Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCO.C([O:11][C:12]1[CH:13]=[C:14]([CH:19]=[C:20]([C:22]2[N:26]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:25]=[N:24][N:23]=2)[CH:21]=1)[C:15]([O:17][CH3:18])=[O:16])C1C=CC=CC=1.[H][H]>[C].[Pd].C1COCC1>[OH:11][C:12]1[CH:13]=[C:14]([CH:19]=[C:20]([C:22]2[N:26]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:34])[CH3:33])[N:25]=[N:24][N:23]=2)[CH:21]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(-c2nnnn2COCC[Si](C)(C)C)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)c1cc(O)cc(-c2nnnn2COCC[Si](C)(C)C)c1

Procedure:
In a nitrogen atmosphere, 10% palladium-carbon (2.4 g) was added to an EtOH (35 mL)-THF (35 mL) mixed solution of methyl 3-benzyloxy-5-[({[2-(trimethylsilyl)ethyl]oxy}methyl)-tetrazol-5-yl]benzoate (4.02 g), and in a hydrogen atmosphere this was stirred at room temperature for 2 hours. The reaction liquid was filtered through Celite, concentrated under reduced pressure, and dried to obtain the title compound as a white powder. Not purified, this was used in the next step.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[O:11]1[CH2:14][CH2:13][CH:12]1[CH2:15][OH:16].CC(C)([O-])C.[K+]>CN(C)C=O>[O:11]1[CH2:14][CH2:13][CH:12]1[CH2:15][O:16][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1
Reactant: OCC1CCO1
Reactant: O=C(O)c1cnc(Cl)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1cnc(OCC2CCO2)cn1
Temperature: 120 °C
Yield: 221.7 %

Procedure:
In a microwave vial 5-chloropyrazine-2-carboxylic acid (100.0 mg, 0.631 mmol), dimethylformamide (5 mL), oxetan-2-ylmethanol (83.4 mg, 0.946 mmol) and potassium tert-butoxide (176.9 mg, 1.58 mmol) are added. A small exotherm is observed. After 1 minute at room temperature the vial is sealed and the mixture heated at 120° C. for 30 minutes in the microwave. The reaction mixture is then quenched with aqueous NH4Cl and the solvent evaporated under reduced pressure. The resultant residue is triturated in 2-propanol. The filtrate is concentrated under reduced pressure to give the title compound as a cream solid (0.294 g, 99%) and is used without further purification. ES/MS (m/e): 211.0 (M+1), 208.8 (M−H).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH3:11])[CH3:10])=[CH:5][CH:4]=1.C[I:14].[CH2:15](Cl)Cl>ClC(Cl)C>[I-:14].[CH3:10][N:9]([CH3:11])[C:6]1[CH:7]=[CH:8][C:3]([N+:2]([CH3:15])([CH3:12])[CH3:1])=[CH:4][CH:5]=1
Reactant: CN(C)c1ccc(N(C)C)cc1
Reactant: CI
Reactant: ClCCl
Solvent: CC(Cl)Cl
Product: CN(C)c1ccc([N+](C)(C)C)cc1
Product: [I-]
Temperature: 25 °C
Yield: 70 %

Procedure:
N,N,N′,N′-Tetramethyl-benzene-1,4-diamine (200 mg, 1.22 mmol) was dissolved in dichloroethane (2 mL) and methyl iodide (173 mg, 1.22 mmol) was added dropwise. The reaction was refluxed for 1 hour, cooled to room temperature, the solid filtered out, washed with dichloromethane, dissolved in methanol and purified via flash column chromatography using a gradient of 0-8% MeOH:DCM to give 260 mg of grey solid (70% yield). 1H NMR (DMSO-d6): δ7.67 (d, J=9.3, 2H), 6.77 (d, J=9.3, 2H) 3.49 (s, 9H), 2.92 (s, 6H); MS (ESI, m/z): 179 (M+).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:7][CH2:6][CH:5](O)[CH:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1.CC(C)=CC(O)=[O:20].C1(=O)CCCC=C1.[C-:30]#[N:31].C([Al+]CC)C>O1CCCC1>[C:30]([C:4]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3][C:2]([CH3:15])([CH3:1])[CH2:7][C:6](=[O:20])[CH2:5]1)#[N:31]
Reactant: CC1(C)CCC(O)C(c2ccccc2)C1
Reactant: [C-]#N
Reactant: CC(C)=CC(=O)O
Agent: CC[Al+]CC
Agent: O=C1C=CCCC1
Solvent: C1CCOC1
Product: CC1(C)CC(=O)CC(C#N)(c2ccccc2)C1

