Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([NH:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][CH2:4][CH2:5][CH2:6][C:7](O)=[O:8].[CH3:19][O:20][C:21]1[C:22]([CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=2)=[C:23]([CH2:29][CH2:30][NH2:31])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28].O>ClCCl>[CH3:19][O:20][C:21]1[C:22]([CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=2)=[C:23]([CH2:29][CH2:30][NH:31][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][C:2]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:1])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: O=C(O)CCCCC(=O)NCCc1ccccc1
Reactant: COc1cccc(CCc2c(CCN)ccc(OC)c2OC)c1
Solvent: O
Solvent: ClCCl
Product: COc1cccc(CCc2c(CCNC(=O)CCCCC(=O)NCCc3ccccc3)ccc(OC)c2OC)c1
Reaction time: 16 h
Yield: 80.8 %

Procedure:
A solution of 6-oxo-6-(2-phenylethylamino)hexanoic acid (1.2 g) and N,N'-carbonyldiimidazole (0.77 g) in dry dichloromethane (50 ml) was stirred at 20° for 2 hours and a solution of 3,4-dimethoxy-2-[2-[3-methoxyphenyl]ethyl]benzeneethanamine (1.5 g) in dry dichloromethane (10 ml) was added. The mixture was stirred at 20° for 16 hours. Water (50 ml) was added and the organic phase was separated and washed with 2N hydrochloric acid, aqueous sodium bicarbonate and brine. The organic phase was dried (MgSO4), filtered and the solvent removed in vacuo. The resulting solid was crystallised from isopropanol to yield 2.1 g of the sub-title compound as colourless prisms, mp 150°-151°.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:16]2[CH:17]=[C:18]([CH:24]=[CH:25][C:26]([O:28]CC)=[O:27])[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.Br[CH:32]([OH:35])[CH2:33][CH3:34]>>[OH:35][CH2:32][CH2:33][CH2:34][O:1][C:2]1[C:3]([C:16]2[CH:17]=[C:18]([CH:24]=[CH:25][C:26]([OH:28])=[O:27])[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])=[CH:4][C:5]2[C:6]([CH3:14])([CH3:15])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: CCOC(=O)C=Cc1ccc(OC)c(-c2cc3c(cc2O)C(C)(C)CCC3(C)C)c1
Reactant: CCC(O)Br
Product: COc1ccc(C=CC(=O)O)cc1-c1cc2c(cc1OCCCO)C(C)(C)CCC2(C)C
Yield: 49.7 %

