Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][C:5]2=O.P(Cl)(Cl)([Cl:21])=O.CN(C)[CH:26]=[O:27]>>[Cl:21][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[O:8][CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]=1[CH:26]=[O:27]
Reactant: O=C1CC(c2ccccc2)Oc2ccc(F)cc21
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)C=O
Product: O=CC1=C(Cl)c2cc(F)ccc2OC1c1ccccc1
Reaction time: 1 h

Procedure:
As in example 1, but using 10 g 6-fluoro-flavanone, 100 ml dimethylformamide and 15 ml phosphorous oxychloride. Reaction time is one hour and a half at 50° C. After hydrolysis a precipitate formed which is filtered, washed with water and dried over phosphorous pentoxyde. The residual solid is recrystallised in hexane and pure yellow crystalline 4-chloro-6-fluoro-3-formyl-flav-3-ene is obtained; m.p. 74°-75° C.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([C:8]([O:10][CH2:11][CH:12]2CC=C[CH2:13]2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C[N+]1([O-])CC[O:23]CC1.C(O)CCC.S(=O)(O)[O-].[Na+].[CH3:37][C:38]([CH3:40])=[O:39]>[Os](=O)(=O)(=O)=O.O>[N+:1]([C:4]1[CH:18]=[CH:17][C:7]([C:8]([O:10][CH2:11][CH:12]2[CH2:40][CH:38]([OH:39])[CH:37]([OH:23])[CH2:13]2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(OCC1CC=CC1)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)=O
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCCCO
Solvent: O
Product: O=C(OCC1CC(O)C(O)C1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Osmium tetroxide (235 μL, 0.75 mmol) was added to a solution of cyclopent-3-en-1-ylmethyl 4-nitrobenzoate (3.70 g, 15.0 mmol) and 4-methylmorpholine N-oxide (1.93 g, 16.5 mmol) in tent-butanol (6.7 mL)/water (40 mL)/acetone (13.3 mL). The solution was stirred at room temperature for 16 hours. Aqueous sodium bisulfite solution was added, and the solution was stirred for 30 min. The solution was then extracted with ethyl acetate, and the combined organic layers were dried (magnesium sulfate), filtered, and concentrated in vacua. The residue was purified by silica gel chromatography (Biotage 65i), eluting with 0-100% ethyl acetate/hexanes to give the title compound as a colorless oil. 1H NMR (500 MHz, CHCl3) δ 1.67-1.75 (m, 2H), 1.95-2.00 (m, 2H), 2.80-2.85 (m, 1H), 4.21 (quintet, J=4.1 Hz, 2H), 4.26 (d, J=6.7 Hz, 2H), 8.19 (d, J=8.7 Hz, 2H), 8.29 (d, J=8.7 Hz, 2H).
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].Br[C:19]1[S:23][C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C>[CH3:17][C:3]1([C:1]#[C:2][C:19]2[S:23][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:21][CH:20]=2)[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1
Reactant: Brc1ccc(-c2ccccn2)s1
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1ccc(-c3ccccn3)s1)O2
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.4 %

Procedure:
A mixture of 2.3 g of rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol, 3.6 g (15 mmol) of 2-(5-bromo-2-thienyl)pyridine, 0.39 g of triphenylphosphine, 95 mg of cuprous iodide, 3 ml of triethylamine and 100 ml of acetnitrile was degassed with argon for 10 minutes. Palladium acetate, 110 mg, was then added and the mixture was stirred at room temperature for 18 hrs. After evaporation under reduced pressure, the residue was partitioned between methylene chloride and water. The organic layer was dried and evaporated and the residue was chromatographed over 140 g of silica gel using 5% of ethyl acetate in methylene chloride. The combined clean fractions were evaporated and the residue was crystallized from ether/hexane to yield 2 g of colorless crystals with m.p 159°-162°. The analytical sample was recrystallized from ethanol and had m.p. 160°-162°.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1>ClCCl>[N:8]1([C:5](=[O:7])[CH3:6])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: c1ccc2c(c1)CCCN2