Procedure:
The amines where R0 contains a 5,5-dimethyl-3-phenyl-2-cyclohexanol may be prepared substantially as described in Mestres et al., Tetrahedron, volume 50, page 2571 (1994). For example, in a tandem Michael-Dieckmann decarboxylative annulation of trans-βmethylcinnamic acid and 3,3-dimethylacrylic acid, the cyclohexenone was stirred with diethylaluminum cyanide in tetrahydrofuran at room temperature overnight to provide 3-cyano-5,5-dimethyl-3-phenylcyclohexanone which was then hydrogenated over 5% rhodium on alumina to give the corresponding amine.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH:15]=[C:16]([C:22](OCC)=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:9]=1>>[Cl:3][C:22]1[C:10]2[C:11](=[CH:12][CH:13]=[C:8]([O:7][CH3:6])[CH:9]=2)[N:14]=[CH:15][C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)C(=CNc1ccc(OC)cc1)C(=O)OCC
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2ccc(OC)cc2c1Cl
Temperature: 97.5 °C
Reaction time: 0.25 h
Yield: 61.2 %

Procedure:
132 g of phosphoryl chloride are added, at 25° C., to 50 g of diethyl 2-[(4-methoxyphenylamino)methylene]malonate. The reaction medium is stirred for 15 minutes at this temperature, heated to 95-100° C. over 45 minutes, and then kept at this temperature for 4 hours. The excess phosphoryl chloride is then removed by heating at 125° C. for approximately 2 hours. The mixture is then cooled to 25° C. and 125 ml of dichloromethane are added. The medium is then stirred at 25° C. for 1 hour, and then run into 900 ml of water, over 30 minutes, while maintaining the temperature below 30° C. The pH is then adjusted to 7.5-8 by adding 172 g of a 47% sodium hydroxide solution, while maintaining the temperature at 20-25° C. The 2 phases are separated and the aqueous phase is extracted with dichloromethane. The organic phases are pooled and washed with water. The dichloromethane phase is half-concentrated and 190 ml of ethanol are added. The concentration is continued until the temperature of the reaction mass reaches 82° C. and the vapor temperature reaches 78° C. The reaction mass is cooled to 0-5° C. and then kept at this temperature for 2 hours. The precipitate is filtered off, washed with cold ethanol, and then dried at 50° C. under reduced pressure. 27.7 g (61%) of 4-chloro-3-ethoxycarbonyl-6-methoxyquinoline are obtained in the form of a yellow solid which melts at 93.7-95.7° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([NH2:15])=[C:4]([NH:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[CH:3]=1.C(N(CC)CC)C.[CH2:36]([O:38][CH2:39][C:40](Cl)=[O:41])[CH3:37]>ClCCl>[CH2:36]([O:38][CH2:39][C:40]([NH:15][C:5]1[C:6]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:7][C:2]([CH3:1])=[CH:3][C:4]=1[NH:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)=[O:41])[CH3:37]
Reactant: Cc1cc(NCCOCCCc2cccnc2)c(N)c(Oc2ccccc2)n1
Reactant: CCOCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCC(=O)Nc1c(NCCOCCCc2cccnc2)cc(C)nc1Oc1ccccc1
Reaction time: 0.5 h
Yield: 89.2 %

Procedure:
Under a nitrogen atmosphere, a solution of 6-methyl-2-phenoxy-N4-{2-[3-(pyridin-3-yl)propoxy]ethyl}pyridine-3,4-diamine (5.2 g, 14 mmol), anhydrous dichloromethane (40 mL), and anhydrous triethylamine (2.3 mL, 16.5 mmol) was cooled to 5° C. A solution of ethoxyacetyl chloride (1.77 g, 14.4 mmol) in dichloromethane (10 mL) was then added over a period of ten minutes, and the reaction was stirred for 30 minutes. The reaction mixture was diluted with dichloromethane (25 mL), washed with aqueous saturated sodium bicarbonate (3×) and brine (3×), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 5.8 g of 2-ethoxy-N-(6-methyl-2-phenoxy-4-{2-[3-(pyridin-3 -yl)propoxy]ethylamino}pyridin-3-yl)acetamide as an oil.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH:11]2[CH2:13][CH2:12]2)[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.[O:22]=[C:23]([NH:28][CH2:29][C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32])[CH2:24][C:25](O)=[O:26].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>O1CCCC1>[CH:11]1([CH2:10][N:7]2[C:8](=[O:9])[C@@H:2]([NH:1][C:25](=[O:26])[CH2:24][C:23]([NH:28][CH2:29][C:30]([F:36])([F:35])[C:31]([F:32])([F:34])[F:33])=[O:22])[C:3]3[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=3[C:5]3[CH:17]=[CH:16][CH:15]=[CH:14][C:6]2=3)[CH2:13][CH2:12]1
Reactant: O=C(O)CC(=O)NCC(F)(F)C(F)(F)F
Reactant: N[C@@H]1C(=O)N(CC2CC2)c2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: O=C(CC(=O)N[C@@H]1C(=O)N(CC2CC2)c2ccccc2-c2ccccc21)NCC(F)(F)C(F)(F)F
Temperature: 25 °C
Yield: 90.3 %

