Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:13]3[C@H:17]([CH2:18][CH3:19])[CH2:16][O:15][C:14]3=[O:20])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[CH3:21][N:22](C=O)C>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:18]([C@@H:17]1[CH2:16][O:15][C:14](=[O:20])[N:13]1[C:10]1[S:11][CH:12]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:21]#[N:22])=[CH:3][CH:4]=2)[N:9]=1)[CH3:19]
Reactant: CN(C)C=O
Reactant: CC[C@@H]1COC(=O)N1c1nc(-c2ccc(Br)cc2)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CC[C@@H]1COC(=O)N1c1nc(-c2ccc(C#N)cc2)cs1
Temperature: 145 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To a solution of (4R)-3-[4-(4-bromophenyl)-1,3-thiazol-2-yl]-4-ethyl-1,3-oxazolidin-2-one (1.46 g, 4.13 mmol), prepared in step 2 of Example 9, in dry DMF (15 mL) was added zinc cyanide (0.266 g, 2.27 mmol) and tetrakis(triphenylphosphine)palladium (0) (150 mg), under nitrogen, and the mixture heated to 145° C. After 1 h, the mixture was cooled to room temperature, diluted with ethyl acetate, which was then washed with water, brine, dried (anhydrous sodium sulfate) and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate:hexanes, gradient elution) to afford the title compound (0.67 g, 54%), mp 153-157° C., MS m/z 300 [M+H]+. ANLC 100% at 210-370 nm, 9.5 min; 100% at 240 nm, 9.5 min, Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH:11]=[CH2:12])[CH:5]=[CH:6][CH:7]=1.[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([CH2:19][C:20](=[O:24])[NH:21]2)=[CH:17][CH:16]=1.N1CCCC1>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19](=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH2:9][CH2:10][CH:11]=[CH2:12])[C:20](=[O:24])[NH:21]2)=[CH:17][CH:16]=1
Reactant: C=CCCC(=O)c1cccc(Cl)c1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: C=CCCC(=C1C(=O)Nc2cc(Cl)ccc21)c1cccc(Cl)c1
Temperature: 25 °C

Procedure:
To a mixture of 1-(3-chlorophenyl)pent-4-en-1-one (Example 62, Step A) (14.86 g, 76 mmol) and 6-chloroindolin-2-one (12.79 g, 76 mmol) in toluene (50 mL) at room temperature was added pyrrolidine (6.31 mL, 76 mmol). The slurry was heated at reflux with a Dean Stark trap for 6 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: 10 to 20% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([NH2:17])=[C:13]([NH2:16])[CH:14]=2)[N:9]=[CH:8][N:7]=1.O1CCO[CH:23](O)[CH:22]1O>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]3[N:17]=[CH:23][CH:22]=[N:16][C:13]=3[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: OC1OCCOC1O
Reactant: Nc1cc2ncnc(Nc3cccc(Br)c3)c2cc1N
Solvent: CO
Product: Brc1cccc(Nc2ncnc3cc4nccnc4cc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
A mixture of 4-(3-bromoanilino)-6,7-diaminoquinazoline (90 mg, 0.27 mmol) and 1,4-dioxane-2,3-diol (0.2 g, 1.6 mmol) [Venuti, M. C.; Synthesis, 1982, 61-63] in MeOH (20 mL) is stirred at room temperature overnight to give a precipitate of 4-(3-bromoanilino)pyrazino[2,3-g]quinazoline (80 mg, 83%). 1H NMR (DMSO) δ10.45 (1H, brs), 9.52 (1H, s), 9.09 (1H, d, J=1.6 Hz), 9.06 (1H, d, J=1.6 Hz), 8.71 (1H, s), 8.44 (1H, s), 8.32 (1H, brs), 7.99 (1H, m), 7.45-7.34 (2H, m). ##STR24##
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]1[O:13][C:14]([CH3:34])=[C:15]([CH3:33])[C:16]=1[C:17]([C:19]1[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[C:22]([O:28]C)=[C:21]([CH:30]([CH3:32])[CH3:31])[CH:20]=1)=[O:18].B(Br)(Br)Br.C(Cl)Cl>C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]1[O:13][C:14]([CH3:34])=[C:15]([CH3:33])[C:16]=1[C:17]([C:19]1[CH:20]=[C:21]([CH:30]([CH3:31])[CH3:32])[C:22]([OH:28])=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:24]=1)=[O:18]
Reactant: COc1c(C(C)C)cc(C(=O)c2c(Cc3ccc4ccccc4c3)oc(C)c2C)cc1C(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1oc(Cc2ccc3ccccc3c2)c(C(=O)c2cc(C(C)C)c(O)c(C(C)C)c2)c1C
Yield: 53.7 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 3 using (2-naphthalen-2-ylmethyl-4,5-dimethyl-furan-3-yl)-(3,5-diisopropyl-4-methoxy-phenyl)-methanone (1.04 g, 2.29 mmol) and 1M boron tribromide/CH2Cl2 (4.81 mL) in CH2Cl2. Purification on Biotage KP-Sil eluting with 15% acetone/hexane gave 0.542 g (54%) of the title compound. 1H NMR (DMSO-d6) δ 1.12 (d, 12H), 1.82 (s, 3H), 2.18 (s, 3H), 3.31 (septet, 2H), 4.02 (s, 2H), 7.22 (dd, 1H), 7.43-7.50 (m, 4H), 7.55 (s, 1H), 7.76-7.86 (m, 3H), 9.12 (s, 1H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[N:4][CH:3]=1.[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[C:22]1[C:23]([NH2:37])=[N:24][CH:25]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC.O>[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[C:22]1[C:23]([NH2:37])=[N:24][CH:25]=[C:26]([C:2]2[S:6][C:5]([N:7]3[CH2:12][CH2:11][O:10][CH2:9][CH2:8]3)=[N:4][CH:3]=2)[CH:27]=1
Reactant: Brc1cnc(N2CCOCC2)s1
Reactant: CC1(C)OB(c2cnc(N)c(-c3nc4ccccc4s3)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Nc1ncc(-c2cnc(N3CCOCC3)s2)cc1-c1nc2ccccc2s1
Temperature: 100 °C

