Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21]1[C:29]2[C:25](=[N:26][S:27][N:28]=2)[C:24]([C:30]2[S:31][CH:32]=[CH:33][CH:34]=2)=[CH:23][CH:22]=1.[CH3:35][Sn:36](Cl)([CH3:38])[CH3:37]>C1COCC1.C(OCC)C.O>[CH3:35][Sn:36]([CH3:38])([CH3:37])[C:32]1[S:31][C:30]([C:24]2[C:25]3[C:29](=[N:28][S:27][N:26]=3)[C:21]([C:17]3[S:16][C:20]([Sn:36]([CH3:38])([CH3:37])[CH3:35])=[CH:19][CH:18]=3)=[CH:22][CH:23]=2)=[CH:34][CH:33]=1
Reactant: C[Sn](C)(C)Cl
Reactant: c1csc(-c2ccc(-c3cccs3)c3nsnc23)c1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[Sn](C)(C)c1ccc(-c2ccc(-c3ccc([Sn](C)(C)C)s3)c3nsnc23)s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mechanically stirred solution of 2,2,6,6-tetramethylpiperidine (TMP) (0.55 g, 4 mmol) in dry THF (25 mL) under argon was cooled to −78° C. Next, n-butyllithium (3.9 mmol) was rapidly added to the solution. The resulting solution was allowed to warm to room temperature. It was kept at room temperature for 10 min and subsequently cooled to −78° C. again. A solution of 4,7-bis(2-thienyl)-2,1,3-benzothiadiazole in 5 mL of dry THF was then added drop-wise to the cooled solution. The resulting solution has a deep purple color and was stirred at −78° C. for 30 min. A 1M solution of trimethyltin chloride in hexanes (3.9 mL) was then added. The reaction mixture was allowed to warm to room temperature and stirred overnight. Water was added to quench the reaction. Diethyl ether was added, and the mixture was washed 3 times with 0.1M HCl to remove the TMP. The solution was then dried with MgSO4. The solvent was removed, and the final product (0.42 g, 45%) was re-crystallized in ethanol to yield orange needles. 1H NMR (CDCl3): 8.19 (d, 2H), 7.88 (s, 2H), 7.30 (d, 2H), 0.44 (s, 18H). 13C NMR (CDCl3): 152.7, 145.1, 140.2, 136.1, 128.4, 125.9, 125.8, −8.2.
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C@H:9]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[C:10]([NH:12][N:13]1[CH2:17][CH2:16][C@H:15]([N:18]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH2:14]1)=[O:11].[C:38]([N:45]1[CH2:48][C:47](=O)[CH2:46]1)([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>>[C:38]([N:45]1[CH2:46][CH:47]([NH:8][C@H:9]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[C:10]([NH:12][N:13]2[CH2:17][CH2:16][C@H:15]([N:18]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH2:14]2)=[O:11])[CH2:48]1)([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: CC(C)C(=O)N(C1CCCCC1)[C@H]1CCN(NC(=O)[C@H](N)Cc2ccc(Cl)cc2)C1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(=O)N(C1CCCCC1)[C@H]1CCN(NC(=O)[C@@H](Cc2ccc(Cl)cc2)NC2CN(C(=O)OC(C)(C)C)C2)C1

Procedure:
The title compound was prepared following the procedure described in Step A of Example 3 using (2R)-2-amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA prepared in Example 1 and BOC-3-oxo-azetidine.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[N:10]=[C:9]([CH2:12][CH3:13])[NH:8][C:7]=2[C:6](=O)[N:5]=[CH:4]1)[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:16].[OH-].[Na+]>N1C=CC=CC=1>[CH2:1]([N:3]1[C:11]2[N:10]=[C:9]([CH2:12][CH3:13])[NH:8][C:7]=2[C:6](=[S:16])[N:5]=[CH:4]1)[CH3:2]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCc1nc2c([nH]1)c(=O)ncn2CC
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CCc1nc2c([nH]1)c(=S)ncn2CC
Yield: 63.7 %

