Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2](OC1CCOCC1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].O1CCCCC1OC1C=CC(C=O)=CC=1>CO>[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:4])[CH3:2]
Reactant: O=C(c1ccccc1)C(O)OC1CCOCC1
Agent: O=Cc1ccc(OC2CCCCO2)cc1
Solvent: CO
Product: CC(=O)c1ccccc1

Procedure:
In 210 ml of methanol were dissolved 71.424 g of the mixture of 2-hydroxy-4-tetrahydropyranyloxyacetophenone and 4-tetrahydropyranyloxybenzaldehyde obtained in (1) above and 44.168 g (140 mmol) of barium hydroxide octahydrate, and the solution was agitated at 40° C. for 9 hours. After cooling, 210 ml of methylene chloride was added and then under ice cooling, hydrochloric acid was added slowly and dropwise at a temperature of from 0° to 5° C. to adjust the water layer to pH 6 to 7.
Reaction SMILES: [ClH:1].N[N:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1.[CH:13]1([N:16]2[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]2)[CH2:15][CH2:14]1>>[ClH:1].[CH:13]1([N:16]2[CH2:21][CH2:20][C:19]3[N:3]4[C:8]5[C:9](=[CH:10][CH:11]=[CH:12][C:7]=5[O:6][CH2:5][CH2:4]4)[C:18]=3[CH2:17]2)[CH2:15][CH2:14]1
Reactant: NN1CCOc2ccccc21
Reactant: O=C1CCN(C2CC2)CC1
Agent: Cl
Product: c1cc2c3c(c1)c1c(n3CCO2)CCN(C2CC2)C1

Procedure:
4-Amino-3,4-dihydro-2H-1,4-benzoxazine hydrochloride is reacted with 1-cyclopropyl-4-piperidone according to the procedure of Example 110 to yield the title compound, m.p. 232°-233° .
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][N:3]=1.[N+:10]([N:13]=[C:14]1[NH:18][CH2:17][CH2:16][NH:15]1)([O-:12])=[O:11].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:15]2[CH2:16][CH2:17][NH:18][C:14]2=[N:13][N+:10]([O-:12])=[O:11])=[CH:4][N:3]=1
Reactant: Fc1ccc(CBr)cn1
Reactant: O=[N+]([O-])N=C1NCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=[N+]([O-])N=C1NCCN1Cc1ccc(F)nc1
Temperature: 25 °C
Yield: 50.2 %

Procedure:
A mixture of 2-fluoro-5-pyridylmethyl bromide (9.5 g), 2-(nitroimino)imidazolidine (6.5 g), potassium carbonate (7.6 g) and acetonitrile (100 ml) was refluxed for 2 hours with stirring. After the reaction, the reaction mixture was cooled to room temperature, and cold water (100 ml) was added. The resulting crystals were collected by filtration and washed with ether to give slightly colored 1-(2-fluoro-5-pyridylmethyl)-2-(nitroimino)imidazolidine (6.0 g) as the desired compound.
Reaction SMILES: [C:1]1([C:7]2[N:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.I[C:37]1[CH:57]=[CH:56][C:40]([CH2:41][N:42]2[N:46]=[C:45]([CH2:47][CH3:48])[S:44][C:43]2=[N:49][C:50](=[O:55])[C:51]([F:54])([F:53])[F:52])=[CH:39][CH:38]=1.C(OCC)(=O)C>O1CCCC1.[Cl-].[Zn+2].[Cl-].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:47]([C:45]1[S:44][C:43](=[N:49][C:50](=[O:55])[C:51]([F:53])([F:52])[F:54])[N:42]([CH2:41][C:40]2[CH:39]=[CH:38][C:37]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[C:7]3[N:11]([C:12]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:10]=[N:9][N:8]=3)=[CH:57][CH:56]=2)[N:46]=1)[CH3:48]
Reactant: CCc1nn(Cc2ccc(I)cc2)c(=NC(=O)C(F)(F)F)s1
Reactant: c1ccc(-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Pd]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1nn(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c(=NC(=O)C(F)(F)F)s1
Temperature: -5 °C
Reaction time: 1 h
Yield: 37.3 %

