Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:9]([OH:16])[C:8]([OH:17])=[C:7]1[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:2].Br[CH2:25][CH2:26][CH2:27]Br.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]1[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:8]2[O:17][CH2:25][CH2:26][CH2:27][O:16][C:9]2=[C:10]1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:2]
Reactant: CCOC(=O)Cn1c(C(=O)OCC)c(O)c(O)c1C(=O)OCC
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cn1c(C(=O)OCC)c2c(c1C(=O)OCC)OCCCO2
Temperature: 105 °C
Reaction time: 12 h
Yield: 83.3 %

Procedure:
To a 500-mL round-bottom flask containing a stir bar and an argon atmosphere was added diethyl 1-(2-ethoxy-2-oxoethyl)-3,4-dihydroxy-1H-pyrrole-2,5-dicarboxylate (48.00 g, 146 mmol), 1,3-dibromopropane (29.48 g, 146 mmol), anhydrous potassium carbonate (50.36 g, 364 mmol), and anhydrous dimethylformamide (DMF) (250 mL). The reaction was heated to 105° C. and became lime green after about 30 minutes. The reaction was stirred for 12 hours, during which, it became yellow, and was cooled to room temperature. The mixture was poured into DI water (500 mL), the solids were collected via vacuum filtration, and washed with several portions of DI water. The solids were recrystallized from hot methanol to yield 44.90 g (80%) of a yellow solid. mp 139.7-139.9° C.; 1H NMR (300 MHz, CDCl3): δ 5.43 (s, 2H), 4.30 (q, 4H, J=7.7 Hz), 4.22 (q, 2H, J=8.0 Hz), 4.20 (t, 6H, J=63 Hz), 2.25 (p, 2H, J=6.3 Hz), 1.34 (t, 6H, J=7.7 Hz), 1.28 (t, 3H, J=8.0 Hz); 13C NMR (75 MHz, CDCl3): δ 169.6, 161.0, 142.7, 114.1, 71.7, 61.5, 60.9, 48.0, 33.4, 14.5, 14.4; HRMS (EI): Calcd for C17H23NO8 ([M]+), 369.1424, found m/z, 369.1417; Anal. Calcd for C17H23NO8: C, 55.28; H3, 6.28; N, 3.79%, found: C, 55.29; H, 6.37; N, 3.80
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.COP([O:18][CH3:19])OC.[CH2:20]([C@@H:27]1[N:30]([Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[C:29](=[O:38])C1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O=O>C1COCC1>[CH2:20]([C@@H:27]1[N:30]([Si:31]([C:34]([CH3:36])([CH3:35])[CH3:37])([CH3:32])[CH3:33])[C:29](=[O:38])[C@H:19]1[OH:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COP(OC)OC
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)C[C@@H]1Cc1ccccc1
Agent: O=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)N1C(=O)[C@@H](O)[C@@H]1Cc1ccccc1
Reaction time: 0.25 h
Yield: 60.6 %