Procedure:
The product of stage (i) (8.65 g) and phosphorus pentasulfide (12.0 g) was refluxed in 150 ml of pyridine for 1 hr. Under cooling 59.4 ml of 2N NaOH was added dropwise, the solid filtered off and washed with water. The filtrate was concentrated in vacuo to dryness and the residue suspended in 200 ml of water and collected. The filtrate was extracted three times with 600 ml of chloroform. The residue of the organic phase was combined with the solid collected (total 6.08 g), dissolved in 500 ml of chloroform and filtered through 24 g of silicagel. Fractions 2 and 3 eluted 4.63 g of crude product which was crystallized from 120 ml of methanol to give 3,8-diethyl-6-thiohypoxanthine (3.58 g) with mp (sublimation at 210° C.) 250-270° C. under decomposition. A second crop gave 0.58 g.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][C:5](=[O:9])[C:4]1=[O:10])[CH3:2].[CH2:11]=[O:12]>Cl>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:11][OH:12])[C:5](=[O:9])[C:4]1=[O:10])[CH3:2]
Reactant: CCN1CCNC(=O)C1=O
Reactant: C=O
Agent: Cl
Product: CCN1CCN(CO)C(=O)C1=O
Temperature: 50 °C
Reaction time: 168 h
Yield: 100 %

Procedure:
To a solution of 1-ethylpiperazine-2,3-dione (2.13 g, 15 mmol) in 30% aqueous (methanol free) formaldehyde (15 mmol) potassium hydroxide (150 mg, 2.7 mmol) was added and the mixture stirred at 50° C. for 7 days. It was neutralized with 5 N aqueous hydrochloric acid (50 μl) to pH=7. The mixture was evaporated at 15 mm and then dried in high vacuo (0.0013 mbar) (0.001 mm) to give 1-ethyl-4- (hydroxymethyl)-piperazine-2,3-dione as a colourless solid (100%). NMR-spectrum in CDCl3: 1.15 (broad signal, 1H), 1.15 (t, 3H, J=7 Hz), 3.47 (q, 2H, J=7 Hz), 3.54 (m, 2H), 3.68 (m, 2H), 4.88 (s, 2H) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:26]1([CH2:32][S:33][CH:34]([C:38](O)=[O:39])[C:35](O)=[O:36])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[OH:39][C:38]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=2)[O:10][C:35](=[O:36])[C:34]=1[S:33][CH2:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(=O)c1cccc(O)c1
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2cccc(O)c2)cc(O)c1SCc1ccccc1

Procedure:
The title compound was prepared by Method A using 3'-hydroxyacetophenone (0.722 g, 5.31 mmol), lithium bis(trimethylsilyl)amide (1.95 g, 11.6 mmol), chlorotrimethylsilane (1.48 mL, 11.6 mmol), THF (116 mL), and diethyl ester of [(phenylmethyl)thio]propanedioic acid (1.00 g, 3.54 mmol). m.p. dec. 185° C.; 1H NMR (400 MHz, DMSO-d6) δ4.00 (s, 2 H), 6.66 (s, 1 H), 6.92 (m, 1 H), 7.21 (m, 7 H), 7.32 (m, 1 H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([O:13][C:14]([F:17])([F:16])[F:15])[CH:10]=[CH:9][C:8]=1[F:18].[N:19]1[CH:24]=[CH:23][C:22]([CH:25]=[O:26])=[CH:21][CH:20]=1.O>O1CCCC1.C([Mg]Cl)CCC>[F:18][C:8]1[CH:9]=[CH:10][C:11]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:12][C:7]=1[CH:25]([C:22]1[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=1)[OH:26]
Reactant: O=Cc1ccncc1
Reactant: Fc1ccc(OC(F)(F)F)cc1Br
Agent: CCCC[Mg]Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: OC(c1ccncc1)c1cc(OC(F)(F)F)ccc1F
Temperature: 25 °C