Procedure:
To a solution of 5-phenyl-1-triphenylmethyl-1H-tetrazole (2.3 g) in tetrahydrofuran (20 ml) was added dropwise n-butyl lithium (1.6M hexane solution, 4.0 ml) keeping the temperature below -20° C., followed by stirring at -5° C. for one hour. Zinc chloride (1.0M diethyl ether solution, 7.0 ml) was added dropwise keeping the temperature below -30° C., followed by stirring at room temperature for two hours. To the reaction mixture, 3-(4-iodobenzyl)-5-ethyl-2-trifluoroacetylimino-1,3,4-thiadiazoline (1.4 g) and tetrakis(triphenylphosphine)-palladium (100 mg) were added, followed by heating under reflux overnight. After ethyl acetate (50 ml) was added to the reaction mixture, the resulting mixture was washed with 10% aqueous citric acid solution and dried over anhydrous magnesium sulfate, followed by removal through distillation. The residue so obtained was separated by column chromatography on silica gel, whereby 830 mg of the title compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:9][NH2:10])[CH2:8][CH2:7][CH2:6]1)=[O:4].[C:11]1(=O)[CH2:15][CH2:14][CH2:13][CH2:12]1.C([O-])(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1([CH2:9][NH:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: O=C1CCCC1
Reactant: COC(=O)C1(CN)CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C1(CNC2CCCC2)CCC1

Procedure:
Reaction of 1-aminomethyl-cyclobutanecarboxylic acid methyl ester with cyclopentanone, sodium acetate and sodium triacetoxyborohydride in DCM gave 1-cyclopentylaminomethyl-cyclobutanecarboxylic acid methyl ester
Reaction SMILES: CS(Cl)(=O)=O.[Si:6]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24]O)=[C:20]([O:26][CH3:27])[CH:19]=1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].C(N(C(C)C)CC)(C)C.[Cl-:37].[Li+]>C1COCC1.O.[Cl-].[Na+].O>[C:9]([Si:6]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][Cl:37])=[C:20]([O:26][CH3:27])[CH:19]=1)([CH3:8])[CH3:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: COc1cc(OCCCO[Si](C)(C)C(C)(C)C)ccc1CO
Reactant: [Cl-]
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cc(OCCCO[Si](C)(C)C(C)(C)C)ccc1CCl
Reaction time: 0.67 h
Yield: 111.8 %

Procedure:
Methanesulfonyl chloride (4.02 mL) was added to the mixture of the product from step (ii) (8.47 g), diisopropylethylamine (13.4 mL) and lithium chloride (3.29 g) in THF (105 mL) at RT and stirred for 40 mins. The mixture was diluted with water and brine, and extracted with EtOAc. The combined organic solutions were washed with brine, dried and concentrated to give 10.0 g of the subtitle compound as a yellow oil; 1H NMR: 7.23 (1H, dd), 6.44-6.49 (2H, m), 4.63 (2H, s), 4.06 (2H, t), 3.85 (3H, s), 3.79 (2H, t), 1.94-2.02 (2H, m), 0.89 (9H, s), 0.04 (6H, s).
Reaction SMILES: Br.Br.[NH:3]1[CH2:6][CH:5]([NH:7][C:8]2[C:13](=[O:14])[NH:12][CH:11]=[C:10]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH3:22])[CH:16]=3)[CH:9]=2)[CH2:4]1.[C:23](O)(=[O:32])[CH:24]=[CH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:23]([N:3]1[CH2:6][CH:5]([NH:7][C:8]2[C:13](=[O:14])[NH:12][CH:11]=[C:10]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH3:22])[CH:16]=3)[CH:9]=2)[CH2:4]1)(=[O:32])/[CH:24]=[CH:25]/[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(O)C=Cc1ccccc1
Reactant: CNc1cc(-c2c[nH]c(=O)c(NC3CNC3)c2)ccn1
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: CNc1cc(-c2c[nH]c(=O)c(NC3CN(C(=O)/C=C/c4ccccc4)C3)c2)ccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.2 %

