Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:29])[C:10]([C:12]1[S:21][C:20]2[C:19]3[CH:22]=[C:23]([C:26]([OH:28])=O)[CH:24]=[CH:25][C:18]=3[O:17][CH2:16][CH2:15][C:14]=2[CH:13]=1)=[O:11].[CH2:30]([CH2:32][NH2:33])[OH:31]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:29])[C:10]([C:12]1[S:21][C:20]2[C:19]3[CH:22]=[C:23]([C:26]([NH:33][CH2:32][CH2:30][OH:31])=[O:28])[CH:24]=[CH:25][C:18]=3[O:17][CH2:16][CH2:15][C:14]=2[CH:13]=1)=[O:11]
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(C(=O)O)ccc1OCC2)c1ccc(Cl)cc1Cl
Reactant: NCCO
Product: CN(C(=O)c1cc2c(s1)-c1cc(C(=O)NCCO)ccc1OCC2)c1ccc(Cl)cc1Cl

Procedure:
2-[(2,4-Dichloro-phenyl)-methyl-carbamoyl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-9-carboxylic acid and ethanolamine were reacted by General Procedure B to give 361. NMR: (CDCl3): 2.70-2.73 (1 H, m, OH), 3.04-3.07 (2 H, m), 3.38 (3 H, s, Me), 3.66-3.70 (2 H, m), 3.89-3.91 (2 H, m), 4.26-4.29 (2 H, m), 6.48-6.51 (1 H, m, NH), 6.73 (1 H, s, Ar), 7.02 (1 H, d, J 8.4, Ar), 7.32 (1 H, d, 8.4, Ar), 7.38 (1 H, dd, J 8.4 and 2.2, Ar), 7.56-7.61 (2 H, m, Ar) and 7.94 (1 H, s, Ar). MS: (ESI+) MH+=532.08
Reaction SMILES: C(SCCC#N)CCCCCCCCC.[CH2:16]([S:26]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])(=[O:28])=[O:27])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[OH:34]O>CS(O)(=O)=O>[CH2:16]([S:26]([CH2:29][CH2:30][C:31]([O:33][OH:34])=[O:32])(=[O:27])=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: OO
Reactant: CCCCCCCCCCS(=O)(=O)CCC(=O)O
Agent: CCCCCCCCCCSCCC#N
Agent: CS(=O)(=O)O
Product: CCCCCCCCCCS(=O)(=O)CCC(=O)OO
Temperature: 10 °C
Yield: 87.6 %

Procedure:
The product of Example 9 was converted to the corresponding carboxylic acid by alkaline hydrolysis followed by acidification and then to the corresponding sulfone carboxylic acid by oxidation in accordance with a procedure found in U.S. Pat. No. 3,857,875 to Brady et al. A stirred mixture of 5 g of 3-(n-decylsulfonyl)propionic acid and 50 mL of methanesulfonic acid was heated to 40°±3° C. The 3-(n-decylsulfonyl)propionic acid dissolved only partially in the methanesulfonic acid at this temperature. Then 2.04 g of 90% hydrogen peroxide was added dropwise via pipette over ten minutes. Before the addition of the hydrogen peroxide was completed, the reaction mixture became thick from precipitation of a solid. After the addition of the 90% hydrogen peroxide was completed, the heating of the reaction mixture was continued at 40°±3° C. until the reaction time totalled ninety minutes beginning at the start of the addition of the hydrogen peroxide. The reaction mixture was then cooled in an ice bath at 10° C. The solid was then filtered from solution using a coarse sintered-glass funnel, then transferred to a beaker containing 200 mL of ice water prepared from deionized water. The product was washed twice with ice water, filtered and dried to provide 4.63 g of the desired product (87.6% of theoretical based upon the weight of starting 3-(n-decylsulfonyl)propionic acid). The product was found to have 5.32% active oxygen. The product was stabilized with an equal weight of boric acid and put through a #30 polyethylene sieve which provided a particle size of less than 600 microns. The stabilized product contained 2.58% by weight active oxygen.
Reaction SMILES: Cl[C:2]1[C:7]([N:8]([CH3:20])[C:9]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([CH3:17])[C:12]=2[NH:18][CH3:19])=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1>ClC1C=CC(Cl)=CC=1Cl>[CH3:16][N:15]1[C:11]2[C:9](=[O:10])[N:8]([CH3:20])[C:7]3[CH:6]=[CH:5][CH:4]=[N:3][C:2]=3[N:18]([CH3:19])[C:12]=2[C:13]([CH3:17])=[N:14]1
Reactant: CNc1c(C)nn(C)c1C(=O)N(C)c1cccnc1Cl
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: Cc1nn(C)c2c1N(C)c1ncccc1N(C)C2=O

