Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[O:21][CH3:22].[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[CH:33]=[O:34]>CCCCCC.O1CCCC1.O>[Br:13][C:14]1[C:15]([O:21][CH3:22])=[C:16]([CH:33]([C:24]2[CH:25]=[CH:26][C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:23]=2)[OH:34])[C:17]([F:20])=[CH:18][CH:19]=1
Reactant: O=Cc1ccc2ccccc2c1
Reactant: COc1cc(F)ccc1Br
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: COc1c(Br)ccc(F)c1C(O)c1ccc2ccccc2c1
Reaction time: 1 h
Yield: 82.7 %

Procedure:
In an atmosphere of nitrogen gas, 2.38 ml of a 2.66 M solution of n-butyllithium in hexane was added to a solution of 0.64 g of N,N-diisopropylamine in 9 ml tetrahydrofuran at −78° C. After stirring at the same temperature for 1 hour, 1.18 g of 1-bromo-4-fluoro-2-methoxy-benzene obtained in Production Example II-1-a was added dropwise. After stirring at the same temperature for 1 hour and 20 minutes, a solution of 0.99 g of 2-naphthoaldehyde in 4 ml tetrahydrofuran was added dropwise. After stirring at the same temperature for 1 hour and 20 minutes, water was added under ice-cooling and the mixture was extracted with diethyl ether for two times. The extract was sequentially washing with water and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography, to give 1.72 g of the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8]([C:12]([O:14]CC)=[CH2:13])=[C:7]([Cl:17])[N:6]=1)=[O:4].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8]([C:12](=[O:14])[CH3:13])=[C:7]([Cl:17])[N:6]=1)=[O:4]
Reactant: C=C(OCC)c1nc(N)c(C(=O)OC)nc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1nc(Cl)c(C(C)=O)nc1N
Yield: 105.4 %

Procedure:
A solution of 3-amino-6-chloro-5-(1-ethoxy-vinyl)-pyrazine-2-carboxylic acid methyl ester (46 mg, 0.190 mmol) and para-toluenesulfonic acid monohydrate (73.8 mg, 0.388 mmol) in THF (2.85 ml) was stirred at rt for 1 h. Saturated aq. NaHCO3 was added and the mixture was extracted twice with DCM. The combined organic layers were washed with brine, dried with Na2SO4, filtered and concentrated under reduced pressure to obtain a yellow solid (46 mg). This material was used for the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[CH2:26]2.N1CCCCC1>C(O)C>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[C:26]2=[CH:20][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Reactant: O=C1Cc2cc(F)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(C=C2C(=O)Nc3ccc(F)cc32)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.4 %

Procedure:
A stirred solution of 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde (52 mg, 0.18 mmol), 5-fluoro-1,3-dihydro-indol-2-one (25 mg, 0.4 mmol) in 0.4 ml of ethanol was added dropwise with anhydrous piperidine (0.04 ml). The mixture was stirred at room temperature overnight. The precipitate was filtered under reduced pressure. The resulting solid was washed with anhydrous ethanol (0.2 ml×5), purified by silica gel column chromatography with dichloromethane:methanol (15:1) as eluents to give 2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-piperidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (30 mg, 38%) as a yellow solid
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH2:7][N:6]1[C:20]1[N:21]([CH:26]2[CH2:29][CH2:28][CH2:27]2)[N:22]=[C:23]([CH3:25])[CH:24]=1)=[O:4].[OH-].[Li+]>>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[S:10]([C@H:8]1[CH2:7][N:6]([C:20]2[N:21]([CH:26]3[CH2:29][CH2:28][CH2:27]3)[N:22]=[C:23]([CH3:25])[CH:24]=2)[C@H:5]([C:3]([OH:4])=[O:2])[CH2:9]1)(=[O:12])=[O:11]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1c1cc(C)nn1C1CCC1
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccccc3Cl)C[C@H]2C(=O)O)n(C2CCC2)n1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-(2-cyclobutyl-5-methyl-2H-pyrazol-3-yl)-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give the title compound as yellow oil which was used in the next step without further purification. MS (ESI): m/z=424.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:20])[NH:8][N:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:11]=1)=[O:5])[CH3:2].[CH2:21](Br)[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:21]([N:8]1[C:7](=[O:20])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][C:10]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)=[N:9]1)[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCC=Cc1ccccc1
Reactant: CCOC(=O)c1cc(-c2ccc(OC)cc2)n[nH]c1=O
Product: CCOC(=O)c1cc(-c2ccc(OC)cc2)nn(CC=Cc2ccccc2)c1=O
Yield: 92.1 %

