Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:7][O:6][C:5]2([CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)[O:4][CH2:3]1.[H-].[Na+].F[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1>CN(C=O)C>[CH3:1][C:2]1([CH3:14])[CH2:3][O:4][C:5]2([CH2:8][CH2:9][CH:10]([O:13][C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=3)[CH2:11][CH2:12]2)[O:6][CH2:7]1
Reactant: CC1(C)COC2(CCC(O)CC2)OC1
Reactant: N#Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)COC2(CCC(Oc3ccc(C#N)cc3)CC2)OC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Add dropwise a solution of 3,3-dimethyl-1,5-dioxa-spiro[5.5]undecan-9-ol, (NE4-A05445-029, 1377 mg, 6.88 mmol) in DMF (2.0 mL) to a suspension of sodium hydride (412 mg, 10.32 mmol) in DMF (8.0 mL). Let the reaction mixture stir at room temperature for 1 h, then heat while stirring at 50° C. for 20 minutes (min). Add dropwise a solution of 4-fluoro-benzonitrile (1000 mg, 8.26 mmol) in DMF (4.2 mL). Continue the heating at 60° C. and stirring for 2 hours (h). Concentrate the reaction mixture to remove DMF. Wash the residue with water (15 mL) and extract with EtOAc/hexanes (20 mL). Dry the organic layer over sodium sulfate, filter and concentrate. Purify the residue by flash chromatography (eluent CH2Cl2/hexanes 2/1) to give xxx mg (xx % yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8]O)[N:3]=1.CCN(S(F)(F)[F:16])CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][F:16])[N:3]=1
Reactant: OCc1nccc(Cl)n1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: FCc1nccc(Cl)n1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
(4-Chloropyrimidin-2-yl)methanol (Example 548, Step 1) (121 mg, 0.84 mmol) was taken up in DCM (2.5 mL) and cooled to 0° C. DAST (0.122 mL, 0.92 mmol) was added and the resulting mixture stirred at 0° C. for 15 minutes and room temperature for 90 minutes. Saturated NaHCO3 was added and the products extracted into EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification of the residue by silica gel chromatography (2-40% EtOAc-hexanes) gave the title compound as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10](Br)[N:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[CH2:13]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[CH3:14]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N:18]3[CH2:19][CH2:20][N:15]([CH2:13][CH3:14])[CH2:16][CH2:17]3)[N:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: CCN1CCNCC1
Reactant: Brc1cc2cccnc2c(Br)n1
Product: CCN1CCN(c2nc(Br)cc3cccnc23)CC1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 98 %

Procedure:
6,8-Dibromo-1,7-naphthyridine (3.464 g) was added to 1-ethylpiperazine (10 ml), and the resulting mixture was stirred at 100° C. for 15 min. The reaction mixture was evaporated, and then partitioned between ethyl acetate and water. The resulting organic layer was washed with water, dried (over MgSO4) and evaporated. The resulting residue was purified by (NH) silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a yellowish orange solid (3.780 g, yield; 98%).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[CH3:15][N:16]([CH2:18][CH2:19][N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[CH:27]=2)[CH:22]=[CH:21]1)[CH3:17]>C(O)(=O)C>[C:1]1([C:22]2[C:23]3[C:28](=[CH:27][C:26]([C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)=[CH:25][CH:24]=3)[N:20]([CH2:19][CH2:18][N:16]([CH3:17])[CH3:15])[CH:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: O=C1CCCCC1
Reactant: CN(C)CCn1ccc2ccc(-c3cccnc3)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: CN(C)CCn1cc(C2=CCCCC2)c2ccc(-c3cccnc3)cc21
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 64 %

Procedure:
In a 20 mL vial equipped with a screw cap and a stir bar was added cyclohexanone (0.1 mL; 0.88 mmol), trifluoroacetic acid (1 mL) and acetic acid (0.75 mL). The mixture was heated at 110° C. under argon for 15 minutes. A solution of compound (a), above, (0.07 g; 0.25 mmol) in acetic acid (1 mL) was added. The resulting mixture was stirred for an additional 20 minutes at 110° C. The reaction mixture was quenched with potassium hydroxide (1N) (pH: 10; 80 mL) and extracted with ethyl acetate (30 mL). The organic phase was successively washed with water (3×30 mL), brine (30 mL), dried (sodium sulfate), filtered and solvent was removed in vacuo. The residue was purified by column chromatography on silica gel using chloroform:methanol (95:5) to yield the title compound (0.6 g; 64%). 13C NMR (CDCl3): δ 148.6, 147.8, 138.0, 137.3, 134.5, 131.5, 130.9, 125.9, 123.5, 122.5, 121.8, 118.9, 118.4. 107.8, 45.8, 44.8, 34.2, 28.6, 25.8, 23.2, 22.5.
