9]=1)#[N:29]
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2Cl)c1
Reactant: N#CCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(OCCCCCC#N)cc(OS(=O)(=O)c2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 74.2 %

Procedure:
Sodium hydride (24 mg, 1 mmol; 100%) was added to solution of 250 mg (0.855 mmol) of 2-chlorobenzenesulfonic acid 3-hydroxy-5-methylphenyl ester, as prepared in step (c) of Example 1, in 2 mL of N,N-dimethylformamide. After 5 min, 130 μL (0.93 mmol) of 6-bromohexanenitrile was added to the reaction mixture. The reaction mixture was stirred for 2 h at ambient temperature, quenched with brine (50 mL), extracted into diethyl ether (50 mL), washed with water (3×10 mL), dried (MgSO4), and concentrated in vacuo. The residue was purified by flash chromatography (methylene chloride/petroleum ether 4:1 to 100:0) to give 250 mg of the title compound as a colorless oil which solidified upon standing. 1H-NMR (300 MHz, CDCl3) δ 7.97 (dd, 1 H, J=1.4, 7.8 Hz), 7.56-7.65 (m, 2 H), 7.36-7.41 (m, 1 H), 6.59 (br s, 1 H), 6.53 (br, s 1 H), 6.48 (t, 1 H, J=1.1 Hz), 3.85 (t, 2 H), 2.38 (t, 2 H), 2.24 (s, 3 H), and 1.6-1.8 (m, 6 H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C19H20NClO4S: 416.1 (M+Na). Found: 416.1.
Reaction SMILES: Br[C:2]1[C:3](=[O:20])[N:4]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([O:14]C)=O)[CH:5]=[C:6](Br)[N:7]=1.C([N:24](CC)[CH:25]([CH3:27])[CH3:26])(C)C.[C:30]1([C@H:36]([CH3:39])[CH2:37][NH2:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C1(N)CC1.C1([Mg]Br)CCCC1>O1CCCC1>[CH:25]1([NH:24][C:12](=[O:14])[C:11]2[CH:16]=[CH:17][C:18]([CH3:19])=[C:9]([N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH:38][CH2:37][C@H:36]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH3:39])[C:3]3=[O:20])[CH:10]=2)[CH2:26][CH2:27]1
Reactant: C[C@H](CN)c1ccccc1
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)c1ccc(C)c(-n2cc(Br)nc(Br)c2=O)c1
Agent: Br[Mg]C1CCCC1
Agent: NC1CC1
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC[C@@H](C)c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methyl ester (Example 1b, 0.1 g), N,N-diisopropylethylamine (0.1 mL), (S)-2-phenyl-1-propylamine (0.05 mL) and tetrahydrofuran (1 mL) was stirred at room temperature overnight. Cyclopropylamine (0.2 mL) was added followed by the addition of cyclopentylmagnesium bromide (2M in diethyl ether, 0.8 mL). The mixture was stirred for 10 min., quenched with sat. NH4Cl and extracted into ethyl acetate. The organic phase concentrated in vacuo. The residue was treated with ethanol (5 mL), wet 10% palladium on carbon (45 mg) was added followed by N,N-diisopropylethylamine (0.1 mL) and ammonium formate (0.4 g). The mixture was stirred under nitrogen atmosphere at 70° C. for 30 min. The mixture was filtered through a pad of Celite and the filtrate concentrated in vacuo. Purification by preparative HPLC (Gemini column, 0.1% ammonia:acetonitrile eluent) afforded the title compound as a solid (64 mg).
Reaction SMILES: O.Br[CH2:3][C:4]1[C:5]([Cl:22])=[CH:6][C:7]([Cl:21])=[C:8]([C:10]2[C:14]([Cl:15])=[C:13]([O:16][CH:17]([F:19])[F:18])[N:12]([CH3:20])[N:11]=2)[CH:9]=1.C1N2CN3CN(C2)CN1C3.S(=O)(=O)(O)[OH:34]>C(O)(=O)C>[Cl:15][C:14]1[C:10]([C:8]2[C:7]([Cl:21])=[CH:6][C:5]([Cl:22])=[C:4]([CH:9]=2)[CH:3]=[O:34])=[N:11][N:12]([CH3:20])[C:13]=1[O:16][CH:17]([F:19])[F:18]
Reactant: Cn1nc(-c2cc(CBr)c(Cl)cc2Cl)c(Cl)c1OC(F)F
Reactant: O=S(=O)(O)O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Solvent: CC(=O)O
Product: Cn1nc(-c2cc(C=O)c(Cl)cc2Cl)c(Cl)c1OC(F)F
Yield: 56.3 %

