Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[C:8]([OH:12])([CH3:11])([CH3:10])[CH3:9]>C1C=CC=CC=1>[C:8]([O:12][C:6](=[O:7])[NH:5][S:2]([Cl:1])(=[O:4])=[O:3])([CH3:11])([CH3:10])[CH3:9]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)O
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)NS(=O)(=O)Cl
Reaction time: 2 h
Yield: 65.4 %

Procedure:
To a stirred solution of chlorosulfonyl isocyanate (3.20 mL, 36.0 mmol) in benzene (15.0 mL) in a water bath at rt was added tert-butyl alcohol (3.50 mL, 36.2 mmol) dropwise via syringe under an atmosphere of nitrogen. After 2 h, the mixture was diluted with hexanes (30.0 mL) and the resulting white precipitate was filtered and washed with hexanes (3×20 mL). The collected solid was dried in a vacuum desiccator under house vacuum for 10 min to afford the title compound as a white solid (5.08 g, 65%). The product was stored under nitrogen in a freezer. 1H NMR (300 MHz, CDCl3, δ): 8.44 (br s, 1H), 1.57 (s, 9H) ppm. LC/MS: Rt=0.939 min, ES+ 215 (AA standard). Reference: F. Hirayama et al., Biorg. Med. Chem., 2002, 10, 1509-1523.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[CH3:25]>>[F:18][C:19]1[CH:20]=[C:21]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=2)[CH:22]=[CH:23][C:24]=1[CH3:25]
Reactant: Cc1ccc(B(O)O)cc1F
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Product: Cc1ccc(-c2cc(C#N)cc3cc4n(c23)CCNC4=O)cc1F

Procedure:
The title compound, off-white solid (72 mg, 90%), MS (ISN) m/z=320.4 [(M+H)+], mp 278.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 3-fluoro-4-methyl-phenylboronic acid (50.0 mg, 0.325 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH:5]([O:23][CH2:24][CH3:25])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)[CH3:2].[CH2:27]([N:34]=[C:35]=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4](=[O:26])[CH:5]([O:23][CH2:24][CH3:25])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][C:35](=[O:36])[NH:34][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:20][CH:21]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: O=C=NCc1ccccc1
Reactant: CCOC(=O)C(Cc1ccc(OCCc2ccc(O)cc2)cc1)OCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(Cc1ccc(OCCc2ccc(OC(=O)NCc3ccccc3)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.4 %

Procedure:
2-Ethoxy-3-{4-[2-(4-hydroxyphenyl)ethoxy]phenyl}propanoic acid ethyl ester (described in Example 26b) (0.36 g; 1.0 mmol) was dissolved in dry dichloromethane (25 ml) and benzylisocyanate (0.20 g; 0.185 ml; 1.5 mmol) was added followed by addition of triethylamine (0.22 ml; 1.5 mmol). The solution was stirred at room temperature for 3 hours. The dichloromethane phase was washed with diluted acid, sodium hydrogen carbonate and brine, dried with sodium sulfate and evaporated to give 0.4 g (81%) of crude 3-{4-[2-(4-benzylcarbamoyloxyphenyl)ethoxy]phenyl}-2-ethoxypropanoic acid ethyl ester. The crude material was purified on preparative reversed phase HPLC using a gradient of acetonitrile-water-ammonium acetate as mobile phase. Fractions containing pure product were pooled and the acetonitrile removed in vacuum. The residue was dissolved in dichloromethane, washed with water, dried with sodium sulfate and evaporated to give 0.23 g (48%) of pure 3-{4-[2-(4-benzylcarbamoyloxyphenyl)ethoxy]phenyl}-2-ethoxypropanoic acid ethyl ester
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH:16][C:17]2[CH:22]=[N:21][CH:20]=[CH:19][N:18]=2)=[O:15])=[C:9]([O:23][CH3:24])[CH:8]=1)=[O:5].[CH:25]1([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:25]1([NH:30][CH2:2][CH2:3][C:4]([NH:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH:16][C:17]3[CH:22]=[N:21][CH:20]=[CH:19][N:18]=3)=[O:15])=[C:9]([O:23][CH3:24])[CH:8]=2)=[O:5])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COc1cc(NC(=O)CCCl)ccc1NC(=O)Nc1cnccn1
Reactant: NC1CCCC1
Product: COc1cc(NC(=O)CCNC2CCCC2)ccc1NC(=O)Nc1cnccn1
Temperature: 80 °C