Procedure:
A solution of 4-(5-bromothiazol-2-yl)-morpholine (0.0600 g, 0.241 mmol), 3-benzothiazol-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-2-ylamine (BB8) (0.110 g, 0.313 mmol), potassium carbonate (0.106 g, 0.771 mmol), and Pd(PPh3)4 (0.02 g, 0.02 mmol) in previously degassed DME/Water (4:1) (2.7 mL) was placed in a microwave tube and evacuated and charged with N2 (2×). The reaction mixture was heated in the microwave reactor at 100° C. for 45 min. The reaction mixture was partitioned between CHCl3 and H2O and the layers were separated. The aqueous layer was re-extracted with CHCl3 (3×), and the combined organic extracts were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo. The crude material was submitted for MDP for purification. The pure fractions were combined and the organic was concentrated in vacuo then diluted with CHCl3 and neutralized with sat. NaHCO3. The layers were separated, and the aqueous layer was re-extracted with CHCl3 (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo, giving the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=3.44 (d, J=5.1 Hz, 4H), 3.73 (d, J=5.1 Hz, 4H), 7.49 (t, J=7.7 Hz, 1H), 7.57 (t, J=7.7 Hz, 1H), 7.61 (s, 1H), 8.00 (d, J=2.2 Hz, 1H), 8.03 (br. s., 2H), 8.10 (d, J=7.7 Hz, 1H), 8.15 (d, J=7.3 Hz, 1H), 8.36 (d, J=2.2 Hz, 1H). MS (ES+): m/z=396.07 (100) [MH+]. HPLC: tR=3.57 min (ZQ2, polar—5 min).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH:3]([O:5][C:6]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][N:7]=1)[CH3:4].[CH3:15][O:16][C:17]([C:19]1[S:28][C:22]2[N:23]=[CH:24][N:25]=[C:26](Cl)[C:21]=2[C:20]=1[CH3:29])=[O:18]>>[CH3:29][C:20]1[C:21]2[C:26]([NH:12][C:11]3[C:6]([O:5][CH:3]([CH3:4])[C:2]([F:1])([F:13])[F:14])=[N:7][CH:8]=[CH:9][CH:10]=3)=[N:25][CH:24]=[N:23][C:22]=2[S:28][C:19]=1[C:17]([O:16][CH3:15])=[O:18]
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Reactant: CC(Oc1ncccc1N)C(F)(F)F
Product: COC(=O)c1sc2ncnc(Nc3cccnc3OC(C)C(F)(F)F)c2c1C
Temperature: 110 °C

