Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2([CH3:24])[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][S:26]([CH2:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:28])=[O:27]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2([CH3:24])[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:33]4[CH:32]=[CH:31][C:30]([CH2:29][S:26]([CH3:25])(=[O:28])=[O:27])=[CH:35][CH:34]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C2(C)Cc3cc(Cl)ncc3O2)CC1
Reactant: CS(=O)(=O)Cc1ccc(B(O)O)cc1
Product: CC(C)(C)OC(=O)N1CCC(C2(C)Cc3cc(-c4ccc(CS(C)(=O)=O)cc4)ncc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2-methyl-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 4-(methylsulfonylmethyl)phenylboronic acid following a procedure analogous to that described in Example 28. LC (method 6): tR=1.06 min; Mass spectrum (ESI+): m/z=487 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([O:13]CC)=O)=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH:16]1([C:19]2[C:27]3[C:26]([NH2:28])=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=3)[N:20]=2)[CH2:18][CH2:17]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.CC(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:28][C:26]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:27]=3[C:19]([CH:16]3[CH2:18][CH2:17]3)=[N:20][N:21]4[CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=3)=[O:13])=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: CCOC(=O)c1cnc2cc(Cl)ccn12
Reactant: Cc1cccc(Cn2nc(C3CC3)c3c(N)cccc32)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Cc1cccc(Cn2nc(C3CC3)c3c(NC(=O)c4cnc5cc(Cl)ccn45)cccc32)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
A mixture of ethyl 7-chloroimidazo[1,2-a]pyridine-3-carboxylate (10.0 g, 44.5 mmol) and 3-cyclopropyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (12.4 g, 44.5 mmol) in THF (100 mL) was cooled to 0° C. using an ice/water bath. A solution of 1.0M lithium bis(trimethylsilyl)amide (102 mL, 102 mmol) was added slowly over 40 minutes keeping the internal temperature below 5° C. The mixture was stirred at 0° C. for 30 minutes, diluted with IPA (100 mL), and then concentrated under reduced pressure. The residue was diluted with IPA (100 mL) and concentrated under reduced pressure. The residue was dissolved in IPA (100 mL) and treated with a 10% aqueous ammonium chloride solution (200 mL) to give a slurry which was filtered and dried to give 7-chloro-N-(3-cyclopropyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide as a light brown solid (18.4 g).
Reaction SMILES: O[C:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1C=CC=CC=1>[C:13]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:14]=[CH:15][C:10]([C:2]([CH3:9])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:11][CH:12]=1
Reactant: CCOC(=O)CC(C)(O)c1ccc(-c2ccccc2)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: c1ccccc1
Product: CCOC(=O)C=C(C)c1ccc(-c2ccccc2)cc1
Yield: 106.8 %

Procedure:
To a solution of ethyl 3-hydroxy-3-([1,1′-biphenyl]-4yl)-butanoate (2e, 11 g) in benzene (250 ml) was added phosphorus pentoxide (4 g) and refluxed for 3 h. The benzene layer was decanted and then concentrated. The crude product was purified by column chromatography on silica gel to furnish 11 g (57.3% yield) of ethyl 3-([1,1′-biphenyl]-4yl)-but-2-enoate (3e, formula 3, R=Ph) m.p. 76-78° C.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[C:10]([CH3:13])[C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl[CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([NH:31][CH3:32])=[O:30])=[C:27]([F:35])[CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[F:35][C:27]1[CH:26]=[C:25]([CH:34]=[CH:33][C:28]=1[C:29](=[O:30])[NH:31][CH3:32])[CH2:24][C:9]1[C:10]([CH3:13])=[C:11]([CH3:12])[C:2]([OH:1])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)c(C)c1O
Reactant: CNC(=O)c1ccc(CCl)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: CNC(=O)c1ccc(Cc2cc(C(=O)OC)c(O)c(C)c2C)cc1F
Temperature: 80 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
To a mixture of methyl 2-hydroxy-3,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.35 g), 4-(chloromethyl)-2-fluoro-N-methylbenzamide (0.23 g) and sodium carbonate (0.24 g) in 1,2-dimethoxyethane (5.40 mL)-water (1.80 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.07 g), and the mixture was stirred overnight at 80° C. under argon atmosphere. To the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.37 g).
Reaction SMILES: COC(N[C@@H]([C@@H](C)CC)C([N:9]1[C@H:13]([C:14]([OH:16])=[O:15])[CH2:12][C@@H:11]2[CH2:17][CH2:18][CH2:19][C@H:10]12)=O)=O.COC(N[C@@H](C(C)C)C(O)=O)=O>>[NH:9]1[CH:13]([C:14]([OH:16])=[O:15])[CH2:12][CH:11]2[CH2:17][CH2:18][CH2:19][CH:10]12
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N1[C@H](C(=O)O)C[C@@H]2CCC[C@@H]21
Agent: COC(=O)N[C@H](C(=O)O)C(C)C
Product: O=C(O)C1CC2CCCC2N1