Procedure:
A solution of 5-(azetidin-3-ylamino)-2′-(methylamino)-[3,4′-bipyridin]-6(1H)-one di-hydrobromide (80.0 mg, 0.185 mmol) in DMF (1 mL) was added cinnamic acid (60 mg, 0.41 mmol), HATU (105 mg, 0.277 mmol), and DIPEA (120 mg, 0.924 mmol). The reaction mixture was stirred at RT under nitrogen for 16 h. The residue was purified by Prep HPLC (ethyl acetate/hexane) to afford (E)-5-((1-cinnamoylazetidin-3-yl)amino)-2′-(methylamino)-[3,4′-bipyridin]-6(1H)-one (41 mg, 55%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 11.25 (s, 1H), 8.11 (d, J=5.4 Hz, 1H), 7.69 (d, J=15.6 Hz, 1H), 7.52 (dd, J=6.7, 3.0 Hz, 2H), 7.37 (dd, J=5.0, 2.0 Hz, 3H), 7.09 (d, J=2.2 Hz, 1H), 6.63 (dd, J=5.4, 1.6 Hz, 1H), 6.48 (d, J=15.6 Hz, 1H), 6.38 (d, J=1.9 Hz, 2H), 5.48 (d, J=6.6 Hz, 1H), 4.80-4.65 (m, 2H), 4.63-4.50 (m, 1H), 4.46-4.32 (m, 1H), 4.26-4.05 (m, 2H), 2.98 (d, J=4.8 Hz, 3H); MS (ES) m/z 402 (M+H).
Reaction SMILES: Br[C:2]1[C:3](C2C=CC=CC=2)=[N:4][NH:5][CH:6]=1.C1C=C[C:16](/[CH:19]=[CH:20]/[C:21](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=O)=[CH:17][CH:18]=1.C1C=C[C:34](/[CH:37]=[CH:38]/[C:39](/[CH:41]=[CH:42]/[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:40])=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd:67].[Pd].Cl.[Pd]>CC(C)=O.C1COCC1>[CH2:2]([C:3]1[N:4]([C:48]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[C:42]2[CH:34]=[CH:37][CH:38]=[C:39]([OH:40])[CH:41]=2)[N:5]=[C:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:23]=1[C:21]1[CH:18]=[CH:17][CH:16]=[CH:19][CH:20]=1)[CH3:6].[Pd:67]
Reactant: Brc1c[nH]nc1-c1ccccc1
Reactant: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CCc1c(-c2ccccc2)c(-c2ccccc2)nn1-c1ccccc1-c1cccc(O)c1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
The reaction of Example 1 (reaction scale: 10 mmol of bromophenyl pyrazole) was conducted with 0.1 mole % of Pd2(dba)3. After the reaction was judged to be essentially complete, the reaction mixture was neutralized with 1N aqueous HCl to a pH of 7.0 to 7.5. The crude product, whose palladium level was 270 ppm, was dissolved in acetone (16 mL/g of bromophenyl pyrazole starting material) and THF (2.65 mL/g) at 50° C. TMT (0.23 equiv.) was added, and the mixture was stirred at 50° C. for 15 min, cooled to room temperature, and filtered three times through a Darco zeta pad. A sample of filtrate was evaporated to dryness, affording a solid containing 92 ppm of palladium. The remaining filtrate was concentrated and recrystallized by adding water, affording 2′-(5-ethyl-3,4-diphenyl-1H-pyrazol-1-yl)-[1,1′]-biphenyl-3-ol containing 51 ppm of palladium.
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:24][CH2:25][OH:26])[CH3:23])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:33]=1>>[F:27][C:28]1[CH:33]=[C:32]([C:2]2[C:3]([N:22]([CH2:24][CH2:25][OH:26])[CH3:23])=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])[CH:21]=2)[CH:31]=[N:30][CH:29]=1
Reactant: CN(CCO)c1ncc(C(=O)Nc2ccc(SC(F)(F)F)cc2)cc1Br
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Product: CN(CCO)c1ncc(C(=O)Nc2ccc(SC(F)(F)F)cc2)cc1-c1cncc(F)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 185 using 5-bromo-6-((2-hydroxyethyl)(methyl)amino)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage 192.1) and 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine to afford an off-white foam. HPLC (Condition 4) tR=5.7 min, UPLC-MS (Condition 3) tR=1.10 min, m/z=467.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.69 (s, 3H) 3.41-3.63 (m, 4H) 4.66 (t, J=5.28 Hz, 1H) 7.68 (d, J=8.99 Hz, 2H) 7.82-7.97 (m, 3H) 8.11 (d, J=2.35 Hz, 1H) 8.49-8.63 (m, 2H) 8.74 (d, J=2.35 Hz, 1H) 10.31 (s, 1H).
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH2:12][CH2:11][C:10]=2[CH:14]=1)[C:3]([OH:5])=[O:4].O1CCOCC1.O.C(N(CC)CC)C.[C:29]([O:33][C:34](N=[N+]=[N-])=[O:35])([CH3:32])([CH3:31])[CH3:30]>O>[C:29]([O:33][C:34]([C:2]([NH2:1])([C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH2:12][CH2:11][C:10]=2[CH:14]=1)[C:3]([OH:5])=[O:4])=[O:35])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Reactant: NC(C(=O)O)c1ccc2c(c1)CCO2
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)C(N)(C(=O)O)c1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
α-Amino(2,3-dihydro-5-benzofuranyl)acetic acid (192 mg, 1 mmole) is added to 10 ml of 1:1 dioxane-water mixture with 4 mM of triethylamine and 0.17 or tertbutoxycarbonylazide. This mixture is stirred overnight at room temperature. The mixture is diluted with water and extracted with chloroform. The chloroform is dried and evaporated. The residue is taken up in ethyl acetate and washed with dilute aqueous hydrochloric acid. The organic layer is dried over magnesium sulfate and evaporated to give the title compound in a yield of about 80%.
Reaction SMILES: [N+:1]([CH:4]=[CH:5][C:6]1[CH:7]=[C:8]([NH:12][C:13]([C:15]2[C:16]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:14])[CH:9]=[CH:10][CH:11]=1)([O-])=O.[ClH:31]>[Pd].C(O)C>[ClH:31].[NH2:1][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([NH:12][C:13]([C:15]2[C:16]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=3)=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:14])[CH:9]=[CH:10][CH:11]=1
Reactant: O=C(Nc1cccc(C=C[N+](=O)[O-])c1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NCCc1cccc(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)c1
Reaction time: 19 h