Procedure:
A mixture of 3-chloro-N-[3-methoxy-4-(3-pyrazin-2-yl-ureido)phenyl]-propionamide (Compound 8, Example 12) and cyclopentylamine (0.5 mL, large excess) was warmed at 80° C. for 1 h and cooled to room temperature. The product was precipitated from ether (10 mL), collected by filtration, washed with ether, and dried in vacuo (24 mg, 60%). 1H NMR (300 Mhz, d6-DMSO) δ: 10.14 (s, 1H), 10.03 (s, 1H), 9.93 (s, 1H), 8.87 (d, J=1.1 Hz, 1H), 8.31 (dd, J=2.6, 1.5 Hz. 1H), 8.23 (d, J=2.7 Hz, 1H), 8.03 (d, J=8.7 Hz, 1H), 7.47 (d, J=2.1 Hz, 1H), 7.04 (dd, J=8.7, 2.1 Hz, 1H), 3.87 (s, 3H), 3.05 (quintet, J=6.3 Hz, 1H), 2.80 (t, J=6.6 Hz, 2H), 2.44 (t, J=6.6 Hz, 2H), 1.80-1.67 (m, 2H), 1.65-1.56 (m, 2H), 1.53-142 (m, 2H), 1.37-1.27 (m, 2H). LRMS (ESI, positive) m/e 399.1 (M+1).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:7]=[CH:6][N:5]([CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[N:4]=1.FC(F)(F)C(O)=O>ClCCl>[F:22][C:2]([F:1])([F:21])[C:3]1[CH:7]=[CH:6][N:5]([CH:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[N:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ccc(C(F)(F)F)n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1ccn(C2CCNCC2)n1
Yield: 127.7 %

Procedure:
To a dichloromethane solution (1.5 mL) of tert-butyl 4-[3-(trifluoromethyl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (150 mg, 0.50 mmol) synthesized in Reference Synthesis Example 33, trifluoroacetic acid (0.7 mL) was added at room temperature, and the resultant solution was stirred for 3 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure and water was added to the concentrated reaction solution, followed by extraction from the resultant mixture with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (140 mg, quantitative).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:15]2[CH2:20][CH2:19][C:18]([CH2:27][C:28](O)=[O:29])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:17][C:16]2=[O:31])[CH:10]=1.C1C=CC2N(O)N=[N:38]C=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:15]2[CH2:20][CH2:19][C:18]([CH2:27][C:28]([NH2:38])=[O:29])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:17][C:16]2=[O:31])[CH:10]=1
Reactant: O=C(O)CC1(c2ccccc2)CCN(c2cccc(-c3ccc(F)cc3F)c2)C(=O)O1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NC(=O)CC1(c2ccccc2)CCN(c2cccc(-c3ccc(F)cc3F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.5 %