Procedure:
Prepared analogously to example 1.1 by heating under microwave irradiation at 110° C. using 2-(1,1,1-trifluoropropan-2-yloxy)pyridin-3-amine and 4-Chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH3:16][N:17]1[C:22]2=[C:23]3[N:28]([C:29]([C:30]4[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=4)[C:33]#[N:34])=[C:21]2[C:20](=[O:39])[N:19]([CH3:40])[C:18]1=[O:41])[CH2:27][CH2:26][CH2:25][C:24]3=O.N1C(C)=CC=CC=1C>C(Cl)Cl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:24]1[C:23]2[N:28]([C:29]([C:30]3[CH:37]=[CH:36][CH:35]=[C:32]([C:33]#[N:34])[CH:31]=3)=[C:21]3[C:20](=[O:39])[N:19]([CH3:40])[C:18](=[O:41])[N:17]([CH3:16])[C:22]3=2)[CH2:27][CH2:26][CH:25]=1)(=[O:5])=[O:4]
Reactant: Cn1c(=O)c2c(-c3cccc(C#N)c3)n3c(c2n(C)c1=O)C(=O)CCC3
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: Cn1c(=O)c2c(-c3cccc(C#N)c3)n3c(c2n(C)c1=O)C(OS(=O)(=O)C(F)(F)F)=CCC3
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Trifluoromethanesulfonic anhydride (221 μL, 1.31 mmol) was added to an ice-cooled solution of 3-(1,3-dimethyl-2,4,10-trioxo-1,2,3,4,7,8,9,10-octahydropyrimido[4,5-a]indolizin-5-yl)benzonitrile (step 7) (350 mg, 1.01 mmol) and 2,6-lutidine (176 μL, 1.51 mmol) in DCM (5 mL). The solution was stirred at ice-bath temperature for 2 hours, further portions of 2,6-lutidine (88 μL, 0.78 mmol) and trifluoromethanesulfonic anhydride (85 μL, 0.50 mmol) were added. The reaction mixture was diluted with dichloromethane (40 mL) and was washed with water (2×20 mL) and sat. brine (1×20 mL). The organic phase was dried with magnesium sulfate and the solvent was removed under vacuum.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:25]=[CH:24][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:12]=2)=[O:9])=[CH:6][CH:5]=1.[NH:26]1[CH2:30][CH2:29][N:28]=[C:27]1N1C(C)=CC(C)=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:8](=[O:9])[C:7]2[CH:6]=[CH:5][C:4]([CH2:3][NH:2][C:27]3[NH:28][CH2:29][CH2:30][N:26]=3)=[CH:25][CH:24]=2)=[CH:12][C:13]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: Cc1cc(C)n(C2=NCCN2)n1
Reactant: NCc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CNC2=NCCN2)cc1

Procedure:
100 mg of the crude HCl salt of 4-(aminomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide was reacted with 80 mg of 1-(4,5-dihydro-1H-imidazol-2-yl)-3,5-dimethyl-1H-pyrazole and 110 of DIPEA in 1 mL of DMF in the microwave at 150° C. for 5 minutes. The crude product was concentrated to dryness and purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((4,5-dihydro-1H-imidazol-2-ylamino)methyl)benzamide. MS (Q1) 406 (M)+.
Reaction SMILES: C(OC([N:8]1[CH2:12][C:11]([F:14])([F:13])[CH2:10][C@H:9]1[C:15]([OH:17])=[O:16])=O)(C)(C)C.O1CCOCC1.Cl>CO>[F:13][C:11]1([F:14])[CH2:12][NH:8][C@H:9]([C:15]([OH:17])=[O:16])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1C(=O)O
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(O)[C@@H]1CC(F)(F)CN1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of (S)-1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidine-2-carboxylic acid (500 mg, 1.99 mmol) in methanol (30 mL) was added 4N HCl dioxane (3 mL). The reaction mixture was stirred at rt for 6 h. Concentration gave an oil which was used for the next step without purification (480 mg, 100%). 1H NMR (CD3OD, 400 MHz) δ 4.76 (1H, t, J=8.5 Hz), 3.79-3.87 (2H, m), 2.91-3.03 (1H, m), 2.73-2.82 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:5][N:6]([CH3:20])[C:7]([C:9]1[CH2:13][N:12]([CH2:14][C:15]([OH:17])=O)[C:11](=[O:18])[C:10]=1[OH:19])=[O:8].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:5][N:6]([CH3:20])[C:7]([C:9]1[CH2:13][N:12]([CH2:14][C:15]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:17])[C:11](=[O:18])[C:10]=1[OH:19])=[O:8]
Reactant: C1COCCN1
Reactant: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CC(=O)O)C1
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CC(=O)N2CCOCC2)C1