Procedure:
0.11 g (0.38 mmol) (S)-7-Amino-5-cyclopropylmethyl-5H,7H-dibenzo[b,d]azepin-6-one and 0.09 g (0.38 mmol) 3-oxo-3-(2,2,3,3,3-pentafluoro-propylamino)-propanoic acid in 10 ml tetrahydrofuran were reacted with 0.06 g (0.38 mmol) 1-hydroxybenzotriazole hydrate, 0.13 ul (0.76 mmol) diisopropylethylamine and 0.7 g (0.38 mmol) N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimid-hydrochlorid at 0° C. for 4 hours. After stirring at room temperature over night the solvent was removed by distillation and the residue purified by chromatography on silicagel with heptane/ethylacetate (gradient 100–0/0-100) to yield 0.17 g (89%) N-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide as white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH2:4].[CH3:5][CH:6]1[CH:11]2[CH2:12][CH2:13][CH:8]([CH2:9][CH2:10]2)[CH:7]1[CH2:14][CH2:15][C:16](=O)[CH2:17][CH2:18][CH:19]1[CH:24]([CH3:25])[CH:23]2[CH2:26][CH2:27][CH:20]1[CH2:21][CH2:22]2.N[N].[C:31](#[N:34])[CH:32]=[CH2:33]>>[CH3:5][CH:6]1[CH:11]2[CH2:12][CH2:13][CH:8]([CH2:9][CH2:10]2)[CH:7]1[CH2:14][CH2:15][CH:16]([NH:1][CH2:2][CH2:3][NH:4][CH2:33][CH2:32][CH2:31][NH2:34])[CH2:17][CH2:18][CH:19]1[CH:24]([CH3:25])[CH:23]2[CH2:26][CH2:27][CH:20]1[CH2:21][CH2:22]2
Reactant: NCCN
Reactant: CC1C2CCC(CC2)C1CCC(=O)CCC1C2CCC(CC2)C1C
Reactant: C=CC#N
Agent: [N]N
Product: CC1C2CCC(CC2)C1CCC(CCC1C2CCC(CC2)C1C)NCCNCCCN

Procedure:
As an alternative to using an unsymmetrical amine V and obtaining a mixture of Schiff bases VI and VI(a) or VI(b), the reaction can be conducted stepwise. For example, 1,2-diaminoethane may be converted to a Schiff base with 1,5-di-(3-methylbicyclo[2.2.2]oct-2-yl)-3-pentanone, catalytically reduced, then the remaining primary amino nitrogen selectively cyanoethylated with acrylonitrile, followed by catalytic hydrogenation to furnish 1-[1,5-di-(3-methylbicyclo[2.2.2]oct-2-yl)-3-pentyl]-1,4,8-triazaoctane.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[C:9]([S:11]([O-:13])=[O:12])[S:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[Li+].[F:15][C:16]([F:30])([F:29])[C:17]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:18]=1[CH2:19]Br.[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>C(#N)C>[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][N:41]([C:2]2[C:7]3[CH:8]=[C:9]([S:11]([CH2:19][C:18]4[CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=[CH:24][C:17]=4[C:16]([F:30])([F:29])[F:15])(=[O:13])=[O:12])[S:10][C:6]=3[CH:5]=[CH:4][N:3]=2)[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: FC(F)(F)c1ccc(C(F)(F)F)c(CBr)c1
Reactant: O=S([O-])c1cc2c(Cl)nccc2s1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Li+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2nccc3sc(S(=O)(=O)Cc4cc(C(F)(F)F)ccc4C(F)(F)F)cc23)CC1