Procedure:
Using 4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and cinnamyl bromide as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 92.1%.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].[CH2:21]([N:23]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]1)[CH2:24][CH3:25])[CH3:22].Cl>C(O)CC>[CH2:21]([N:23]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4])[CH2:24][CH3:25])[CH3:22]
Reactant: CCN(CC)CC1CCCCN1
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Agent: Cl
Solvent: CCCO
Product: CCN(CC)CC1CCCCN1CC(=O)N1c2ccccc2C(=O)Nc2cccnc21

Procedure:
The title compound is prepared analogously to Example 2 from 11-(chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and (+)-2-[(diethylamino)methyl]piperidine to give colorless crystals, mp. 210°-211.5° C. (n-propanol/activated charcoal): [α]D20 =-12° (dilute aqueous hydrochloride acid).
Reaction SMILES: [CH2:1]([O:3][CH:4]=[C:5]([CH3:8])[CH:6]=O)[CH3:2].[CH3:9][N:10]([CH3:12])[NH2:11].C(O)(=O)C>C(OCC)C>[CH3:9][N:10]([CH3:12])[N:11]=[CH:6][C:5]([CH3:8])=[CH:4][O:3][CH2:1][CH3:2]
Reactant: CCOC=C(C)C=O
Reactant: CN(C)N
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC=C(C)C=NN(C)C

Procedure:
A mixture of 3-ethoxy-2-methyl-2-propenal, (E)-- and (Z)-- (4.0 g, 35 mmol), 1,1-dimethylhydrazine (2.73 g, 46 mmol) and acetic acid (0.04 g, 0.7 mmol) in diethyl ether is refluxed for one hour, cooled, washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title product as a yellow oil.
Reaction SMILES: Br[C:2]1[C:3]([Cl:32])=[CH:4][C:5]([O:30][CH3:31])=[C:6]([NH:8][C@@H:9]([CH3:29])[C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]3[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19]3)[CH2:14][CH2:13]2)=[O:11])[CH:7]=1.[Zn](CC)[CH2:34][CH3:35]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:32][C:3]1[C:2]([CH2:34][CH3:35])=[CH:7][C:6]([NH:8][C@@H:9]([CH3:29])[C:10]([N:12]2[CH2:13][CH2:14][N:15]([CH:18]3[CH2:19][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[CH2:21]3)[CH2:16][CH2:17]2)=[O:11])=[C:5]([O:30][CH3:31])[CH:4]=1
Reactant: CC[Zn]CC
Reactant: COc1cc(Cl)c(Br)cc1N[C@@H](C)C(=O)N1CCN(C2CN(C(=O)OC(C)(C)C)C2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Product: CCc1cc(N[C@@H](C)C(=O)N2CCN(C3CN(C(=O)OC(C)(C)C)C3)CC2)c(OC)cc1Cl
Temperature: 80 °C
Reaction time: 4 h
Yield: 69.3 %