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)N1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
Acetic anhydride (55.5 g; 1.05 equiv.) was slowly added dropwise, at 0° C., to a solution of 1,2,3,4-tetrahydroquinoline (69 g; 1 equiv.) in 690 ml of dichloromethane. The reaction mixture was stirred for 30 minutes at room temperature and, when the conversion was complete, was washed with cold water and sodium hydrogen carbonate solution. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. 1-(3,4-Dihydroquinolin-1(2H)-yl)ethanone (85 g; 94.4%) was obtained in the form of a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]OS(C)(=O)=O)=[N:6][CH:7]=1.[N-:14]=[N+]=[N-].[Na+]>CN(C=O)C.CCCCCC.CCOC(C)=O>[NH2:14][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCc1ccc(F)cn1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: NCc1ccc(F)cn1
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
Dissolve methanesulfonic acid (5-fluoro-pyridin-2-yl)-methyl ester (1.5 g, 7.3 mmol) in DMF (5 mL) and add sodium azide (950 mg, 14.6 mmol). Stir the mixture for 30 min, then dilute with hexane/EtOAc (1:1, 50 mL). Wash the mixture with 10% aqueous NaCl (3×10 mL). Dry the combined organic extracts over Na2SO4 and remove half of the solvent in vacuo. Add EtOAc (20 mL) and a suspension of 10% Pd/C (200 mg) in EtOAc (2 mL). Stir the mixture for 1 h at ambient temperature in a pressurized vessel under 50 psi of hydrogen. Filter the slurry through Celite® and concentrate in vacuo to obtain 2-aminomethyl-5-fluoro-pyridine (613 mg, 60% yield, 80% purity by GC/MS). GC-MS m/z: 126 (M+).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH2:9](Br)[CH:10]=[CH2:11].[H-].[Na+].Br[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1>>[O:4]=[C:3]([CH2:5][CH2:11][CH:10]=[CH2:9])[CH2:2][C:1]([O:7][CH3:8])=[O:6].[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH:9]=[CH:10][CH2:11][CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH3:8])=[O:6])[CH:17]=1
Reactant: Brc1cccnc1
Reactant: COC(=O)CC(C)=O
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Product: C=CCCC(=O)CC(=O)OC
Product: COC(=O)CC(=O)CCC=Cc1cccnc1

Procedure:
Methyl 3-oxo-hept-6-enoate is prepared e.g. by condensation of methyl acetoacetate with allyl bromide in the presence of sodium hydride. Condensation with 3-bromopyridine under conditions of a Heck condensation yields methyl 7-(3-pyridyl)-3-oxo-hept-6-enoate. Condensation thereof with e.g. 4-iodobutyronitrile in the presence of sodium hydride leads to methyl 2-(3-cyanopropyl)-7-(3-pyridyl)-3-oxo-hept-6-enoate. Decarboxylation thereof e.g. with sodium chloride in dimethylsulfoxide/water yields 10-(3-pyridyl)-6-oxo-dec-9-enenitrile. This is subjected to Wittig type condensation with triethyl phosphonoacetate followed by hydrogenation e.g. with Raney nickel catalyst in e.g. methanol/ammonia to yield ethyl 7-(3-pyridyl)-3-(5-aminopentyl)-hept-2-enoate. Further hydrogenation with Pd/C catalyst yields the amine of formula XII wherein Het represents 3-pyridyl, A represents 1,5-pentylene, B represents 1,4-butylene and M represents methylene, as the ethyl ester.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.Br.[CH2:35]1[C:38]2([CH:42]([NH:43][C:44]3[C:45]4[N:46]([CH:53]=[C:54]([C:56]5[CH:57]=[N:58][N:59]([CH3:61])[CH:60]=5)[CH:55]=4)[N:47]=[CH:48][C:49]=3[C:50]([NH2:52])=[O:51])[CH2:41][NH:40][CH2:39]2)[CH2:37][CH2:36]1.[CH:62]1([C:65]([O-])=[O:66])[CH2:64][CH2:63]1>CN(C=O)C>[CH:62]1([C:65]([N:40]2[CH2:41][C@@H:42]([NH:43][C:44]3[C:45]4[N:46]([CH:53]=[C:54]([C:56]5[CH:57]=[N:58][N:59]([CH3:61])[CH:60]=5)[CH:55]=4)[N:47]=[CH:48][C:49]=3[C:50]([NH2:52])=[O:51])[C:38]3([CH2:37][CH2:36][CH2:35]3)[CH2:39]2)=[O:66])[CH2:64][CH2:63]1