Procedure:
A solution of 2-(3-(2′,4′-difluorobiphenyl-3-yl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)acetic acid (30 mg, 0.072 mmol), HOBt (18 mg, 0.144 mmol), EDCl (30 mg, 0.144 mmol) and DIEA (0.2 ML) in anhydrous CH2Cl2 (3 mL) was stirred at 0° C. under NH3. Then the solution was stirred at rt overnight. Solvent was removed in vacuo, the residue was purified by HPLC to get 2-(3-(2′,4′-difluorobiphenyl-3-yl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)acetamide (1.68 mg, 6%). 1H-NMR (400 MHz, CDCl3): δ=2.58 (m, 2H), 2.80-3.00 (m, 2H), 3.27 (m, 1H), 3.50 (m, 1H), 6.00 (s, 1H), 6.36 (s, 1H), 6.78-6.90 (m, 2H), 7.05 (m, 1H), 7.23-7.55 (m, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:9]([O:16]C)=[N:10][C:11]([O:14]C)=[N:12][CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1>CO>[ClH:1].[Cl:1][C:2]1[C:7]([C:8]2[C:9](=[O:16])[NH:10][C:11](=[O:14])[NH:12][CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COc1ncc(-c2cccnc2Cl)c(OC)n1
Solvent: CO
Product: Cl
Product: O=c1[nH]cc(-c2cccnc2Cl)c(=O)[nH]1

Procedure:
5-(2-Chloro-pyridin-3-yl)-2,4-dimethoxy-pyrimidine (Prep94, 3.76 mmol) was dissolved in MeOH (10 ml), then 2N HClaq (8 ml) was added. After refluxing the reaction mixture for 4 hours, the solvent was removed under vacuum to give the title compound (quantitative yield)
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=2[CH2:15]O)=[CH:8][CH:7]=1.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[F:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=2[CH2:15][Cl:3])=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccccc1Sc1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: Fc1ccc(Sc2ccccc2CCl)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
8.5 g of thionyl chloride are added dropwise over a 10 minute span to a stirring mixture of 13.0 g of 2-(4-fluorophenylthio)benzyl alcohol in 80 ml of benzene at ambient temperature. After total addition, the reaction mixture is stirred for 16 hours before being carefully poured onto 350 ml of crushed ice containing 8 ml of sodium bicarbonate. The mixture is stirred until the ice melts. The layers separate and the benzene layer is successively washed twice with 40 ml portions of a half saturated sodium bicarbonate solution, washed twice with 40 ml portions of water, washed once with a 25 ml portion of a saturated sodium chloride solution, dried and rotary evaporated to provide 2-(4-fluorophenylthio)benzyl chloride.
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15])([O:3]CC)=[O:2].Cl.C(O)(=O)C>O>[C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15])([OH:3])=[O:2]
Reactant: CCOC(=O)CCCCC1CCCC1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)CCCCC1CCCC1=O
Reaction time: 0.5 h

Procedure:
A stirred mixture of 274 g. of 2-carbalkoxy (mixed methyl and ethyl esters)-2-(4-carbethoxybutyl)cyclopentan-1-one (Example 4), 600 ml. of 20% hydrochloric acid and 325 ml. of acetic acid is heated at reflux for 20 hours. Solution occurs in approximately 1/2 hour. The solution is cooled and diluted with water and extracted with ether. The combined extracts are washed with saline and dried over magnesium sulfate and evaporated. The residue is evaporated twice with toluene to give 144 g. of an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:20](O)(=O)[CH2:21][OH:22].[OH-].[NH4+]>Cl>[C:14]1([CH2:13][N:12]2[C:11]3[C:10]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[N:4]=[CH:3][C:2]=3[N:1]=[C:20]2[CH2:21][OH:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1cnc2ccccc2c1NCc1ccccc1
Reactant: O=C(O)CO
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: OCc1nc2cnc3ccccc3c2n1Cc1ccccc1
Temperature: 150 °C
Yield: 82 %