Procedure:
To a solution of (S)-tert-butyl 3-(4-(2-((5-bromo-4-chloro-2-methoxyphenyl)amino)propanoyl)piperazin-1-yl)azetidine-1-carboxylate (400 mg, 0.75 mmol), PdCl2(dppf) (95 mg, 0.13 mmol) in THF (20 mL) at RT, Et2Zn (2.86 mL, 2.86 mmol, 1.0 M in hexane) was added. The resulting mixture was stirred under argon at 80° C. for 4 h and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (methanol/dichloroethane=1:80) to afford the desired product (250 mg, 69% yield). ESI-MS m/z: 481.2[M+H]+.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:8]=[C:7]2[C:18]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)=[O:19].Br[CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>CN(C=O)C>[C:35]([O:34][C:32]([CH2:31][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:8]=[C:7]2[C:18]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)=[O:19])=[O:33])([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCCCCn1cc(C(=O)c2cccc3ccccc23)c2cc(O)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCn1cc(C(=O)c2cccc3ccccc23)c2cc(OCC(=O)OC(C)(C)C)ccc21
Temperature: 60 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
To a suspension of sodium hydride (452 mg, 13.4 mmol, 60% in mineral oil) in DMF (25 ml) under nitrogen was added dropwise a solution of 6 (3.7 g, 10.35 mmol) in DMF (50 ml) and the mixture was stirred at 60° C. for 1 h. The solution was then cooled to room temperature and to this mixture was added a solution of tert-butyl bromoacetate (2.62 g, 13.4 mmol) in DMF (25 ml). The mixture was stirred at 60° C. for 3 h. The DMF was removed under high vacuum and the crude product was suspended in water (100 ml) and the mixture was extracted by ethyl acetate (2×100 ml). The combined ethyl acetate phases were washed by water (1×50 ml), brine (1×50 ml), dried over sodium sulphate filtered and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using hexane/ethyl acetate (9/1) to give the title compound 7 (3.5 g, 72%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:3]=1.C(C1C=CC=CC=1)(=O)C1C=CC=CC=1.C[O-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC([O-])=O.[Na+].Cl.[NH2:83]O>C1(C)C=CC=CC=1.CO>[C:10]([O:9][C:4]1[CH:3]=[C:2]([NH2:83])[CH:7]=[C:6]([F:8])[CH:5]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: NO
Reactant: CC(C)(C)Oc1cc(F)cc(Br)c1
Agent: CC(=O)[O-]
Agent: C[O-]
Agent: Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)(C)Oc1cc(N)cc(F)c1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
1-Bromo-3-tert-butoxy-5-fluorobenzene (56.1 g), benzophenone (50.9 g), NaOMe (50.5 g) and 2,2′-Bis-diphenylphosphanyl-[1,1′]binaphthalenyl (17.5 g) are dissolved in toluene (500 ml). The reaction mixture is flushed with argon, Pd2(dba)3 (5.4 g) is added and the reaction mixture is heated to 80° C. for 40 hours. The reaction mixture is quenched with water. The organics are separated, dried over MgSO4, filtered and the solvent removed in vacuo. The intermediate is obtained by flash column chromatography (silica, eluent dichloromethane). The resulting product is then dissolved in MeOH (1 L). NaOAc (46.1 g), hydroxylamine hydrochloride (29.1 g) are added and the reaction mixture is stirred at room temperature for 2.5 hours. The reaction mixture is quenched with 0.1M NaOH, extracted into DCM (2×), dried over MgSO4, filtered and the solvent removed in vacuo to give the title compound. 1H nmr (CDCl3, 400 MHz); 6.20 (m, 3H), 3.75 (br s, 2H), 1.4 (s, 9H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11](OC)=[O:12].[BH4-].[Li+].O>O1CCCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH2:11][OH:12]
Reactant: COC(=O)c1cc2ccccc2n1C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(CO)cc2ccccc21
Yield: 99.9 %

Procedure:
A solution of 5.05 g of methyl 1-methylindole-2-carboxylate (prepared as described in Preparation 22) in 20 ml of anhydrous tetrahydrofuran was added dropwise to a mixture of 1.85 g of lithium borohydride and 80 ml of anhydrous tetrahydrofuran, and the resulting mixture was heated under reflux for 4 hours. At the end of this time, the reaction mixture was poured into water, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, to give 4.30 g of the title compound, melting at 92.8-95.2° C.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[C@H:15]([OH:24])[CH2:16][C@H:17]([OH:23])[CH2:18][C:19]([O:21]C)=[O:20])=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].[OH-].[Na+:33]>C(#N)C.O>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:24])[CH2:16][CH:17]([OH:23])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:33]
Reactant: COC(=O)C[C@@H](O)C[C@@H](O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.5 %