Procedure:
In a manner similar to that of Example 16(a), by reaction of 1.2 g (2.9 mmol) of ethyl 3-[3-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl]acrylate obtained in Example 13(f) with 490 mg (3.5 mmol) of 1-bromopropanol, 632 mg (47%) of the expected compound were obtained in the form of a yellow oil.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[N:11]=[CH:10][NH:9][C:7](=[O:8])[C:5]=2[CH:6]=1.Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:16][CH:15]=1>>[CH2:2]([C:10]1[N:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:16][CH:15]=2)[C:7](=[O:8])[C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=2)[N:11]=1)[CH2:1][CH2:6][CH3:5]
Reactant: O=c1[nH]cnc2ccccc12
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Product: CCCCc1nc2ccccc2c(=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
The quinazolinone prepared as described in Example 17 was alkylated with 4-bromomethyl-2'-t-butoxycarbonyl-biphenyl. The product was purified by flash chromatography over silica gel eluting with 1% EtOAc/methylene chloride. 1H-NMR (300 MHz, CDCl3): 8.32 (m, 1H), 7.76 (m, 2H), 7.46 (m, 2H), 7.38 (m, 1H), 7.32-7.18 (m, 5H), 5.46 (bs, 2H), 2.79 (3 line m, 2H), 1.80 (m, 2H), 1.44 (m, 2H), 1.23 (s, 9H), 0.95 (t, 3H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]Cl)[C:5]=1[NH:12][C:13](=[O:29])[CH2:14][CH:15]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:22][C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)([CH3:3])[CH3:2].[NH:30]1[CH:34]=[CH:33][N:32]=[CH:31]1.[I-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:31]2[NH:30][CH:34]=[CH:33][N:32]=2)[C:5]=1[NH:12][C:13](=[O:29])[CH2:14][CH:15]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:22][C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)([CH3:3])[CH3:2]
Reactant: c1c[nH]cn1
Reactant: CC(C)c1cccc(CCl)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(Cc2ncc[nH]2)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Temperature: 90 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
A suspension of 500 mg (1.23 mmol) of N-(2-isopropyl-6-chloromethylphenyl)-2-(9H-xanthen-9-yl)acetamide [prepared as described in Preparation 28(iv)], 847 mg (12.3 mmol) of imidazole and 277 mg (1.9 mmol) of sodium iodide in 10 ml of N,N-dimethylformamide was stirred at 90° C. for 2 hours and then the temperature was lowered to room temperature. The resulting mixture was diluted with ethyl acetate. The diluted mixture was washed several times with water and once with a saturated aqueous solution of sodium chloride. The organic phase was dried over anhydrous sodium sulfate, and then the solvent was removed by distillation under reduced pressure. The resulting residue was triturated with a mixture of diethyl ether and hexane, and the resulting crystallized product was collected to give 471 mg (yield 88%) of the title compound as crystals, melting at 193°-195° C. (after recrystallization from a mixture of methanol, diethyl ether and hexane).
Reaction SMILES: [CH2:1]([C@@H:4]1[C@H:10]2[C@H:8]([O:9]2)[CH:7]=[C:6]([C:11]([O:13][CH3:14])=[O:12])[CH2:5]1)[CH:2]=[CH2:3].[N-:15]=[N+:16]=[N-:17].[Na+].[NH4+].[Cl-]>CO.O>[CH2:1]([C@H:4]1[CH2:5][C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][C@H:8]([N:15]=[N+:16]=[N-:17])[C@H:10]1[OH:9])[CH:2]=[CH2:3]
Reactant: C=CC[C@H]1CC(C(=O)OC)=C[C@H]2O[C@@H]12
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C=CC[C@H]1CC(C(=O)OC)=C[C@H](N=[N+]=[N-])[C@H]1O

Procedure:
A solution of Example 1I, sodium azide (2.8 g, 43.1 mmol) and NH4Cl (1.0 g, 18.8 mL) in methanol (30 mL) and H2O (10 mL) was refluxed for 5 hours, diluted with H2O and extracted with ethyl acetate. The combined ethyl acetate layers were dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel using hexanes/ethyl acetate (1/1) to afford 1.4 g (67% over steps I and J) of the desired product as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[C:11]([F:22])[CH:10]=2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-])=O)[CH:24]=2)[N:3]=1.[H][H]>[Pd].C(O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15][C:16]3[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=3)=[C:11]([F:22])[CH:10]=2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=2)[N:3]=1
Reactant: [H][H]
Reactant: Nc1nc(Nc2ccc(Sc3ccncc3)c(F)c2)cc(-c2cccc([N+](=O)[O-])c2)n1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cccc(-c2cc(Nc3ccc(Sc4ccncc4)c(F)c3)nc(N)n2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 64.5 %

Procedure:
A dry flask under argon was charged with 10% palladium on carbon (20 mg). A solution of N-[2-amino-6-(3-nitrophenyl)-4-pyrimidinyl]-N-[3-fluoro-4-(4-pyridinylsulfanyl)phenyl]amine (Example 20, 200 mg, 0.46 mmol) in ethanol (12 mL) and EtOAc (1 mL) was added via syringe through a septa to the palladium on carbon. The flask was then fitted with a hydrogen balloon and stirred at room temperature for 48 h. At this time the palladium was filtered through a pad of Celite®. The filtrate was coated on silica and purified on the MPLC (Biotage) with 2-8% MeOH in CH2Cl2 to afford the desired product as a solid (120 mg, 64%). TLC (6% MeOH in CH2Cl2) Rf0.26; MS (ES) 405 [M+H]+; 1H-NMR (DMSO-d6) δ 5.22 (bs, 2H), 6.45 (s, 1H), 6.49 (bs, 2H) 6.62-6.65 (m, 1H), 6.98 (d, J=6.4 Hz, 2H), 7.02-7.16 (m, 3H), 7.43-7.55 (m, 2H), 8.30-8.35 (m, 3H), 9.75 (bs, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][OH:5].[OH:6][C:7]1[CH:8]=[CH:9][C:10]([N+:15]([O-:17])=[O:16])=[C:11]([CH:14]=1)[CH:12]=[O:13].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>C(#N)C>[N+:15]([C:10]1[CH:9]=[CH:8][C:7]([O:6][CH2:2][CH2:3][CH2:4][OH:5])=[CH:14][C:11]=1[CH:12]=[O:13])([O-:17])=[O:16]
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: O=Cc1cc(OCCCO)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 95.7 %

