Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[CH:4][C:5]2[C:6]([CH:11]=1)=[N+:7]([O-])[O:8][N:9]=2.C(OP(OCC)OCC)C>C(O)C>[Br:1][C:2]1[C:3]([F:12])=[CH:4][C:5]2=[N:9][O:8][N:7]=[C:6]2[CH:11]=1
Reactant: [O-][n+]1onc2cc(F)c(Br)cc21
Agent: CCOP(OCC)OCC
Solvent: CCO
Product: Fc1cc2nonc2cc1Br
Temperature: 45 °C
Reaction time: 1.5 h
Yield: 72.4 %

Procedure:
6-bromo-5-fluorobenzo[c][1,2,5]oxadiazole 1-oxide (3.2 g, 14 mmol) was stirred in 30 mL ethanol, treated with triethylphosphite (3.4 g, 21 mmol) and heated to 45° C. After 90 min, the mixture was cooled and the volatiles were removed by rotary evaporation. The crude product was chromatographed on silica gel with a 0-10% ethyl acetate-hexane gradient to give the title compound as tan crystals (2.2 g, 73%): mp 59-61° C.; 1H NMR (400 MHz, CDCl3) δ 8.23 (dt, J=2.8, 1.4 Hz, 1H), 7.53 (m, 1H); 19F NMR (376 MHz, CDCl3) δ −96.99; EIMS m/z 216.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([N:13]([CH2:17][CH2:18][OH:19])[CH2:14][CH2:15][OH:16])=[N:10][C:9]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>ClCCl>[CH2:1]([C:8]1[S:12][C:11]([N:13]([CH2:17][CH2:18][OH:19])[CH2:14][CH2:15][OH:16])=[N:10][C:9]=1[C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2nc(N(CCO)CCO)sc2Cc2ccccc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: OCCN(CCO)c1nc(-c2ccc(O)cc2)c(Cc2ccccc2)s1
Yield: 54.7 %

Procedure:
A procedure similar to that in Example 74 was used. 2-[[5-benzyl-4-(4-methoxy-phenyl)-thiazol-2-yl]-(2-hydroxy-ethyl)-amino]-ethanol prepared in Example 73 and a solution of boron tribromide in dichloromethane were used as starting materials. The obtained crude product was recrystallized with acetone to give a product as a white solid in a yield of 54.7%, mp: 167-168 └. 1H-NMR (DMSO-d6, 400 MHz) δ: 3.46 (2H, t, J=6.40 Hz, CH2), 3.59 (2H, t, J=6.40 Hz, CH2), 4.04 (2H, s, CH2), 4.88 (2H, t, J=5.20 Hz, 2×OH), 6.78 (2H, d, J=8.80 Hz, ArH), 7.15˜7.28 (5H, m, ArH), 7.36 (2H, d, J=8.80 Hz, ArH), 9.54 (1H, br, OH); EI-MS m/e (%): 370.1 (M+, 75), 339.1 (74), 309.0 (17), 295.0 (100); HREI-MS Calcd. for C20H22N2O3S: 370.1351. found: 370.1349. Anal. Calcd. for C20H22N2O3S: C, 64.84; H, 5.99; N, 7.56. found: C, 64.86; H, 5.89; N, 7.61.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][O:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][C:12]([CH2:18][N:19]1[C:24](=[O:25])[CH:23]=[CH:22][C:21]([CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:20]1)=[CH:13]2)=[O:5])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:44]>ClCCl>[CH2:1]([O:3][C:4]([CH2:6][O:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][C:12]([CH2:18][N:19]1[C:24](=[O:25])[CH:23]=[CH:22][C:21]([CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:20]1)([OH:44])[CH2:13]2)=[O:5])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)COc1cccc2c1CCC(Cn1nc(C(c3ccccc3)c3ccccc3)ccc1=O)=C2
Solvent: ClCCl
Product: CCOC(=O)COc1cccc2c1CCC(O)(Cn1nc(C(c3ccccc3)c3ccccc3)ccc1=O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.6 %

