Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[S:18][C:19]([C:23]([NH:25][CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[O:24])=[C:20]([CH3:22])[N:21]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:17]2[S:18][C:19]([C:23]([NH:25][CH2:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[O:24])=[C:20]([CH3:22])[N:21]=2)[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(Br)sc1C(=O)NCc1cccnc1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Product: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)NCc1cccnc1
Yield: 47 %

Procedure:
Following the procedure as described in Example 3, making variations only as required to use 4-(benzyloxy)pyridin-2(1H)-one in place of 4-aminopyridin-2(1H)-one to react with 2-bromo-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide in place of N-benzyl-2-bromo-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 47% yield: mp 208-209° C.; 1H-NMR (300 MHz, DMSO-d6) δ 8.86 (br s, 1H), 8.68-8.60 (m, 1H), 7.81-7.72 (m, 1H), 7.51-7.33 (m, 7H), 6.35-6.48 (m, 1H), 6.27 (s, 1H), 5.19 (s, 2H), 4.47 (s, 2H), 2.58 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 167.0, 161.5, 161.1, 153.5, 150.1, 135.2, 131.6, 128.5, 128.3, 128.0, 122.9, 103.9, 97.0, 70.3, 17.0; MS (ES+) m/z: 433.3 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH:8]([C:11]([O:13]CC)=O)[C:6](=[O:7])[N:5]([CH3:16])[C:3]1=[O:4].[CH:17]([C:20]1[N:25]=[C:24]([O:26][C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=2)[CH:23]=[C:22]([CH3:34])[N:21]=1)([CH3:19])[CH3:18]>C1(C)C=CC=CC=1>[CH3:16][N:5]1[C:6](=[O:7])[CH:8]([C:11](=[O:13])[NH:31][C:30]2[CH:29]=[CH:28][C:27]([O:26][C:24]3[CH:23]=[C:22]([CH3:34])[N:21]=[C:20]([CH:17]([CH3:19])[CH3:18])[N:25]=3)=[CH:33][CH:32]=2)[C:9](=[O:10])[N:2]([CH3:1])[C:3]1=[O:4]
Reactant: Cc1cc(Oc2ccc(N)cc2)nc(C(C)C)n1
Reactant: CCOC(=O)C1C(=O)N(C)C(=O)N(C)C1=O
Solvent: Cc1ccccc1
Product: Cc1cc(Oc2ccc(NC(=O)C3C(=O)N(C)C(=O)N(C)C3=O)cc2)nc(C(C)C)n1

Procedure:
3.0 g (0.013 mole) of 1,3-dimethyl-5-ethoxycarbonylbarbituric acid and 3.2 g (0.013 mole) of 4-(2-isopropyl-6-methylpyrimidin-4-yloxy)aniline are suspended in 30 ml of toluene and heated for 18 hours at reflux temperature in an inert gas atmosphere (nitrogen). After cooling, the precipitate is isolated by filtration, washed with alcohol and dried.
Reaction SMILES: [OH:1][CH:2]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:3][CH2:4][C@@H:5]1[C@@H:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])[C:8](=[O:21])[CH2:7][CH2:6]1.[OH-].[K+].Cl.[Cl-].[Na+]>CO>[OH:1][CH:2]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:3][CH2:4][C@@H:5]1[C@@H:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:8](=[O:21])[CH2:7][CH2:6]1
Reactant: CCCCCC(O)CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OCC
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Product: CCCCCC(O)CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)O
Reaction time: 18 h

Procedure:
A suspension of 15 g. of 15-hydroxy-9-oxoprostanoic acid, ethyl ester in 230 ml. of aqueous methanol (1:1) containing 6.45 g. of potassium hydroxide is stirred at 50° C. for 1 hour and then at room temperature for 18 hours. The resulting solution is acidified with 1N hydrochloric acid, saturated with sodium chloride, and extracted several times with diethyl ether. The combined ether extracts are washed twice with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and taken to dryness to give 13.1 g. (94%) of product as an oil. There is essentially no uv absorption; [α]D25 0° (1.0% in CHCl3); λmaxKBr 2.80-3.70 (broad), 5.75, 5.87 μ; nmr 2H singlet δ 6.65 (hydroxyl and carboxyl protons), 1H broad singlet 3.63 (carbinolic proton), and 3H distorted triplet 0.93 (terminal methyl); mass spectrum: m/e 340.
Reaction SMILES: ClC1(C(F)(F)F)CC(O)(C([O-])=O)NN1C1C=CC=CN=1.[Cl:21][C:22]1[C:23]([N:28]2[C:32](O)([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:31][C:30]([C:39]([F:42])([F:41])[F:40])=[N:29]2)=[N:24][CH:25]=[CH:26][CH:27]=1>S(=O)(=O)(O)O.C(O)(=O)C>[Cl:21][C:22]1[C:23]([N:28]2[C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:31][C:30]([C:39]([F:42])([F:40])[F:41])=[N:29]2)=[N:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)C1(O)CC(C(F)(F)F)=NN1c1ncccc1Cl
Agent: O=C([O-])C1(O)CC(Cl)(C(F)(F)F)N(c2ccccn2)N1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 65 °C
Yield: 77 %