Procedure:
An amount of 5.9 gm of N-(2-chloro-3-pyridinyl)-N-methyl-1,3-dimethyl-4-methylamino-1H-pyrazole-5-carboxamide was stirred in 6 ml of 1,2,4-trichlorobenzene for 5 hours at 180° C. After cooling, the crystal slurry was subjected to suction filtration, washed with cyclohexane, and recrystallized from aqueous ethanol.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[CH:6]([CH3:8])[NH2:7])[CH3:3].[OH-].[Na+].[O-]S([O-])(=O)=O.[Mg+2].F[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27].C(N(CC)CC)C>ClCCl.C1(C)C=CC=CC=1.C(Cl)(Cl)Cl.C(OCC)(=O)C.CCCCCC>[CH2:2]([O:4][C:5](=[O:9])[C@H:6]([CH3:8])[NH:7][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27])[CH3:3]
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: CCOC(=O)C(C)N
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](C)Nc1ccc(F)cc1[N+](=O)[O-]
Reaction time: 0.25 h
Yield: 43.3 %

Procedure:
Using the methods of Lumma (J. Med. Chem., 1981, 24, 93-101), a suspension of DL-alanine ethyl ester hydrochloride (24.1 g, 157 mmol) in dichloromethane (200 mL) was treated with 16 mL of 10 N NaOH (160 mmol) and the mixture stirred 15 min. Anhydrous MgSO4 was added and the mixture stirred until a thick paste formed. The dichloromethane was decanted from the aqueous paste and further dried over anhydrous MgSO4. The organic solution was filtered, and concentrated to approximately 50 mL in volume. This was added to a solution of 2,5-difluoronitrobenzene (25 g, 157 mmol) in toluene (50 mL). The reaction was heated at reflux until the total volume was less than 50 mL. A reflux condenser was added to the reaction flask and the solution heated at reflux for 2 hours. After this time, triethylamine (22 mL, 158 mmol) was added and the reaction heated at reflux for an additional 1 hour. The reaction mixture was then cooled, diluted with chloroform and adsorbed on to silica. Chromatography through silica (20×4.5 cm i.d.) using a gradient of hexane to ethyl acetate afforded 17.4 g (43%) of N-(4-fluoro-2-nitrophenyl)alanine ethyl ester:
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([S:21][CH3:22])[C:10]([S:11]([C:14]3[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=3)(=[O:13])=[O:12])=[C:6]2[N:5]=[C:4]([CH3:23])[CH:3]=1.[NH3:24]>CO>[CH3:23][C:4]1[CH:3]=[C:2]([NH2:24])[N:7]2[N:8]=[C:9]([S:21][CH3:22])[C:10]([S:11]([C:14]3[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=3)(=[O:13])=[O:12])=[C:6]2[N:5]=1
Reactant: CSc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1cccc(C)c1
Reactant: N
Solvent: CO
Product: CSc1nn2c(N)cc(C)nc2c1S(=O)(=O)c1cccc(C)c1