Procedure:
A Parr® hydrogenation flask was charged with the title product of Example 2 (1.90 g, 4.61 mmol), 10% Pd/C (0.58 g), 95% ethanol (20 mL), and conc. HCl (0.96 mL, 12 mmol). The mixture was hydrogenated, under hydrogen at 276 kPa (40 psi), for 19 hours. The catalyst was removed by filtration through Celite®, and the filtrate was concentrated to provide an oily, yellow-white solid, which was 85% pure by HPLC analysis. A portion of this material was purified as its free base (i.e., the HCl salt was dissolved in methanol, treated with one molar equivalent of K2CO3 filtered and concentrated) by silica gel chromatography, eluting with 500:50:1 CH2Cl2 -methanol-NH4OH, providing the title product as a white solid which was homogenous by HPLC analysis.
Reaction SMILES: [CH3:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[BH4-].[Na+]>C(O)C>[CH3:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3][CH2:4][CH:5]([OH:8])[CH2:6][CH2:7]1
Reactant: CC1(c2ccccc2)CCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC1(c2ccccc2)CCC(O)CC1
Yield: 79 %

Procedure:
To a solution of the oily 4-methyl-4-phenylcyclohexanone in 50 ml. of ethanol, 1.25 g. of sodium borohydride is added. At the end of about 5 hours the solvent is removed and then dissolved in ether and water. The organic layer is washed successively with sodium bicarbonate solution and brine and then evaporated to dryness. The crude product is chromatographed on a column of 500 ml. of silica gel with elution by 1% acetone in methylene chloride. There is first obtained 1.4 g. of the starting ethylene ketal having a melting point of 44° to 48°C., followed by 3.08 g. (79% yield) of 4-methyl-4-phenylcyclohexanol, having a melting point of 56° to 72°C. The NMR of the 4-methyl-4-phenylcyclohexanol shows a 3:2 ratio of equatorial to axial compounds. Separation of the mixture by additional chromatography yields 4-cis-methyl-4-trans-phenylcyclohexanol and 4-trans-methyl-4-cis-phenylcyclohexanol.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10](F)=[C:9]([F:14])[C:8]=2[F:15])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>CN(C)C(=O)C>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:10]2[CH:11]=[CH:12][C:7]([S:4]([CH:1]3[CH2:3][CH2:2]3)(=[O:6])=[O:5])=[C:8]([F:15])[C:9]=2[F:14])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: O=S(=O)(c1ccc(F)c(F)c1F)C1CC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(S(=O)(=O)C3CC3)c(F)c2F)CC1
Temperature: 90 °C