Procedure:
3-amino-4-(benzylamino)quinoline (9.5 g; 0.038 mol) and glycolic acid (6.8 g; 0.089 mol) were mixed and the mixture was heated at 150° C. for about 4 hr. The dark mixture was then dissolved in dilute hydrochloric acid with heating. Upon cooling a precipitate formed and was filtered from the mixture. The solid was dissolved in hot water. The solution was then made basic with ammonium hydroxide to precipitate the product. A second, less pure, small crop was obtained from the original filtrate by making it basic with ammonium hydroxide. The solid was triturated in ethyl acetate to give a green colored powder. Total yield was 82%. The product was recrystallized from methanol to give a pure sample m.p. 211-213° C. Analysis: Calculated: C, 74.7; H, 5.2; N, 14.5. Found: C, 74.4; H, 5.1; N, 14.4.
Reaction SMILES: [NH2:1][C:2](=[S:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Br[CH:10]([CH3:21])[C:11](=O)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1>CN(C=O)C.CCOC(C)=O>[Br:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][C:11]1[N:1]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[S:8][C:10]=1[CH3:21]
Reactant: CCOC(=O)C(N)=S
Reactant: CC(Br)C(=O)Cc1cccc(Br)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(Cc2cccc(Br)c2)c(C)s1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
A mixture of ethyl 2-amino-2-thioxoacetate (50.9 mg, 0.38 mmol) and 3-bromo-1-(3-bromophenyl)butan-2-one (0.38 mmol, crude from previous step) in DMF (2 mL) was stirred at 70° C. for 12 h. The mixture was diluted with EtOAc and washed with H2O. The organic layer was concentrated, and purified by silica gel column chromatography(0-50% EtOAc/Hexane) to yield a yellowish solid (71 mg, 55% over 2 steps). MS (ES+) C14H14BrNO2S requires: 339, 341 found: 340, 342 [M+H]+(1:1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[CH:12]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1(C)C=CC=CC=1>[Cl:8][C:9]1[CH:10]=[C:11]([CH2:12][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18]
Reactant: O=Cc1ccc([N+](=O)[O-])c(Cl)c1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CN1CCN(Cc2ccc([N+](=O)[O-])c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.2 %