Procedure:
In an analogous manner to that described in Example 4)) from 7-chloro-5-methyl-2-methylsulphanyl-3-(toluene-3-sulphonyl)-pyrazolo[1,5-a]pyrimidine and NH3 in MeOH there was obtained 5-methyl-2-methylsulphanyl-3-(toluene-3-sulphonyl)-pyrazolo[1,5-a]pyrimidine-7-ylamine as colorless crystals, m.p.>2500.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:26][CH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[C:33](=[O:37])[N:32]([C:38]1([CH3:46])[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]1=[O:45])[C:31]2=[O:47].CCOC(C)=O>CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:26][CH2:27][C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[C:33](=[O:37])[N:32]([C:38]2([CH3:46])[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]2=[O:45])[C:31]3=[O:47])=[O:10])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CC1(N2C(=O)c3ccc(CN)cc3C2=O)CCC(=O)NC1=O
Reactant: CCOc1ccc(C(=O)O)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2(C)CCC(=O)NC2=O)C3=O)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
A stirred mixture of 4-ethoxybenzoic acid (0.33 g, 2.00 mmol) and CDI (0.34 g, 2.10 mmol) in N,N-dimethylformamide (20 mL) was heated to 40° C. under nitrogen. After 2 h, 5-aminomethyl-2-(3-methyl-2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.67 g, 2.00 mmol) was added and the mixture was heated at 40° C. for 18 h. The mixture was cooled to rt and EtOAc (75 mL) was added. The organic layer was washed with sat. aq. NaHCO3 (3×100 mL) then concentrated. The residue was triturated in Et2O, then EtOAc and isolated by filtration followed by drying in vacuo to give 4-ethoxy-N-[2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-benzamide as a white solid (0.27 g, 30% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 5.73 min (97.04%); mp: 163-165° C.; 1H NMR (DMSO-d6) δ 1.34 (t, J=7.0 Hz, 3H), 1.81-1.95 (m, 3H), 1.97-2.12 (m, 1H), 2.53-2.61 (m, 2H), 2.61-2.78 (m, 1H), 4.09 (q, J=6.9 Hz, 3H), 4.60 (d, J=5.9 Hz, 2H), 7.00 (d, J=8.7 Hz, 2H), 7.44-8.44 (m, 5H), 9.06 (t, J=5.9 Hz, 1H), 11.01 (s, 1H); 13C NMR (DMSO-d6) δ 14.53, 21.02, 28.57, 29.11, 42.52, 58.76, 63.31, 113.99, 121.56, 123.16, 125.97, 129.09, 129.55, 131.37, 133.35, 147.73, 161.02, 165.89, 167.75, 167.89, 172.13, 172.19; LCMS: MH=450; Anal Calcd for C24H23N3O6+0.75H2O: C, 62.26; H, 5.33; N, 9.08. Found: C, 62.25; H, 5.13; N, 9.17.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[S:10][C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:12][C:13]=2[CH3:14])O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:23])=O>C1(C)C=CC=CC=1>[Cl:23][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[S:10][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:12][C:13]=1[CH3:14]
Reactant: Cc1cc(-c2ccccc2)sc1C(O)C1CCCCC1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ccccc2)sc1C(Cl)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of cyclohexyl(3-methyl-5-phenylthiophen-2-yl)methanol (0.8 g) in toluene (20 mL) was added thionyl chloride (0.3 mL), and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure to give the title compound (0.9 g, 100%).
Reaction SMILES: [F:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([CH2:9][C:10]([O-:12])=O)=[N:4][C:3]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[Na+].[CH3:20][CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][C:25]([F:30])=[CH:26][CH:27]=2)[NH:22]1>>[F:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([CH2:9][C:10]([N:22]2[C:23]3[C:28](=[CH:27][CH:26]=[C:25]([F:30])[CH:24]=3)[CH2:29][CH:21]2[CH3:20])=[O:12])=[N:4][C:3]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)c(F)c(=O)[nH]1
Reactant: CC1Cc2ccc(F)cc2N1
Agent: [Na+]
Product: CC1Cc2ccc(F)cc2N1C(=O)Cc1nc(N2CCOCC2)c(F)c(=O)[nH]1
Yield: 46.2 %