Procedure:
Sulfuric acid (concentrated, 2 drops) was added to ethyl 1-(3-chloro-2-pyridinyl-4,5-dihydro-5-hydroxy-3-(trifluoromethyl)-1H-pyrazole-5-carboxylate (i.e. the product of Step C) (1 g, 2.96 mmol) in acetic acid (10 mL) and the mixture was warmed to 65° C. for about 1 hour. The mixture was allowed to cool to 25° C. and most of the acetic acid was removed under reduced pressure. The mixture was partitioned between saturated aqueous sodium carbonate solution (100 mL) and ethyl acetate (100 mL). The aqueous layer was further extracted with ethyl acetate (100 mL). The combined organic extracts were dried and evaporated to give the product as an oil (0.66 g, 77% yield).
Reaction SMILES: I[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([C:14]3[S:15][C:16]([CH3:19])=[CH:17][CH:18]=3)=[O:13])=[N:7][C:6]=2[C:5]([O:20][CH3:21])=[CH:4][CH:3]=1.I[C:23]1[CH:31]=[C:30]2[C:26]([CH2:27][CH2:28][NH:29]2)=[CH:25][CH:24]=1>>[NH:29]1[C:30]2[C:26](=[CH:25][CH:24]=[C:23]([C:2]3[C:10]4[S:9][C:8]([NH:11][C:12]([C:14]5[S:15][C:16]([CH3:19])=[CH:17][CH:18]=5)=[O:13])=[N:7][C:6]=4[C:5]([O:20][CH3:21])=[CH:4][CH:3]=3)[CH:31]=2)[CH2:27][CH2:28]1
Reactant: Ic1ccc2c(c1)NCC2
Reactant: COc1ccc(I)c2sc(NC(=O)c3ccc(C)s3)nc12
Product: COc1ccc(-c2ccc3c(c2)NCC3)c2sc(NC(=O)c3ccc(C)s3)nc12

Procedure:
The title compound was prepared from 5-methyl-thiophene-2-carboxylic acid (7-iodo-4-methoxy-benzothiazol-2-yl)-amide (100 mg, 0.23 mmol) and 6-iodo-2,3-dihydro-1H-indole using the general procedure B in Example 54 as light brown crystals (26%), MS: m/e=422(M+H+).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH:8]=1)(=O)=O.[C:22]([O:26][C:27](=[O:46])[NH:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][C:30]=1[O:44][CH3:45])([CH3:25])([CH3:24])[CH3:23].C([O-])(O)=O.[Na+].C(OCC)(=O)C>COCCOC.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>[C:22]([O:26][C:27]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([C:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH:8]=2)=[CH:31][C:30]=1[O:44][CH3:45])=[O:46])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)OC(C)(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: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)ccc1NC(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
To a solution of tert-butyl 4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate (I16) (474 mg, 1.43 mmol), tert-butyl(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (I17) (500 mg, 1.43 mmol) and Pd(PPh3)4 (165 mg, 0.143 mmol) in DME (15 mL) was added a solution of 3.5 M aqueous NaHCO3 (2.00 mL, 5.0 eq) and the resulting suspension was heated at 80° C. for 16 hours. On cooling to room temperature ethyl acetate (70 mL) was added and the resulting solution was washed with water (50 mL). The organic layer was dried (MgSO4) and evaporated to dryness. The residue was chromatographal (SiO2, 0-20% ethyl acetate/petroleum benzine 40-60° C.) to give the title compound (I18) (520 mg, 90%) as a pale yellow liquid; 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J=8.1 Hz, 1H), 7.09 (s, 1H), 6.96 (dd, J=8.4, 1.3 Hz, 1H), 6.88 (d, J=1.7 Hz, 1H), 5.98 (s, 1H), 4.08 (d, J=1.9 Hz, 2H), 3.89 (s, 3H), 3.64 (t, J=5.6 Hz, 2H), 2.52 (s, 2H), 1.54 (s, 9H), 1.51 (s, 9H). LCMS Method C: rt 6.87 min; m/z 349.1 [M-t-Bu+2]+.
Reaction SMILES: [N+]([O-])(O)=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[Ce].C[O:27][C:28]1[CH:37]=[CH:36][C:35]([O:38]C)=[C:34]2[C:29]=1[C:30]1([S:47][CH2:46][CH2:45][S:44]1)[CH2:31][CH:32]([C:40]([O:42][CH3:43])=[O:41])[CH2:33]2>O.C(#N)C.C(OCC)C>[O:27]=[C:28]1[CH:37]=[CH:36][C:35](=[O:38])[C:34]2[CH2:33][CH:32]([C:40]([O:42][CH3:43])=[O:41])[CH2:31][C:30]3([S:44][CH2:45][CH2:46][S:47]3)[C:29]1=2
Reactant: COC(=O)C1Cc2c(OC)ccc(OC)c2C2(C1)SCCS2
Agent: [Ce]
Solvent: CCOCC
Solvent: O=[N+]([O-])O
Solvent: CC#N
Product: COC(=O)C1CC2=C(C(=O)C=CC2=O)C2(C1)SCCS2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 82.8 %

