Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:4]1=[O:13].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18]Br>CN(C)C=O>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:4]1=[O:13]
Reactant: BrCCCCBr
Reactant: O=C1CCc2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCc2ccccc2N1CCCCBr
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
A suspension of sodium hydride (6.8 g, 60% dispersion in mineral oil) and dimethyl formamide (200 mL) was kept at 20–30° C. followed by the addition of a solution of 3,4-dihydroquinolin-2(1H)-one (25 g) in dimethyl formamide (100 mL). The resulting mixture was stirred at room temperature for 30 min followed by the addition of a solution of 1,4-dibromobutane (184 g) in dimethyl formamide (200 mL) at a temperature of 20–40° C. The reaction mixture was stirred at room temperature for 30 min and evaporated in vacuo. The remaining oil was poured into ice water and extracted with ethyl acetate. The combined organic phases were washed with water and brine, treated with charcoal, dried (MgSO4) and evaporated in vacuo. The remaining oil was purified by flash chromatography (eluent:ethyl acetate/heptane 1:1) giving the title compound as a red oil (36 g).
Reaction SMILES: Cl.[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:8][O:9][C:5]=2[CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[CH:31][C:30]=1[CH3:38].[C:39]([OH:46])(=[O:45])/[CH:40]=[CH:41]/[C:42]([OH:44])=[O:43]>CN(C)C=O.C(O)C>[C:39]([OH:46])(=[O:45])/[CH:40]=[CH:41]/[C:42]([OH:44])=[O:43].[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:25][CH2:26][CH2:27][O:28][C:29]4[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[CH:31][C:30]=4[CH3:38])[CH2:14][CH2:15]3)=[N:8][O:9][C:5]=2[CH:4]=1.[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:25][CH2:26][CH2:27][O:28][C:29]4[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[CH:31][C:30]=4[CH3:38])[CH2:14][CH2:15]3)=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CC(=O)c1ccc(OCCCBr)c(C)c1
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCCCN2CCC(c3noc4cc(F)ccc34)CC2)c(C)c1
Temperature: 95 °C

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (3.0 g; 11.7 moles), K2CO3 (3.0 g), 1-[4-(3-bromopropoxy)-3-methylphenyl]ethanone (3.19 g) in dimethylformamide (20ml) acetonitrile (50ml) was heated at 95° C. for 4 hr. At the end of the reaction, the solvent was concentrated down to about 30 ml, then partitioned between water (200 ml) and dichloromethane (300 ml). The dichloromethane solution was separated and washed with water and brine then dried over MgSO4. The crude product from the evaporated solution was purified by flash chromatography over a silica gel column (SiO2, 60 g, eluted with 1% methanol in ethane, 600 ml; 2% methanol in dichloromethane, 600 ml). The material thus obtained was a light yellow oil, weight: 2.07 g (43%). The oil was dissolved in ethanol and treated with a solution of fumaric acid (585 mg) in ethanol. The 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methylphenyl]ethanone hemifumarate crystals formed on cooling at 0° C. This was collected and weighed 1.5 g, m.p,=185°-187° C.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[C:6]([CH3:21])=[N:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>O1CCCC1>[CH3:21][C:6]1[C:5]([CH2:4][CH2:3][OH:2])=[CH:10][CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:18])[F:20])=[CH:13][CH:12]=2)[N:7]=1
Reactant: COC(=O)Cc1ccc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.60 g (8.40 mmol) of the above prepared [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester, dissolved in 15 ml of dry tetrahydrofuran, was added under an argon atmosphere within 15 minutes to a stirred suspension of 0.38 g (10 mmol) of lithium aluminum hydride in 5 ml of tetrahydrofuran. The reaction was exothermic. Subsequently, the mixture was stirred at room temperature for 1 hour to complete the reduction. Then, 1 ml of ethyl acetate was added dropwise to destroy the excess of reagent, followed by water, drop after drop, under argon, with stirring and cooling. The reaction mixture was diluted with 50 ml of ethyl acetate, dried over sodium sulfate, and filtered. The filtrate was evaporated i. V. and the residue was purified by chromatography on SiO2 with a mixture of dichloromethane and tert.-butyl methyl ether (4:1) as eluent. Thereby, 1.88 g of the title compound was obtained as white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([Cl:11])=[CH:4][N:3]=1.O.O.[Sn](Cl)Cl.[BH4-].[Na+].C(OCC)(=O)C>CC(O)(C)C>[Cl:11][C:5]1[CH:6]=[C:7]([NH2:8])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ncc(Cl)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cc(Cl)cnc1N