Procedure:
To a solution in tetrahydrofuran (3 mL) at 0° C. of 2.3M n-butyllithium in hexanes (0.95 mL) and 2M n-butylmagnesium chloride in tetrahydrofuran (0.55 mL) is added a solution of 2-bromo-1-fluoro-4-trifluoromethoxybenzene in tetrahydrofuran (4 mL). After stirring at 0° C. for 20 minutes 4-pyridinecarboxaldehyde (193 μL) is added and the mixture stirred at room temperature for one night. After hydrolysis with water, the aqueous phase is extracted with ethyl acetate. The pooled organic extracts are washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (gradient heptane/ethyl acetate from 2/1 to 1/1) to give pure (2-fluoro-5-trifluoromethoxyphenyl)pyridin-4-ylmethanol.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:31][CH:32]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:33](Cl)=[O:34]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Cl:31][CH:32]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:33]([NH:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1)=[O:34]
Reactant: O=C(Cl)C(Cl)c1ccccc1
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)C(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.9 %

Procedure:
To a solution of 0.61 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 8 ml of methylene chloride is added 0.30 g of triethylamine followed by 0.47 g of (±)-2-chloro-2-phenylacetyl chloride in 2 ml of methylene chloride. The mixture is stirred at room temperature for 1 hour and then diluted with 10 ml of 50% NaHCO3. The methylene chloride is evaporated and the residue is extracted with ethyl acetate. The separated organic layer is washed with saturated NaHCO3 and brine and then dried with Na2SO4 followed by filtering through a pad of hydrous magnesium silicate. The filtrate is evaporated to a residue which is stirred with etherhexane to give 0.98 g of pink solid. MS(CI): 456(M+H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[NH:5][C:6]=1Br.[O-]S([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[Br:1][C:2]1[NH:3][C:4]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[N:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(Br)c(Br)[nH]1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(Br)[nH]1
Yield: 52.2 %

Procedure:
A mixture of Example 126D (12.5 g, 31.5 mmol) in dioxane (400 mL) and H2O (400 mL) had a solution of Na2SO3 (43.7 g, 347 mmol) in H2O (400 mL) added and was heated to reflux for 21 hours. The mixture was concentrated to half volume and extracted with CH2Cl2 (3×200 mL). The organic was then washed with brine, dried (MgSO4), filtered and concentrated. Purification by trituration (CH2Cl2, tBuOMe, and Hexanes) afforded 5.2 g (52%) of the title compound. MS (ESI) m/z 317 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:10]=[C:9]([OH:11])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:7][C:6]=2[N:18]=1.[NH2:19][NH2:20].O1CCOCC1>C(OCC)(=O)C>[NH:19]([C:2]1[CH:3]=[CH:4][C:5]2[C:6]([N:18]=1)=[N:7][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:9]([OH:11])[N:10]=2)[NH2:20]
Reactant: NN
Reactant: Oc1nc2ccc(Cl)nc2nc1-c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: NNc1ccc2nc(O)c(-c3ccccc3)nc2n1
Temperature: 100 °C

Procedure:
To a flask was added 6-chloro-3-phenylpyrido[2,3-b]pyrazin-2-ol (8-2, 3.41 g, 13.23 mmol), anhydrous hydrazine (5.0 mL, 159 mmol), and finally 1.4 Dioxane (60 mL). The stirred reaction mixture was then heated to 100° C. in a hot oil bath under an atmosphere of nitrogen with an air cooled reflux condenser attached. Upon completion of the reaction the mixture was cooled to room temperature, suspended in ethyl acetate and washed with a saturated solution of sodium bicarbonate, followed by water, then brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 8-3 as an orange/tan foam. HRMS (M+H)+: observed=254.1041, calculated=254.1037.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)=[N:16][CH:17]=2)=[O:9])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[CH:38][C:39]([N:42]3[CH2:46][CH2:45][CH2:44][C:43]3=[O:47])=[N:40][CH:41]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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>[O:47]=[C:43]1[CH2:44][CH2:45][CH2:46][N:42]1[C:39]1[N:40]=[CH:41][C:36]([C:2]2[CH:7]=[N:6][C:5]([C:8]([NH:10][CH2:11][C:12]3[CH:13]=[CH:14][C:15]([C:18]4[CH:23]=[CH:22][N:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)=[N:16][CH:17]=3)=[O:9])=[CH:4][CH:3]=2)=[CH:37][CH:38]=1
Reactant: O=C(NCc1ccc(-c2ccnc(C(F)(F)F)c2)nc1)c1ccc(Br)cn1
Reactant: CC1(C)OB(c2ccc(N3CCCC3=O)nc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(NCc1ccc(-c2ccnc(C(F)(F)F)c2)nc1)c1ccc(-c2ccc(N3CCCC3=O)nc2)cn1
Temperature: 96 °C
Reaction time: 8 h