Procedure:
After addition of 100 ml water to a solution of 3-(5-bromomethyl-2,4-dichlorophenyl)-4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazole (26.60 g, 63.3 mmoles) in 100 ml glacial acetic acid, hexamethylenetetramine (8.87 g, 63.3 mmoles) was added and reacted under reflux for 2 hours. Further, 40 ml conc. sulfuric acid was added and reacted under reflux for 13 hours. Then the reaction product mixture, poured into ice-cold water, was extracted with ethyl acetate. The extract solution was washed with 5% aqueous NaHCO3 and then with water, dehydrated, and concentrated. Purification of the residue by column chromatography gave the title compound (12.66 g), m.p. 138.2° C., yield 56.3%.
Reaction SMILES: Br[CH:2]1[C:6](=O)[CH2:5][CH2:4][CH:3]1[C:8]#[N:9].[NH2:10][C:11]([NH2:13])=[S:12]>O1CCOCC1>[NH2:13][C:11]1[S:12][C:2]2[CH:3]([C:8]#[N:9])[CH2:4][CH2:5][C:6]=2[N:10]=1
Reactant: N#CC1CCC(=O)C1Br
Reactant: NC(N)=S
Solvent: C1COCCO1
Product: N#CC1CCc2nc(N)sc21
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of 2-bromo-3-oxocyclopentanecarbonitrile (crude from A.1.7.1.; ca. 13 g) and thiourea (13.77 g, 181 mmol) in dioxane (600 mL) was stirred at 80° C. for 1 h. The mixture was allowed to cool to RT, quenched with aq. sat. NaHCO3 and extracted with EtOAc. The comb. org. layers were washed with brine, dried over MgSO4, and conc. in vacuo. Purification by means of CC (2-20% MeOH (0.5% Et3N)/DCM) provided a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)(Cl)Cl.ClCCl>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][S:18]([CH3:17])(=[O:20])=[O:19])[CH:5]=[CH:4][N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccnc(F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)OCc1ccnc(F)c1
Reaction time: 1.5 h

Procedure:
To a stirred solution of (2-Fluoro-pyridin-4-yl)-methanol (37) (381 mg, 3 mmol) in chloroform (30 ml) at 0° C. (ice bath), was added triethylamine (630 μl, 4.5 mmol) followed by methanesulfonyl chloride (270 μl, 3.6 mmol). After stirring for 1.5 hr., the mixture was diluted with dichloromethane, washed with aqueous saturated sodium bicarbonate solution, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was further dried in high vacuo to provide Methanesulfonic acid 2-fluoro-pyridin-4-ylmethyl ester (38). A flask was charged with Methanesulfonic acid 2-fluoro-pyridin-4-ylmethyl ester (38) from above, 3-(5-Isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl)-5-methyl-benzonitrile (32) (891 mg, 3 mmol), anhydrous powdered potassium carbonate (408 mg, 3 mmol), and lithium iodide (402 mg, 3 mmol). Anhydrous DMF (15 ml) was then added into the mixture and stirred for 5.5 hr at room temperature. The mixture was evaporated in vacuo. The residue was dissolved in methanol-dichloromethane (1:9), filtered through celite pad, and evaporated in vacuo to give a pale yellow foam. The crude product was purified by silica gel column chromatography (eluent, methanol:chloroform (2:98)) to afford 366 mg (30%) of Example H as a pale yellow foam, which was recrystallized from chloroform-ether to give a white solid; 1H NMR (200 MHz, CDCl3) δ: 1.12 (3H, d, J=6.8 Hz), 1.23 (3H, d, J=6.8 Hz), 2.25 (1H, m), 2.42 (3H, s), 4.66 (1H, d, J=16.7 Hz), 4.93 (1H, d, J=16.7 Hz), 6.61 (1H, s), 6.90 (1H, d, J=5.3 Hz), 7.71 (2H, s), 7.91 (1H, s), 8.04 (1H, d, J=5.3 Hz), 9.44 (1H, s); m/z (EI): 406 (M+); HRMS (EI) Calcd. 406.144104, Found 406.144119.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)OC(C)C)#[N:2].[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:19][NH2:20]>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=1)=[N:20][CH2:19][C:18]1[CH:21]=[CH:22][C:23]([Cl:24])=[C:16]([Cl:15])[CH:17]=1)#[N:2]
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: CC(C)OC(=NC#N)c1ccncc1
Solvent: CO
Product: N#CNC(=NCc1ccc(Cl)c(Cl)c1)c1ccncc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.8 %