Procedure:
A procedure similar to that described in Preparation 42 was repeated, except that 12.5 g of 2-amino-5-chloro-3-nitropyridine (prepared as described in Preparation 61), 82.0 g of tin(II) chloride dihydrate, 1.35 g of sodium borohydride and 300 ml of a 9: 1 by volume mixture of ethyl acetate and 2-methyl-2-propanol were used, to give the title compound as a crude product. This crude product was crystallized by trituration with a mixture of ethyl acetate and hexane, to give 8.14 g of the title compound, melting at 164°-165° C.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH3:8])[NH:5][C:6]=1[Br:7].[H-].[Na+].[CH3:11][Si:12]([CH3:19])([CH3:18])[CH2:13][CH2:14][O:15][CH2:16]Cl>CN(C)C=O>[Br:1][C:2]1[N:3]=[C:4]([CH3:8])[N:5]([CH2:16][O:15][CH2:14][CH2:13][Si:12]([CH3:19])([CH3:18])[CH3:11])[C:6]=1[Br:7]
Reactant: C[Si](C)(C)CCOCCl
Reactant: Cc1nc(Br)c(Br)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(Br)c(Br)n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
4,5-Dibromo-2-methylimidazole (4.91 g) was dissolved in N,N-dimethylformamide (50 ml), and 60% sodium hydride (901 mg) was added gradually under ice-cooling. After stirring at room temperature for 1 hour, 2-(trimethylsilyl)ethoxymethyl chloride (3.75 g) was gradually added dropwise under ice-cooling, and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure and ethyl acetate was added to the residue. The reaction mixture was washed with saturated aqueous sodium hydrogencarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to give 4,5-dibromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)imidazole (7.6 g) as a colorless oil.
Reaction SMILES: Cl.[F:2][C:3]([F:17])([F:16])[CH2:4][N:5]=[C:6]([NH2:15])[NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13]Cl)[N:12]=1.[SH:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22].[OH-].[Na+]>O>[F:2][C:3]([F:17])([F:16])[CH2:4][N:5]=[C:6]([NH2:15])[NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][S:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[N:12]=1
Reactant: NC(=NCC(F)(F)F)Nc1nc(CCl)cs1
Reactant: COC(=O)CCS
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)CCSCc1csc(NC(N)=NCC(F)(F)F)n1
Reaction time: 1 h

Procedure:
A mixture of 2-[2,2,2-trifluoroethyl]guanidino-4-chloromethylthiazole hydrochloride (4.6 g.) in EtoH (75 ml.) and methyl 3-mercaptopropionate (2.47 ml.) at 5° was treated dropwise with aqueous sodium hydroxide (1.8 g. in 15 ml. of water) over 10 minutes. The resulting solution was allowed to reach room temperature and was stirred for 1 hour. It was then poured into water and the precipitate filtered and crystallised from EtOH to give methyl 3-[2-(2-[2,2,2-trifluoroethyl]guanidino)thiazol-4-ylmethylthio]propionate (1.93 g), m.p. 96°-98°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[N:14]=[C:15]([O:25][C@H:26]4[C@H:30]5[O:31][CH2:32][C@@H:33]([OH:34])[C@H:29]5[O:28][CH2:27]4)[N:16](COCC[Si](C)(C)C)[C:11]3=[CH:10][C:9]=2[Cl:35])=[CH:4][CH:3]=1.S([O-])(O)(=O)=O.[K+].C(=O)(O)[O-].[Na+]>C(O)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[N:14]=[C:15]([O:25][C@H:26]4[C@H:30]5[O:31][CH2:32][C@@H:33]([OH:34])[C@H:29]5[O:28][CH2:27]4)[NH:16][C:11]3=[CH:10][C:9]=2[Cl:35])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(-c3ccc(Br)cc3)c(Cl)cc21
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O=CO
Product: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(Br)cc3)c(Cl)cc2[nH]1
Temperature: 50 °C
Reaction time: 9 h