Procedure:
A solution of 4.90 g (0.009 mol) of ammonium ceric nitrate in 20 ml of water was added to a stirred solution of 1.20 g (0.0035 mol) of methyl rac-1',2',3',4'-tetrahydro-5',8'-dimethoxyspiro[1,3-dithiolane-2,4'-naphthalene]-2'-carboxylate in 100 ml of acetonitrile. The mixture was stirred at room temperature for 5 minutes, then diluted with 100 ml of water and extracted with three 200 ml portions of diethyl ether. The combined diethyl ether extracts were washed with water, dried and evaporated to yield 1.23 g of crude product in the form of an orange gum. This was taken up in diethyl ether and crystallised to yield 0.90 g (82%) of methyl rac-1',2',3',4',5',8'-hexahydro-5',8'-dioxospiro-[1,3-dithiolane-2,4'-naphthalene]-2'-carboxylate in the form of a bright orange solid of melting point 140°-141° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:50][CH:51]1[C@H:55]2[C@H:56](OC3CCCCO3)[N:57](C(OC(C)(C)C)=O)[C:58]3[CH:65]=[C:64]([O:66][CH3:67])[CH:63]=[CH:62][C:59]=3[C:60](=[O:61])[N:54]2[CH2:53][CH2:52]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH:19]1[C@H:23]2[C@H:24](OC3CCCCO3)[N:25](C(OC(C)(C)C)=O)[C:26]3[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:27]=3[C:28](=[O:29])[N:22]2[CH2:21][CH2:20]1.C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH2:17]([O:18][CH:19]1[C@@H:23]2[CH:24]=[N:25][C:26]3[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:27]=3[C:28](=[O:29])[N:22]2[CH2:21][CH2:20]1)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:50][CH:51]1[C@@H:55]2[CH:56]=[N:57][C:58]3[CH:65]=[C:64]([O:66][CH3:67])[CH:63]=[CH:62][C:59]=3[C:60](=[O:61])[N:54]2[CH2:53][CH2:52]1
Reactant: COc1ccc2c(c1)N(C(=O)OC(C)(C)C)[C@@H](OC1CCCCO1)[C@@H]1C(OCCCCCCCCCCOC3CCN4C(=O)c5ccc(OC)cc5N(C(=O)OC(C)(C)C)[C@@H](OC5CCCCO5)[C@H]34)CCN1C2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1ccc2c(c1)N=C[C@H]1C(OCCCCCCCCCCOC3CCN4C(=O)c5ccc(OC)cc5N=C[C@@H]34)CCN1C2=O
Reaction time: 1 h
Yield: 88.9 %