Reactant: Cn1cc(-c2cc3c(NC4CNCC45CCC5)c(C(N)=O)cnn3c2)cn1
Reactant: O=C([O-])C1CC1
Agent: Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2cc3c(N[C@@H]4CN(C(=O)C5CC5)CC45CCC5)c(C(N)=O)cnn3c2)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 200 uL aliquot of HATU (23.41 mg, 0.062 mmol) and diisopropylethylamine (21.51 μl, 0.123 mmol) were added to a 200 uL aliquot of 4-(6-azaspiro[3.4]octan-8-ylamino)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide HBr (from Step 6, 15 mg, 0.041 mmol) and cyclopropane carboxylate (1.5 equiv.) in DMF. The reaction was stirred for 3 h at room temperature. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 0-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound (3.9 mg). 1H NMR (500 MHz, METHANOL-d4/CDCl3) δ 8.11 (d, J=11.9 Hz, 1H), 7.80 (d, J=9.9 Hz, 1H), 7.78-7.71 (m, 2H), 6.91 (dd, J=14.1, 1.7 Hz, 1H), 4.83-4.75 (m, 1H), 4.13 (dd, J=10.4, 5.0 Hz, 1H), 4.07-3.99 (m, 1H), 3.96 (s, 1.5H), 3.94 (s, 1.5H), 3.98-3.76 (m, 2H), 2.37 (dd, J=11.1, 7.2 Hz, 1H), 2.28-1.95 (m, 5H), 1.12-0.70 (m, 4H)
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].[N:21]1[NH:22][C:23](=[O:27])[CH:24]=[CH:25][CH:26]=1.O>CN(C=O)C>[O:27]=[C:23]1[N:22]([CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[N:21]=[CH:26][CH:25]=[CH:24]1
Reactant: O=c1cccn[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC(Br)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncccc2=O)CC1
Temperature: 45 °C
Yield: 17 %

Procedure:
tert-Butyl 4-bromo-1-piperidinecarboxylate (1.00 g, 3.78 mmol) in DMF (20 mL) was treated with K2CO3 (523 mg, 3.78 mmol) and 3(2H)-pyridazinone (340 mg, 3.78 mmol) and then heated at 45° C. for 60 hours. The reaction mixture was allowed to cool to room temperature, poured into water (80 mL) and extracted with ethyl acetate (80 mL). The organic layer was washed with brine (3×50 mL), dried over MgSO4, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (elution with hexanes:ethyl acetate, 3:1) to provide the title compound (180 mg, 17% yield). 1H NMR (300 MHz, DMSO-d6) δ 1.41 (s, 9H), 1.66 (m, 4H), 2.91 (m, 2H), 4.05 (m, 2H), 4.96 (m, 1H), 6.93 (dd, 1H, J=1.5, 9.0 Hz), 7.39 (dd, 1H, J=3.0, 9.0 Hz), 7.95 (dd, 1H, J=3.0, 9.0 Hz); (MS (DCI/NH3) m/e 280 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][C:3]=1[NH2:4].CC(C)=O.[C:15](Cl)(=[O:19])[C:16]([CH3:18])=[CH2:17]>COC1C=CC(O)=CC=1.N1C=CC=CC=1>[OH:1][C:2]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:15](=[O:19])[C:16]([CH3:18])=[CH2:17]
Reactant: N#Cc1ccc(N)c(O)c1
Reactant: C=C(C)C(=O)Cl
Agent: COc1ccc(O)cc1
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: C=C(C)C(=O)Nc1ccc(C#N)cc1O
Yield: 58 %

Procedure:
400 g of o-hydroxy-p-cyanoaniline, 4 g of hydroquinone monomethyl ether, 4 litres of acetone, and 360 g of pyridine were mixed and the mixture was cooled externally with a freezing medium. At a point when the internal temperature of the solution had dropped to -10° C., 420 g of methacrylic acid chloride was added dropwise to the mixture with stirring. Thereafter the mixture was treated in the same way as in Synthesis Example 1 to obtain 350 g of o-hydroxy-p-cyanomethacrylanilide. 76.8 g (0.38 mol) of this o-hydroxy-p-cyanomethacrylanilide was dissolved together with 68.4 g (0.60 mol) of ethyl methacrylate, 1.44 g (0.02 mol) of acrylic acid and 0.7 g of α,α'-azobisisobutyronitrile in 300 ml of an acetone/ethanol (1/2) mixed solvent. After replacing the atmosphere with nitrogen gas, the solution was heated at 65° C. for 4 hours to obtain a polymer solution. This polymer solution was poured into 3 litres of aqueous 5% HCl solution and the produced white precipitate was filtered and dried, giving 75 g of a white polymer. Determination of molecular weight of this polymer by the GPC method showed Mn=4,700 and Mw=33,000.