Procedure:
Lithium 4-chlorothieno[3,2-c]pyridine-2-sulfinate (0.44 mmol) was treated with 2,5-bis(trifluoromethyl)benzylbromide (0.59 mmol) as described in Method P above and then reacted further with tert-butyl-piperazine-1-carboxylate as described in Method Q. Yield 0.01 g (4% over two steps). Beige solid. 1H NMR (300 MHz, CDCl3) δ 8.16 (d, J=5.8 Hz 1H), 8.00 (s, 1H), 7.74-7.85 (m, 3H), 4.76 (s, 2H), 3.56-3.64 (m, 4H), 3.47-3.56 (m, 4H), 1.49 (s, 9H); MS (ESI+) for C25H25F6 N3O4S2 m/z 610 (M+H)+. HPLC 73%, RT 2.36 min (YMC ODS AQ, 33×3 mm, 10-90% acetonitrile in 3 min).
Reaction SMILES: [CH:1]([C:3]1[C:19]2[CH:18]=[C:17](C(OCC)=O)[O:16][C:15]=2[C:14]2[CH:13]=[CH:12][C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]=2[CH:4]=1)=[O:2].[OH-].[Na+].C1COCC1.Cl>O>[CH:18]1[C:19]2[C:3]([CH:1]=[O:2])=[CH:4][C:5]3[C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=4[CH:12]=[CH:13][C:14]=3[C:15]=2[O:16][CH:17]=1
Reactant: CCOC(=O)c1cc2c(C=O)cc3c4ccccc4ccc3c2o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cc2c3ccccc3ccc2c2occc12
Yield: 37 %

Procedure:
To a RB flask equipped with magnetic stirring bar, condenser, and N2 inlet line with bubbler was added ethyl 11-formyl-phenanthro[1,2-b]furan-2-carboxylate (15A, 2.5 g. 7.8 mmol), 1N NaOH solution (25 mL), THF (50 mL) and H2O (25 mL). The mixture was refluxed for 2 h until it became homogeneous. The mixture was acidified with 1N HCl and the solvent removed by rotary evaporation. The crude solid was then heated to 150° with copper powder (0.9 g) and quinoline (Aldrich, 25 mL) for 1 h. The reaction mixture was cooled and the quinoline removed under vacuum to give a crude dark green solid. After chromatography and crystallization (CH2Cl2 /hexane) 0.71 g (37% yield) of phenanthro[1,2-b]furan-11-carbaldehyde, mp 145°-150°, (C,H).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:16]=[C:8]2[C:9]3[C:14]([CH2:15][N:7]2[N:6]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3)(=O)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OC(C)C)(C)C>C(COC)OC>[CH2:1]([NH:4][C:5]1[N:16]=[C:8]2[C:9]3[C:14]([CH2:15][N:7]2[N:6]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2]
Reactant: CC(=O)Nc1nc2n(n1)Cc1ccccc1-2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: COCCOC
Solvent: CC(C)OC(C)C
Product: CCNc1nc2n(n1)Cc1ccccc1-2
Yield: 60 %

Procedure:
2-Acetamido-5H-s-triazolo[5,1-a]isoindole is reduced with lithium aluminum hydride at 0-10°C in dimethoxyethane. Yield 60%. M.p. 150-2°C (isopropyl ether).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH3:11].[Mn]([O-])(=O)(=O)=[O:13].[K+].[OH-:18].[K+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[C:11]([OH:13])=[O:18]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1c(Cl)cccc1[N+](=O)[O-]
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: O=C(O)c1c(Cl)cccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 77.7 gm (0.453 mol) of 2-chloro-6-nitro-toluene, 190 gm (1.2 mol) of potassium permanganate, 500 ml of 1 N potassium hydroxide and 4 liters of water was heated for 8.5 hours at 100° C. After standing overnight, 25 gm (0.16 mol) of potassium permanganate were added, and the reaction mixture was heated for 2.5 hours more at 100° C. The unreacted starting material was distilled off by steam distillation. The remaining reaction solution was filtered, the filter cake was washed with hot water, and the combined filtrates were evaporated to about 750 ml. After acidifying with hydrochloric acid a precipitate was obtained, which was filtered off and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][N:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[N:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2cnccc21
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CC1c2ccncc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-methyl-1,2,3,4-tetrahydro-[2,6]naphthyridine to provide the title compound in moderate yield.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH:8]=[N:9][CH:10]=[CH:11][C:5]2=[N:4][C:3]=1[N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[CH2:14][CH2:13]1.CCN(CC)CC.Cl.[O:35]1[CH2:39][CH2:38][C@H:37]([NH2:40])[CH2:36]1>CN(C=O)C>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[CH2:18][N:15]1[CH2:16][CH2:17][N:12]([C:3]2[N:4]=[C:5]3[CH:11]=[CH:10][N:9]=[CH:8][C:6]3=[N:7][C:2]=2[NH:40][C@H:37]2[CH2:38][CH2:39][O:35][CH2:36]2)[CH2:13][CH2:14]1
Reactant: N[C@H]1CCOC1
Reactant: Fc1ccc(CN2CCN(c3nc4ccncc4nc3Cl)CC2)c(F)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Fc1ccc(CN2CCN(c3nc4ccncc4nc3N[C@H]3CCOC3)CC2)c(F)c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 23.5 %