Procedure:
N-methyl piperazine (2.50 mL, 22.5 mmol) was added dropwise to a solution of 3-chloro-4-nitrobenzaldehyde (2.09 g, 11.3 mmol) and acetic acid (0.29 mL, 5.14 mmol) in toluene (11.7 mL) at room temperature. The reaction mixture was stirred for 1.5 h at room temperature before the addition of further toluene (4.4 mL) and sodium triacetoxyborohydride (3.58 g, 16.9 mmol). The reaction mixture was stirred at room temperature overnight and then quenched by the addition of MeOH (3 mL) and saturated aqueous NaHCO3 (23 mL). The reaction mixture was stirred for 30 min. The phases were separated and the aqueous layer was extracted with toluene (2×30 mL). The combined organic extracts were concentrated under reduced pressure and purified by flash column chromatography (EtOAc:MeOH:NEt3 9:1:0.1) to give the title compound (2.17 g, 71%) as an orange oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][CH:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]2=[O:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][S:11][CH2:10][CH2:9]1.[CH3:25][C:26]1[CH:27]=[CH:28][C:29]([S:32]([NH:35]Cl)(=[O:34])=[O:33])=[CH:30][CH:31]=1.CO.C(Cl)(Cl)Cl>C(Cl)Cl.[Br-].C([P+](CCCC)(CCCC)CCCC)CCCCCCCCCCCCCCC.ClCl>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]2=[O:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][S:11](=[N:35][S:32]([C:29]2[CH:30]=[CH:31][C:26]([CH3:25])=[CH:27][CH:28]=2)(=[O:33])=[O:34])[CH2:12][CH2:13]1
Reactant: Cc1ccc(S(=O)(=O)NCl)cc1
Reactant: CC(=O)NCC1CN(c2ccc(N3CCSCC3)c(F)c2)C(=O)O1
Agent: CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC
Agent: ClCl
Agent: [Br-]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCS(=NS(=O)(=O)c4ccc(C)cc4)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
The N-[[3-[3-fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (213 mg, 0.603 mmol) was dissolved in dry CH2Cl2 (11.5 mL) and then treated with hexadecyl-tributylphosphonium bromide (138 mg, 0.271 mmol). To this clear, colorless solution, the chloramine-T (165 mg, 0.723 mmol) was added. The resultant cloudy solution was stirred at room temperature for three hours. At this time, the reaction was determined to be complete by TLC (10% MeOH/CHCl3, UV short wave). The reaction mixture was transferred to a separatory funnel and diluted with CH2 Cl2 (10 mL). This solution was washed with cold 5% NaOH (20 mL), water (20 mL), and brine (20 mL). The aqueous portions were combined and then back-extracted with more CH2Cl2 (3×20 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resultant material was chromatographed on silica gel (100 g), eluting with a gradient of 0-6% MeOH in 10% CH3CN/CHCl3 to give 314 mg (99%) of the title compound as a white solid which decomposes at 79° C. and has a HRMS (FAB) calculated for C23H28FN4O5S2 (M+H)+, 523.1485, found 523.1477.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2CC[C@:13]([CH2:22][C:23]([CH3:25])=[CH2:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][C:11]2=O)[CH3:9])=[CH:4][CH:3]=1.S([C:37]#[N:38])(C1C=CC(C)=CC=1)(=O)=O.C1([SiH3])C=CC=CC=1.[CH3:46][CH2:47][OH:48]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:11][CH2:12][C@:13]([CH2:22][C:23]([CH3:25])([CH3:24])[C:37]#[N:38])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:46][C:47]2=[O:48])[CH3:9])=[CH:4][CH:3]=1
Reactant: C=C(C)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)C1
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Reactant: CCO
Agent: [SiH3]c1ccccc1
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)CC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
A solution of (S)-1-((S)-1-(4-bromophenyl)ethyl)-4-(2-methylallyl)-4-phenylpiperidin-2-one (30 mg, 0.07 mmol), the cobalt(II) complex whose preparation is described below (0.46 mg, 0.0007 mmol), TsCN (19.8 mg, 0.11 mmol) and PhSiH3(8.4 mg, 0.08 mmol) in anhydrous EtOH (5 mL) was stirred at rt for 4 h. After the solvent was removed under reduced pressure, the residue was purified by preparative TLC to give 3-((S)-1-((S)-1-(4-bromophenyl)ethyl)-2-oxo-4-phenyl piperidin-4-yl)-2,2-di methylpropanenitrile (15 mg, 50%). LC-MS Method
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].[H-].[Na+].Cl.[CH3:11][Si:12]([CH3:38])([CH3:37])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>COCCOC>[CH3:11][Si:12]([CH3:38])([CH3:37])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([CH:3]([C:2](=[O:7])[CH3:1])[C:4](=[O:6])[CH3:5])=[O:33])=[CH:30][CH:29]=1
Reactant: CC(=O)CC(C)=O
Reactant: C[Si](C)(C)CCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(=O)C(C(C)=O)C(=O)c1ccc(NCCCCCCCCCCCCCC[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 14.2 g. of 2,4-pentanedione and 20 ml. of 1,2-dimethoxyethane is added to a suspension of 6.8 g. of sodium hydride in 110 ml. of 1,2-dimethoxyethane under argon. A solution of 14.0 g. of 4-[14-(trimethylsilyl)tetradecylamino]benzoyl chloride hydrochloride in 1,2-dimethoxyethane is then added. The reaction mixture is stirred at room temperature for 12 hours, cooled, poured on ice and extracted with ether. The ether solution is washed with water and saturated sodium chloride solution, dried with anhydrous sodium sulfate and evaporated. The residue is then chromatographed over silica gel to yield the product as a white solid.
Reaction SMILES: P(Br)(Br)[Br:2].[Cl:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[N:11]([C:17]1[CH:18]=[N:19][CH:20]=[C:21]([CH:23](O)[CH3:24])[CH:22]=1)[CH2:10][CH2:9]2>C(Cl)Cl>[Br:2][CH:23]([C:21]1[CH:22]=[C:17]([N:11]2[CH2:10][CH2:9][C:8]3[C:13](=[CH:14][CH:15]=[C:6]([Cl:5])[CH:7]=3)[C:12]2=[O:16])[CH:18]=[N:19][CH:20]=1)[CH3:24]
Reactant: BrP(Br)Br
Reactant: CC(O)c1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Solvent: ClCCl
Product: CC(Br)c1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
PBr3 (541 mg, 2 mmol) was added dropwise into a solution of 6-chloro-2-[5-(1-hydroxy-ethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one (example 13) (302 mg, 1 mmol) in 5 mL DCM at 0° C. The reaction was stirred at RT for 2 hours before it was neutralized with satd. aq. NaHCO3 solution and extracted with DCM (10 mL, 2×). The organic layers were washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to afford a crude product as an oil which was used in the next step without further purification (380 mg, 100%). MS: 365.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[CH:14]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.Cl[C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[N:26][N:25]=1.CC(O)(C)C>C(OCC)C.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:20][NH:19][C:15]1[CH:14]=[C:13]([C:12]2[C:7]([O:6][C:5]3[CH:21]=[CH:22][C:2]([NH:1][C:24]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[C:27]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)=[N:26][N:25]=4)=[CH:3][CH:4]=3)=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:18]=[CH:17][N:16]=1
Reactant: Clc1nnc(-c2ccccc2)c2ccccc12
Reactant: CNc1cc(-c2cccnc2Oc2ccc(N)cc2)ccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CCOCC
Product: CNc1cc(-c2cccnc2Oc2ccc(Nc3nnc(-c4ccccc4)c4ccccc34)cc2)ccn1
Temperature: 100 °C