Procedure:
Compound 758 was prepared from {4-[(3,4-dichloro-benzyl)-methyl-carbamoyl]-3-hydroxy-2-oxo-2,5-dihydro-pyrrol-1-yl}-acetic acid, Compound 20, and morpholine using the method described for compound 751. The title compound was isolated as a white powder (0.0088 g, 20% yield). HRMS (M+H) calcd for C19H22N3Cl2O5: 442.09366. found: 442.0951.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12]CC)=[O:11])=[C:4]([CH3:15])[CH:3]=1.[ClH:16]>CC(O)=O>[ClH:16].[NH2:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])=[C:4]([CH3:15])[CH:3]=1
Reactant: CCOC(=O)/C=C/c1cnc(N)cc1C
Agent: Cl
Solvent: CC(=O)O
Product: Cc1cc(N)ncc1/C=C/C(=O)O
Temperature: 100 °C
Reaction time: 10 h

Procedure:
To ethyl (E)-3-(6-amino-4-methylpyridin-3-yl)acrylate (1.50 g, 7.3 mmole) was added HOAc (15 mL) and cone. HCl (15 mL). The solution was stirred at 100° C. for 10 hr, cooled to RT, and concentrated to dryness. Trituration with Et2O, filtration and drying under vacuum gave the title compound (1.65 g, quantitative) as a white solid: LCMS (ES) m/e 179.2 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1H), 8.28 (br s, 3H), 7.51 (d, J=16.0 Hz, 1H), 6.86 (s, 1H), 6.46 (d, J=16.0 Hz, 1H), 2.41 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[CH3:24])(O)[CH2:9][C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)=[C:4]([CH3:25])[CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[CH3:24])=[CH:9][C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)=[C:4]([CH3:25])[CH:3]=1
Reactant: Cc1cc(F)ccc1C(O)(Cc1nnnn1C)c1ccc(F)cc1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1cc(F)ccc1C(=Cc1nnnn1C)c1ccc(F)cc1C
Yield: 61.3 %

Procedure:
A mixture of 1,1-bis-(4-fluoro-2-methylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethanol (0.5 g, 1.5 mmoles) and p-toluenesulfonic acid (0.2 g) was heated at reflux in toluene (30 mL) for 16 hours. The mixture was cooled, diluted with diethyl ether (50 mL) and extracted with saturated sodium bicarbonate solution and water. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was triturated with diethyl ether to give 0.3 g of the title compound; m.p.=120°-125° C.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]([NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][CH:17]=[N:18]3)=[O:11])[CH2:3]1.[C:23]([C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)#[N:24]>>[CH3:1][C@H:2]1[N:7]([S:31]([C:28]2[CH:27]=[CH:26][C:25]([C:23]#[N:24])=[CH:30][CH:29]=2)(=[O:33])=[O:32])[C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]([NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][CH:17]=[N:18]3)=[O:11])[CH2:3]1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@@H]1CN(CC(=O)Nc2cccc3ncccc23)C[C@H](C)N1
Product: C[C@@H]1CN(CC(=O)Nc2cccc3ncccc23)C[C@H](C)N1S(=O)(=O)c1ccc(C#N)cc1