Procedure:
To a solution of 3-chloro-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazine (3.0 g, 7.98 mmol) and Et3N (10 mL, 71.7 mmol) in DMF (30 mL) was added (S)-tetrahydrofuran-3-amine hydrochloride (2.96 g, 23.95 mmol) at room temperature. The mixture was stirred at 60° C. for 16 h then separated between water and EtOAc. The organic layer was washed with brine and water, then dried and concentrated to yield the crude residue, which was purified by column to give the title compound (800 mg) as a yellow oil. ESI-MS m/z [M+H]+ 427.1.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][C:12]#N)=[N:2]1.CC[O:16][CH2:17]C.C[OH:20]>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][C:12]([O:16][CH3:17])=[O:20])=[N:2]1
Reactant: N#CCCc1noc2ccccc12
Reactant: CCOCC
Reactant: CO
Product: COC(=O)CCc1noc2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The nitrile was dissolved in methanol (200 ml) and HCI-saturated ether (200 ml) was added followed by stirring for 16 h at room temperature. The reaction mixture was concentrated in vacuo, water and ether added, and the phases separated. Drying of the ether phase over magnesium sulfate and removal of solvent in vacuo gave methyl 3-(1,2-benzisoxazol-3-yl)propionate (13 g) as an oil.
Reaction SMILES: O=[CH:2][CH2:3][C@H:4]([NH:11]C(=O)OC(C)(C)C)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[ClH:19].[NH2:20][C:21]1([C:26]([O:28][CH3:29])=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.O>[ClH:19].[ClH:19].[NH2:11][C@H:4]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH2:3][CH2:2][NH:20][C:21]1([C:26]([O:28][CH3:29])=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COC(=O)C1(N)CCCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)C1(NCC[C@H](N)c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of tert-butyl [(1S)-3-oxo-1-phenylpropyl]carbamate from Step B (0.820 g, 3.29 mmol) and methyl 1-aminocyclopentanecarboxylate hydrochloride (0.591 g, 3.29 mmol) in chloroform (33 mL) was added Hunig's base (0.574 mL, 3.29 mmol). After stirring at ambient temperature for 20 min, NaHB(OAc)3 (1.74 g, 8.22 mmol) was added as a solid. Upon completion of the reaction, saturated aqueous NaHCO3 (3 mL) was added and the mixture was allowed to stir for at least 2 h. Water (5 mL) and additional saturated NaHCO3 (3 mL) was then added to form two layers. The aqueous layer was extracted once with chloroform (50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give an oil. This oil was purified by silica gel chromatography, eluting with a gradient of MeOH:DCM 1:99 to 6:94, to give the title compound. MS: nm/z=377 (M+1).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13](=[O:18])[C:12]=2[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:26](OC(=O)C)(=[O:28])[CH3:27].C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[C:26]([NH:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[O:15][C:14]([CH3:16])([CH3:17])[C:13](=[O:18])[C:12]=2[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)=[CH:9][CH:10]=1)(=[O:3])=[O:4])(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)OC(c2ccc(S(N)(=O)=O)cc2)=C(c2cccc(F)c2)C1=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NS(=O)(=O)c1ccc(C2=C(c3cccc(F)c3)C(=O)C(C)(C)O2)cc1