Procedure:
Isopropyl N-cyano-4-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), and 3,4-dichlorobenzylamine (0.52 g, 3.0 mmol) was added. The mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residual concentrate was crystallized from methanol-diethyl ether to give the title compound (0.42 g, 1.4 mmol, yield: 52%) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][C@H:7]([C:10](O)=[O:11])[CH2:6]1)=[O:4].CSC.B>C1COCC1>[OH:11][CH2:10][C@H:7]1[CH2:8][CH2:9][C@@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6]1
Reactant: COC(=O)[C@@H]1CC[C@H](C(=O)O)C1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CC[C@H](CO)C1
Temperature: -78 °C
Yield: 89 %

Procedure:
(1S,3R)-3-(methoxycarbonyl)cyclopentanecarboxylic acid (15.9 gm, 92.3 mmol, 1 equi.) was dissolved in anhydrous THF (250 mL) and cooled down to −78° C. under nitrogen atmosphere. To this was added borane dimethyl sulfide complex (2M solution in THF, 1.66 equi., 147.7 mmol, 74 mL) and stirring was maintained for one hour allowing the temperature to raise to 0° C. temperature and stirred at room temperature for another three hours. The mixture was cooled down to −20° C. and quenched with a slow addition of 1M KH2PO4. Reaction was warmed up to room temperature and stirred for further 20 min and extracted with ether. Organic layer was washed with brine and dried over MgSO4, filtered and concentrated to dryness. The residue was purified by silica gel chromatography with (10% to 80% EtOAc in hexanes) to provide 13 g of (1R,3S)-methyl 3-(hydroxymethyl)cyclopentanecarboxylate 99.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[C:12]=2[F:19])[CH:10]=1)CCC.[C:28]([CH:30]1[CH2:33][N:32]([C:34](=[O:52])[C@H:35]([NH:39][C:40]([C:42]2[C:50]3[C:45](=[N:46][CH:47]=[C:48](Br)[N:49]=3)[NH:44][CH:43]=2)=[O:41])[CH:36]2[CH2:38][CH2:37]2)[CH2:31]1)#[N:29]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:28]([CH:30]1[CH2:31][N:32]([C:34](=[O:52])[C@H:35]([NH:39][C:40]([C:42]2[C:50]3[C:45](=[N:46][CH:47]=[C:48]([C:6]4[N:7]=[CH:8][N:9]([C:11]5[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[C:12]=5[F:19])[CH:10]=4)[N:49]=3)[NH:44][CH:43]=2)=[O:41])[CH:36]2[CH2:38][CH2:37]2)[CH2:33]1)#[N:29]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2cc(F)cc(F)c2F)cn1
Reactant: N#CC1CN(C(=O)[C@H](NC(=O)c2c[nH]c3ncc(Br)nc23)C2CC2)C1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: N#CC1CN(C(=O)[C@H](NC(=O)c2c[nH]c3ncc(-c4cn(-c5cc(F)cc(F)c5F)cn4)nc23)C2CC2)C1
Temperature: 80 °C
Reaction time: 16 h
Yield: 5 %

Procedure:
To the crude 4-tributylstannanyl-1-(2,3,5-trifluoro-phenyl)-1H-imidazole from Step 3 was added crude 2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide (0.087 g, from Step 1) in 3 mL of DMF, Pd(PPh3)4 (0.032 g, 0.027 mmol) and CuI (0.021 g, 0.110 mmol). The dark yellow mixture was stirred at 80° C. for 16 h, then allowed to cool. The mixture was partitioned between 20 mL of ethyl acetate and 20 mL of a sat. aq. NH4Cl solution. The organic layer was washed with 20 mL of water+20 mL of a sat. aq. NaCl. The organic layer was dried over Na2SO4, filtered and concentrated. Column chromatography (0-10% MeOH/EtOAc) of the residue afforded 0.005 g (5%) of 2-[1-(2,3,5-trifluoro-phenyl)-1H-imidazol-4-yl]-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide as a yellow solid, ca. 85% pure. MS: (M+Na)+=543.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][N:12]([C:14]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([C:24]4([CH3:27])[CH2:26][CH2:25]4)=[O:23])[CH2:18][CH2:17]3)=[O:15])[CH2:11][C@@H:10]2[N:28]([CH3:32])[C:29](Cl)=[O:30])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:33]1([CH2:36][CH2:37][NH:38][CH3:39])[CH2:35][CH2:34]1.C(N(CC)C(C)C)(C)C>C1COCC1.C(OCC)(=O)C>[CH:33]1([CH2:36][CH2:37][N:38]([CH3:39])[C:29]([N:28]([C@@H:10]2[C@@H:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:13][N:12]([C:14]([CH:16]3[CH2:17][CH2:18][N:19]([C:22]([C:24]4([CH3:27])[CH2:25][CH2:26]4)=[O:23])[CH2:20][CH2:21]3)=[O:15])[CH2:11]2)[CH3:32])=[O:30])[CH2:35][CH2:34]1
Reactant: CN(C(=O)Cl)[C@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Reactant: CNCCC1CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCC1CC1)C(=O)N(C)[C@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Yield: 71.7 %