Procedure:
The title compound was prepared from the product of Example 58 step (i) (0.503 mmol) and 4-cyanobenzenesulphonyl chloride (0.503 mmol) by the method of Example 58 step (ii) as a white solid. Yield: 4 mg
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1)(=O)C.[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[ClH:19]>C(O)C>[ClH:19].[C:12]1([CH:11]=[C:8]2[C:7](=[O:10])[C:6](=[CH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:5][NH:4][CH2:9]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)N1CCC(=O)CC1
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: CCO
Product: O=C1C(=Cc2ccccc2)CNCC1=Cc1ccccc1
Reaction time: 8 h

Procedure:
A mixture of 14 g. (0.1 mole) of N-acetyl-4-piperidinone and 32 g. (0.3 mole) of benzaldehyde in 150 ml. of ethanol containing 33 ml. of conc. HCl is refluxed for 6 hours and then kept overnight at room temperature. The light yellow solid is filtered, washed with ethanol, washed with ether, and air-dried to yield 26 g. of product; m.p. 273°-275° (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([OH:19])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:23])[C:6]=2[CH:24]=1.O[CH:26]1[CH2:30][CH2:29][O:28][CH2:27]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([O:19][CH:26]3[CH2:30][CH2:29][O:28][CH2:27]3)=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:23])[C:6]=2[CH:24]=1
Reactant: Cc1c(S(=O)(=O)Nc2cccc(C(=O)O)c2)sc2ccc(Cl)cc12
Reactant: OC1CCOC1
Product: Cc1c(S(=O)(=O)Nc2cccc(C(=O)OC3CCOC3)c2)sc2ccc(Cl)cc12
Yield: 63 %

Procedure:
The product was prepared from 3-{[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]amino}benzoic acid (21 mg, 0.055 mmol) (Intermediate 19) and 3-hydroxytetrahydrofuran (8.8 mg, 0.100 mmol) according to the General Procedure 7, described in Example 107. The title compound was obtained in 63% yield (15.6 mg). 1H NMR (500 MHz, CDCl3) δ ppm 2.07 (ddddd, J=13.81, 6.79, 4.51, 1.93, 1.05 Hz, 1 H) 2.25 (dddd, J=13.81, 8.43, 8.43, 6.32 Hz, 1 H) 2.47 (s, 3 H) 3.86-3.96 (m, 3 H) 3.97 (dd, J=10.65, 4.64 Hz, 1 H) 5.46-5.50 (m, 1 H) 7.00 (s, 1 H) 7.37 (dd, J=8.05, 7.69 Hz, 1 H) 7.44 (ddd, J=8.05, 2.35, 1.17 Hz, 1 H) 7.44 (dd, J=8.72, 1.95 Hz, 1 H) 7.70 (dd, J=2.35, 1.57 Hz, 1 H) 7.72 (dd, J=8.72, 0.57 Hz, 1 H) 7.72 (dd, J=1.95, 0.57 Hz, 1 H) 7.82 (ddd, J=7.69, 1.57, 1.17 Hz, 1 H). MS (ESI+) m/z 452 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13]([C:18]([OH:20])=[O:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:21].[CH3:22]O>>[ClH:21].[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13]([C:18]([O:20][CH3:22])=[O:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)c1ccc2c(n1)CCN(Cc1ccccc1)C2
Agent: Cl
Product: COC(=O)c1ccc2c(n1)CCN(Cc1ccccc1)C2
Temperature: 80 °C
Yield: 100 %

Procedure:
In a sealed container, 6-benzyl-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylic acid (1.00 g, 3.73 mmol) was dissolved in MeOH (40.0 mL) and HCl (3.29 mL, 14.9 mmol, 4.0 M in 1,4-dioxane). The resulting solution was heated at 80° C. for 13 h. The solvent and acid were completely evaporated to yield methyl 6-benzyl-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylate hydrochloride (1.25 g, 100%). LC-MS: (FA) ES+ 283; 1H NMR (Methanol-d4, 400 MHz) δ 8.08 (d, J=8.0 Hz, 1 H), 7.92 (d, J=8.3 Hz, 1 H), 7.63 (m, 2 H), 7.54 (m, 3 H), 4.88 (s, 2 H), 4.58 (s, 4 H), 3.99 (s, 3 H), 3.40 (s, 2 H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[O:10][C:11]([C:14]3[N:15](C(OC(C)(C)C)=O)[C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[C:14]1[C:11]1[O:10][C:9]([NH:8][C:4]2[CH:3]=[C:2]([OH:1])[CH:7]=[CH:6][CH:5]=2)=[N:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2cnc(Nc3cccc(O)c3)o2)cc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Oc1cccc(Nc2ncc(-c3cc4ccccc4[nH]3)o2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.1 %