Procedure:
To a solution of diisopropylamine (800 μL, 5.7 mmol) in anhydrous THF (40 mL) at −20° was added butyllithium (3.56 mL, 5.7 mmol, 1.6 M in hexane). After 15 min., the reaction was cooled to −78°, and freshly distilled trimethylphosphite (1.12 mL, 7.6 mmol) was added followed by a solution of 4(S)-benzyl-1-(tert-butyldimethylsilyl)azetidin-2-one (from example 1, step C, 1.05 g, 3.8 mmol) in THF (10 mL). A constant stream of oxygen was introduced and the mixture was stirred at −78° for 3 h. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc (120 mL). The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (SiO2, 10% EtOAc-hexane to 30% EtOAc in hexane) to give 4(S)-benzyl-1-(tert-butyldimethylsilyl)-3(S)-hydroxyazetidin-2-one (671 mg , 60% yield) as a white solid. 1H-NMR (400 MHz, CDCl3) δ7.25-7.21 (m, 5H), 4.51 (d, J=2 Hz, 1H), 3.75-3.71 (m, 1H), 3.26 (bs, 1H), 3.20 (dd, J=14, 3.8 Hz, 1H), 2.66 (dd, J=14, 11.1 Hz, 1H), 1.00 (s, 9H), 0.30 (d, J=3.5 Hz, 6H).
Reaction SMILES: O=P(Cl)(Cl)Cl.CN(C)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:15]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:38]=[C:37]3[C:32]([CH:33]=[CH:34][CH:35]=[N:36]3)=[C:31]([Cl:39])[N:30]=2)=[C:25]([Cl:40])[CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:41]([O-])([O-])=O.[Na+].[Na+]>>[CH2:15]([N:22]([CH2:41][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:38]=[C:37]3[C:32]([CH:33]=[CH:34][CH:35]=[N:36]3)=[C:31]([Cl:39])[N:30]=2)=[C:25]([Cl:40])[CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C([O-])[O-]
Reactant: CN(C)c1ccccc1
Reactant: Clc1cc(NCc2ccccc2)ccc1-c1cc2ncccc2c(Cl)n1
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1cc(N(Cc2ccccc2)Cc2ccccc2)ccc1-c1cc2ncccc2c(Cl)n1

Procedure:
To a suspension of 2-methylnicotinic acid, 1 (274 mg, 2.0 mmol, 1 eq) in freshly distilled THF (5 mL) was added at −78° C. a solution of LDA (2.5 mL, 5.0 mmol, 2.5 eq) under Ar(g). The resulting purple solution was stirred at −78° C. for 30 min, and then warmed up to 0° C. for 1.5 h. The mixture was then cooled down to −78° C., and a solution of 2-chloro-4-dibenzylamino-benzonitrile, 2 (800 mg, 2.4 mmol, 1.2 eq) in THF (5 mL) was added. The reaction mixture was left to warm up to rt overnight, and was then quenched at 0° C. with H2O (20 mL), and extracted with CHCl3 (3×10 mL) and EtOAc (2×10 mL). The combined organic extracts were dried over MgSO4 and the solvent was removed in vacuo to give a crude pale red oil (1.15 g). To a solution of this residue in POCl3 (4.0 mL, 44 mmol, 22 eq) was added dimethylaniline (51 μL, 0.4 mmol, 0.20 eq). The mixture was refluxed at 100° C. under Ar(g) overnight; once cooled down, the solution was poured very slowly into a saturated Na2CO3 solution (50 mL) at 0° C., and was then partitioned and extracted with CH2Cl2 (3×20 mL). The combined organic extracts were dried over MgSO4 and the solvent was removed in vacuo. The residue was further purified by silica gel column chromatography with hexane/EtOAc (3:1-0:1) to yield an inseparable mixture of the product, 3, and the by-product benzyl-[3-chloro-4-(5-chloro-[1,6]naphthyridin-7-yl)-phenyl]-amine as a pale yellow oil (183 mg, 1:1 ratio; 3=10%, by-product=12% over 2 steps)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][O:13][CH2:14][CH3:15].C(N(CC)CC)C.Cl[C:24]([O:26][CH3:27])=[O:25].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH3:27][O:26][C:24](=[O:25])[N:10]([CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[CH2:11][CH2:12][O:13][CH2:14][CH3:15]
Reactant: COC(=O)Cl
Reactant: CCOCCNCCc1ccccc1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOCCN(CCc1ccccc1Br)C(=O)OC
Reaction time: 20 h