Reaction SMILES: Cl[C:2]1[C:3]([C:19]#[N:20])=[N:4][CH:5]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[CH3:18])[CH:7]=1.[Si:21]([O:28][CH2:29][C:30]1[CH:31]=[CH:32][C:33](B2OC(C)(C)C(C)(C)O2)=[C:34]([NH:36]C(=O)OC(C)(C)C)[CH:35]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C(O)CCC>[Si:21]([O:28][CH2:29][C:30]1[CH:31]=[CH:32][C:33]2=[C:2]3[C:3](=[C:19]([NH2:20])[N:36]=[C:34]2[CH:35]=1)[N:4]=[CH:5][C:6]([C:8]#[C:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[CH3:18])=[CH:7]3)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: COc1ccc(C#Cc2cnc(C#N)c(Cl)c2)c(C)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(CO[Si](C)(C)C(C)(C)C)ccc1B1OC(C)(C)C(C)(C)O1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCCCO
Product: COc1ccc(C#Cc2cnc3c(N)nc4cc(CO[Si](C)(C)C(C)(C)C)ccc4c3c2)c(C)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a round bottom flask with refluxing condenser were added 3-chloro-5-((4-methoxy-2-methylphenyl)ethynyl)picolinonitrile (from the step 3) (1 equiv.), tert-butyl 5-((tert-butyldimethylsilyloxy)methyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (from step 2) (1.25 equiv.), K3PO4 (2 equiv.), tris(dibenzylideneacetone)dipalladium(0) (0.05 equiv.), and 2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.1 equiv.). n-Butanol and water (5:2, 0.2 M) were added, and the content were degassed (vacuum followed by nitrogen flush) for three times. The reaction mixture was stirred vigorously under nitrogen at 100° C. overnight in an oil bath. The contents were cooled down and were taken up in water followed by extraction with methylene chloride. Combined organic layers were dried (Na2SO4) and concentrated. Flash chromatography (silica gel, 0-50% EtOAc in CH2Cl2) afforded 8-((tert-butyldimethylsilyloxy)methyl)-2-((4-methoxy-2-methylphenyl)ethynyl)benzo[f][1,7]naphthyridin-5-amine as a solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].O1[C:22]2([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[O:21]CC1.C(#N)C>O>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([N:25]2[CH2:26][CH2:27][C:22](=[O:21])[CH2:23][CH2:24]2)=[CH:3][CH:4]=1
Reactant: Fc1ccc(C(F)(F)F)cc1
Reactant: C1CC2(CCN1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C1CCN(c2ccc(C(F)(F)F)cc2)CC1
Yield: 2.4 %

Procedure:
A mixture of 25 g (0.1523 mol) of p-fluorobenzotrifluoride, 31 g (0.224 mol) of K2CO3, 65 g (0.4539 mol) of 1,4-dioxa-8-azaspiro[4.5]decane, and 150 ml of acetonitrile is stirred at reflux for 3 days. The reaction mixture is cooled, diluted with water, and extracted with methylene chloride. The combined extracts are washed with water, dried over Na2SO4 and concentrated in vacuo. The residue, 600 ml of 10% sulfuric acid solution and 300 ml of tetrahydrofuran is stirred at ambient temperature for 7 days, diluted with water and extracted with methylene chloride. The extracts are washed with brine, dried over Na2SO4, and concentrated in vacuo. Trituration with ether gives 0.9 g of title compound: IR (KBr) 1715, 1610, 1520 and 1330 cm-1 ; NMR (CDCl3) δ7.55 (d, 2H), 6.95 (d, 2H)m 3.73 (t, 4H), and 2.59 (t, 4H).