Procedure:
The product is prepared by following the procedure described in example 1a (step 5a) using 123 mg of sodium (5-fluoro-4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetate obtained in step 2a of example 6a and 62 mg of (−)-2-methyl-6-fluoro-2,3-dihydro-1H-indole (reference example 6a). After silica column purification: eluent 98/02 dichloromethane/methanol, 74 mg of 5-fluoro-2-[2-((+)-6-fluoro-2-methyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one are obtained in the form of a solid, the characteristics of which are the following:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:17]=[N:18][N:19]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:20]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[CH3:47][O:48][CH2:49][C:50](Cl)=[O:51].C(N(CC)CC)C>O1CCCC1>[CH3:47][O:48][CH2:49][C:50]([NH:46][C:42]1[CH:43]=[CH:44][CH:45]=[C:40]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[C:12]([C:16]4[N:17]=[N:18][N:19]([C:21]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)([C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)[C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[N:20]=4)[CH:11]=3)[N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[N:8]=2)[CH:41]=1)=[O:51]
Reactant: COCC(=O)Cl
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4nnn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCC(=O)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4nnn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[2-(triphenylmethyl)(1,2,3,4-tetrazol-5-yl)]-1H-indazol-3-yl}phenylamine (0.246 g, 0.407 mmol) in tetrahydrofuran (4 mL) was added 2-methoxyacetyl chloride (0.056 mL, 0.61 mmol) and triethyl amine (0.284 mL, 2.035 mmol). The reaction mixture was stirred overnight at room temperature before being partitioned between ethyl acetate and water. The product was purified by column chromatography (40% ethyl acetate in hexanes) (0.104 g, 38% yield): ES-MS (m/z) M+ was not detected.
Reaction SMILES: [H][H].[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]([OH:27])/[CH:9]=[CH:10]/[C@@H:11]1[C@@H:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:14](=[O:15])[CH2:13][C@H:12]1[OH:26]>[Pd].C(OCC)(=O)C>[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]([OH:27])[CH2:9][CH2:10][C@@H:11]1[C@@H:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:14](=[O:15])[CH2:13][C@H:12]1[OH:26]
Reactant: [H][H]
Reactant: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCC[C@H](O)CC[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)O

Procedure:
R2 is methyl, R4 is hydrogen, V is --(CH2)5 --, and W is 1-pentyl. A solution of PGE1, 15-methyl ether (100 mg.) in 10 ml. of ethyl acetate is shaken with hydrogen at about 1 atmosphere pressure at 25°C. in the presence of 5% palladium on charcoal (15 mg.). One equivalent of hydrogen is absorbed in about 90 minutes. The hydrogenation is then stopped, and the catalyst is removed by filtration. The filtrate is evaporated, and the residue is chromatographed on 25 g. of silica gel, eluting with a 50-100% ethyl acetate gradient in Skellysolve B. Those fractions shown by TLC to contain the desired product free of the starting produuct and dehydration products are combined and evaporated to give the Formula-V 13,14-dihydro-PGE1 -type title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.C([Li])CCC.[B:26](OC)([O:29]C)[O:27]C.Cl>O1CCCC1>[C:7]1([N:6]2[C:5]3[CH:13]=[CH:14][C:2]([B:26]([OH:29])[OH:27])=[CH:3][C:4]=3[C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COB(OC)OC
Reactant: Brc1ccc2c(c1)c1ccccc1n2-c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc2c(c1)c1ccccc1n2-c1ccccc1
Reaction time: 2 h
Yield: 80 %

Procedure:
In a 500 mL three-neck flask were stirred 29 g (90 mmol) of 3-bromo-9-phenylcarbazole obtained by the above Step 3 described in Synthesis Example 1 and 200 mL of tetrahydrofuran (abbreviation: THF) at −78° C. to provide a solution. Then, 10 mL (69 mmol) of n-butyllithium (1.6 mol/L hexane solution) was dropped therein, and the mixture was stirred for 2 hours at the same temperature. Furthermore, 13 mL (140 mmol) of trimethyl borate was added therein, and the mixture was stirred for 24 hours at room temperature. After the reaction, 200 mL of 1.0 mol/L hydrochloric acid was added therein, and the mixture was stirred for 1 hour at room temperature. This mixture was washed with water, aqueous sodium hydroxide, and water in this order, and magnesium sulfate was added so that the moisture was removed. This suspending solution was filtered and the obtained filtrate was concentrated. Then, chloroform and hexane were added therein, ultrasonic waves were applied thereto, and then recrystallization thereof was performed. Accordingly, 21 g of a powdery white solid of 9-phenyl-9H-carbazol-3-boronic acid, which was the object of the synthesis, was obtained in a yield of 80% (synthesis scheme (b-1)).
Reaction SMILES: [F:1][C:2]1[C:13]([F:14])=[C:12]([F:15])[CH:11]=[CH:10][C:3]=1[NH:4][C@@H:5]([CH3:9])[C:6]([OH:8])=[O:7].Cl.[CH3:17]O>>[F:1][C:2]1[C:13]([F:14])=[C:12]([F:15])[CH:11]=[CH:10][C:3]=1[NH:4][C@@H:5]([CH3:9])[C:6]([O:8][CH3:17])=[O:7]
Reactant: C[C@H](Nc1ccc(F)c(F)c1F)C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)[C@H](C)Nc1ccc(F)c(F)c1F