Procedure:
To a solution of rac-{(3R,4S)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid chloride (250 mg, 0.50 mmol) in THF (1 mL) was added (2-cyclopropyl-ethyl)-methyl-amine (99 mg, 1.0 mmol) and N,N-diisopropyl ethyl amine (256, 1.50 mmol). The solution was irradiated in the microwave for 900 sec. at 130° C. before it was diluted with ethyl acetate (15 mL) and washed with an aqueous solution of sodium carbonate (1 M, 15 mL). The organic layer was separated and washed with brine (15 mL) and the aqueous layers were extracted with ethyl acetate (20 mL). The combined organic layers were dried over sodium sulfate and concentrated. Purification by chromatography (SiO2,ethyl acetate:methanol=100:0 to 85:15) afforded the title compound (202 mg, 72%) as a white foam. MS m/e: 563.4 [M]+.
Reaction SMILES: C[CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[C:22](=O)([O-])[O-].[Na+].[Na+]>CO>[F:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:3]1([C:7]([O:9][CH3:22])=[O:8])[CH2:4][CH2:5][CH2:6][CH2:2]1
Reactant: O=C([O-])[O-]
Reactant: CC1CCCC1(C(=O)O)c1ccccc1F
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1(c2ccccc2F)CCCC1

Procedure:
To a solution of methyl 1-(2-fluorophenyl)cyclopentanecarboxylic acid (5.0 g, 24.01 mmol) in anhydrous methanol was added 1 mL of the concentration of sulfuric acid. The mixture was refluxed for overnight. The mixture was neutralized to pH 4-5 with sodium carbonate. The solvent was evaporated. The residue was dissolved in ethyl acetate (50 mL), washed with brine (3×10 mL), dried over MgSO4. The crude product was used for the next reaction without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10]OS(C)(=O)=O)=[N:8][CH:9]=1)([O-:3])=[O:2].[CH3:16][C:17]1([OH:21])[CH2:20][NH:19][CH2:18]1.C(N(CC)CC)C>CO.CO.C1COCC1>[CH3:16][C:17]1([OH:21])[CH2:20][N:19]([CH2:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=2)[CH2:18]1
Reactant: CC1(O)CNC1
Reactant: CS(=O)(=O)OCc1ccc([N+](=O)[O-])cn1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: CC1(O)CN(Cc2ccc([N+](=O)[O-])cn2)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 71.3 %

Procedure:
To a solution of 52 (0.5 g, 2.2 mmol) in MeOH (25 mL) was added Ambersep-900 OH resin (50 g) filtered to separate the resin and concentrated to obtain the free base. The free base was dissolved in MeOH-THF (10 mL, 1:1) and cooled to 0° C. 3-methyl-azetidin-3-ol (0.53 g, 4.3 mmol) and triethylamine (0.7 mL, 4.3 mmol) were added and the reaction mixture warmed to rt and stirred for 16 h. The reaction mixture was concentrated and the crude compound was purified by silica gel column chromatography (100-200 mesh), eluting with 3% MeOH/CHCl3 to give the desired compound (0.35 g, 48%, over two steps) as a pale yellow liquid. Rf: 0.3 (10% MeOH/DCM); (m/z): 224 [MH]+; 1H NMR (400 MHz, DMSO-d6): δ 9.27 (1H, d, J=2.4 Hz), 8.56 (1H, dd, J=8.8, 2.8 Hz), 7.64 (1H, d, J=8.8 Hz), 5.22 (1H, s), 3.85 (2H, s), 3.36-3.26 (2H, m), 3.02-3.00 (2H, m), 1.38 (3H, s).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.[C:8](#[N:11])[CH:9]=[CH2:10]>C(Cl)Cl>[OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:10][CH2:9][C:8]#[N:11]
Reactant: C=CC#N
Reactant: OC[C@H]1CCCN1
Solvent: ClCCl
Product: N#CCCN1CCC[C@@H]1CO
Temperature: 25 °C