Procedure:
Fluvastatin methyl ester (5.0 g) was dissolved in acetonitrile (100 ml) by heating. At 50EC a solution of NaOH (1 eq.) in water (1.25 ml) was added and the mixture was stirred at this temperature for 2 h, then cooled to room temperature and stirred over night. The product was isolated by filtration under nitrogen, washed with acetonitrile (30 ml) and dried at 50EC in a vacuum oven for 24 h to obtain 1.75 g (34.5%) of fluvastatin sodium Form CV.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:29][C:28]([C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)[C:33]#[N:34])=[CH:27][C:26](=O)[O:25]1>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:21][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:37]=[CH:36][CH:35]=[C:32]([C:33]#[N:34])[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1NC(=O)CC(=O)c1cccc(C#N)c1

Procedure:
Prepared from (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G39) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according to the general procedure K. Obtained as a yellow solid (257 mg).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:37]1(=[O:47])[NH:42][CH2:41][CH2:40][N:39]2[CH2:43][CH2:44][NH:45][CH2:46][CH:38]12.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.ClCCl>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:45]3[CH2:44][CH2:43][N:39]4[CH2:40][CH2:41][NH:42][C:37](=[O:47])[CH:38]4[CH2:46]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C1NCCN2CCNCC12
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1cc(F)ccc1-c1cc(N2CCN3CCNC(=O)C3C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 24 h
Yield: 61.7 %

Procedure:
To a solution of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide [WO 2005/002577] (50 mg, 0.092 mmol) in 0.5 mL of DMSO was added hexahydro-2H-pyrazino[1,2-a]pyrazin-1(6H)-one (D78, 33 mg, 0.213 mmol) and potassium carbonate (39 mg, 0.28 mmol) and the reaction was left at 150° C. for 24 h. It was worked up by diluting with dichloromethane and extracting with brine. The organics were dried (Na2SO4), and the solvent removed. The product was purified by flash chromatography: silica, cyclohexane: EtOAc 50:50 to EtOAc. Obtained 37 mg of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11](C)[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])[CH3:2].BrC1C=C([F:25])C=CC=1C(OC)=O>>[CH2:1]([C:3]1[CH:12]=[C:11]([F:25])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])[CH3:2]
Reactant: CCc1cc(C)ccc1C(=O)OC
Reactant: COC(=O)c1ccc(F)cc1Br
Product: CCc1cc(F)ccc1C(=O)OC
Yield: 93 %

Procedure:
The title compound (colorless oil, 14.5 g, 93%) was prepared using a procedure similar to that used for the preparation of compound 48.1 and using of methyl 2-bromo-4-fluorobenzoate (compound 470.1, 20.0 g) in place of methyl 2-bromo-4-methylbenzoate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[CH2:11](O)[CH3:12].Cl>O1CCOCC1>[CH2:11]([O:9][C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=1)=[O:10])[CH3:12]
Reactant: O=C(O)c1ccc(F)cn1
Reactant: CCO
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc(F)cn1
Yield: 49.3 %