Procedure:
To 4.2 mmol 1-cyclopropanesulfonyl-2,3,4-trifluoro-benzene in 20 ml N,N-dimethylacetamide was added 8.9 mmol tert-butyl-1-piperazine carboxylate, and the mixture was heated at 90° C. for 1 h. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: dichloromethane/ethyl acetate gradient) to afford the title compound. MS (m/e): 403.3 (M+H+, 100%)
Reaction SMILES: CS(O[CH2:6][CH:7]([N:9]1[C:22]2[CH:21]=[C:20]([C:23]#[N:24])[CH:19]=[CH:18][C:17]=2[S:16][C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH3:8])(=O)=O.[CH3:25][CH:26]1[CH2:30][CH2:29][CH:28]([CH3:31])[NH:27]1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:25][CH:26]1[CH2:30][CH2:29][CH:28]([CH3:31])[N:27]1[CH2:6][CH:7]([N:9]1[C:22]2[CH:21]=[C:20]([C:23]#[N:24])[CH:19]=[CH:18][C:17]=2[S:16][C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH3:8]
Reactant: CC(COS(C)(=O)=O)N1c2ccccc2Sc2ccc(C#N)cc21
Reactant: CC1CCC(C)N1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(CN1C(C)CCC1C)N1c2ccccc2Sc2ccc(C#N)cc21
Reaction time: 2 h
Yield: 19.8 %

Procedure:
A solution of 2-(2-cyano-10-phenothiazinyl)-1-propyl methanesulphonate (5 g) and (2RS,5RS)-2,5-dimethylpyrrolidine (5 g) in toluene (50 cc) is heated for 4 days to a temperature in the region of 100° C. After cooling, the reaction mixture is diluted with ethyl acetate (200 cc) and extracted successively with N aqueous hydrochloric acid solution (50 cc and 2×25 cc). The combined aqueous phases are alkalinized with 10N aqueous sodium hydroxide solution to pH 13, and extracted successively with ethyl ether (200 cc and 50 cc). The combined organic phases are dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C. The residual yellow gum (2.8 g) is purified by chromatography on a column (height: 30 cm; diameter: 2 cm) of silica gel (0.2-0.063 mm), eluting with a mixture (80:20 by volume) (500 cc) of cyclohexane and ethyl acetate and collecting 30-cc fractions. The combined fractions 5 to 11 are concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The viscous yellow residue (2.4 g) is dissolved in isopropyl ether (15 cc) under reflux. The solution is cooled and then kept for 2 hours at a temperature in the region of 5° C. The crystals formed are drained, washed with isopropyl ether (2 cc) and dried under reduced pressure (5 mm Hg; 0.68 kPa) at 40° C. 10-((2RS)-1-[(2RS,5RS)-2,5-dimethyl-1-pyrrolidinyl]-2-propyl}-2-phenothiazine carbonitrile (1 g) is thereby obtained in the form of pale yellow crystals, m.p. 105° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]([OH:12])=[O:11])=[N:4][N:5]([CH3:9])[C:6](=[O:8])[CH:7]=1.Cl.[CH3:14]COC(C)=O>CO>[Cl:1][C:2]1[C:3]([C:10]([O:12][CH3:14])=[O:11])=[N:4][N:5]([CH3:9])[C:6](=[O:8])[CH:7]=1
Reactant: CCOC(C)=O
Reactant: Cn1nc(C(=O)O)c(Cl)cc1=O
Agent: Cl
Solvent: CO
Product: COC(=O)c1nn(C)c(=O)cc1Cl
Temperature: 25 °C
Yield: 17 %