Procedure:
(2S)-2-(2,3,4-trifluoroanilino)propionic acid (1.1 g; 99% ee) was dissolved in methanol (10 ml) and hydrochloric acid (5 mol/l; 1 ml) was added thereto at room temperature. The liquid reaction mixture was heated under reflux for 6 hours and then the solvent was evaporated. To the obtained residue was added chloroform (10 ml). Next, the organic layer was washed with a saturated aqueous solution of sodium chloride and water and dried over anhydrous magnesium sulfate. After evaporating the solvent, the obtained residue was subjected to silica gel column chromatography (ethyl acetate-normal hexane=1:4) to give the title compound (1.17 g) as an oily substance. The optical purity of the product was 99% ee. The 1H-NMR and IR spectral data of this product was identical with those of the compound obtained in Example 5.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].F[C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:12]=1[C:13]#[N:14]>CN(C=O)C.O>[O:7]([C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:12]=1[C:13]#[N:14])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: N#Cc1c(F)cccc1N1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1c(Oc2ccccc2)cccc1N1CCCCC1
Reaction time: 1 h

Procedure:
To a solution of phenol (415 mg, 4.5 mmol) in 60 mL of DMF was added NaH (60%, 6.0 mmol) at 0° C. The reaction was stirred for 1 h, then 2-fluoro-6-(piperidin-1-yl)benzonitrile (CAS#646989-68-6) (612 mg, 3.0 mmol) was added and the reaction stirred for 48 h at RT. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, then concentrated in vacuo. Purification by normal phase silica gel column chromatography (EtOAc/heptane) provided 2-phenoxy-6-(piperidin-1-yl)benzonitrile as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:19][C:20]([CH3:23])=[N:21][N:22]=4)[CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)=[CH:5][CH:4]=1.O1CCCC1.[H][H]>[C].[Pd].CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:19][C:20]([CH3:23])=[N:21][N:22]=4)[CH:16]=[CH:17][C:12]=3[O:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2coc3ccc(-c4nnc(C)o4)cc23)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(C2COc3ccc(-c4nnc(C)o4)cc32)cc1
Yield: 74.4 %

Procedure:
A mixture of 2-[3-(4-methoxyphenyl)-1-benzofuran-5-yl]-5-methyl-1,3,4-oxadiazole (447 mg, 1.46 mmol), 10% palladium carbon (50% containing water, 450 mg), tetrahydrofuran (5 mL) and methanol (15 mL) was stirred at room temperature for 48 hr under 1 atm hydrogen atmosphere. Palladium on carbon was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate), and crystallized from hexane/ethyl acetate to give the title compound (335 mg, yield 74%) as colorless crystals.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[S:13][C:12]([CH2:14][CH3:15])=[N:11][C:10]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=2)[CH:6]=[CH:5][N:4]=1.[C-:23]#[N:24].[K+].C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:23]([CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[S:13][C:12]([CH2:14][CH3:15])=[N:11][C:10]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=2)[CH:6]=[CH:5][N:4]=1)#[N:24]
Reactant: [C-]#N
Reactant: CCc1nc(-c2cccc(C)c2)c(-c2ccnc(CCl)c2)s1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCc1nc(-c2cccc(C)c2)c(-c2ccnc(CC#N)c2)s1
Yield: 49.6 %

Procedure:
A suspension of 5-(2-chloromethyl-4-pyridyl)-2-ethyl-4-(3-methylphenyl)-1,3-thiazole (0.40 g, 1.2 mmol), potassium cyanide (0.095 g, 1.5 mmol), 18-crown-6 (0.14 g, 0.51 mmol) in acetonitrile (5 mL) was heated under reflux for 6 hours. After cooling, an aqueous potassium carbonate solution was added, and extracted with ethyl acetate. The extracts were washed with brine, then, dried, and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=2:1). The resulting crystal was washed with hexane-isopropyl ether to obtain a title compound (0.19 g, 48%).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH3:12][S:13][C:14]1[N:19]=[C:18]([C:20]2[C:28]3[C:23](=[N:24][C:25]([NH:29][CH2:30][CH2:31][OH:32])=[N:26][CH:27]=3)[NH:22][N:21]=2)[CH:17]=[CH:16][N:15]=1>ClCCl.CO>[CH3:12][S:13]([C:14]1[N:19]=[C:18]([C:20]2[C:28]3[C:23](=[N:24][C:25]([NH:29][CH2:30][CH2:31][OH:32])=[N:26][CH:27]=3)[NH:22][N:21]=2)[CH:17]=[CH:16][N:15]=1)=[O:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nccc(-c2n[nH]c3nc(NCCO)ncc23)n1
Solvent: ClCCl
Solvent: CO
Product: CS(=O)c1nccc(-c2n[nH]c3nc(NCCO)ncc23)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 257.8 %