Procedure:
360 mg of 5-{4-(aminosulfonyl)phenyl}-2,2-dimethyl-4-(3-fluorophenyl)-3(2H)-furanone (Example 129) in 30 ml in dichloromethane was reacted with 0.8 ml acetic anhydride in the presence of 0.5 ml triethylamine and 50 mg of 4-(N,N-dimethylamino)pyridine at room temperature for 12 hours. The reaction mixture was concentrated in vacuo, which was followed by extraction with 30 ml water and dichloromethane (30 ml×3). The organic layer was concentrated under reduced pressure and then was purified by column chromatography (hexane/ethylacetate 2:1) to afford 397 mg of 5-[4-{(acetylamino)sulfonyl}phenyl]-2,2-dimethyl-4-(3-fluoro-phenyl)-3(2H)-furanone as a solid. mp: 178-179° C. NMR: δ1.57 (s, 6H), 2.08 (s, 3H), 7.05 (m, 3H), 7.34 (m, 1H), 7.82 (d, J=8.4 Hz, 2H), 8.05 (d, J=8.4 Hz, 2H), 8.20 (br s, 1H). IR (cm−1): 3238, 3198, 1431, 1261, 1159.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:14]([NH2:18])[CH2:15][CH2:16][CH3:17].C(O)(=O)C.C([BH3-])#N.[Na+]>CO.O>[CH2:14]([NH:18][CH2:4][C:3]1[CH:6]=[CH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:9][C:2]=1[F:1])[CH2:15][CH2:16][CH3:17]
Reactant: O=Cc1ccc(C(F)(F)F)cc1F
Reactant: CCCCN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: CCCCNCc1ccc(C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 25.7 %

Procedure:
To a solution of 2-fluoro-4-(trifluoromethyl)benzaldehyde (3.84 g, 20.0 mmol) and n-butylamine (1.46 g, 20.0 mmol) in methanol (100 mL) were added acetic acid (4.6 mL, 80 mmol) and sodium cyanoborohydride (1.51 g, 24.0 mmol) and the solution was stirred at room temperature for 3 days. Water (10 mL) was added and the mixture was concentrated in vacuo. The residue was taken, up in aqueous 1 M KOH (125 mL) and ethyl acetate (100 mL) and the phases were separated. The aqueous phase was extracted with ethyl acetate (2×100 mL) and the combined organic phase was dried over Na2SO4 and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 70 g/150 mL) with ethyl acetate (33-100% gradient) in heptane as the eluent and collection of pure fractions yielded 1.28 g (26%) of a colourless oil of low viscosity.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Cl:26][C:27]([Cl:31])([Cl:30])[CH2:28]O>ClCCl>[Br:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([O:12][CH2:28][C:27]([Cl:31])([Cl:30])[Cl:26])=[O:11])=[CH:7][CH:8]=1
Reactant: OCC(Cl)(Cl)Cl
Reactant: O=C(O)Cc1ccc(CBr)cc1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C(Cc1ccc(CBr)cc1)OCC(Cl)(Cl)Cl
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
4-Bromomethylphenylacetic acid (12) (10.3 g, 44.8 mmol) was suspended in dichloromethane (30 ml). Trifluoroacetic anhydride (9.28 ml, 67.2 mmol) was added at 0° C., and the resulting mixture was stirred for 30 min. Then, 2,2,2-trichloroethanol (6.47 ml, 67.2 mmol) was added dropwise, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was washed with water, saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give a colorless oil. The oil was left standing overnight to give 2,2,2-trichloroethyl 4-bromomethylphenylacetate (13) as white crystals (15.9 g, yield 98%).
Reaction SMILES: N1CCCCC1[CH2:7][CH2:8][CH:9]1[NH:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10]1.[CH3:17][S:18](Cl)(=[O:20])=[O:19].[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[CH3:17][S:18]([CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27][N:22]1[CH2:7][CH2:8][CH:9]1[NH:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10]1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: c1ccncc1
Reactant: O=C1CCCCC(CCC2CCCCN2)N1
Solvent: ClCCl
Product: CS(=O)(=O)C1CCCCN1CCC1CCCCC(=O)N1
Reaction time: 8 h

Procedure:
Example 296 B) To the hexahydro-7-[2-(2-piperidyl) ethyl]-1H-azepin-2-one product of Example 296 A (2-3 g, 10 mmol) in anhydrous pyridine (8 mL) and CH2Cl2 (4 mL) was added dropwise methanesulfonyl chloride (0.74 mL) in CH2Cl2 (2 mL). The contents were stirred overnight, concentrated in vacuo and partitioned between CH2Cl2 and water. The CH2Cl2 layer was dried over MgSO4 and concentrated in vacuo leaving an oil. The oil was purified by C18 reverse phase chromatography eluding with a CH3CN/H2O (0.05% TFA) gradient to give hexahydro-7-[2-(2-methylsulfonylpiperidyl)ethyl]-1H-azepin-2-one (1.5 g).