Reaction SMILES: Cl[CH2:2][C:3](=[O:18])[C:4]([NH:7][C:8](=[O:17])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=1)([CH3:6])[CH3:5].[C-:19]#[N:20].[Na+].O.C(Cl)Cl>C(#N)C.C1OCCOCCOCCOCCOCCOC1>[C:19]([CH2:2][C:3](=[O:18])[C:4]([NH:7][C:8](=[O:17])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=1)([CH3:6])[CH3:5])#[N:20]
Reactant: [C-]#N
Reactant: CC(C)(NC(=O)c1cc(Cl)cc(Cl)c1)C(=O)CCl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: CC(C)(NC(=O)c1cc(Cl)cc(Cl)c1)C(=O)CC#N
Yield: 43 %

Procedure:
N-(3'-chloro-1',1'-dimethylacetonyl)-3,5-dichlorobenzamide (30 gm, 0.0972 m), sodium cyanide (15 gm, 0.306 m) and 18-crown-6 (1 gm) were dissolved in 300 ml of acetonitrile in a round bottom flask under a nitrogen atmosphere. The mixture was heated to reflux for about 4 hours. The contents of the flask were then cooled and transferred to a separatory funnel along with 100 ml of water and 500 ml of methylene chloride and mixed well. The aqueous layer was discarded and the organic layer was washed sequentially with water and brine, dried and the solvents stripped off to yield 12.5 gm of the product after recrystallization from methylene chloride and hexane.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12](C(=O)C)=[C:11]([F:18])[C:10]=1[CH3:19])([CH3:7])[CH3:6])[CH3:2].ClC1C=CC=[C:24]([C:28]([O:30]O)=[O:29])C=1>>[CH2:1]([O:3][C:4](=[O:20])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:30][C:28](=[O:29])[CH3:24])=[C:11]([F:18])[C:10]=1[CH3:19])([CH3:6])[CH3:7])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C(C)=O)c(F)c1C
Product: CCOC(=O)C(C)(C)Oc1ccc(OC(C)=O)c(F)c1C

Procedure:
In analogy to the procedure described in example 32D], 2-(4-acetyl-3-fluoro-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester was oxidized with a total of 4.5 equivalent of 3-chloro perbenzoic acid during 6 day to give the title compound as orange semisolid residue.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:18]([NH:26][CH2:27][CH:28]([C:30]2[CH:31]=[CH:32][C:33]([O:41]CC3C=CC=CC=3)=[C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:35]=2)[OH:29])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17].[H][H]>[Pd].CO>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:18]([NH:26][CH2:27][CH:28]([C:30]2[CH:31]=[CH:32][C:33]([OH:41])=[C:34]([NH:36][S:37]([CH3:40])(=[O:38])=[O:39])[CH:35]=2)[OH:29])[CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: COc1ccc(C(Cc2ccccc2)NCC(O)c2ccc(OCc3ccccc3)c(NS(C)(=O)=O)c2)cc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(Cc2ccccc2)NCC(O)c2ccc(O)c(NS(C)(=O)=O)c2)cc1OC
Yield: 97.4 %

Procedure:
N-[5-[2-[[1-(3,4-Dimethoxyphenyl)-2-phenylethyl]amino]-1-hydroxyethyl]-2-(phenylmethoxy)phenyl]methanesulfonamide, trifluoroacetate salt (220 mg, 0.38 mmol) was hydrogenated using 10% Pd/C (120 mg) and MeOH (25 mL, AR grade) at 40 psi of hydrogen in a Parr apparatus for one hour at room temperature. The catalyst was filtered through Celite and washed with MeOH. The filtrate and MeOH washings were combined and concentrated to afford 178 mg (0.37 mmol, 96% yield) of the title compound as a pale yellow crystalline powder. The title compound is a racemic mixture of diastereomers.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])[C:3]([OH:5])=[O:4].[C:13]1([C@H:19]([OH:24])[C@@H:20]([NH2:23])[CH2:21][OH:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(OC(=O)C)C.O>[OH:1][C@@H:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])[C:3]([O-:5])=[O:4].[C:13]1([C@H:19]([OH:24])[C@@H:20]([NH2:23])[CH2:21][OH:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)C(O)c1ccccc1Cl
Agent: N[C@@H](CO)[C@@H](O)c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C([O-])[C@@H](O)c1ccccc1Cl

Procedure:
(The compound of the general formula (II)—wherein R1 is a hydroxy-methyl group, R2 is a phenyl group, R3 is a hydroxy group) Racemic 2-hydroxy-2-(2-chlorophenyl)acetic acid (20.0 g 107 mmol) was dissolved in 60 cm3 of ethylacetate saturated with water and (1S, 2S)-(+)-1-phenyl-2-amino-1,3-propane-diol (18.0 g 107.5 mmol) was added thereto and then the mixture was seed by a salt formed from (S)-(+)-2-hydroxy-2-(2-chlorophenyl)acetate and (1S, 2S)-(+)-1-phenyl 2-amino-1,3-propane-diol at room temperature.