Procedure:
(R)-2-hydroxymethylpyrrolidine (Tokyo Kasei Kogyo Co., Ltd.) (50 g) was dissolved in methylene chloride (500 mL), and acrylonitrile (36 mL) was added dropwise to the solution with stirring at room temperature Subsequently, the mixture was stirred overnight at room temperature. After the completion of the reaction, the solvent was concentrated to give (R)-3-(2-hydroxymethylpyrrolidin-1-yl)propionitrile (76 g).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:13]2[NH:14][C:15](=[O:26])[C:16]3[C:17](=[C:19]([CH2:23][CH2:24][CH3:25])[N:20]([CH3:22])[N:21]=3)[N:18]=2)[C:5]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[N:6][CH:7]=1.[OH:27][N:28]=[C:29]([NH2:31])[CH3:30].[CH2:32](N(CC)CC)C.[C]=O>C1(C)C=CC=CC=1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:9]([O:8][C:5]1[C:4]([C:13]2[NH:14][C:15](=[O:26])[C:16]3[C:17](=[C:19]([CH2:23][CH2:24][CH3:25])[N:20]([CH3:22])[N:21]=3)[N:18]=2)=[CH:3][C:2]([C:32]2[O:27][N:28]=[C:29]([CH3:30])[N:31]=2)=[CH:7][N:6]=1)[CH:10]([CH3:12])[CH3:11]
Reactant: CCN(CC)CC
Reactant: CC(N)=NO
Reactant: CCCc1c2nc(-c3cc(I)cnc3OCC(C)C)[nH]c(=O)c2nn1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [C]=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCc1c2nc(-c3cc(-c4nc(C)no4)cnc3OCC(C)C)[nH]c(=O)c2nn1C
Reaction time: 14 h
Yield: 39.4 %

Procedure:
5-(5-Iodo-2-isobutoxy-3-pyridinyl)-2-methyl-3-propyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (Example 22) (200 mg, 0.42 mmol) and N′-hydroxyethanimidamide (EP 795 328) (95 mg, 1.28 mmol) were suspended in toluene (4 mL) and triethylamine (86 mg, 0.85 mmol) was added. Pd(PPh3)2Cl2 (15 mg, 0.02 mmol) was added and placed in a preheated oil bath at 95° C. under 1 atmosphere carbon monoxide. After 4 h a further portion of acetamidoxime (50 mg), triethylamine (43 mg) and Pd(PPh3)2Cl2 (15 mg) were added and stirring was continued at 95° C. for 14 h. The cooled reaction mixture was diluted with ethyl acetate and washed with water and brine, dried (MgSO4), filtered and evaporated. Purification by flash column chromatography (gradient elution from dichloromethane:1% methanol:dichloromethane) gave 70 mg product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH2:12]O.C(Br)(Br)(Br)[Br:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH2:12][Br:15]
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cc(C(F)(F)F)ccc1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)c1ccc(Br)c(CBr)c1
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 70.1 %

Procedure:
To a solution of (2-bromo-5-(trifluoromethyl)phenyl)methanol (4.7 g, 18 mmol) in methylene chloride (50 mL) at −10° C. was added carbon tetrabromide (CBr4) (7.17 g, 21.6 mmol). The resulting mixture was stirred at −10° C. for 15 minutes. Triphenylphosphine (5.61 g, 21.4 mmol) was then slowly added portionwise. This mixture was stirred at room temperature for 16 hours. The mixture was partitioned between saturated ammonium chloride (NH4Cl) (50 ml) and methylene chloride (2×50 mL). The combined organic layers were washed with saturated NaCl (50 mL), dried (MgSO4) and concentrated. The residue was purified by flash chromatography (silica gel) (eluted with 3:1 hexanes-ethyl acetate) to yield the title compound as a white solid (4.01 g). 1H NMR (400 MHz, CDCl3) δ 4.6 (s, 2H) 7.5 (dd, J=8.3, 1.6 Hz, 1H) 7.8 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.C1C(=O)N([Br:17])C(=O)C1.[OH-].[Na+]>S(=O)(=O)(O)O.O>[Br:17][C:5]1[C:6]([O:8][CH3:9])=[CH:7][C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccnc(Cl)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(Cl)ncc1Br
Temperature: 25 °C

Procedure:
To a solution of 2-chloro-4-methoxypyridine (10.0 g, 69.7 mmol) in 50 mL of sulfuric acid at 0° C. was added NBS. The reaction mixture was allowed to stir and warm up to room temperature for 2 hour and then heated at 60° C. for 5 h. Then it was cooled to room temperature and neutralized with 1 N NaOH (pH˜7), diluted with water (50 mL) and the aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layers were washed with water (2×50 mL), sat. NaHCO3, brine, dried over Mg2SO4 and concentrated to provide an oil, which was chromatographed. On elution with 0-25% EtOAc/hexanes, of the final product was obtained.