Procedure:
(3R,3aR,6R,6aR)-6-((5-(4-bromophenyl)-6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol (intermediate 7, 527 mg, 0.904 mmol) was placed under nitrogen in formic acid (2.5 mL). A saturated aqueous solution of potassium hydrogen sulfate (0.4 mL) was added and the resulting mixture was allowed to stir at 50° C. for 9 hours. The mixture was cooled and added slowly to saturated aqueous sodium bicarbonate (200 mL). The mixture was extracted with ethyl acetate (2×150 mL) and concentrated under reduced pressure. The resulting white solid was dissolved in methanol (5 mL) and basified with 3N aqueous sodium hydroxide (2 mL). The mixture was stirred at room temperature for 10 minutes, then neutralized with 1N aqueous hydrochloric acid (6 mL). The mixture was poured into saturated aqueous sodium bicarbonate (25 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The resulting white solid was chromatographed using a Biotage 25 g silica gel cartridge eluted with 0-5% methanol in dichloromethane over 20 minutes. The product fractions were combined, concentrated under reduced pressure, and dried under high vacuum to obtain a white solid. LC-MS: calculated for C18H15BrClN3O4 452.69 observed m/e: 454.02 (M+H)+ (Rt 1.84/4 min).
Reaction SMILES: O[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:11].BrCC(OC)=O>CN(C=O)C>[C:6]1(=[O:11])[C:7]2[C:3](=[CH:2][CH:10]=[CH:9][CH:8]=2)[CH2:4][NH:5]1
Reactant: O=C1NCc2c(O)cccc21
Agent: COC(=O)CBr
Solvent: CN(C)C=O
Product: O=C1NCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
To a solution of 4-hydroxy 2,3-dihydro-1H-isoindol-1-one (27) (0.250 gm, 1.67 mmol) in DMF (5 ml) K2CO3 and was added, followed by addition of methyl bromoacetate, and the reaction mixture was stirred at room temperature for 2 hr. Then the reaction mixture was then poured on ice and extracted with ethyl acetate (2×15 ml). After the standard workup, the residue was dissolved in methanol (3 ml), and treated with NaOH (5 ml, 1N) at 0° C. and then stirred for and additional hour. After the standard workup, the solid was recrystalized in methanol to give compound 29 (0.140 gm, 60%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[Cl:11][CH2:12][CH2:13]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[NH:6]1[C:7]2[C:3](=[C:2]([O:1][CH2:13][CH2:12][Cl:11])[CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1
Reactant: Oc1cccc2[nH]ccc12
Reactant: OCCCl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: ClCCOc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 50.1 %

Procedure:
To a solution of 4-hydroxyindole (4 g, 30 mmol), 2-chloroethanol (4.83 g, 60 mmol), triphenylphosphine (15.7 g, 60 mmol) in anhydrous tetrahydroufuran (40 ml) was slowly added diisopropyl azodicarboxylate (12.1 g, 60 mmol). The reaction was allowed to stir for 2.5 hours at room temperature, then poured into methylene chloride (250 ml), washed with water (3×100 ml) and dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum. Chromatography (20% hexanes-ethyl acetate) to remove triphenylphosphine (20% methylene chloride-hexanes) afforded 2.94 g (50%) of product as a white solid: mp 69.5-72° C.
Reaction SMILES: OS(O)(=O)=O.[NH2:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[CH3:16]O>>[NH2:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([O:11][CH3:16])=[O:10]
Reactant: CO
Reactant: Nc1ncccc1C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccnc1N
Temperature: 25 °C
Reaction time: 72 h
Yield: 71 %