Reaction SMILES: [N:1]([C:4]1[C:5]([Cl:23])=[C:6]2[CH:12]=[CH:11][N:10]([Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[C:7]2=[N:8][CH:9]=1)=[N+]=[N-].[H][H]>C(OCC)(=O)C.[Pd]>[Cl:23][C:5]1[C:4]([NH2:1])=[CH:9][N:8]=[C:7]2[N:10]([Si:13]([CH:17]([CH3:19])[CH3:18])([CH:20]([CH3:22])[CH3:21])[CH:14]([CH3:15])[CH3:16])[CH:11]=[CH:12][C:6]=12
Reactant: [H][H]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)c(N=[N+]=[N-])cnc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)c(N)cnc21
Temperature: 25 °C
Yield: 49 %

Procedure:
4-Chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (10 g, 32.5 mmol) was dissolved in THF (250 mL) and cooled to −78° C. Sec-Butyllithium ( 54.8 mL, 1.3M/cyclohexane, 71.4 mmol.) was then added dropwise and the solution was stirred for 20 min. A solution of tosylazide (16 g, 81.2 mmol.) in THF (100 mL) was added and the mixture was stirred for 1 h. The reaction mixture was quenched with saturated ammonium chloride (50 mL) and warmed to RT. This mixture was extracted with hexanes (2×200 mL) and the combined organic layers were dried. The organic phase was filtered and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 100% hexanes) to afford 5-azido-4-chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine as a mixture with starting material (10.2 g). This mixture was directly used in next step. B. 5-Azido-4-chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (1.6 g, 4.6 mmol) was dissolved in ethyl acetate (100 mL) and Pd/C (10%, 100 mg) was added. This suspension was stirred at RT and under 1 atmosphere. of hydrogen for 18 h. The solid was removed by filtration over Celite® and the solution was evaporated in vacuo. The crude product was purified by flash chromatography (silica gel, 95% hexanes, 5% ethyl acetate) to afford 4-chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-ylamine (730 mg, 43.5%, 2 steps). C. 4-Chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-ylamine (10.2 g, 31.5 mmol) was diluted in ethyl acetate (200 mL) and acetic acid (100 mL). Zinc dust (50 g, 0.8 mol.) was added in small portions at RT. After stirring the suspension at RT for 4 h, the mixture was filtered over Celite and the filtrate was slowly neutralized with saturated sodium bicarbonate and extracted with ethyl acetate (2×300 mL). The combined organic layers were dried, filtered and evaporated in vacuo. The crude product was purified by flash chromatography (silica gel, 5% ethyl acetate in hexanes) to afford 1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-ylamine (6.38 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])[O:28][C:29](Cl)(Cl)Cl)Cl.[F:35][C:36]1[CH:46]=[CH:45][CH:44]=[CH:43][C:37]=1[O:38][CH2:39][CH2:40]CO>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:28][CH2:29][CH2:40][CH2:39][O:38][C:37]2[CH:43]=[CH:44][CH:45]=[CH:46][C:36]=2[F:35])=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: OCCCOc1ccccc1F
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCCCOc4ccccc4F)cc3)c2cc1OC
Temperature: 25 °C
Yield: 51.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (70 mg) was added to toluene/triethylamine=10/1 (7 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (106 mg) in methylene chlorides was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-(2-fluorophenoxy)-1-propanol (60 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (60 mg, yield 55%).