Procedure:
3-Bromo-1-propanol (3.34 g, 24 mmol) was refluxed in 80 ml of anhydrous acetonitrile with 5-hydroxy-2-nitrobenzaldehyde (3.34 g, 20 mmol), K2CO3 (3.5 g), and KI (100 mg) overnight (15 hr). The reaction mixture was cooled to room temperature and 150 ml of methylene chloride was added. The mixture was filtered and the solid residue was washed with methylene chloride. The combined organic solution was evaporated to dryness and redissolved in 100 ml methylene chloride. The resulted solution was washed with saturated NaCl solution and dried over sodium sulfate. 4.31 g (96%) of desired product was obtained after removal of the solvent in vacuo.
Reaction SMILES: C(O)(=O)C.[CH:5]([NH2:7])=[NH:6].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16][CH:17]([C:22](OC)=[O:23])[C:18](OC)=[O:19].C[O-].[Na+].[Na]>CO>[OH:23][C:22]1[N:7]=[CH:5][NH:6][C:18](=[O:19])[C:17]=1[S:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[O:9][CH3:8]
Reactant: N=CN
Reactant: COC(=O)C(Sc1ccccc1OC)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccccc1Sc1c(O)nc[nH]c1=O
Temperature: 80 °C
Reaction time: 4 h
Yield: 21.6 %

Procedure:
0.86 g of formamidine acetate and 2 g of dimethyl (2-methoxy -phenylsulfanyl)-malonate (J. Org. Chem. 55, 33-38 [1990]) were added to a sodium methylate solution from 40 ml of MeOH and 0.54 g of sodium. The reaction mixture was stirred at 80° C. for 4 hours and concentrated. The residue was partitioned between toluene and water and the aqueous phase was adjusted to pH 3. The precipitate was filtered off under suction, washed with ether and dried. There was obtained 0.4 g of 6-hydroxy-5-(2-methoxy-phenylsulfanyl)-3,4-dihydro-pyrimidin-4-one. M.p. 291 ° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[C:10]=2[CH3:18])=[N:5]1.[S:20]1[CH:24]=[C:23]([C:25]([O-])=[O:26])[N:22]=[C:21]1[C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[Cl:17][C:11]1[C:10]([CH3:18])=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:25]([C:23]3[N:22]=[C:21]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[S:20][CH:24]=3)=[O:26])[CH3:19])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: Cc1c(-c2ccn(C[C@H](C)N)n2)ccc(C#N)c1Cl
Reactant: CCOC(=O)c1nc(C(=O)[O-])cs1
Product: CCOC(=O)c1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3C)n2)cs1
Yield: 16.1 %

Procedure:
(S)-ethyl 4-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-ylcarbamoyl)thiazole-2-carboxylate was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile (400 mg, 1.165 mmol) and 2,4-thiazoledicarboxylic acid, 2-ethyl ester 234 mg, 1.165 mmol). The product was purified by Flash-chromatography. Yield 16.1%. 1H-NMR (400 MHz; CDCl3): δ 1.31 (d, 3H), 1.44 (t, 3H), 2.55 (s, 3H), 4.31-4-46 (m, 2H), 4.50 (q, 2H), 4.56-4.68 (m, 1H), 6.42 (d, 1H), 7.50 (d, 1H), 7.54-7.61 (m, 2H), 7.80 (bd, 1H), 8.34 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:17](OC(=O)C)(=[O:19])[CH3:18]>O1CCCC1>[C:17]([O:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: OC[C@H]1CC[C@H](O)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1CC[C@H](O)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of trans-4-(hydroxymethyl)cyclohexanol (1.8 g, 14 mmol, Tetrahedron Lett. 1970, 11, 4281-4284.), triethylamine (2.4 mL, 17 mmol), and N,N-dimethylaminopyridine (0.34 g, 3.0 mmol) in tetrahydrofuran (70 mL) was added acetic anhydride (1.4 mL, 15 mmol) at room temperature. After being stirred at room temperature for 48 h, the mixture was concentrated in vacuo to give an oil. The residual oil was extracted with ethyl acetate (100 mL). The organic layer was washed with successively 2N hydrochloric acid, aq. sodium hydrogencarbonate, and brine. The extract was dried over magnesium sulfate and concentrated in vacuo give an oil. The residual oil was purified by silica gel column chromatography (hexane/ethyl acetate 1:1 to 1:2) to give 1.2 g (50%) the title compound as a colorless oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.O[N:14]=[C:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1.N>>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[O:12][N:22]=[C:15]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[N:14]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: N
Product: c1cncc(-c2noc(-c3ccc4[nH]ccc4c3)n2)c1