Procedure:
95% TFA (3 mL) was added drop-wise to dimer compound 8h (191 mg, 0.18 mmol) at 0° C. This was then stirred for 1 hr and the mixture was poured into saturated NaHCO3 (30 mL) solution to naturalize the reaction mixture. The mixture was extracted with chloroform (3×20 mL). The organic layer was then washed water (20 mL), brine (20 mL) then dried (MgSO4) and filtrated. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to flash column chromatography (SiO2, 2% methanol-chloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 9h (103 mg, 0.16 mmol, 90%) as a solid: [α]20D=+387° (c=0.17, CHCl3); 1H NMR (CDCl3, 400 MHz): δ 1.25-1.50 (m, 12H, 14-H, 14′-H, 15-H, 15′-H, 16-H, 16′-H), 1.72-1.92 (m, 4H, 13-H, 13′-H), 1.98-2.09 (m, 4H, 2-H, 2′-H), 2.25-2.38 (m, 4H, 1-H, 1′-H), 3.52-3.62 (m, 2H, 3-H, 3′-H), 3.68-3.73 (m, 2H, 11a-H, 11a′-H), 3.76-3.85 (m, 2H, 3-H, 3′-H), 3.90 (s, 6H, 7-OMe, 7′-OMe), 3.95-4.19 (m, 4H, 12-H, 12′-H), 6.79 (s, 2H, 9-H; 9′-H), 7.50 (s, 2H, 6-H, 6′-H), 7.64 (d, 2H, J=4, 11-H, 11′-H); 13C NMR (CDCl3, 400 MHz): δ 24.1, 25.9, 29.0, 29.3, 29.4, 29.6, 46.6, 53.7, 56.0, 69.7, 109.6, 112.5, 120.2, 140.5, 147.1, 151.6, 162.2, 164.6; IR (neat): 3325, 2931, 1600, 1506, 1448, 1388, 1262, 1217, 1092, 1024 cm−1; MS (FAB) m/z (relative intensity) 695 ([M+2×MeOH]+., 14), 663 ([M+MeOH]+., 20), 631 (M+., 100).
Reaction SMILES: [C:1]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][N:16]([NH:19]C(OCC)=O)[CH2:15][CH2:14]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C.O>[C:1]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][N:16]([NH2:19])[CH2:15][CH2:14]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)NN1CCN(CCCCC(=O)c2ccccc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NN1CCN(CCCCC(=O)c2ccccc2)CC1
Yield: 114.8 %

Procedure:
30.0 g of 4-(4-benzoylbutyl)-1-(ethoxycarbonylamino)piperazine was dissolved in 250 ml of ethanol, and a solution of 50.5 g of potassium hydroxide in 50 ml of water was added. The mixture was heated under reflux for 3 hours. Ethanol was evaporated, and water was added. Extraction with chloroform gave 27.0 g of the title compound. The hydrochloride of this product had a melting point of 213° to 215° C. (decomp.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH2:11][CH:12]=C)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].CSC.C[OH:18]>>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH2:11][CH:12]=[O:18])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: C=CCc1ccc(C#N)c(OC)c1
Reactant: CO
Solvent: CSC
Product: COc1cc(CC=O)ccc1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 25 mL flask containing a stir bar was added compound 2-(methyloxy)-4-prop-2-en-1-ylbenzonitrile (0.15 g, 0.87 mmol) and MeOH (8 mL). The flask was placed in a cold bath of −78° C. Ozone was bubbled through the flask for about 10 min. followed by addition of dimethyl sulfide (1.5 mL, 24 mmol). The flask was taken out of the cold bath and stirred at room temperature for 1 h; LC indicated completion of the reaction. The reaction mixture was concentrated to dryness to give 2-(methyloxy)-4-(2-oxoethyl)benzonitrile. LC-MS (IE, m/z): 176 [M+1]+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:9])([F:8])[CH:5]([OH:7])[CH3:6].[Cl:10][C:11]1[C:12]([C:19]#[N:20])=[N:13][CH:14]=[C:15]([Cl:18])[C:16]=1Cl.[Cl-].[NH4+]>O1CCCC1>[Cl:10][C:11]1[C:12]([C:19]#[N:20])=[N:13][CH:14]=[C:15]([Cl:18])[C:16]=1[O:7][CH:5]([CH3:6])[C:4]([F:9])([F:8])[F:3]
Reactant: N#Cc1ncc(Cl)c(Cl)c1Cl
Reactant: CC(O)C(F)(F)F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(Oc1c(Cl)cnc(C#N)c1Cl)C(F)(F)F
Reaction time: 0.17 h
Yield: 97.5 %