Procedure:
To 4-(2-(4-aminophenoxy)pyridin-3-yl)-N-methylpyridin-2-amine (0.070 g, 0.24 mmol) and 1-chloro-4-phenylphthalazine (0.048 g, 0.20 mmol) was added tBuOH (1.0 mL). The resulting mixture was heated at 100° C. in a sealed tube for 16 hours. The reaction was diluted with diethyl ether and saturated sodium carbonate and vigorously shaken. The resulting solids were filtered and washed with water, diethyl ether and air dried to yield N-(4-(3-(2-(methylamino)pyridin-4-yl)pyridin-2-yloxy)phenyl)-4-phenylphthalazin-1-amine as an off-white solid. MS m/z=497 [M+H]+. Calc'd for C31H24N6O: 496.58.
Reaction SMILES: [S:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][C:3]2[CH2:9][CH2:10][CH2:11][CH2:12][C:2]1=2.S(Cl)(Cl)=O.[C:17]([NH2:21])([CH3:20])([CH3:19])[CH3:18]>ClCCl>[C:17]([NH:21][C:6]([C:5]1[S:1][C:2]2[CH2:12][CH2:11][CH2:10][CH2:9][C:3]=2[CH:4]=1)=[O:8])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)N
Reactant: O=C(O)c1cc2c(s1)CCCC2
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1cc2c(s1)CCCC2
Yield: 88.9 %

Procedure:
A mixture of 4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylic acid (500 g, 2.75 mol, 1.0 equiv) and thionyl chloride (655 g, 5.5 mol, 2.0 equiv) was boiled under reflux for 3 h. Excess thionyl chloride was removed by distillation under reduced pressure. The residue was taken up in dichloromethane (1.0 L) and a solution of tert-butylamine (402 g, 5.5 mol, 2.0 equiv) in dichloromethane (500 mL) was added with stirring while the temperature of the mixture was kept below 10° C. The resulting solution was stirred at 25° C. for 16 h. Most of the solvent was removed under reduced pressure. The residue was chilled in an ice-bath and 2M KOH solution was introduced slowly to adjust the pH to 11 with stirring. The suspension was filtered and the solid was collected, washed three times with water, and dried in vacuo to afford 117a as a white solid (580 g, 80%, over two steps). MS: [M+H]+ 238. 1H NMR (500 MHz, CDCl3) δ 7.02 (s, 1H), 5.77 (s, 1H), 2.65 (t, J=6.0 Hz, 1H), 2.47 (t, J=6.0 Hz, 1H), 1.74-1.70 (m, 4H), 1.35 (s, 9H).