Procedure:
The title compound was prepared according to Method C using 1H-indole-5-carboxylic acid (Aldrich) and N′-hydroxynicotinimidamide (Tyger). 1H NMR (300 MHz, DMSO-d6) δ 6.69 (dt, J=2.3, 1.4 Hz, 1 H), 7.55 (t, J=2.7 Hz, 1 H), 7.62-7.70 (m, 2 H), 7.94 (dd, J=8.8, 1.7 Hz, 1 H), 8.46 (dt, J=8.1, 1.9 Hz, 1 H), 8.49-8.52 (m, 1 H), 8.81 (dd, J=4.7, 1.7 Hz, 1 H), 9.27 (dd, J=2.2, 0.8 Hz, 1 H) ppm; MS (DCI/NH3) m/z 263 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1OS(C(F)(F)F)(=O)=O)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4].[CH3:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1[C:36]1[CH:37]=[CH:38][C:33]([CH3:32])=[CH:34][CH:35]=1)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)c2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Reactant: Cc1ccc(B(O)O)cc1
Product: COC(=O)c1c(-c2ccc(C)cc2)c2cc(Cl)ccc2c(=O)n1Cc1ccccc1

Procedure:
The present compound was synthesized by a method similar to that in Example 272 and using 2-benzyl-6-chloro-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (100 mg) and 4-methylphenylboronic acid. Colorless crystals (24 mg).
Reaction SMILES: [CH3:1][S:2][CH:3]([S:6][CH3:7])[S:4][CH3:5].[Li]CCCC.Br[CH:14]1[C:24]2=[C:25]3[C:20](=[CH:21][CH:22]=[CH:23]2)[CH:19]=[CH:18][CH:17]=[C:16]3[CH2:15]1>C1COCC1.CCCCCC>[CH3:1][S:2][C:3]([S:6][CH3:7])([S:4][CH3:5])[CH:15]1[C:16]2=[C:25]3[C:20](=[CH:19][CH:18]=[CH:17]2)[CH:21]=[CH:22][CH:23]=[C:24]3[CH2:14]1
Reactant: CSC(SC)SC
Reactant: BrC1Cc2cccc3cccc1c23
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CSC(SC)(SC)C1Cc2cccc3cccc1c23
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Tris(methylthio)methane (22 g) was dissolved in THF (100 ml) under N2 at -78° C. 1.6 M BuLi in hexane solution (95 ml) was added slowly to yield a dense white precipitate. 1-Bromoacenaphthene (31.4 g) was dissolved in 20 ml of dry THF and added slowly to the above suspension to yield, after 10 minutes, a colorless solution. This was allowed to warm to room temperature, with the development of a brown color, and stirred overnight.
Reaction SMILES: Br[C:2]1[CH:15]=[N:14][C:5]2[NH:6][C:7]3[CH:12]=[N:11][C:10]([F:13])=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[CH2:16](C1CCN(B(O)O)CC1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(#N)C.[F-].[K+]>[F:13][C:10]1[N:11]=[CH:12][C:7]2[NH:6][C:5]3[N:14]=[CH:15][C:2]([C:20]4[CH:19]=[CH:18][C:17]([CH2:16][N:11]5[CH2:12][CH2:7][CH2:8][CH2:9][CH2:10]5)=[CH:22][CH:21]=4)=[CH:3][C:4]=3[C:8]=2[CH:9]=1
Reactant: OB(O)N1CCC(Cc2ccccc2)CC1
Reactant: Fc1cc2c(cn1)[nH]c1ncc(Br)cc12
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: Fc1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Temperature: 150 °C