Procedure:
5-Fluoro-pyridine-2-carboxylic acid (200 mg, 1.13 mmol) was mixed with ethanol (6 mL) and 4 M HCl in dioxane (0.5 mL) at 90° C. for 20 h. The mixture was concentrated and mixed with saturated sodium carbonate and dichloromethane. The dichloromethane layer was washed with brine, dried to give 94 mg (49.3%) of 5-fluoro-pyridine-2-carboxylic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH2:12][C:11]3([CH2:18][C@@H:17](O)[CH2:16][C@H:15]([NH:20][C:21]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[N:24]=4)=[O:22])[CH2:14]3)[C:10]2=[O:30])[CH:5]=[C:6]([F:8])[CH:7]=1.CCN(S(F)(F)[F:37])CC>C(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C:11]3([CH2:18][C@@H:17]([F:37])[CH2:16][C@H:15]([NH:20][C:21]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[N:24]=4)=[O:22])[CH2:14]3)[C:10]2=[O:30])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: Cc1nccc(C(=O)N[C@H]2C[C@H](O)CC3(CCN(c4cc(F)cc(F)c4)C3=O)C2)n1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: Cc1nccc(C(=O)N[C@H]2C[C@H](F)CC3(CCN(c4cc(F)cc(F)c4)C3=O)C2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of trans-2-Methyl-pyrimidine-4-carboxylic acid [2-(3,5-difluorphenyl)-9-hydroxy-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide (crude, <0.121 mmol) in DCM (5 mL) was added DAST (20.3 μL, 0.154 mmol) at 0° C. The reaction mixture was stirred at room temperature overnight and quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was chromatographed on silica gel (0 to 70% EtOAc in hexanes) to give 2 mg of the title compound, trans-2-methyl-pyrimidine-4-carboxylic acid [2-(3,5-difluoro-phenyl)-9-fluoro-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide. 1H NMR (400 MHz, CDCl3) δ 8.79 (d, J=5.0 Hz, 1H), 8.00 (d, J=8.5 Hz, 1H), 7.82 (t, J=5.0 Hz, 1H), 7.26-7.21 (m, 1H), 6.54 (tt, J=8.8, 2.2 Hz, 1H), 5.22-5.05 (m, 1H), 4.55-4.43 (m, 1H), 3.79-3.66 (m, 2H), 2.71 (s, 3H), 2.45-2.25 (m, 3H), 2.09-1.92 (m, 3H), 1.74-1.54 (m, 2H). ESI-MS m/z: 419 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:25]=[CH:24][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:23])=[CH:6][CH:5]=1)(=O)[CH3:2].[CH:26]([NH:28][CH:29](NC=O)[NH:30]C=O)=O.C(N)=O.[OH-].[Na+]>O>[N:28]1[CH:26]=[CH:2][C:1]([C:4]2[CH:25]=[CH:24][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]3[C:21](=[O:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]3=[O:23])=[CH:6][CH:5]=2)=[N:30][CH:29]=1
Reactant: O=CNC(NC=O)NC=O
Reactant: CC(=O)c1ccc(OCCCCN2C(=O)c3ccccc3C2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: NC=O
Product: O=C1c2ccccc2C(=O)N1CCCCOc1ccc(-c2ccncn2)cc1

Procedure:
A mixture of 10.0 g of 2-[4-(4-acetylphenoxy]-butyl]-1H-isoindole-1,3(2H)-dione (Example 42) 10.0 g of tris(formamido)methane, and 20 ml of formamide are combined and the mixture stirred and heated at 160°-165° C. for 8 hours. After dilution with 100 ml of water, the mixture is rendered basic with 10N NaOH, the precipitate collected, washed with water, and air dried. Recrystallization from ethanol gives the pure compound, m.p. 100°-102° C.; yield, 5.0 g.
Reaction SMILES: O[CH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:14]=[C:13]([CH3:15])[NH:12][N:11]=2)[CH:6]=[CH:5][CH:4]=1.S(Cl)([Cl:18])=O>C(Cl)(Cl)Cl.CN(C)C=O>[Cl:18][CH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:14]=[C:13]([CH3:15])[NH:12][N:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: Cc1cc(Nc2cccc(CO)n2)n[nH]1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cc(Nc2cccc(CCl)n2)n[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 114.9 %

Procedure:
68 mg (340 μmol) of 3-(6-hydroxymethylpyridin-2-yl)amino-5-methyl-1H-pyrazole was dissolved in 4 mL of a 6:1 mixed solvent of chloroform and dimethylformamide. Under cooling on an ice bath, 250 μL (3.4 mmol) of thionyl chloride was added thereto. After stirring at room temperature for 18 hours, the reaction solution was concentrated. The resulting residue was purified by a silica gel thin-layer chromatography to give 87 mg of a brown oil. This oil was used as it was for the next reaction.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([N:19]([CH2:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][CH:32]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:31][CH2:30]2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:18])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CO.[C].[Pd]>[CH2:35]([CH:32]1[CH2:33][CH2:34][N:29]([CH2:28][CH2:27][CH2:26][N:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:17]([CH:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)=[O:18])[CH2:30][CH2:31]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(OCc1ccccc1)N1CCC(C(=O)N(CCCN2CCC(Cc3ccccc3)CC2)c2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: O=C(C1CCNCC1)N(CCCN1CCC(Cc2ccccc2)CC1)c1ccccc1
Yield: 97.6 %

Procedure:
The compound obtained in Example 1 (2.32 g, 4.2 mmol) was dissolved in methanol (30 ml). To the solution was added 10% palladium carbon (water content:50%, 0.93 g), and the mixture was subjected to catalytic hydrogenation reaction at room temperature for 16 hours. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the titled compound (1.70 g, 4.1 mmol, Yield 97%).