Reaction SMILES: C(O[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(C)(C)C.[NH2:13][CH2:14][CH2:15][CH2:16][NH2:17]>C(Cl)Cl>[C:8]([O:7][C:6]([NH:13][CH2:14][CH2:15][CH2:16][NH2:17])=[O:12])([CH3:9])([CH3:10])[CH3:11]
Reactant: NCCCN
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCN
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of 46 g of di-tert-butyl-carbonate in 120 ml of methylene chloride was added at +5° C. without exceeding +10° C. to a solution of 36 ml of 1,3-diamino-propane in 160 ml of methylene chloride and after stirring for 16 hours at 20° C., the insoluble part was filtered off. The filtrate was evaporated to dryness under vacuum to obtain 63 g of residue which was chromatographed on silica (eluant: methanol with 2% ammonia) to obtain 23 g of the expected product melting at <60° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH2:5]Cl.[C-:11]#[N:12].[Na+]>CS(C)=O.C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][C:11]#[N:12])[CH:7]=[C:8]([Cl:10])[CH:9]=1
Reactant: [C-]#N
Reactant: ClCc1cc(Cl)cc(Cl)c1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: N#CCc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 51.8 %

Procedure:
3,5-Dichlorobenzyl chloride (315.6 mg, 1.615 mmol), 0.2 molar in DMSO, was treated with sodium cyanide (158.2 mg, 3.229 mmol) and allowed to stir at ambient temperature for 24 hours. After 24 hours the reaction mixture was diluted with diethyl ether and partitioned between saturated aqueous sodium chloride. The organic layer was dried with magnesium sulfate, filtered, and concentrated to provide the title compound (155.5 mg, 0.836 mmol, 51.8% yield) as a dark red oil.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17]([N:22]3[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][N:30]([CH3:40])[S:31]([C:34]4[CH:35]=[N:36][N:37]([CH3:39])[CH:38]=4)(=[O:33])=[O:32])[CH2:24][CH2:23]3)=[N:18][CH:19]=[CH:20][N:21]=2)=[CH:12][CH:11]=1.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>ClCCl.[Cl-].[Na+].O>[CH3:40][N:30]([S:31]([C:34]1[CH:35]=[N:36][N:37]([CH3:39])[CH:38]=1)(=[O:33])=[O:32])[CH2:29][CH2:28][N:25]1[CH2:24][CH2:23][N:22]([C:17]2[C:16]([C:13]3[CH:14]=[CH:15][C:10]([CH2:9][O:8][S:42]([CH3:41])(=[O:44])=[O:43])=[CH:11][CH:12]=3)=[N:21][CH:20]=[CH:19][N:18]=2)[CH2:27][CH2:26]1
Reactant: CN(CCN1CCN(c2nccnc2-c2ccc(CO)cc2)CC1)S(=O)(=O)c1cnn(C)c1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CN(CCN1CCN(c2nccnc2-c2ccc(COS(C)(=O)=O)cc2)CC1)S(=O)(=O)c1cnn(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Add triethylamine (0.653 mmol, 0.091 mL) to a stirred solution of 1-methyl-1H-pyrazole-4-sulfonic acid {2-[3′-(4-hydroxymethyl-phenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl]-ethyl}-methyl-amide (0.594 mmol, 0.280 g) in dry dichloromethane (5 mL) at room temperature under nitrogen. Add methanesulfonyl chloride (0.653 mmol, 0.051 mL). Allow the mixture to warm to room temperature and stir 1 hr. Dilute with dichloromethane and brine. Separate and extract the aqueous phase with dichloromethane. Combine organics, dry over Na2SO4, and concentrate to dryness to afford the title preparation (0.330 g, crude). The material is used without further purification. MS ES: m/z=550 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH2:10]O)=[C:4]([O:12][CH3:13])[CH:3]=1.[BrH:14]>C(Cl)Cl>[Br:14][CH2:10][C:5]1[CH:6]=[C:7]([O:8][CH3:9])[C:2]([Cl:1])=[CH:3][C:4]=1[O:12][CH3:13]