Procedure:
A mixture of 3-bromo-6-fluoro-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (100 mg, 0.38 mmol), 4-benzylpiperidine boronic acid (123 mg, 0.56 mmol) and 1,1′-[bis(diphenylphosphino) ferrocene]dichloropalladium(II) (31 mg, 0.038 mmol) in acetonitrile (1.5 mL) and 2N aqueous potassium fluoride solution (1.5 mL) was degassed with nitrogen for 20 minutes. The reaction mixture was then heated under microwave irradiation at 150° C. for 30 minutes, allowed to cool to ambient temperature and diluted with water (3 mL). The resultant precipitate was collected by filtration, washed with water (5 mL) and ethyl acetate (10 mL). The resultant solid residue was purified by flash chromatography (silica, 4 g column, ISCO, 0-20% methanol in DCM) to afford the title compound as an off white solid (90 mg, 67%). 1H NMR (DMSO-D6, 300 MHz): 12.27 (s, 1H), 9.00 (d, J=2.3 Hz, 1H), 8.93 (d, J=2.3 Hz, 1H), 8.49 (d, J=1.5 Hz, 1H), 7.98 (d, J=2.3 Hz, 1H), 7.74 (d, J=8.0 Hz, 2H), 7.43 (d, J=7.9 Hz, 2H), 3.48 (s, 2H), 2.42-2.29 (m, 4H), 1.54-1.47 (m, 4H), 1.44-1.34 (m, 2H). LCMS (Method A): RT=5.87 min, M+H+=361.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH2:12][CH2:11][C@@:10]3([CH2:16][CH2:15][N:14]([CH3:17])[C:13]3=[O:18])[N:9]=2)[CH:3]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC#N.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:17][N:14]1[CH2:15][CH2:16][C@:10]2([N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:24]4[CH:25]=[CH:26][C:21]([C:20]([F:31])([F:30])[F:19])=[CH:22][CH:23]=4)[CH:7]=[CH:6][N:5]=3)[CH2:12][CH2:11]2)[C:13]1=[O:18]
Reactant: CN1CC[C@@]2(CCC(c3cc(Br)ccn3)=N2)C1=O
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CN1CC[C@@]2(CCC(c3cc(-c4ccc(C(F)(F)F)cc4)ccn3)=N2)C1=O
Temperature: 120 °C
Yield: 89.6 %

Procedure:
To a solution of (5S)-2-(4-bromo-2-pyridyl)-7-methyl-1,7-diazaspiro[4.4]non-1-en-6-one (which may be prepared as described in Description 3) (640 mg, 2.0768 mmol) in MeCN (8 mL) and water (1 mL) in a Smith microwave vessel was added [4-(trifluoromethyl)-phenyl]boronic acid (394.44 mg, 2.0768 mmol), bis(triphenylphosphine)palladium (II) dichloride (60 mg, 0.0855 mmol) and sodium carbonate (484.26 mg, 4.5689 mmol). The reaction vessel was sealed and purged with nitrogen. The reaction mixture was heated by microwave at 120° C. for 25 min. The reaction mixture was treated with water and was extracted with DCM twice and the organic layers were collected by passing down a PhaseSep cartridge, and evaporated. The crude residue was purified by silica gel chromatography (50 g, SiO2) eluting with ethyl acetate in iso-hexane (10-100%). Evaporation of desired fractions gave (5S)-7-methyl-2-[4-[4-(trifluoromethyl)phenyl]-2-pyridyl]-1,7-diazaspiro[4.4]non-1-en-6-one (D118) (695 mg, 1.8614 mmol, 89.6% yield);
Reaction SMILES: C([O:8][C:9]1[C:17]2[C:16](=[O:18])[NH:15][N:14]=[C:13]([CH3:19])[C:12]=2[N:11]2[CH2:20][CH2:21][N:22]([CH3:25])[C:23](=[O:24])[C:10]=12)C1C=CC=CC=1.[H-].[Na+].[Cl:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[Cl:37])[CH2:32]Cl.Br>CN(C=O)C.C(O)(=O)C>[Cl:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[Cl:37])[CH2:32][N:15]1[C:16](=[O:18])[C:17]2[C:9]([OH:8])=[C:10]3[C:23](=[O:24])[N:22]([CH3:25])[CH2:21][CH2:20][N:11]3[C:12]=2[C:13]([CH3:19])=[N:14]1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: Cc1n[nH]c(=O)c2c(OCc3ccccc3)c3n(c12)CCN(C)C3=O
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cc1nn(Cc2ccc(Cl)c(Cl)c2)c(=O)c2c(O)c3n(c12)CCN(C)C3=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 10-(benzyloxy)-4,8-dimethyl-7,8-dihydropyrazino[1′,2′:1,5]-pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (0.05 g, 0.15 mmol) in DMF (1 mL) was treated with sodium hydride (5 mg, 0.17 mmol). The resultant mixture was stirred at room temperature for 5 minutes. After bubbling ceased, 3,4-dichlorobenzyl chloride (0.02 mL, 0.16 mmol) was added and the reaction mixture was stirred at room temperature for overnight. The reaction was then treated with 33% HBr solution in acetic acid (2 mL) and stirred at room temperature overnight. The reaction mixture was concentrated under vacuum. The residue was treated with water and the solid precipitated was collected by filtration to provide the titled compound as white solid.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[OH-].[K+].Cl.[CH2:9]([C:16]([NH2:18])=[NH:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O.ClCCCl>[CH3:5][O:4][C:2]([NH:18][C:16]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[NH:17])=[O:3]
Reactant: COC(=O)Cl
Reactant: N=C(N)Cc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: O
Product: COC(=O)NC(=N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93 %