Reaction SMILES: [CH:1]([C:4]1[CH:43]=[CH:42][C:7]([O:8][CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][NH:25][C:26](=[O:41])[C:27]3[CH:32]=[CH:31][C:30]([C:33]4[N:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=4)=[CH:29][CH:28]=3)=[CH:18][CH:17]=2)[C:10]([O:12]CC)=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH-].[Na+]>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][NH:25][C:26](=[O:41])[C:27]3[CH:32]=[CH:31][C:30]([C:33]4[N:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=4)=[CH:29][CH:28]=3)=[CH:20][CH:21]=2)[C:10]([OH:12])=[O:11])=[CH:42][CH:43]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3ccc(OC)cn3)cc2)cc1)Oc1ccc(C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(-c2ccc(C(=O)NCCOc3ccc(CC(Oc4ccc(C(C)C)cc4)C(=O)O)cc3)cc2)nc1
Yield: 92.6 %

Procedure:
In a similar manner to that described in Example 2, ethyl 2-(4-isopropylphenoxy)-3-[4-[2-[4-(3-methoxypyridine-6-yl)benzoylamino]ethoxy]phenyl]propionate (210 mg), which is the product of Example 110, was reacted with aqueous sodium hydroxide solution (1N, 0.72 ml) and the reaction mixture was treated to give the title compound (185 mg) as a white powder.
Reaction SMILES: C(O)(=O)C.Cl.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14]N)=[CH:10][CH:9]=1.O=[C:17]1[CH2:21][CH2:20][CH:19]([C:22]([OH:24])=[O:23])[CH2:18]1>O>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]2[NH:14][C:17]3[CH2:18][CH:19]([C:22]([OH:24])=[O:23])[CH2:20][C:21]=3[C:10]=2[CH:9]=1
Reactant: O=C1CCC(C(=O)O)C1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2[nH]c3c(c2c1)CC(C(=O)O)C3
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.1 %

Procedure:
To 250 ml of 80% acetic acid in water were added 4-methoxyphenylhydrazine hydrochloride (21 g, 0.12 mole) and 3-oxocyclopentane carboxylic acid (20 g, 0.15 mole). After stirring at ambient temperature for two hours, the mixture was stirred at 100° C. for three hours. After cooling, the mixture was filtered, and the tan precipitate washed with water, and dried to give 15 g of a solid, mp ~200° C. A sample of this material was recrystallized from ethanol/ether (1:2) to give a tan solid, mp 210° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.Cl[CH2:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].CCCCCCC>CN(C=O)C.C(OCC)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][CH:10]=2)[CH:6]=1
Reactant: Brc1cn[nH]c1
Reactant: NC(=O)c1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: NC(=O)c1ccc(Cn2cc(Br)cn2)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 4-bromo-1H-pyrazole (400 mg, 2.72 mmol), 4-(chloromethyl)benzamide (462 mg, 2.72 mmol), and potassium carbonate (940 mg, 6.80 mmol) in DMF (5 mL) was stirred for 2 hours at 80° C. The reaction mixture was then cooled to ambient temperature and diluted with diethyl ether (400 mL). The mixture was washed with water (2×100 mL) and brine (25 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford the crude product residue. The crude product residue was suspended in ethyl acetate (10 mL) and then diluted by the drop wise addition of n-heptane (40 mL). After stirring for 18 hours, the mixture was filtered and the collected solids were washed with n-heptane (3×10 mL). The collected solids were dried under reduced pressure to afford 4-((4-bromo-1H-pyrazol-1-yl)methyl)benzamide. MS ESI calcd. for C11H11BrN3O [M+H]+ 280 and 282. found 280 and 282. 