Procedure:
(2S,3aS,6aS)-1-(S)-2-(methoxycarbonylamino)-3-methylbutanoyl)octahydrocyclopenta[b]pyrrole-2-carboxylic acid was synthesized in a similar manner as (2S,3aS,6aS)-1-((2S,3S)-2-(methoxycarbonylamino)-3-methylpentanoyl)octahydrocyclopenta[b]pyrrole-2-carboxylic acid substituting (2S,3S)-2-(methoxycarbonylamino)-3-methylpentanoic acid with (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid. LCMS-ESI+ calc'd for C15H25N2O5: 313.17. Found: 313.12.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16](OC3C=CC(N)=CC=3)[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:30]=1[C:36](Cl)=[O:37]>CCOC(C)=O>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16]([C:4]3[CH:3]=[CH:8][C:7]([C:36]([C:30]4[C:29]([F:28])=[CH:34][CH:33]=[CH:32][C:31]=4[F:35])=[O:37])=[CH:6][C:5]=3[NH2:13])[N:15]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: COc1cc(Nc2cncc(Oc3ccc(N)cc3)n2)cc(OC)c1OC
Solvent: CCOC(C)=O
Product: COc1cc(Nc2cncc(-c3ccc(C(=O)c4c(F)cccc4F)cc3N)n2)cc(OC)c1OC
Yield: 30 %

Procedure:
Using Method LL with 2-(3,4,5-trimethoxyphenylamino)-6-(4-aminophenyloxy)-pyrazine (50 mg, 0.14 mmol) and 2,6-difluoro-phenylcarbonyl chloride (30 mg, 0.17 mmol), and purification by column chromatography (AcOEt), the title compound was obtained (21 mg). Yield: 30%. 1H NMR (250 MHz, DMSO-d6) δ 3.65 (s, 3H, [CH3O]4), 3.85 (s, 6H, [CH3O]3+5), 7.27 (s, 2H, Harom2′+6′), 7.45-7.47 (m, 1H, Harom 3″), 7.79-7.84 (m, 2H, Harom 4″+5″), 7.86 (d, 2H, Harom 3+5, J=8.3 Hz), 8.14 (s, 1H, HPz 5), 8.15 (d, 2H, Harom 2+6, J=6.7 Hz), 8.52 (s, 1H, HPz 3), 9.56 (s, 1H, NH), 10.61 (s, 1H, NHamide). m/z 493.2 [(M+H)+ calcd for C26H22F2N4O6 492.2].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[CH:20][C:21](O)=[O:22])=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:26]1[CH2:31][CH2:30][S:29][CH2:28][CH2:27]1>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[CH:20][C:21]([N:26]3[CH2:31][CH2:30][S:29][CH2:28][CH2:27]3)=[O:22])=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: C1CSCCN1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(C=CC(=O)O)cc2)=C(C)C1=O
Product: COC1=C(OC)C(=O)C(Cc2ccc(C=CC(=O)N3CCSCC3)cc2)=C(C)C1=O
Yield: 56.9 %

Procedure:
3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]acrylic acid (200 mg, 0.58 mmol) obtained in Example 2 and thiomorpholine (77 mg, 0.75 mmol) were used, and a method similar to that described in Example 3 was employed to obtain the title compound (140 mg, 0.33 mmol, yield 56%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Br[CH:10]1[CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)S)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH:10]1[CH2:12][CH2:11]1
Reactant: Sc1ccccc1Br
Reactant: BrC1CC1
Agent: O=C([O-])[O-]
Agent: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccccc1SC1CC1
Temperature: 80 °C
Reaction time: 24 h
Yield: 81.4 %

Procedure:
To a solution of 2-bromobenzenethiol (50 g) in DMF (500 mL) were added bromocyclopropane (41.6 g), potassium carbonate (54.8 g), and triphenylmethanethiol (1.46 g), followed by stirring at an internal temperature of 80° C. for 24 hours. After cooling to room temperature, water and ethyl acetate were added thereto, and the organic layer was then separated. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1-bromo-2-(cyclopropylsulfanyl)benzene (49.3 g).
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:30]3[C:29]4[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=4[C:23](=[O:31])[NH:22][C:21]=3[N:20]([CH3:32])[N:19]=2)=[CH:14][CH:13]=1)C1C=CC=CC=1>FC(F)(F)C(O)=O>[NH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:30]3[C:29]4[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=4[C:23](=[O:31])[NH:22][C:21]=3[N:20]([CH3:32])[N:19]=2)=[CH:14][CH:13]=1
Reactant: Cn1nc(-c2ccc(CNC(=O)OCc3ccccc3)cc2)c2c3c(c(=O)[nH]c21)CCCC3
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(-c2ccc(CN)cc2)c2c3c(c(=O)[nH]c21)CCCC3
Yield: 113.5 %