Procedure:
2.45 g of 2-(2-bromophenyl)-N-(2-ethoxyethyl)ethanamine and 1.4 cm3 of triethylamine in solution in 22 cm3 of anhydrous tetrahydrofuran are stirred under an inert atmosphere at 0° C. 1.3 cm3 of methyl chloroformate in solution in 4 cm3 of tetrahydrofuran are poured into the reaction mixture. This mixture is then stirred for 20 h at a temperature close to 20° C. 50 cm3 of a saturated aqueous solution of ammonium chloride and 50 cm3 of ethyl acetate are added. After decanting, the organic phase is washed twice with 20 cm3 of water then 20 cm3 of a saturated aqueous solution of sodium chloride, it is dried over magnesium sulfate and filtered through a bed of silica of 30 g. The latter is washed twice with 75 cm3 of ethyl acetate. The filtrate is concentrated using a rotary evaporator under reduced pressure (5 kPa). 2.97 g of methyl[2-(2-bromophenyl)ethyl](2-ethoxyethyl)carbamate are obtained in the form of a yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[O:12])[C:10]=2[CH:11]=1)[CH3:2].[H-].[Na+].C1(S(OC)=O)C=CC=CC=1.O>O1CCCC1.C(O)(=O)C>[CH2:1]([C:3]1[N:4]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]2[C:10]([CH:11]=1)=[C:9]([OH:12])[CH:8]=[CH:7][CH:6]=2)[CH3:2]
Reactant: CCc1cc2c(n1Cc1ccccc1-c1ccccc1)CCCC2=O
Agent: COS(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCc1cc2c(O)cccc2n1Cc1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 39.3 %

Procedure:
2-Ethyl-1,5,6,7-tetrahydro-1-(2-phenyl-phenylmethyl)-4H-indol-4-one (2.17 g, 0.0066 mol) dissolved in 10 mL of tetrahydrofuran was added to a slurry of sodium hydride (0.58 g) in 3 mL of tetrahydrofuran and the mixture was stirred for 15 min at room temperature. Methyl benzene sulfinate (1.13 g) was added and the solution stirred overnight. The reaction mixture was poured into water, the pH adjusted to 6 with acetic acid and extracted with toluene. The organic layer was separated, washed with water and brine, dried with sodium sulfate, concentrated, taken up in toluene (80 mL) and heated at reflux for 1.5 h. After cooling, the mixture was concentrated, dissolved in ether (100 mL), washed with saturated sodium bicarbonate solution, dried over sodium sulfate, concentrated and purified by flash chromatography on silica eluting with 10:1 hexane/ethyl acetate to afford 0.85 g of subtitled material.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:19]=[CH:18][C:17]2[O:16][C:15]3[C:10](=[CH:11][C:12]([C:20](=[O:24])[CH2:21][CH2:22]Cl)=[CH:13][CH:14]=3)[CH2:9][C:8]=2[CH:7]=1)=[O:5].[I-].[K+].[CH2:27]([NH:29][CH2:30][CH3:31])[CH3:28].[ClH:32]>O1CCCC1>[OH2:5].[ClH:1].[ClH:32].[CH2:27]([N:29]([CH2:30][CH3:31])[CH2:2][CH2:3][C:4]([C:6]1[CH:19]=[CH:18][C:17]2[O:16][C:15]3[C:10](=[CH:11][C:12]([C:20](=[O:24])[CH2:21][CH2:22][N:29]([CH2:30][CH3:31])[CH2:27][CH3:28])=[CH:13][CH:14]=3)[CH2:9][C:8]=2[CH:7]=1)=[O:5])[CH3:28]
Reactant: O=C(CCCl)c1ccc2c(c1)Cc1cc(C(=O)CCCl)ccc1O2
Reactant: CCNCC
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCN(CC)CCC(=O)c1ccc2c(c1)Cc1cc(C(=O)CCN(CC)CC)ccc1O2
Product: O
Reaction time: 72 h