Procedure:
Into 5 ml of tetrahydrofuran was suspended 0.12 g of sodium hydride (60% oily), and 0.3 g of 1,1,1-trifluoro-2-propanol was added at 10° C. After stirring for 10 minutes, 0.5 g of 3,4,5-trichloropyridine-2-carbonitrile was added, the mixture was stirred for 1 hour, and the reaction solution was poured into an aqueous saturated ammonium chloride solution, followed by extraction with tert-butyl=methyl=ether three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.67 g of 3,5-dichloro-4-(2,2,2-trifluoro-1-methylethoxy)pyridine-2-carbonitrile.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[N:8][N:9]2[CH2:14][CH2:13][CH2:12][O:11][C:10]=12)=[O:5].[CH3:16][Mg]Br.CCOCC>O1CCCC1>[N:8]1[N:9]2[C:10]([O:11][CH2:12][CH2:13][CH2:14]2)=[C:6]([C:4](=[O:5])[CH3:16])[CH:7]=1
Reactant: CON(C)C(=O)c1cnn2c1OCCC2
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)c1cnn2c1OCCC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
A solution of 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid methoxy-methyl-amide (9.02 g, 42.7 mmol) in tetrahydrofuran (300 mL) was cooled to 0° C. 3 M methylmagnesium bromide in ether (15.3 mL, 43 mmol) was added and the reaction was stirred at 0° C. for 30 minutes, then warmed to room temperature. Additional 3 M methylmagnesium bromide in ether (15.3 mL, 43 mmol) was added after 1 hour, and the mixture was stirred at room temperature overnight, then the volatiles were removed in vacuo. The residue was partitioned between EtOAc (100 mL) and saturated NaHCO3 solution (150 mL). The aqueous layer was extracted with EtOAc (2×100 mL), and the combined organic layers were washed with brine (3×50 mL), dried (Na2SO4), filtered and concentrated. Flash chromatography (0 to 4% MeOH in DCM) afforded the ketone (5.79 g, 82%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ7.69 (s, 1H), 4.44 (t, 2H, J=5.25 Hz), 4.09 (t, 2H, J=6.10 Hz), 2.23 (s, 3H), 2.22-2.17 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1.CN(C)C([N:15]1[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16]1)=O.[I-].[Na+].N>C(#N)C>[CH3:20][C:18]1[NH:17][C:16]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=2)=[N:15][CH:19]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: Cc1cn(C(=O)N(C)C)cn1
Agent: N
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1cnc(Cc2ccc(C#N)cc2)[nH]1

Procedure:
A solution containing alpha-bromo-4-tolunitrile (11.0 g), 1-(dimethylcarbamoyl)-4-methylimidazole (8.6 g) and sodium iodide (8.4 g) in acetonitrile (75 mL) is heated and stirred at reflux for 15 hours. The mixture is cooled to 0° (ice-bath) and ammonia gas is bubbled through the solution for 15 minutes. The volatiles are then evaporated and the residue is partitioned between water (150 mL) and ethyl acetate (150 mL). The organic solution is washed with water (2×50 mL) and is then extracted with 3N hydrochloric acid. The combined acidic extracts are made basic (pH 9) with 6N sodium hydroxide and the product is extracted into ethyl acetate (3×60 mL). After drying (MgSO4), solvent evaporation affords crude 4-[1-(5-methylimidazolyl)methyl]-benzonitrile which forms a hydrochloride salt, m.p. 203°-205°, when its solution in acetone is treated with ethereal HCl.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([NH:9][CH:10]=[O:11])=[C:4]([Cl:12])[N:3]=1.C(N(CC)C(C)C)(C)C.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>O1CCOCC1>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:6]2[C:5]([NH:9][CH:10]=[O:11])=[C:4]([Cl:12])[N:3]=[C:2]([NH2:1])[N:7]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: Nc1nc(Cl)c(NC=O)c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2nc(N)nc(Cl)c2NC=O)CC1
Temperature: 55 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To a suspension of N-(2-amino-4,6-dichloropyrimidin-5-yl)formamide (10.0 g, 48.3 mmol) in 1,4-dioxane (400 mL) were added N,N-diisopropylethylamine (12.7 mL, 72.5 mmol) and piperazine-1-carboxylic acid tert-butyl ester (9.8 g, 53.1 mmol). The mixture was stirred at 55° C. for 1 h. The solvent was removed in vacuo and the residue was partitioned between DCM and water. The aqueous phase was extracted with further DCM and the combined organic fractions were washed with brine, then dried (Na2SO4) and evaporated in vacuo to give the title compound (17.1 g, 100%) as a white solid. LCMS (ES+) 357.4 (M+H)+, RT 1.08 minutes (method 3).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([OH:14])=O)=[C:5]2[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1.C(N(CC)CC)C.[CH3:33][O:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=1>S(Cl)(Cl)=O.O1CCCC1>[CH3:33][O:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH:40][C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)=[N:3][C:2]([Cl:1])=[CH:11][CH:10]=3)=[O:14])=[CH:37][CH:36]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=C(O)c1cnc2ccc(Cl)nc2c1Nc1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: COc1ccc(CNC(=O)c2cnc3ccc(Cl)nc3c2Nc2cccc(C(F)(F)F)c2)cc1
Temperature: 75 °C
Yield: 94.3 %