1H NMR (500 MHz, DMSO-d6) δ 8.10 (s, 1H), 7.93 (s, 1H), 7.81 (d, J=8.5 Hz, 2H), 7.57 (s, 1H), 7.35 (s, 1H), 7.26 (d, J=8.0 Hz, 2H), 5.35 (s, 2H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][N:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:15][CH2:14][C:13](=[O:16])[NH:12][C:11]=3[CH:17]=2)[C:4](=[O:18])[CH2:3]1.[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]2[N:29]=[CH:28][C:27](=[O:30])[N:26]([CH2:31][CH2:32][CH:33]=O)[C:25]=2[N:35]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>CN(C)C=O.ClCCl>[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]2[N:29]=[CH:28][C:27](=[O:30])[N:26]([CH2:31][CH2:32][CH2:33][NH:1][CH:2]3[CH2:3][C:4](=[O:18])[N:5]([C:7]4[CH:8]=[CH:9][C:10]5[O:15][CH2:14][C:13](=[O:16])[NH:12][C:11]=5[CH:17]=4)[CH2:6]3)[C:25]=2[N:35]=1
Reactant: NC1CC(=O)N(c2ccc3c(c2)NC(=O)CO3)C1
Reactant: COc1ccc2ncc(=O)n(CCC=O)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc2ncc(=O)n(CCCNC3CC(=O)N(c4ccc5c(c4)NC(=O)CO5)C3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
In N,N-dimethylformamide (3 ml) were dissolved 6-(4-Amino-2-oxopyrrolidin-1-yl)-2H-1,4-benzoxazin-3(4H)-one (Reference Example 6; 159 mg, 0.643 mmol) and 3-(6-methoxy-3-oxopyrido[2,3-b]pyrazin-4(3H)-yl)propanal (synthesized with reference to WO2008/9700; 150 mg, 0.643 mmol). Sodium sulfate (1.0 g) was added to the solution and the mixture was stirred overnight at room temperature. Sodium triacetoxyborohydride (164 mg, 0.772 mmol) was added to the reaction solution and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane, basified by adding a saturated sodium hydrogen carbonate aqueous solution and the organic layer was then separated. The organic layer was washed sequentially with saturated sodium chloride solution, water (3×) and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to yield 219 mg (73%) of the title compound in the form of a colorless foamy solid.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([F:9])=[CH:7][C:6]([OH:10])=[C:5]([O:11][CH3:12])[CH:4]=1)[CH3:2].[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1F)[C:17]#[N:18].[OH-].[K+]>C(#N)C>[CH2:1]([C:3]1[C:8]([F:9])=[CH:7][C:6]([O:10][C:21]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=2[F:13])=[C:5]([O:11][CH3:12])[CH:4]=1)[CH3:2]
Reactant: N#Cc1ccc(F)c(F)c1
Reactant: CCc1cc(OC)c(O)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CCc1cc(OC)c(Oc2ccc(C#N)cc2F)cc1F
Temperature: 80 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
A suspension of 4-ethyl-5-fluoro-2-methoxyphenol (1 g, 5.87 mmol), 3,4-difluorobenzonitrile (899 mg, 6.46 mmol) and potassium hydroxide (395 mg, 7.04 mmol) in anhydrous acetonitrile (35 mL) under argon was stirred at 80° C. overnight. The reaction mixture was concentrated under vacuum and diluted with ethyl acetate and a saturated aqueous solution of ammonium chloride. The aqueous layer was separated and extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtrated and concentrated in vacuo to give a brown oil (1.6 g). The crude product was purified by flash chromatography on silica gel, using cyclohexane/ethyl acetate (9:1) as eluent. The title product was obtained as a colourless oil that crystallized slowly (1.42 g, 84%).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][C:4]2([CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]2)[C:3]1=[O:19].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]1[CH2:6][CH2:5][C:4]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[C:3]1=[O:19]
Reactant: CN1CCC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCC2(CCNCC2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