Procedure:
A solution of 2-[(3,4-dihydro-5-ethoxycarbonylmethoxy-2-naphthyl)methyl]-6-diphenylmethyl-3(2H)-pyridazinone (0.20 g) and 3-chloroperoxybenzoic acid (94 mg) in dichloromethane (5 ml) was allowed to stand in a freezer (about -15° C.) for overnight. The reaction mixture was evaporated in vacuo and the residue was partitioned between ethyl acetate and sodium hydrogencarbonate solution. The organic layer was separated and washed with water, brine, dried over magnesium sulfate and evaporated in vacuo. The residue and 10% palladium on carbon in ethyl acetate (5 ml) and acetic acid (one drop) were stirred under hydrogen (1 atm) at room temperature for 4 hours. The catalyst was filtered off and the filtrate was evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane-ethyl acetate=2:1~1:1) to give 2-[(1,2,3,4-tetrahydro-5-ethoxycarbonylmethoxy-2-hydroxy-2-naphthyl)methyl]-6-diphenylmethyl-3(2H)-pyridazinone (0.08 g) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3]([NH2:5])=[NH:4].C(=O)([O-])[O-].[K+].[K+].C([O:16][C:17](=O)[CH2:18][C:19]([CH2:21][Cl:22])=O)C>O>[Cl:22][CH2:21][C:19]1[N:5]=[C:3]([C:2]([Cl:7])([Cl:6])[Cl:1])[N:4]=[C:17]([OH:16])[CH:18]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: N=C(N)C(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Oc1cc(CCl)nc(C(Cl)(Cl)Cl)n1
Reaction time: 18 h
Yield: 36.1 %

Procedure:
A mixture of 30.0 g (0.18 mole) trichloroacetamidine, 25.2 g (0.18 mole) potassium carbonate, 30.3 g (0.18 mole) ethyl-4-chloroacetoacetate and 400 ml water was stirred 18 hours. The aqueous solution was filtered and acidified with hydrochloric acid to give a precipitate. The precipitate was washed and dried to give 17.0 g (36% yield) of crude product. An analytical sample recrystallized from ligroin had mp 138°-144° C. The structure was confirmed via infrared and elemental analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([CH2:21]OS(C)(=O)=O)[C:13](=[O:20])[N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[N:27]1([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[C:36]([O:35][C:33]([N:27]1[CH2:32][CH2:31][N:30]([CH2:21][C:12]2[C:13](=[O:20])[N:14]([CH2:16][CH:17]([CH3:18])[CH3:19])[N:15]=[C:10]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[CH:3]=3)[CH:11]=2)[CH2:29][CH2:28]1)=[O:34])([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)cc1Cl
Product: COc1ccc(-c2cc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(=O)n(CC(C)C)n2)cc1Cl
Yield: 89 %

Procedure:
Following the procedure of Example 1(10), 6-(3-chloro-4-methoxyphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reacted to yield the title compound as a yellow oil (yield: 89.0%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.Cl[CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: ClCCCN1CCOCC1
Reactant: COc1cc2c(Cl)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Cl)ccnc2cc1OCCCN1CCOCC1
Temperature: 90 °C

Procedure:
To a solution of 4-chloro-6-methoxyquinolin-7-ol (1.0 g, 4.77 mmol) and 4-(3-chloropropyl)morpholine (0.86 g, 5.25 mmol)in DMF (9.5 mL), was added potassium carbonate (2.0 g, 14.3 mmol). The mixture was heated to 90° C. for 15 h. After cooling RT, the mixture was diluted with H2O (30 mL). The mixture was extracted with EtOAc (3×25 mL) and the organic extracts were washed with H2O and brine. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (5% MeOH/CH2Cl2) to yield the title compounds as a light yellow solid. MS (ESI, pos. ion) m/z: 337 (M+1). Mass Calc'd for C17H22ClN2O3: 336.1.
Reaction SMILES: [C:1]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]=[C:21]([P:26](=[O:29])([OH:28])[OH:27])[P:22](=[O:25])([OH:24])[OH:23])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[O-]CC.[Na+:33].C(O)C>O1CCCC1>[C:1]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]=[C:21]([P:26](=[O:27])([O-:28])[O-:29])[P:22](=[O:23])([OH:24])[OH:25])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[Na+:33].[Na+:33]
Reactant: CCCCCCCCCCCC#Cc1ccccc1C=C(P(=O)(O)O)P(=O)(O)O
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCCCCCCCCC#Cc1ccccc1C=C(P(=O)([O-])[O-])P(=O)(O)O
Reaction time: 0.33 h
Yield: 94 %