Procedure:
A solution of 4-chloro-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (390 mg, 2.07 mmol) and conc. HCl (0.10 mL) in MeOH (6 mL) was refluxed for 8 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give the crude material that was redissolved into EtOAc. The organic layer was washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that was purified by silica gel flash column chromatography (100% hexanes to 10 to 20 to 30 to 50% EtOAc in hexanes) to afford 72 mg (17%) of the desired product.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:5]P(=O)(OC)OC.[CH3:19][O:20][C:21](=[O:37])[CH2:22][CH2:23][CH2:24][C:25]#[C:26][CH2:27][N:28]1[C:33](=[O:34])[CH2:32][CH2:31][CH2:30][C@@H:29]1[CH:35]=O>C1COCC1>[CH3:19][O:20][C:21](=[O:37])[CH2:22][CH2:23][CH2:24][C:25]#[C:26][CH2:27][N:28]1[C@@H:29](/[CH:35]=[CH:5]/[C:4](=[O:3])[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:30][CH2:31][CH2:32][C:33]1=[O:34]
Reactant: COP(=O)(CC(=O)Cc1ccccc1)OC
Reactant: COC(=O)CCCC#CCN1C(=O)CCC[C@@H]1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CCCC#CCN1C(=O)CCC[C@@H]1/C=C/C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 17.5 h
Yield: 42.2 %

Procedure:
Sodium hydride (60% dispersion in oil, 3.8 mg, 0.095 mmol) was added to a solution of dimethyl 2-oxo-3-phenylpropylphosphonate (21 mg, 0.087 mmol) in THF (0.5 mL) at 0° C. After 1 h at 0° C. rt, 7-((R)-2-formyl-6-oxo-piperidin-1-yl)-hept-5-ynoic acid methyl ester (prepared in accordance with example 7, step 1, crude, ˜0.095 mmol) in THF (0.5 mL) was added via cannula. The reaction was allowed to warm to rt. After 17.5 h at rt, the reaction was quenched with acetic acid (50% aqueous, 5 mL) and extracted with EtOAc (3×5 mL). The combined organic phase was washed brine (10 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→30% EtOAc/CH2Cl2, gradient) afforded 14 mg (42%) of 7-[(R)-2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-hept-5-ynoic acid methyl ester.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[OH:9][CH2:10][C@@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1.Br[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][C:28]([O:30][CH3:31])=[O:29]>C(#N)C.ClCCl>[OH:9][CH2:10][C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)Cc1ccccc1OCCCBr
Reactant: OC[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: COC(=O)Cc1ccccc1OCCCN1CCC[C@H]1CO
Temperature: 70 °C
Yield: 81 %

Procedure:
0.92 g of potassium carbonate, 0.22 g of sodium iodide and then 0.63 g of 2-hydroxymethyl-(S)-pyrrolidine are successively added to a solution of 1.8 g of methyl 2-(3-bromopropoxy)phenylacetate in 20 cm3 of acetonitrile. The reaction mixture is heated at 70° C. for 5 hours and then, after cooling, diluted with 100 cm3 of dichloromethane, washed with 100 cm3 of water and then with 100 cm3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a Merck silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 30 cm), eluting under a nitrogen pressure of 0.4 bar with an ethyl acetate and methanol mixture (90/10 by volume) and collecting fractions of 100 cm3. Fractions 7 to 20 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). 1.55 g of methyl 2-[3-(2-hydroxymethyl-(S)-1-pyrrolidinyl)propoxy]-phenylacetate are obtained in the form of an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][N:9]([CH2:11][CH3:12])[C:8](=[O:13])[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)[O:18][B:17](B2OC(C)(C)C(C)(C)O2)[O:16]1.C([O-])(=O)C.[K+].ClCCl>O1CCOCC1.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:11]([N:9]1[CH2:10][C:4]2[C:5](=[N:6][CH:7]=[C:2]([B:17]([OH:18])[OH:16])[CH:3]=2)[C:8]1=[O:13])[CH3:12]
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: CCN1Cc2cc(Br)cnc2C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCN1Cc2cc(B(O)O)cnc2C1=O
Temperature: 100 °C
Reaction time: 6 h
Yield: 53.4 %

Procedure:
A mixture of 3-bromo-6-ethyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (240 mg, 1.0 mmol), 4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (250 mg, 1.0 mmol), potassium acetate (290 mg, 3.0 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complexed with dichloromethane (1:1) (30 mg, 0.04 mmol) in 1,4-dioxane (10 mL) was degassed and stirred at 100° C. for 6 h. After cooling it was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (0.11 g). LCMS (M+H)+=207.1.