Procedure:
A mixture of 5-bromo-N-((2′-(trifluoromethyl)-[2,4′-bipyridin]-5-yl)methyl)picolinamide 72-1 (22 mg, 0.05 mmol), 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrrolidin-2-one 72-2 (29 mg, 0.1 mmol), Pd(PPh3)4 (12 mg, 0.01 mmol) and K3PO4 (21 mg, 0.1 mmol) in dioxane (0.5 mL) and water (0.1 mL) was stirred at 96° C. under argon overnight. After cooling to room temperature, the mixture was filtered through celite (washed with ethyl acetate) and the filtrate was redistributed between ethyl acetate and water. The organic phase was dried over Na2SO4 and concentrated with rotavap. The residue was subjected to preparative reverse phase HPLC separation to give 6′-(2-oxopyrrolidin-1-yl)-N-((2′-(trifluoromethyl)-[2,4′-bipyridin]-5-yl)methyl)-[3,3′-bipyridine]-6-carboxamide 72 as a solid. MS m/z 519.2 (M+1). 1H NMR 400 MHz (CDCl3) δ 8.83 (d, 1H), 8.79 (d, 1H), 8.76 (dd, 1H), 8.62 (dd, 1H), 8.57 (dd, 1H), 8.52 (t, 1H), 8.34-8.29 (m, 2H), 8.10-8.02 (m, 2H), 7.96-7.88 (m, 2H), 7.84 (d, 1H), 4.79 (d, 2H), 4.16 (t, 2H), 2.71 (t, 2H), 2.18 (t, 2H).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.Cl[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: Clc1ccccc1
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: Clc1cccnc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: c1ccc(-c2ccccc2)cc1
Yield: 28 %

Procedure:
Ali et al., Tetrahedron, vol 48 (1992), pp. 8117-8126 discloses Suzuki-type cross-coupling reactions of arylboronic acids with pi-electron deficient heteroaryl chlorides (chloropyridines, chloropyrimidines, and chloropyrazines, chloroquinolines). These authors state, "It is widely accepted that palladium-catalyzed cross coupling reactions of arylboronic acids, and indeed of other organometallic species, proceed best with aryl or heteroaryl bromides or iodides, and either poorly, or more commonly, not at all with the corresponding chlorides." These investigators confirmed early literature reports that reaction of phenylboronic acid with either chlorobenzene or 3-chloropyridine in the presence of tetrakis(triphenylphosphine) palladium failed to prcoduce any coupled product. Using Pd(bis-1,4-(diphenylphosphino)butane)Cl2, however, they were able to get chlorobenzene to react to give 28% of biphenyl, and 3-chloropyridine was converted to 3-phenylpyridine in 71% yield. Among 2-chloropyridines, the reaction tolerated some (3-nitro, 5-chloro) but not other (3-OH, 3-CONH2) substituents.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[CH3:22][C:23]1[N:24]=[N:25][N:26]([CH:28]2[CH2:32][CH2:31][NH:30][CH2:29]2)[CH:27]=1.C1CCN2C(=NCCC2)CC1>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:30]4[CH2:31][CH2:32][CH:28]([N:26]5[CH:27]=[C:23]([CH3:22])[N:24]=[N:25]5)[CH2:29]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: Cc1cn(C2CCNC2)nn1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: Cc1cn(C2CCN(c3c(F)cc4c(=O)c(C(=O)O)cn(C5CC5)c4c3F)C2)nn1
Yield: 81.8 %