Procedure:
[2-[2-(1-Tridecynyl)phenyl]ethenylidene]bisphosphonic acid (0.101 g, 0.228 mmol) prepared according to Example 10 was dissolved in dry tetrahydrofuran (10 ml) and stirred while sodium ethoxide in ethanol (0.177M, 2.58 ml, 0.457 mmol) was added. After 20 minutes, the solvent was removed under reduced pressure to give a yellowish solid. This solid was pulverized and washed successively with dry ether, tetrahydrofuran, acetone, acetonitrile, and ethanol, then dried on the vacuum line, 0.104 g, 0.214 mmol, 94% yield. 1H NMR (D2O) ∂ 0.74 (m, 3H), 1.17 (m, 14H), 1.35 (m, 2H), 1.52 (m, 2H), 2.39 (t, J=7.1H, 2H), 7.24 (m, 2H), 7.37 (m, 1H), 7.92 (dd+m, J=43.8, 27.0 Hz, 2H); FAB mass spectrum m/z 443 (M-2Na+3H)+, 465 (M-Na+2H)+, 487 (M+H)+.
Reaction SMILES: O1CCCC1.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14]#[N:15])=[CH:9][CH:8]=1.CC(C)([O-])C.[K+].[CH3:31][N:32]=[C:33]=[S:34]>O>[CH3:31][NH:32][C:33](=[S:34])[C:13]([C:10]1[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=1)([C:14]#[N:15])[CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CN=C=S
Reactant: N#CC(CCCc1ccccc1)c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CNC(=S)C(C#N)(CCCc1ccccc1)c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
To a tetrahydrofuran solution containing 1.78 g (6.6 mmole) of 2-(4-chlorophenyl)-5-phenylvaleronitrile was added a tetrahydrofuran solution containing 0.77 g (6.9 mmole) of potassium tert-butoxide at 0° C. After stirring for 30 minutes, a tetrahydrofuran solution containing 0.5 g (6.8 mmol) of methyl isothiocyanate was added to the mixture and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, dried and condensed under reduced pressure, and then purified by silica gel chromatography to obtain 1.19 g (yield: 52.4 %) of N-methyl-2-(4-chlorophenyl)-2-cyano-5-phenylthiovaleroamide as a crystal.
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]([NH2:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22].C(O[Na])(C)(C)C>C1(C)C=CC=CC=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[NH:7][C:2]1[C:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccccc1Br
Reactant: Nc1ccccc1-c1ccccc1
Agent: CC(C)(C)O[Na]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: COc1ccccc1Nc1ccccc1-c1ccccc1
Temperature: 110 °C
Yield: 82.1 %

Procedure:
Trisdibenzylideneacetonedipalladium (0.276 g, 0.3 mmol) and tri-tert-butylphosphine (0.121 g, 0.6 mmol) were put into a flask, and then dissolved in 40 mL of toluene. Subsequently, 2-biphenylamine (2.53 g, 15 mmol), 1-bromo-2-methoxybenzene (2.81 g, 15 mmol) and tert-butoxy sodium (2.16 g, 22.5 mmol) were added into the flask, and then refluxed at a temperature of 110° C. for 12 hours. After cooling the flask including the reactant mixture to room temperature, the reactant mixture was washed using an ammonium chloride aqueous solution (150 mL) to separate an organic layer. The separated organic layer was washed with distilled water three times, and was then dried with magnesium sulfate. Thereafter, residues from which volatile components were removed at reduced pressure were purified using a silica gel chromatography tube in a mixed solvent of hexane and ethylacetate (1:10), and were then recrystallized in normal hexane to produce 3.39 g of N-(2′-methoxyphenyl)biphenyl-2-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[N:3]=1.[B-](F)(F)(F)F.[N:22]([OH:24])=[O:23]>C(#N)C>[N+:22]([C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:9]=1[NH:8][C:4]1[N:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=1)[C:13]#[N:14])([O-:24])=[O:23]
Reactant: O=NO
Reactant: N#Cc1ccc(Nc2nccc(Cl)n2)cc1
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: N#Cc1ccc(Nc2nccc(Cl)n2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 129.1 %