Procedure:
A mixture of 18.2 g (0.05 mole) of 2,7-bis(3-chloropropionyl)xanthene, 2 g of potassium iodide, 100 ml. of diethylamine and 100 ml. of tetrahydrofuran was allowed to stand for 3 days then filtered. The filtrate was evaporated to dryness leaving a residue which was treated with 10% HCl and filtered. The filtrate was made alkaline, extracted with methylene chloride and treated with ethereal HCl. The resulting precipitate was filtered, recrystallized from methanol-diethyl ether and hydrated in a constant humidity chamber to give the desired product. M.P. 184.5°-185.5°C.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([N:15]2[CH2:19][CH:18]([O:20][CH3:21])[CH:17]([O:22][CH3:23])[CH2:16]2)[CH:11]=[CH:12][C:13]=1I)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([C@:26]1([OH:34])[CH:31]2[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]2)[CH2:27]1)#[CH:25].C(N(CC)CC)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.CO.C(OCC)(=O)C>[CH2:1]([C:8]1[CH:9]=[C:10]([N:15]2[CH2:19][C@H:18]([O:20][CH3:21])[C@H:17]([O:22][CH3:23])[CH2:16]2)[CH:11]=[CH:12][C:13]=1[C:25]#[C:24][C@:26]1([OH:34])[CH:31]2[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]2)[CH2:27]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC1CN(c2ccc(I)c(Cc3ccccc3)c2)CC1OC
Reactant: C#C[C@@]1(O)CN2CCC1CC2
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CO[C@H]1CN(c2ccc(C#C[C@@]3(O)CN4CCC3CC4)c(Cc3ccccc3)c2)C[C@H]1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Then, a mixture of 340 mg of (3R,4S)-1-(3-benzyl-4-iodophenyl-3,4-dimethoxypyrrolidine, 134 mg of (3R)-3-ethynyl-3-quinuclidinol (Production Example 22), 9 mg of tetrakis(triphenylphosphine)palladium (0), 8 mg of copper (I) iodide, 0.22 ml of triethylamine and 0.8 ml of methanol was stirred under nitrogen atmosphere at room temperature for 4 hours. After ethyl acetate and methanol were added to the reaction mixture for dissolution, NH-silica gel was added thereto and the reaction mixture was evaporated. The residue was subjected to column chromatography using NH-silica gel with 50% ethyl acetate/hexane and 0–2.5% methanol/ethyl acetate, to give 220 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12](OC)=[O:13])[C:3]=1[C:16]([O:18]C)=O.O.[NH2:21][NH2:22]>C(O)C>[NH2:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[C:12](=[O:13])[NH:21][NH:22][C:16](=[O:18])[C:3]=12
Reactant: COC(=O)c1nc2ccccc2c(N)c1C(=O)OC
Reactant: NN
Solvent: CCO
Solvent: O
Product: Nc1c2ccccc2nc2c(=O)[nH][nH]c(=O)c12
Temperature: 25 °C
Yield: 98.8 %

Procedure:
To a stirred solution of dimethyl 4-aminoquinoline-2,3-dicarboxylate (0.15 g, 0.58 mM) in ethanol (4 mL) was added hydrazine hydrate (1.46 g, 29.2 mM) and the resulting solution was refluxed for 3 hr. The reaction mixture was cooled to room temperature and filtered to separate the yellow precipitate (0.12 g). This material was stirred in refluxing acetic acid (4.5 mL) for 1 hr. After cooling to room temperature the react!ion mixture was filtered and the collected solids washed with acetic acid and ethyl acetate. Air drying provided the title compound (0.13 g, 68%) as an orange solid, mp >400° C.; MS(CI): 229 (M+H).
Reaction SMILES: [F:1][C:2]1[C:14]([Sn](C)(C)C)=[CH:13][C:5]2[CH2:6][C:7](=[O:12])[CH:8]3[CH2:11][CH:10]([C:4]=2[CH:3]=1)[CH2:9]3.[I:19]I.BrC1C(F)=CC2C3CC(C(=O)CC=2C=1)C3.[SnH4]>C(Cl)(Cl)Cl>[F:1][C:2]1[C:14]([I:19])=[CH:13][C:5]2[CH2:6][C:7](=[O:12])[CH:8]3[CH2:11][CH:10]([C:4]=2[CH:3]=1)[CH2:9]3
Reactant: II
Reactant: C[Sn](C)(C)c1cc2c(cc1F)C1CC(C1)C(=O)C2
Agent: O=C1Cc2cc(Br)c(F)cc2C2CC1C2
Agent: [SnH4]
Solvent: ClC(Cl)Cl
Product: O=C1Cc2cc(I)c(F)cc2C2CC1C2
Yield: 45 %