Procedure:
1-Cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (150 mg, 0.53 mmol) was reacted with 249 mg (1.33 mmol) of 3-(4-methyl-1,2,3-triazol-1-yl)pyrrolidine hydrochloride in the presence of 201 mg (1.33 mmol) of DBU in 15 ml of dry pyridine under nitrogen at 120° C. for 3 days. Small amounts of the solid present were removed by filtration, and the supernatant was concentrated under reduced pressure. Water and small amounts of acetonitrile were added to the residue and the grey solid was collected and dried to afford 180 mg (82%) of the desired product, m.p. 219°-220° C. 1H NMR (CDCl3) δ: 8.73 (s, 1H), 7.85 (dd, J=13.7Hz, 1.9HZ, 1H), 7.42 (s, 1H), 5.4-5.3 (m, 1H), 4.4-3.7 (m, 5H), 2.7-2.5 (m, 2H), 2.37 (s, 3H), 1.4-1.05 (m, 4H). Anal. calcd. for C20H19F2N5O3 : C, 57.83; H, 4.57; N, 16.86. Found: C, 57.81; H, 4.60; N, 16.31.
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:5][CH:4]=1)=O.C[Mg]Br.[Cl-].[NH4+].[CH2:21]([O:23]CC)C>>[OH:23][CH2:21][CH2:1][C:3]1[CH:15]=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)c1ccc(C=O)cc1
Reactant: CCOCC
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)(C)OC(=O)c1ccc(CCO)cc1

Procedure:
t-Butyl p-formylbenzoate (20 g, 97 mmol) was dissolved in dry diethyl ether (300 ml), followed by the dropwise addition of methylmagnesium bromide (3M ethereal solution, 33 ml) under cooling with ice and stirring. The obtained mixture was stirred for one hour and poured into a saturated aqueous solution of ammonium chloride, and the obtained mixture was extracted with ether. The ethereal phase was washed with water, dried and distilled to remove the solvent. The pale-yellow viscous liquid residue thus obtained was subjected to silica gel column chromatography and eluted with a solvent (ethyl acetate/hexane=1:4) to give 21.8 g of t-butyl 4-(hydroxyethyl)benzoate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[CH2:9][OH:10].Cl[C:12](Cl)([O:14]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[Br:8][C:4]1[C:3]2[CH2:9][O:10][C:12](=[O:14])[NH:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(Br)c1CO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: O=C1Nc2cccc(Br)c2CO1
Temperature: 25 °C
Yield: 268.6 %

Procedure:
A solution of (2-Amino-6-bromo-phenyl)-methanol (549 mg, 2.72 mmol) and triphosgen (282 mg, 0.95 mmol) in THF (20 ml) was heated at 50° C. for an hours. After cooling to room temperature, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed by water and brine. After drying over MgSO4, the solution was concentrated under vacuum to give 5-bromo-1,4-dihydro-benzo[d][1,3]oxazin-2-one (582 mg, 94%) as a white solid. MS: 226.1 (M−H)−. (M+H)−.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][C@@H:10]([CH2:12][CH2:13][CH3:14])[N:9]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:8]2=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=[C:23]([CH3:37])[CH2:24][CH2:25][N:26]1[C:34](=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]1=[O:36].[BH3-]C#N.[Na+]>CC(O)=O.CO>[O:21]=[C:8]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:11][C@@H:10]([CH2:12][CH2:13][CH3:14])[N:9]1[CH:15]1[CH2:20][CH2:19][N:18]([CH:23]([CH3:37])[CH2:24][CH2:25][N:26]2[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]2=[O:36])[CH2:17][CH2:16]1
Reactant: CCC[C@@H]1CN(c2ccccc2)C(=O)N1C1CCNCC1
Reactant: CC(=O)CCN1C(=O)c2ccccc2C1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCC[C@@H]1CN(c2ccccc2)C(=O)N1C1CCN(C(C)CCN2C(=O)c3ccccc3C2=O)CC1

Procedure:
Following general procedure B: a solution of (R)-1-phenyl-3-piperidin-4-yl-4-propyl-imidazolidin-2-one (152 mg, 0.53 mmol), 2-(3-oxo-butyl)-isoindole-1,3-dione (230 mg, 1.06 mmol), NaBH3CN (108 mg, 1.72 mmol) and glacial AcOH (8 drops) in MeOH (2.5 ml) was stirred at 60° C. for 16.5 hours. Standard workup and purification by flash column chromatography on silica (CH2Cl2/MeOH, 29:1) gave 2-{3-[4-((R)-2-oxo-3-phenyl-5-propyl-imidazolidin-1-yl)-piperidin-1-yl]-butyl}-isoindole-1,3-dione, contaminated with alcohol resulting from reduction of excess ketone (302 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])([CH3:10])[CH:7](O)[C:6]=2[CH:17]=1.S(Cl)([Cl:20])=O>C(Cl)Cl.N1C=CC=CC=1>[Cl:20][CH:7]1[C:6]2[CH:17]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:9][C:8]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:10]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)C1(C)Oc2ccc(Cl)cc2C1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C1(C)Oc2ccc(Cl)cc2C1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 91 %