Procedure:
A mixture of 4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile (0.005 mol) and nitryl tetrafluoroborate (0.0025 mol) in acetonitrile (5 ml) was stirred at room temperature for 4 h. The material was quenched with saturated bicarbonate (50 ml) on cracked ice. The mixture was allowed to reach room temperature, and the yellow solid was filtered off. The solid was adsorbed onto silica and purified by column chromatography (eluent: 30%, 50%, 60%, 70% CH2Cl2 in hexanes). The solvent of the desired fraction was evaporated and the residue was dried, yielding 0.89 g (64%) of 3-nitro-4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile.(interm. 51)
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11](=[O:20])[NH:12][C@@H:13]1[CH2:17][C:16](=[O:18])[NH:15][C:14]1=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CN(C=O)C>C1COCC1>[CH2:3]([O:10][C:11](=[O:20])[NH:12][C@@H:13]1[CH2:17][C:16](=[O:18])[N:15]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:14]1=[O:19])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: O=C1C[C@@H](NC(=O)OCc2ccccc2)C(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(N[C@@H]1CC(=O)N(Cc2ccccc2)C1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
1.2.2 (via two steps; 2nd step): A suspension of 48.4 mg of 60% NaH in 3 ml of THF was treated with 300 mg of (R)-(2,5-dioxo-pyrrolidin-3-yl)-carbamic acid benzyl ester at 0° C. followed by 161.3 μL of benzyl bromide. After 30 min the resulting precipitate was warmed to rt and treated with 3 ml of DMF to give after 15 min a solution which was stirred for 16 h at rt then quenched with 60 ml of H2O and extracted with 40 ml of toluene. The combined organic layers were dried over MgSO4 and concentrated to give 409 mg (74%) of the (R)-(2,5-dioxo-pyrrolidin-3-yl)-carbamic acid benzyl ester as white crystals; m.p. 145.1-145.5° C. Overall yield for the two step process: 78%.
Reaction SMILES: [N:1]1[C:14]2[C:5](=[CH:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][NH:10][C:9]3=[O:15])[CH:4]=[CH:3][CH:2]=1.[CH3:16][CH2:17][OH:18]>[Ni]>[OH:18][C@H:17]1[CH2:12][CH2:13][CH2:8][CH2:7][C@@H:16]1[N:10]1[CH:11]=[CH:12][C:13]2[C:8](=[CH:7][C:6]([CH2:6][C:5]3[CH:14]=[N:1][CH:2]=[CH:3][CH:4]=3)=[C:5]3[C:14]=2[N:1]=[CH:2][CH:3]=[CH:4]3)[C:9]1=[O:15]
Reactant: CCO
Reactant: O=c1[nH]ccc2c1ccc1cccnc12
Agent: [Ni]
Product: O=c1c2cc(Cc3cccnc3)c3cccnc3c2ccn1[C@H]1CCCC[C@@H]1O
Reaction time: 1 h