Procedure:
m-CPBA (797 mg, 4.62 mmol) was added slowly to a solution of 2-[3-(2-Methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-ethanol (from Example 20 supra) (0.7 g, crude) in a mixture of dichloromethane and methanol (40 mL, 1:1). The reaction mixture was stirred at room temperature for 30 minutes. The solvent was then removed under reduced pressure and the solid was purified by column chromatography (silica gel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 5:1) to afford 2-[3-(2-methanesulfinyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-ethanol (Yield 1.9 g, crude). LC-MS: [M+H]+ 320.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[C:16]4[N:17]([CH:31]=[CH:32][N:33]=4)[N:18]=[C:19]([C:21]4[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=4)[C:24]([O:26]C)=[O:25])[CH:20]=3)[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[OH-].[Na+]>O1CCOCC1.O>[CH3:1][C:2]1([CH3:34])[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[C:16]4[N:17]([CH:31]=[CH:32][N:33]=4)[N:18]=[C:19]([C:21]4[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=4)[C:24]([OH:26])=[O:25])[CH:20]=3)[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: COC(=O)c1cccc(-c2cc(Nc3cccc(N4CCC(C)(C)CC4)n3)c3nccn3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)CCN(c2cccc(Nc3cc(-c4cccc(C(=O)O)c4)nn4ccnc34)n2)CC1
Temperature: 40 °C
Reaction time: 2 h
Yield: 9.2 %

Procedure:
A mixture of methyl 3-(8-(6-(4,4-dimethylpiperidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoate (200 mg, 0.44 mmol) and NaOH (200 mg, 5 mmol) in 1,4-dioxane (5 mL) and water (5 mL) was stirred for 2 h at 40° C. Then the mixture was concentrated to 5 mL and adjusted to pH=2 with 2M HCl. The precipitate was filtered and purified by prep-HPLC to give 3-(8-(6-(4,4-dimethylpiperidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (18 mg, 9%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 10.53 (s, 1H), 8.94 (s, 1H), 8.52 (s, 2H), 8.18-8.12 (m, 3H), 7.72 (t, 1H, J=7.8 Hz), 7.57 (t, 1H, J=7.8 Hz), 6.76 (d, 1H, J=7.8 Hz), 6.54 (d, 1H, J=8.1 Hz), 3.59-3.57 (m, 4 h), 1.38-1.36 (m, 4 h), 0.98 (s, 6H). LC-MS: [M+H]+, 443, tR=1.788 min, HPLC: 100% at 214 nm, 100% at 254 nm, tR=6.762 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:10][O:11][CH3:12])[CH2:9][CH2:8][NH:7][CH2:6]1)=[O:4].C(N(CC)CC)C.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>C(#N)C>[CH3:1][O:2][C:3]([C:5]1([CH2:10][O:11][CH3:12])[CH2:9][CH2:8][N:7]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:6]1)=[O:4]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COCC1(C(=O)OC)CCNC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COCC1(C(=O)OC)CCN(CC(=O)OC(C)(C)C)C1
Reaction time: 0.25 h
Yield: 50.7 %

Procedure:
To a stirred mixture of 3-methoxymethyl-pyrrolidine-3-carboxylic acid methyl ester (140 mg, 0.81 mmol), triethylamine (112 μl, 0.82 mmol) and cesium carbonate (263 mg, 0.81 mmol) in acetonitrile (2 ml) was added tert-butyl bromoacetate (119 μl, 0.81 mmol) slowly. The mixture was stirred for 15 minutes, filtered and concentrated. The residue was purified by column chromatography on silica gel. Elution with a solution of ethyl acetate and hexanes (1:2) provided 118 mg (51%) of the title compound.