Procedure:
137.2 parts of methyl chloroformate and a solution of 162.7 parts of potassium hydroxide in 180 parts of water are added via two inlets to a mixture of 246 parts of benzylmethanamidine hydrochloride in 530 parts of 1,2-dichloroethane and 85 parts of water, at from 10° to 15° C., in the course of 35 minutes. The mixture is stirred at 25° C. for 20 minutes, the organic phase is separated off and the aqueous phase is extracted twice more with 1,2- dichloroethane. The organic extracts are concentrated to give 259.8 parts (93% of theory) of N-methoxycarbonylbenzylmethanamidine of nD25 1.5247.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].C(O)(=O)C.[NH2:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:5]=1[C:10](=[O:11])[N:19]([CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[C:7]2=[O:9])([O-:3])=[O:2]
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: NCc1cccnc1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: O=C1c2cccc([N+](=O)[O-])c2C(=O)N1Cc1cccnc1
Yield: 93.6 %

Procedure:
To a mixture of 15.0 g of 3-nitrophthalic acid anhydride, 233 ml of acetic acid and 80 ml of toluene was added 10.1 g of 3-aminomethylpyridine, and the resultant mixture was refluxed for 1.5 hours under heating. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate, washed with 1N aqueous sodium hydroxide and water in order, dried over anhydrous magnesium sulfate and concentrated in vacuo to give 20.6 g of the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH:9]1(Br)[CH2:13][CH2:12][CH2:11][CH2:10]1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: O=c1ccc(Br)c[nH]1
Reactant: BrC1CCCC1
Solvent: Cc1ccccc1
Product: Brc1ccc(OC2CCCC2)nc1
Temperature: 60 °C
Reaction time: 48 h
Yield: 91.4 %

Procedure:
A mixture of 5-bromo-1H-pyridin-2-one (4.0 g, 23 mmol), Ag2CO3 (3.77 g, 1.37 mmol), cyclopentyl bromide (7.4 mL, 29 mmol) and toluene (30 ml) was stirred at 60° C. for 2 days. The reaction was filtered through Celite® and the filter cake was washed with EtOAc. Concentration and vacuum distillation gave the sub-title compound (5.09 g, 92%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([F:22])[CH:21]=1)[CH2:5][C@H:6]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C@H:7]([OH:10])[CH2:8][OH:9].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCl>[C:23]([O:9][CH2:8][C@@H:7]([OH:10])[C@@H:6]([NH:11][C:12]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:18])[CH2:5][C:4]1[CH:3]=[C:2]([F:1])[CH:21]=[C:20]([F:22])[CH:19]=1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)COC(=O)c1ccccc1

Procedure:
BOC-Protected aminodiol 28 was dissolved in dichloromethane with tritethyamine and cooled to 0°. Benzoylchloride (1.0 eq.) was added and the solution stirred until all of the starting material was consumed. After extraction, the benzoyl ester (29) was purified using silica gel chromatography.