Procedure:
A solution of 8-[(1S,2S)-2-hydroxycyclohexyl]-5-{[6-methylsulfanyl)pyridin-3-yl]methyl}-1,8-phenanthrolin-7(8H)-one (40 mg, 0.093 mmol) in EtOH (1.9 mL) was treated with 0.22 g of Raney nickel slurry and heated at reflux for 3 h. Additional Raney nickel slurry (0.25 g) was added and heating continued for 1 hour (h). The gray suspension was filtered through Celite. The resulting filtrate was concentrated and dried in vacuo. The crude material was purified via silica gel chromatography, eluting with 25-100% ethyl acetate in hexanes, followed by elution with 0-15% MeOH in CH2Cl2. The resultant off-white solid gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 386.0 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 8.95 (dd, J=4.4, 1.6 Hz, 1H), 8.55 (d, J=1.6 Hz, 1H), 8.42 (dd, J=4.4, 1.2 Hz, 1H), 8.21 (s, 1H), 8.13 (dd, J=8.4, 1.6 Hz, 1H), 7.90 (d, J=7.2 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.44 (dd, J=8.4, 4.0 Hz, 1H), 7.34-7.36 (m, 1H), 7.11 (dd, J=8.0, 4.8 Hz, 1H), 4.97 (br s, 1H), 4.39 (s, 2H), 3.90 (br s, 1H), 2.25-2.30 (m, 1H), 2.00-2.04 (m, 1H), 1.87 (d, J=8.0 Hz, 1H), 1.69-1.78 (m, 1H), 1.37-1.64 (m, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]([CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][N:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:21]3=[O:27])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=[O:4].Br[CH2:30][C:31]1[S:32][CH:33]=[CH:34][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:28][N:2]([CH3:1])[C:3]([CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][N:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:30][C:31]4[S:32][CH:33]=[CH:34][CH:35]=4)=[CH:22][C:21]3=[O:27])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: CN(C)C(=O)C1CCN(Cc2ccc(CCn3ccc(O)cc3=O)cc2)CC1
Reactant: BrCc1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)C1CCN(Cc2ccc(CCn3ccc(OCc4cccs4)cc3=O)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 50 mg (0.13 mmol) 1-{4-[2-(4-hydroxy-2-oxo-2H-pyridin-1-yl)-ethyl]-benzyl}-piperidine-4-carboxylic acid dimethylamide (example 17.1a) in 2.0 mL DMF is added 130 μL (1 M solution in 1,4-dioxane, 0.13 mmol) 2-bromomethyl-thiophene and 45 mg (0.33 mmol) potassium carbonate at 0° C. The reaction mixture is stirred overnight at RT, filtered and the solvent is evaporated. The residue is dissolved in 2.5 mL of DMF and is purified via reverse HPLC chromatography (Waters symmetry, C18, 7 μm; water (0.15% formic acid)/acetonitrile 95:5 to 5:95).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH3:9].[CH3:11][C:12]([S@:15]([NH2:17])=[O:16])([CH3:14])[CH3:13]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[N:17][S@@:15]([C:12]([CH3:14])([CH3:13])[CH3:11])=[O:16])[CH3:9]
Reactant: CC(=O)c1ccccc1F
Reactant: CC(C)(C)[S@](N)=O
Solvent: C1CCOC1
Product: CC(=N[S@](=O)C(C)(C)C)c1ccccc1F
Temperature: 25 °C
Yield: 78.3 %

Procedure:
1-(2-Fluorophenyl)ethanone (15 g, 109 mmol) and (R)-2-methylpropane-2-sulfinamide (15.79 g, 130 mmol) were placed in a round bottom flask fitted with a reflux condenser. Tetrahydrofuran (90 ml) (dried over 4 Å MS) was added followed by Ti(OEt)4 (49.5 g, 217 mmol) and the resulting yellow solution was stirred at gentle reflux overnight. The reaction was allowed to cool to room temperature and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (200 mL) and brine (100 mL) was added dropwise while stirring vigorously. The addition of brine resulted in immediate formation of copious amounts of a white precipitate. After 10 min stirring at room temperature the suspension was filtered through a plug of celite using ethyl acetate for elution. The filtrate was transferred to a separation funnel, the layers were separated, and the organic layer was washed with brine (150 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure and was purified using a CombiFlash system (330 g SiO2, gradient elution; heptanes:ethyl acetate 100:0→70:30) to afford (R)—N-(1-(2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide (20.6 g, 70.8% yield) 1H NMR (600 MHz, CDCl3) δ 7.69 (t, J=7.1 Hz, 1H), 7.43 (dd, J=13.0, 6.0 Hz, 1H), 7.18 (td, J=7.7, 1.0 Hz, 1H), 7.11 (ddd, J=11.3, 8.3, 0.8 Hz, 1H), 2.78 (d, J=3.4 Hz, 3H), 1.32 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=O)[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl(O)(=O)(=O)=O>C(O)(=O)C.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc(F)cc2)cc1
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Product: O=C(O)CCCc1ccc(-c2ccc(F)cc2)cc1