Procedure:
To a stirred solution of tert-butyl 2-(2-((3-hydroxyphenyl)amino)oxazol-5-yl)-1H-indole-1-carboxylate 22 (0.125 g, 0.319 mmol) in anhydrous CH2Cl2 (20 mL) was added 1:1 mixture of CH2Cl2:Trifluoroacetic acid (5 mL) at 0° C. Reaction was stirred for 1 hour at ambient temperature. It was quenched with aq. saturated NaHCO3 and CH2Cl2 layer was separated. After evaporation of solvent, crude product was purified using preparative-TLC to obtain 3-((5-(1H-indol-2-yl)oxazol-2-yl)amino)phenol 23 (0.027 g, 16% yield).
Reaction SMILES: [Cl:1][SiH:2]([Cl:4])[Cl:3].[CH2:5]=[CH:6][CH:7]([Cl:10])[CH2:8][Cl:9]>>[Cl:10][CH:7]([CH2:8][Cl:9])[CH2:6][CH2:5][Si:2]([Cl:4])([Cl:3])[Cl:1]
Reactant: C=CC(Cl)CCl
Reactant: Cl[SiH](Cl)Cl
Product: ClCC(Cl)CC[Si](Cl)(Cl)Cl
Yield: 67.7 %

Procedure:
596 g trichlorosilane (4.4 moles, excess) and 500 g 3,4-dichlorobutene-1 (4 moles) are mixed. 0.4 g Pt(II)-acetyl acetonate are added to 30 ml of this mixture, at which time the temperature gradually rises by itself to 95° C. At this temperature, the remaining trichlorosilane/olefin mixture is added and allowed to react for an additional half hour at 92° C. Excess trichlorosilane and other readily volatile constituents are drawn off in a vacuum. The crude product obtained in this manner (826 g≅79.3% of theory) is subsequently purified by distillation. 705 g 3,4-dichlorobutyl trichlorosilane 67.7% of theory are obtained as the main fraction (see table 1 for composition data).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([C:15]([Cl:20])=[O:17])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Oc2ccc(F)cc2)nc1
Reactant: O=S(Cl)Cl
Solvent: C1COCCO1
Product: O=C(Cl)c1ccc(Oc2ccc(F)cc2)nc1
Yield: 100.7 %

Procedure:
6-[(4-Fluorophenyl)oxy]-3-pyridinecarboxylic acid (D14) (0.232 g, 0.994 mmol) was dissolved in 1,4-dioxane (6 mL) and thionyl chloride (0.363 mL, 4.972 mmol) added dropwise. The mixture was heated at reflux for 3.5 h, then cooled and concentrated in vacuo. DCM was added to the residue which was then re-concentrated to yield 6-[(4-fluorophenyl)oxy]-3-pyridinecarbonyl chloride as a yellow oil (0.252 g) which was used directly in step 2. Step 2: The acid chloride from step 1 was taken up in DCM (3 mL) and added to 1,1-dimethylethyl (2S)-2-methyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazinecarboxylate (D3) (0.288 g, 0.904 mmol) in DCM (3 mL). Triethylamine (0.251 mL, 1.808 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM and washed with water. The aqueous was extracted with DCM (×2) and the combined organic layers were dried and concentrated. The crude product was purified by column chromatography. Elution with a 0-50% EtOAc/petroleum ether gradient gave the title compound as a colourless oil (0.518 g). δH (CDCl3, 400 MHz) 8.07 (1H, m), 7.65 (1H, dd), 7.24 (2H, d), 7.03 (6H, m), 6.70 (1H, d), 4.18 (1H, br.s), 3.80 (1H, d), 3.48 (3H, s), 3.46 (1H, d), 3.34 (1H, d), 3.08 (1H, td), 2.70 (1H, d), 2.50 (1H, d), 2.10 (1H, dd), 2.00 (1H, m), 1.46 (9H, s), 1.20 (3H, d). MS (ES): MH+ 535.3. Description 16: Alternative Method (A)