Procedure:
Concentrated H2SO4 (20 mL, 360 mmole) was added dropwise over 5 minutes to a suspension of 2-aminonicotinic acid (25 g, 181 mmole) in MeOH (400 mL), and the mixture was heated at reflux; a homogeneous solution formed within 5 min. After 72 h, the reaction was cooled to room temperature and concentrated under vacuum. The residue was basified with 1.0 N Na2CO3 (500 mL) (Gas evolution!) and extracted with EtOAc (500 mL). The organic layer was washed with brine, dried (Na2SO4), and concentrated to dryness to give the title compound (19.6 g, 71%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.22 (dd, 1 H), 8.13 (dd, 1 H), 6.63 (dd, 1 H), 6.30 (br s, 2 H), 3.89 (s, 3 H).
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>O1CCOCC1>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: Brc1ccccn1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1ccccn1
Temperature: 150 °C

Procedure:
tert-Butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (1.0 g, 5.10 mmol, Aldrich) in 1,4-dioxane (10 mL) in a sealed tube was treated with 2-bromopyridine (0.40 g, 2.50 mmol, Aldrich) and heated at 150° C. for 12 hours. The mixture was allowed to cool to room temperature and was concentrated under reduced pressure. The residue was purified by flash chromatography (5% MeOH/CH2Cl2) to provide the title compound. 1H NMR (CDCl3, 300 MHz) δ 1.48(m, 9H), 1.86–1.94(m, 2H), 3.30–3.58(m, 4H), 4.52(brs, 0.5H), 4.67(brs, 0.5H), 4.80(brs, 0.5H), 4.92(brs, 0.5H), 6.32(d, J=9.0 Hz, 1H), 6.57(t, J=6.0 Hz, 1H), 7.38–7.55(m, 1H), 8.12(d, J=6.0 Hz, 1H). MS (DCI/NH3) m/z 276 (M+H)+.
Reaction SMILES: C(O)(=O)C.[CH3:5][C:6]1([CH3:17])[C@H:11]2[C@@H:7]1[C@H:8]([C:13](Cl)([Cl:15])[Cl:14])[O:9][C:10]2=[O:12]>CCOCC.O.[Zn]>[Cl:14][C:13]([Cl:15])=[CH:8][C@H:7]1[C@@H:11]([C:10]([OH:12])=[O:9])[C:6]1([CH3:5])[CH3:17]
Reactant: CC1(C)[C@H]2[C@H](C(Cl)(Cl)Cl)OC(=O)[C@H]21
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: O
Product: CC1(C)[C@H](C(=O)O)[C@@H]1C=C(Cl)Cl
Yield: 17.7 %