Procedure:
5.0 gm (0.018 mol) of 4-(4'-fluoro-4-biphenylyl)-4-oxo-butyric acid were hydrogenated in 50 ml of acetic acid under addition of 1.5 ml of perchloric acid in the presence of 1.5 gm of palladium/barium sulfate (5%) as catalyst at room temperature and at a pressure of 5 atmospheres in a Parr-autoclave.
Reaction SMILES: [C:1](=[NH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C:16]1[S:17][CH:18]=[C:19]([CH3:21])[N:20]=1>C1(C)C=CC=CC=1>[C:1](=[N:14][C:16]1[S:17][CH:18]=[C:19]([CH3:21])[N:20]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1csc(N)n1
Reactant: N=C(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1csc(N=C(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C

Procedure:
Benzophenone imine (39.8 g, 0.22 mol) is added to a solution of 2-Amino-4-methyl-1,3-thiazole (30 g, 0.261) in toluene (450 ml) and heated at reflux under an inert atmosphere for 18 h. The mixture is cooled to room temperature and washed with citrate buffer (2×250 ml), water (2×250 ml), brine (2×250 ml), dried (MgSO4 and decolourising charcoal), filtered and evaporated to an orange solid (42.9 g, 70%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:11][C@H:10]([N:12]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[CH:14]=[CH:13]2)[CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O.CO>C(Cl)Cl.CCOC(C)=O>[N:12]1([C@H:10]2[CH2:9][C@H:8]([NH2:7])[CH2:11]2)[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[CH:14]=[CH:13]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](n2ccc3cccnc32)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: N[C@H]1C[C@H](n2ccc3cccnc32)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.3 %

Procedure:
To the solution of tert-butyl(trans-3-(1H-pyrrolo[2,3-b]pyridin-1-yl)cyclobutyl)carbamate (294 mg, 1.02 mmol) in DCM (2.0 ml) was added trifluoroacetic acid, 99% (760 μl, 10.2 mmol). The reaction mixture was stirred at room temperature under N2 for 1 h. The solvent was evaporated and the residue was triturated with DCM three times, redissolved in DCM, and then treated with solid NaHCO3. The solid was filtered off and the filtrate concentrated in vacuo. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 100% EtOAc in hexane, then 15% MeOH in EtOAc, to provide trans-3-(1H-pyrrolo[2,3-b]pyridin-1-yl)cyclobutanamine (75 mg, 0.401 mmol, 39.2% yield) as light-yellow oil. ESI (M+1) 188.0.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=2)[CH:7]=1.[C:15]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)#[CH:16]>>[C:11]([C:9]1[CH:10]=[C:5]2[N:4]=[CH:3][C:2]([C:16]#[C:15][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[CH:7][N:6]2[N:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cc2ncc(Br)cn2n1
Reactant: C#Cc1ccc(C)cc1
Product: Cc1ccc(C#Cc2cnc3cc(C(C)(C)C)nn3c2)cc1

Procedure:
The title compound, light yellow solid, MS: m/e=290.2 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and 1-ethynyl-4-methylbenzene.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10])([O-:3])=[O:2].C(O[CH:14](OCC)[N:15]([CH3:17])[CH3:16])C>CN(C)C=O>[CH3:14][N:15]([CH3:17])/[CH:16]=[CH:10]/[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: CCOC(OCC)N(C)C
Reactant: Cc1ccccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CN(C)/C=C/c1ccccc1[N+](=O)[O-]

Procedure:
A solution of 34.3 g. of 2-nitrotoluene in a mixture of 37 g. of N,N-dimethylformamide diethylacetal and 100 ml. of dimethylformamide was heated under reflux for 26 hours. The dark reaction mixture was concentrated by first removing the lower boiling components on a rotary evaporator and then distilling the unreacted 2-nitrotoluene at about 75°/0.2 mm. The residual dark, red liquid (35 g., 72%), which was trans-β-dimethylamino-2-nitrostyrene, was used directly in the experiments below without further purification.