To a solution of tert-butyl 2-methyl-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (315 mg, 1.174 mmol) in DCM (5 mL) was added TFA (1.718 mL, 22.30 mmol) and the mixture was stirred at room temperature for 2 h. The reaction was concentrated under reduced pressure to obtain crude and purified by SCX cartridge, loading with MeOH, washed with additional MeOH. Product was recovered eluting with 2M NH3 in MeOH. Solvent evaporation gave 2-methyl-2,8-diazaspiro[4.5]decan-1-one (177 mg).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH:11]1([C@@H:17]([N:28]2[CH2:32][C@H:31]([CH2:33][OH:34])[C@@H:30]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=3)[CH2:29]2)[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>C(Cl)Cl>[CH:11]1([C@@H:17]([N:28]2[CH2:32][C@H:31]([CH:33]=[O:34])[C@@H:30]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=3)[CH2:29]2)[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(OCc1ccccc1)[C@@H](C1CCCCC1)N1C[C@H](CO)[C@@H](c2cccc(F)c2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C[C@H]1CN([C@@H](C(=O)OCc2ccccc2)C2CCCCC2)C[C@@H]1c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of oxalyl chloride (1.03 mL, 11.8 mmol) in 60 mL CH2Cl2 was cooled in a dry ice/acetone bath. DMSO (1.67 mL, 23.6 mmol) was added dropwise. The mixture was stirred for 15 min then a solution of benzyl (2R)-cyclohexyl[(3S,4R)-3-(3-fluorophenyl)-4-(hydroxymethyl)pyrrolidin-1-yl]ethanoate (4.2 g, 9.8 mmol, from Step C) in 70 mL CH2Cl2 was added dropwise. After stirring for 15 min TEA (6.8 mL, 49 mmol) was added in 10 mL CH2Cl2. The mixture was warmed to rt and stirred for 2 h. The solution was poured into a speparatory funnel and diluted with 200 mL CH2Cl2 and washed with 1 N NaOH (2×), water and sat'd NaCl. The organic portion was dried over sodium sulfate and concentrated. Flash chromatography (150 g silica, 0→30% EtOAc/hexanes) gave the desired aldehyde. 1H NMR (500 MHz, CDCl3) δ0.95-1.05 (m, 2H), 1.14-1.29 (m, 3H), 1.6 (br d, 1H), 1.66-1.83 (m, 4H), 1.93 (br d, 1H), 2.65-2.69 (m, 1H), 2.88-2.93 m, 1H), 3.15 (dd, 1H), 3.20-3.24 (m, 2H), 3.27-3.30 (m, 1H), 3.55 (dd, 1H), 5.18 (d, 1H), 5.19 (d, 1H), 6.89-6.97 m, 3H), 7.23-7.27 (m, 1H), 7.33-7.4 (m, 5H).
Reaction SMILES: C(O)C.[CH2:4]([N:6]([CH2:30][CH3:31])[CH2:7][CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([N:19]2C(=O)C3=CC=CC=C3C2=O)=[N:11]1)[CH3:5].O.NN>O>[CH2:30]([N:6]([CH2:4][CH3:5])[CH2:7][CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([NH2:19])=[N:11]1)[CH3:31]
Reactant: CCN(CC)CCCn1nc(N2C(=O)c3ccccc3C2=O)c2ccccc21
Agent: NN
Solvent: CCO
Solvent: O
Product: CCN(CC)CCCn1nc(N)c2ccccc21
Reaction time: 3 h
Yield: 82.4 %

Procedure:
To 70 ml of ethyl alcohol was added 3.30 g of 1-(3-diethylaminopropyl)-3-phthalimidoindazole. The mixture was added with 2.50 g of 85% hydrazine hydrate under cooling with ice and stirred for 3 hours under cooling with ice. The reaction mixture was filtered and the filtrate was condensed under reduced pressure. The condensed residue was added with 20 ml of water and the reaction product was extracted with chloroform. The chloroform layer was extracted with 2N-hydrochloric acid and the pH of the hydrochloric acid layer was adjusted to 10 with potassium carbonate. The alkali layer was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate, and chloroform was removed under reduced pressure to give 1.78 g of 1-(3-diethylaminopropyl)-3-aminoindazole having the following analytical values in a yield of 85%.