Procedure:
To a suspension of finely divided zinc dust (0.81 g, 1.23 mmole) in acetic acid (0.99 g, 1.64 mmole) and 4 ml of ether was added, under nitrogen, a solution of (1R,4R,5S)-6,6-dimethyl-2-oxo-4-trichloromethyl-3-oxabicyclo[3.1.0]hexane (0.50 g, 1.84 mmole) from Example IA.8.(a) in 4 ml of ether. The reaction was monitored by glpc. When the glpc results indicated almost complete conversion, the reaction mixture was diluted with additional ether and water, filtered through Celite filter aid, and the organic layer was separated, dried, and evaporated to a yellow oil which was chromatographed on two 20×20 cm preparative tlc plates with CH2Cl2 as eluent. The slow running acid band was removed, extracted with CH2Cl2, and the extract was filtered and evaporated to afford (1R,3R)-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid (68 mg, 18% isolated yield). The optical rotation of the acid prepared in a second identical run was measured; [α]D31 =+6.2 (hexane).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](Cl)=[O:28])=[CH:22][CH:21]=1.C(OCC)(=O)C.CCCCCC>O1CCCC1>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:27](=[O:28])[CH2:26][C:23]1[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(Cc1ccc(F)cc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Combine (S)-4-benzyl-2-oxazolidinone (22.9 g, 129 mmol) and tetrahydrofuran (120 mL). Cool in a dry-ice/acetone bath. Add dropwise a solution of n-butyl lithium (52 mL, 2.5 M, 130 mmol). After 15 minutes, slowly add a solution of 4-fluorophenylacetyl chloride (22.3 g, 129 mmol) in tetrahydrofuran (50 mL). Warm to ambient temperature. After 2 hours, quench the reaction mixture by the addition of a saturated aqueous sodium bicarbonate solution. Separate the layers and extract the aqueous layer with diethyl ether. Combine the organic layers, dry over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting wit 15% ethyl acetate/hexane. Combine the product containing fractions, evaporate, and recrytallize from diethyl ether/hexane to give (S)-4-benzyl-3-(4-fluorophenyl)acetyl-2-oxazolidinone.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7](Br)=[CH:6][C:3]=1[C:4]#[N:5].[Cl:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1>>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:11])[CH:17]=2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: OB(O)c1cccc(Cl)c1
Reactant: N#Cc1cc(Br)ccc1N
Product: N#Cc1cc(-c2cccc(Cl)c2)ccc1N

Procedure:
Prepared from 2-amino-5-bromobenzonitrile and 3-chlorophenyl boronic acid according to procedure A. Off-white solid: mp 118-119° C.; 1H-NMR (DMSO-d6) δ 7.80 (d, 1H, J=2.3 Hz), 7.65-7.72 (m, 2H), 7.57 (d, 1H, J=8.0 Hz), 7.42 (t, 1H, J=7.9 Hz), 7.31 (m, 1H), 6.87 (d, 1H, J=8.7 Hz), 6.29 (br, 2H); Anal. Calc. For C13H9ClN2: C, 68.28; H, 3.97; N, 12.25: Found: C, 67.68; H, 4.06; N, 11.89.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([N:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1)(=[O:9])[CH3:8]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[N:1]1([C:13]2[CH2:14][CH2:15][N:10]([C:7](=[O:9])[CH3:8])[CH2:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: CC(=O)N1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)N1CC=C(N2CCOCC2)CC1
Yield: 100.1 %

Procedure:
According to Scheme 1, step 1: A mixture of morpholine (67.85 g, 0.779 mol), 1-acetyl-4-piperidone (99.95 g, 0.708 mol) and para-toluenesulfonic acid monohydrate (0.366 g, 2.1 mmol) in toluene (300 ml) was heated in a Dean-Stark trap apparatus for 16 h at reflux. Solvents were evaporated in vacuo to give 149 g of 1-(4-morpholin-4-yl-3,6-dihydro-2H-pyridin-1-yl)-ethanone (1) which was used in the next step without any further purification.
Reaction SMILES: [C:1]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[CH2:9][C:10]([OH:12])=O)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]>C(O)(=O)C.C(OC(=O)C)(=O)C>[C:1]([NH:7][C@@H:8]1[C:13](=[O:14])[O:15][C:10](=[O:12])[CH2:9]1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: CC(=O)CC(=O)N[C@@H](CC(=O)O)C(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)CC(=O)N[C@H]1CC(=O)OC1=O
Reaction time: 8 h

Procedure:
1.41 parts of N-acetoacetyl-L-aspartic acid were dissolved in 25 parts by volume of acetic acid, and 5 parts by volume of acetic anhydride were added and the mixture was stirred overnight under nitrogen. Solvent was removed under vacuum at 40°-45° C. 50 parts by volume of acetic acid were added and the evaporation repeated to form N-acetoacetyl-L-aspartic anhydride.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]#[N:6].[N-:7]=[N+:8]=[N-:9].[Na+].[Cl-].[NH4+].[OH-].[Na+]>CN(C)C=O>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]1[NH:9][N:8]=[N:7][N:6]=1
Reactant: N#CCCCCl
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: ClCCCc1nnn[nH]1
Temperature: 140 °C
Reaction time: 20 h