Reactant: COc1cc(CO)c(OC)cc1Cl
Reactant: Br
Solvent: ClCCl
Product: COc1cc(CBr)c(OC)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
(Bloomer et al., Tetrahedron Lett. 1989, 30, 1201-1204.) To a stirred solution of 2 (5.00 g, 24.7 mmol, 1 equiv) in CH2Cl2 (125 mL) at 0° C. was added dropwise HBr (47-49% solution; 4.13 mL, 74.0 mmol, 3 equiv). The resulting solution was allowed to slowly warm to room temperature and stir overnight (˜16 h). The following morning a second batch of HBr (47-49% solution; 4.13 mL, 74.0 mmol, 3 equiv) was added to the reaction mixture, which was allowed to stir for an additional 4 h. The crude mixture was extracted with Et2O (×2), washed with water, a saturated aqueous solution of NaHCO3, brine, dried (MgSO4), filtered, and concentrated under reduced pressure to give 6.55 g (100% yield) of 3 as a white solid: Mp 85-88° C.; Rf 0.31 (EtOAc/hexanes, 3:7); IR (neat) 2962, 2947, 2844, 1732, 1582, 1495, 1458, 1443, 1389, 1301, 1204, 1182, 1033, 882 cm−1; 1H NMR (400 MHz, CDCl3) δ 6.91-6.90 (m, 2 H), 4.50 (s, 2 H), 3.84 (s, 3 H), 3.82 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 151.3, 148.9, 125.1, 123.2, 114.6, 113.6, 56.6, 56.2, 28.2.
Reaction SMILES: Cl[C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=2[CH3:15])=[O:7])=[CH:4][CH:3]=1.[F-:18].[Cs+].CN1CCCC1=O.C1C=CC=CC=1>O>[F:18][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=2[CH3:15])=[O:7])=[CH:4][CH:3]=1
Reactant: [F-]
Reactant: Cc1ccc(C(=O)c2ccc(Cl)cc2)c(C)c1
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: c1ccccc1
Product: Cc1ccc(C(=O)c2ccc(F)cc2)c(C)c1
Reaction time: 15 h
Yield: 78 %

Procedure:
To a mixture of 12.2 g (0.05 mols) of 4-chloro-2',4'-dimethylbenzophenone, 12.1 g (0.08 mols) of cesium fluoride and 20 g of N-methylpyrrolidone were 5 ml of benzene added and water in the reaction system was removed together with benzene by azeotropy. The reaction was carried out under nitrogen atmosphere under reflux by heating while stirring for 15 hours. After cooling, the reaction product obtained was poured into 100 ml of water and then, extracted with 50 ml of diethyl ether and further with 50 ml of ether. The extracts together were dried and distilled and thus, 8.9 g of 4-fluoro-2',4'-dimethylbenzophenone were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:15]3[C:11](=[N:12][N:13]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:33][CH3:34])[C:14]=3[CH:24]([CH3:26])[CH3:25])[C:10]2=[O:35])[CH:5]=[CH:6][C:7]=1[F:8].C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[C:47]([O:49][CH2:50][CH3:51])=[O:48]>>[CH2:50]([O:49][C:47]([C:16]1([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[C:15]2[C:11](=[N:12][N:13]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])[C:14]=2[CH:24]([CH3:26])[CH3:25])[C:10](=[O:35])[N:9]1[C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1)=[O:48])[CH3:51]
Reactant: COc1ccccc1-n1nc2c(c1C(C)C)C(c1ccc(Cl)cc1)N(c1ccc(F)c(Cl)c1)C2=O
Reactant: CCOC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: CCOC(=O)C1(c2ccc(Cl)cc2)c2c(nn(-c3ccccc3OC)c2C(C)C)C(=O)N1c1ccc(F)c(Cl)c1

Procedure:
The title compound was prepared in analogy to the procedure described for example 74 but using the compound prepared in example 88, 1 equivalent of KHMDS and 5 equivalents of ethyl chloroformate. No purification was performed. tR: 1.42 min (LC-MS 1); ESI-MS: 582.2 [M+H]+ (LC-MS 1).