Procedure:
To a rapidly stirred solution of crude of 3-fluoro-2-(trimethylstannyl)-6,7-dihydro-5H-5,7-methanobenzo[7]annulen-8(9H)-one (3.09 g at 37% purity LCMS-UV215) in chloroform (20 mL) at room temperature was introduced dropwise a solution of iodine (1.488 g, 5.86 mmol, 1.0 equivalent with respect to number of moles 5-bromo-4-fluorotricyclo[8.1.1.02,7]dodeca-2(7),3,5-trien-9-one used for stannane synthesis in previous synthetic step, as a saturated solution in chloroform). Following addition of the iodine solution, the reaction mixture was evaporated directly onto silica gel in vacuo. The dry-loaded material was purified by silica gel flash column chromatography (eluent: heptane/ethyl acetate gradient) to furnish the title compound (0.835 g, 2.64 mmol, 45% over 2 steps) as a yellow oil: 1H NMR (500 MHz, CDCl3) δ 2.08-2.14 (m, 2H), 2.87-2.96 (m, 2H), 3.22-3.28 (m, 1H), 3.48 (td, J=8.28, 3.63 Hz, 1H), 4.11 (s, 2H), 6.78 (d, J=8.51 Hz, 1H), 7.53 (d, J=6.31 Hz, 1H); M+H=317
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:14]=[CH:13][NH:12][N:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:8][C:7]1[C:2]([N:12]2[CH:13]=[CH:14][C:10]([Cl:9])=[N:11]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1cccnc1Cl
Reactant: Clc1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccn(-c2ncccc2Cl)n1
Temperature: 100 °C

Procedure:
To a mixture of 2,3-dichloropyridine (92.60 g, 0.629 mol) and 3-chloropyrazole (i.e. the product of Step B) (64.44 g, 0.629 mol) in N,N-dimethylformamide (400 mL) was added potassium carbonate (147.78 g, 1.06 mol), and the reaction mixture was then heated to 100° C. for 36 hours. The reaction mixture was cooled to room temperature and slowly poured into ice water. The precipitated solids were filtered and washed with water. The solid filter cake was taken up in ethyl acetate, dried over magnesium sulfate and concentrated. The crude solid was chromatographed on silica gel using 20% ethyl acetate/hexane as eluent to afford the title product as a white solid (39.75 g). 1H NMR (CDCl3) δ 6.43 (s, 1H), 7.26 (m, 1H), 7.90 (d, 1H), 8.09 (s, 1H), 8.41 (d, 1H).
Reaction SMILES: CCCCC.[CH2:6]([C:8]1([CH2:16][O:17][CH2:18][C:19]2([CH2:27][CH3:28])[CH2:24][O:23][CH:22]([CH:25]=[CH2:26])[O:21][CH2:20]2)[CH2:13][O:12][CH:11]([CH:14]=[CH2:15])[O:10][CH2:9]1)[CH3:7]>[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Fe].C(N(CC)CC)C>[CH2:6]([C:8]1([CH2:16][O:17][CH2:18][C:19]2([CH2:27][CH3:28])[CH2:24][O:23][C:22](=[CH:25][CH3:26])[O:21][CH2:20]2)[CH2:13][O:12][C:11](=[CH:14][CH3:15])[O:10][CH2:9]1)[CH3:7]
Reactant: C=CC1OCC(CC)(COCC2(CC)COC(C=C)OC2)CO1
Agent: [Fe]
Agent: [C-]#[O+]
Solvent: CCN(CC)CC
Solvent: CCCCC
Product: CC=C1OCC(CC)(COCC2(CC)COC(=CC)OC2)CO1
Temperature: 25 °C
Yield: 63.1 %