Procedure:
A mixture of 3.5 g of 4-chlorobutyronitrile, 2.3 g of sodium azide and 1.9 g of ammonium chloride in 50 ml of dimethyl-formamide is stirred at 140° C. for 20 hours. The reaction mixture is poured onto ice, basified with 1N sodium hydroxide and extracted twice with ethyl acetate. The aqueous fraction is acidified with acetic acid and extracted with ethylacetate. Evaporation of the ethyl acetate gives 5-(3-chloropropyl)-tetrazole which is used directly in the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8])([O-:3])=[O:2].CC1C=CC(S([CH2:22][N+:23]#[C-:24])(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CO>[N+:1]([C:4]1[CH:5]=[C:6]([C:7]2[O:8][CH:24]=[N:23][CH:22]=2)[CH:9]=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=[N+]([O-])c1cccc(-c2cnco2)c1
Yield: 95.1 %

Procedure:
Intermediate X-a was prepared as for example I-c using 3-nitrobenzaldehyde (4 g, 26 mmol), TosMIC (5.7 g, 29 mmol) and K2CO3 (4.4 g, 32 mmol) in MeOH to give intermediate X-a as a yellow solid (4.7 g, 93%). 1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.50 (t, J=1.9 Hz, 1H), 8.21 (ddd, J=8.2, 2.3, 1.0 Hz, 1H), 8.17 (ddd, J=7.8, 1.6, 1.0 Hz, 1H), 7.99 (s, 1H), 7.78 (t, J=8.0 Hz, 1H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]=2)O1.[Cl:29][C:30]1[C:31]2[CH:38]=[C:37](I)[N:36]([S:40]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)(=[O:42])=[O:41])[C:32]=2[N:33]=[CH:34][N:35]=1>O1CCCC1.O.C(OCC)(=O)C>[Cl:29][C:30]1[C:31]2[CH:38]=[C:37]([C:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:17][CH:16]=3)[N:36]([S:40]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)(=[O:42])=[O:41])[C:32]=2[N:33]=[CH:34][N:35]=1
Reactant: O=S(=O)(c1ccccc1)n1c(I)cc2c(Cl)ncnc21
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Cl)ncnc3n2S(=O)(=O)c2ccccc2)CC1
Temperature: 65 °C

Procedure:
A mixture of cesium carbonate (7.45 g, 22.88 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.778 g, 0.95 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (3.98 g, 12.87 mmol), and 4-chloro-6-iodo-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (5 g, 9.53 mmol) in tetrahydrofuran (50 mL) and water (8.33 mL) was heated at 65° C. for 16 hours, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica (IntelliFlash Varian 971-FP), eluting with a gradient of 5-80% ethyl acetate in heptanes to provide the title compound. ESI MS: 497.1 (M+Na)+.
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][CH2:10][Mg+].[Br-].B(F)(F)F.CCOCC>CCOCC.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[C:2]1([C:1]2([NH2:8])[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[Mg+]
Reactant: N#Cc1ccccc1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: FB(F)F
Agent: [Br-]
Solvent: CCOCC
Product: NC1(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.5 %

Procedure:
To benzonitrile (1.03 g, 10 mmol) in ether (50 ml) at −70° C. was added Ti(OiPr)4 (3.22 ml, 11 mmol) and EtMgBr (3M in ether, 7.34 mL, 22 mmol) dropwise, the resulting yellow suspension was warmed up to room temperature over 1 h. After stirring for additional 30 min, the dark brown solution was added BF3.Et2O (2.47 mL, 20 mL) at room temperature. The mixture was further stirred for 1 h, and was quenched by 1N HCl (30 mL) and 5N NaOH (30 mL), the suspension was extracted with ether, ether layer was combined, concentrated to give crude residue, which was purified by column (Hexanes/EtOAc, 2:1 to 1:9) to give 1-phenylcyclopropanamine (420 mg).