Procedure:
6-chloro-4-(3-(trifluoromethyl)phenylamino)-1,5-naphthyridine-3-carboxylic acid (3.6 g, 9.8 mmol) was suspended in 50 mL sulfinyl chloride. The resulting mixture was heated under stirring to 75° C. and reacted for 4 hrs while keeping at the same temperature. The reaction was naturally cooled to room temperature, and concentrated to obtain a yellow solid. The resulting solid was dispersed in 100 mL tetrahydrofuran. To the resulting mixture was added dropwise a mixture of triethylamine (3.03 g, 30 mmol) and para-methoxybenzylamine (1.6 g, 13 mmol) at 0° C. The reaction mixture was stirred at room temperature for 4 hrs, and rotary-evaporated to remove the solvent. To the residue was added 300 mL water. The resulting mixture was filtered by suction. The filter cake was washed with ethyl acetate and petroleum ether (volume ratio 1/10, 100 mL) and dried to obtain a pale yellow solid of N-(4-methoxybenzyl)-6-chloro-4-(3-(trifluoromethyl)phenylamino)-1,5-naphthyridine-3-carboxamide (4.5 g).
Reaction SMILES: C(OC([NH:11][C:12](=[NH:37])[C:13]1[CH:36]=[CH:35][C:16]([O:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:23](=[O:33])[C:22]2=[O:34])=[CH:15][CH:14]=1)=O)C1C=CC=CC=1.[ClH:38]>CN(C)C=O.[C].[Pd]>[ClH:38].[NH2:37][C:12](=[NH:11])[C:13]1[CH:14]=[CH:15][C:16]([O:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:23](=[O:33])[C:22]2=[O:34])=[CH:35][CH:36]=1
Reactant: COC(=O)CCN1CCN(CCCOc2ccc(C(=N)NC(=O)OCc3ccccc3)cc2)C(=O)C1=O
Agent: [Pd]
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)CCN1CCN(CCCOc2ccc(C(=N)N)cc2)C(=O)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.74 g of methyl 3-[4-(3-{4-[{[(benzyloxy)carbonyl]amino}(imino)methyl]phenoxy}propyl)-2,3-dioxo-1-piperazinyl]propanoate was dissolved in 10 ml of N,N-dimethylformamide. Thereafter, 0.52 g of 5% palladium-carbon suspended in 7.4 ml of N,N-dimethylformamide and 0.85 ml of 6 mol/L hydrochloric acid were added to the solution, followed by stirring under a hydrogen atmosphere at room temperature under atmospheric pressure for 2 hours. After completion of the reaction, the catalyst was removed by filtration, and the residue was washed with 20 ml of N,N-dimethylformamide. The filtrate was then concentrated under a reduced pressure. 20 ml of xylene was added to the obtained residue, and the mixture was further concentrated under a reduced pressure to obtain 1.37 g of methyl 3-[4-(3-{4-[amino(imino)methyl]phenoxy}propyl)-2,3-dioxo-1-piperazinyl]propanoate hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([OH:26])=O)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[CH3:27][S:28]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)(=[O:30])=[O:29].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([N:34]3[CH2:35][CH2:36][N:31]([S:28]([CH3:27])(=[O:30])=[O:29])[CH2:32][CH2:33]3)=[O:26])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Reactant: CS(=O)(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N1CCN(C(=O)Cn2nc(-c3ccccc3)c3c(Cl)c(-c4ccccc4)nnc32)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 14.4 %

Procedure:
To a suspension of 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid (56 mg, 0.15 mmol) in DMF (1 mL) were added 1-(methylsulfonyl)piperazine (28 mg, 0.17 mmol), diisopropylethylamine (DIPEA) (59 μL, 0.34 mmol) and 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (70 mg, 0.18 mmol). The solution obtained was stirred at room temperature for 18 h then diluted with EtOAc. The organic phase was washed with water and brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified using chromatography (silica gel, gradient 20-40% ethyl acetate/isohexane) followed by a second chromatography purification (silica gel, gradient 10% ether/CH2Cl2) yielding Compound 52 as a solid (11 mg).