Procedure:
To 220 mL pentane in a 500 mL photochemical reactor was added 14.32 g (43.9 mmol) di[(5-ethyl-2-vinyl-[1,3]dioxan-5-yl)methyl]ether from the previous step. The solution was refluxed vigorously for 20 minutes to degas it, then 115 μL (171 μg, 0.87 μmol, 0.2 mol %) iron pentacarbonyl was added, and the solution refluxed for an additional 20 minutes. The resulting solution was irradiated for one hour, by when NMR showed no vinyl signals. After cooling to room temperature and the addition of 0.5 mL triethylamine, the solution was sparged with dry air for 4 hours. The pentane was removed by evaporation under reduced pressure, and the residual oil was distilled in a Kugelrohr apparatus (pot temperature 220° C., pressure 1–3 mbar) to give 9.04 g (63% yield) of di[(5-ethyl-2-ethylidene-[1,3]dioxan-5-yl)methyl] ether as a colorless oil. The identity of the product was confirmed by 1H NMR and mass spectra (observed: 363, 345, calculated for C18H35O7 (M+2H2O+H+): 363; calculated for C18H33O6 (M+H2O+H+): 345).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].[C:10]1([CH2:16][C@H:17]([NH:28][C:29]([O:31]C(C)(C)C)=O)[CH2:18][NH:19][C@H:20]([C:25]([OH:27])=O)[C@H:21]([CH2:23][CH3:24])[CH3:22])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N[C@H:37](C(O)=O)[CH2:38][SH:39]>>[C:10]1([CH2:16][C@H:17]([NH:28][C:29](=[O:31])[CH2:37][CH2:38][SH:39])[CH2:18][NH:19][C@H:20]([C:25]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6])=[O:27])[C@H:21]([CH2:23][CH3:24])[CH3:22])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CSCC[C@H](N)C(=O)O
Reactant: CC[C@H](C)[C@H](NC[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)O
Reactant: N[C@@H](CS)C(=O)O
Product: CC[C@H](C)[C@H](NC[C@H](Cc1ccccc1)NC(=O)CCS)C(=O)N[C@@H](CCSC)C(=O)O

Procedure:
N-(3-phenyl-2(S)-(mercaptopropionylamino)prop-1-yl)isoleucyl-methionine was prepared by coupling resin-bound methionine to N-(3-phenyl-2(S)-t-butoxycarbonylaminopropyl)isoleucine followed by deprotection, coupling with a protected cysteine and further processing under standard solid phase synthesis conditions. FAB MS m/z 484 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[O:6][C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=3[CH2:9][N:10]([C:11]([O:13][C:14](C)([CH3:16])[CH3:15])=[O:12])[C:4]=2[CH:3]=1.[CH:24]([N-]C(C)C)(C)C.[Li+].C1(=O)CCC1>C1COCC1>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[O:6][C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=3[CH:9]3[C:14]4([CH2:16][CH2:24][CH2:15]4)[O:13][C:11](=[O:12])[N:10]3[C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: CC(C)[N-]C(C)C
Agent: O=C1CCC1
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1OC2(CCC2)C2c3ccccc3Oc3ccc(Cl)cc3N12
Reaction time: 0.5 h
Yield: 36 %