Procedure:
A solution of 27.9 grams (0.109 mole) of 5-chloro-2-ethoxycarbonyl-2,3-dihydro-3-hydroxy-2-methylbenzofuran in 200 mL of methylene chloride was stirred, and four drops of pyridine was added. The reaction mixture was cooled in an ice-water bath, and 19.4 grams (0.163 mole) of thionyl chloride was added dropwise. The reaction mixture was then stirred for about 30 minutes at the ice-water bath temperature, and allowed to warm to ambient temperature, where it stirred for about 18 hours. After this time the reaction mixture was concentrated under reduced pressure to a residue, which was diluted with water and ethyl acetate, and washed with a solution saturated with sodium bicarbonate. The aqueous layer was separated and washed with two portions of ethyl acetate. The organic layer and the ethyl acetate washes were combined and dried with magnesium sulfate. The mixture was filtered and the filtrate concentrated under reduced pressure to a residual oil, which was subjected to column chromatography on silica gel, with 1:9 ethyl acetate:heptane as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 27.3 grams of 3,5-dichloro-2-ethoxycarbonyl-2,3-dihydro-2-methylbenzofuran. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Na].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[CH:10]12[O:16][CH:15]1[CH2:14][CH2:13][CH2:12][CH2:11]2>C(O)C>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C@@H:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C@H:15]2[OH:16])=[CH:5][CH:4]=1
Reactant: Oc1ccc(Br)cc1
Reactant: C1CCC2OC2C1
Agent: [Na]
Solvent: CCO
Product: O[C@@H]1CCCC[C@H]1Oc1ccc(Br)cc1

Procedure:
Sodium metal (2.58 g, 112 mmol) was combined with absolute ethanol (200 mL) and allowed to react completely. 4-Bromophenol (19.4 g, 112 mmol) was added, and the reaction was stirred for 20 minutes, at which point 7-oxabicyclo[4.1.0]heptane (10.0 g, 102 mmol) was added, and the solution was heated at reflux for 15 hours. After removal of solvent in vacuo, the residue was partitioned between water (300 mL) and ethyl acetate (100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL), and the combined organic layers were washed with water (2×200 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting light tan solid was recrystallized from heptane (roughly 200 mL) to provide trans-2-(4-bromophenoxy)cyclohexanol as a fluffy white solid. Yield: 12.5 g, 46.1 mmol, 45%. 1H NMR (400 MHz, CDCl3) δ 1.26-1.46 (m, 4H), 1.75-1.79 (m, 2H), 2.08-2.14 (m, 2H), 2.52 (d, J=2.1 Hz, 1H), 3.72 (m, 1H), 3.96 (ddd, J=10.3, 8.6, 4.4 Hz, 1H), 6.84 (d, J=9.0 Hz, 2H), 7.37 (d, J=9.0 Hz, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH:13]=O)=[CH:11][N:10]=[CH:9]2)=[CH:5][C:4]=1[F:17])#[N:2].[CH2:18]([NH2:22])[CH2:19][CH2:20][CH3:21].[BH4-].[Na+].CCOC(C)=O>CO>[C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH2:13][NH:22][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:11][N:10]=[CH:9]2)=[CH:5][C:4]=1[F:17])#[N:2]
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1F
Reactant: CCCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCNCc1cncn1Cc1ccc(C#N)c(F)c1
Reaction time: 18 h

Procedure:
To a solution of the product from Step G (114 mg, 0.498 mmol) in 1 mL of methanol was added n-butylamine (0.059 mL, 0.60 mmol). After 18 hours, sodium borohydride was added (25 mg, 0.66 mmol) and the reaction was stirred for one hour. The solution was poured into EtOAc, washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the titled product as a yellow oil.