Procedure:
To a stirred solution of 1.0 g (3.0 mmol) of 1 in 20 mL of anhydrous THF was added 1.2 equivalent of lithium diisopropylamide at -78°. After 30 minutes, approximately 2 equivalent of cyclobutanone was added as the electrophile. The stirring was continued for 3 hours at -78°, followed by room temperature overnight, and was quenched with saturated ammonium chloride solution. The mixture was diluted with ethyl acetate, washed with brine and dried with magnesium sulfate or sodium sulfate. Purification by HPLC on silica gel with 7% ethyl acetate/hexane as the eluent followed by lyophilization from acetonitrile/water gave 355 mg (36%) of Compound 21. 1H NMR (CDCl3): δ7.62 (s, 1H, ArH), 7.16-7.40 (m, 6H, ArH), 5.19 (s, 1H, ARCH), 2.75-2.84 (m, 1H, c-butyl), 2.45-2.60 (m, 1H, c-butyl), 2.28-2.42 (m, 1H, c-butyl), 2.12- 2.26 (m, 1H, c-butyl), 1.82-2.00 (m, 1H, c-butyl), 1.30-1.45 (m, 1H, c-butyl). FABMS: m/z 334 (M+Li). HRMS calculated for C18H14NO3LiCl (M+Li) 334.0822, found 334.0867. Analysis Calculated for C18H14NO3Cl: C, 65.96; H, 4.31; N, 4.27; Cl, 10.82. Found: C, 65.86; H, 4.31; N, 4.31; Cl, 10.46.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][OH:21])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[Br:35][C:36]1[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:38][C:37]=1[CH2:46]Br.[H-].[Na+]>CN(C=O)C>[CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][O:21][CH2:46][C:37]4[CH:38]=[CH:39][C:40]([C:42]([F:43])([F:45])[F:44])=[CH:41][C:36]=4[Br:35])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CO)nn23)CC1
Reactant: FC(F)(F)c1ccc(CBr)c(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(COCc4ccc(C(F)(F)F)cc4Br)nn23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
To a solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(hydroxymethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.200 g, 0.421 mmol) and 2-bromo-1-(bromomethyl)-4-(trifluoromethyl)benzene (0.268 g, 0.843 mmol) in DMF (1 mL) was added sodium hydride (0.051 g, 1.264 mmol). The mixture was stirred at rt. After 30 min, the reaction was quenched with water and extracted with EtOAc (3×'s). The organic phases were combined and washed with brine, dried, filtered and concentrated. The residue was purified by flash chromatography (Biotage; 0%-100% EtOAc/hexane; 25 CV) to give the title compound (0.200 g, 0.281 mmol, 66.7% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J=0.7 Hz, 1H), 7.73 (d, J=8.1 Hz, 1H), 7.59 (dd, J=8.6, 1.0 Hz, 1H), 6.59 (s, 1H), 6.02 (ddt, J=17.0, 10.4, 5.1 Hz, 1H), 5.95-5.85 (m, 1H), 5.53-5.39 (m, 1H), 5.19 (dd, J=10.5, 1.7 Hz, 1H), 4.87 (s, 2H), 4.77 (s, 2H), 4.30-4.14 (m, 2H), 4.02 (d, J=5.1 Hz, 2H), 2.62 (s, 3H), 2.06-1.61 (m, 3H), 1.35 (s, 3H), 1.25 (s, 12H) 5 piperidine protons not visible. LCMS (M+H) calcd for C33H43BrF3N4O5: 712.33. found: 713.4.
Reaction SMILES: [F:1][CH:2]([F:13])[C:3]1[C:7]([C:8](Cl)=[O:9])=[C:6]([F:11])[N:5]([CH3:12])[N:4]=1.[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[CH:22]([O:26][CH3:27])[CH:23]([NH2:25])[CH3:24].C(N(CC)CC)C.C(OCC)(=O)C>ClCCl>[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[CH:22]([O:26][CH3:27])[CH:23]([NH:25][C:8]([C:7]1[C:3]([CH:2]([F:13])[F:1])=[N:4][N:5]([CH3:12])[C:6]=1[F:11])=[O:9])[CH3:24]
Reactant: COC(c1ccc(Cl)cc1Cl)C(C)N
Reactant: Cn1nc(C(F)F)c(C(=O)Cl)c1F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(c1ccc(Cl)cc1Cl)C(C)NC(=O)c1c(C(F)F)nn(C)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.5 %

Procedure:
At ambient temperature, 233 mg (1.1 mmol) of 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carbonyl chloride and 234 mg (1 mmol) of 1-(2,4-dichlorophenyl)-1-methoxypropan-2-amine are dissolved in 10 ml of dichloromethane. 121 mg (1.2 mmol) of triethylamine are added and the reaction mixture is stirred for 4 hrs at ambient temperature. The mixture is diluted by 50 ml of ethyl acetate and successively washed by a 1 N solution of HCl (twice), a saturated solution of potassium carbonate (twice) and brine and dried over magnesium sulfate. The solvents are removed and the crude amide is purified by column chromatography on silica gel (gradient heptane/ethyl acetate) to yields 400 mg (97% yield) of N-[1-(2,4-dichlorophenyl)-1-methoxypropan-2-yl]-3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxamide as a pale yellow solid (M+H=410).