Procedure:
A solution of Example 39 (90 mg, 0.2 mmol) in trifluoroacetic acid (10 mL) was stirred at 50° C. for 4 hours. After cooling, the mixture was concentrated and the residue purified by HPLC (Zorbax, C-18, 250×2.54 column, Mobile phase A 0.1% trifluoroacetic acid in water, B 0.1% trifluoroacetic acid in acetonitrile, 0-100% gradient) to provide 70 mg of the title compound as the trifluoroacetate salt. 1H NMR (CD3OD) □ 1.53-1.63 (m, 2H), 1.71-1.80 (m, 2H), 2.42-2.54 (m, 4H), 3.92 (s, 3H), 4.21 (s, 2H), 7.52-7.65 (m, 4H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[O:28][C:12]3([CH2:17][CH2:16][N:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=4)[CH2:14][CH2:13]3)[CH2:11][C:10](=O)[C:9]=2[CH:30]=1)(=[O:3])[CH3:2].C(=O)(O)[O-].[Na+].[OH-].[Na+]>C(O)(=O)C.[Cl-].[Ti+3].[Cl-].[Cl-]>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[O:28][C:12]3([CH2:13][CH2:14][N:15]([CH2:18][C:19]4[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=4)[CH2:16][CH2:17]3)[CH2:11][CH2:10][C:9]=2[CH:30]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc2c(c1)C(=O)CC1(CCN(Cc3ccc([N+](=O)[O-])cc3)CC1)O2
Agent: [Ti+3]
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc2c(c1)CCC1(CCN(Cc3ccc(N)cc3)CC1)O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
To a solution of 3,4-dihydro-6-acetamido-1'-(4-nitrobenzyl)spiro[(2H)-1-benzopyran-2,4'-piperidine]-4-one (0.58 g, 1.4 mmol) in acetic acid (6.4 ml) was added titanium (III) chloride (15% wt. in 20-30% wt. hydrochloric acid, 7 ml) dropwise. The reaction mixture was stirred at room temperature for 1 hr, cooled to 0° C. and basified with saturated sodium bicarbonate and 20% sodium hydroxide solutions. Extraction with ethyl acetate, drying and solvent evaporation gave an oil (0.42 g). Chromatography (silica gel, chloroform-methanol-ammonium hydroxide, 95/2/0.5) gave 3,4-dihydro-6-acetamido-1'-(4-aminobenzyl)spiro[(2H)-1-benzopyran-2,4'-piperidine]-4-one (136 mg, 26%);
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:12]3[CH:16]=[CH:15][O:14][CH:13]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C[Mg+].[Br-].[CH2:20]1COCC1.[NH4+].[Cl-]>CCOCC.Cl[Ni]Cl.O.C1(C)C=CC=CC=1>[O:14]1[CH:15]=[CH:16][C:12]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([CH3:20])=[CH:3][CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:13]1
Reactant: Clc1ccc2c(-c3ccoc3)ccnc2c1
Reactant: C1CCOC1
Agent: Cl[Ni]Cl
Agent: C[Mg+]
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: O
Product: Cc1ccc2c(-c3ccoc3)ccnc2c1
Temperature: 0 °C

Procedure:
To a mixture of 7-chloro-4-(3-furyl)quinoline (30.2 g) and NiCl2 (dppp) (7.1 g) in Et2O (950 mL) was added MeMgBr (141 mL of a 1.4M solution in 3:1 THF:toluene) at such a rate to maintain a temperature of 30° C. The mixture was refluxed for 30 min., cooled to 0° C. and saturated NH4Cl (200 mL) was added followed by H2O (100 mL). The layers were separated and the aqueous phase was extracted with EtOAc. The combined organics were washed with NH4OAc buffer, brine, dried (MgSO4) and concentrated. Chromatography (silica gel; EtOAc/hexane (3:7)) provided the title compound as a beige oil.
Reaction SMILES: Cl.[CH2:2]([N:4]1[CH:8]=[C:7]([CH:9]=[CH:10][C:11]([OH:13])=O)[N:6]=[C:5]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:3].C(N(CC)CC)C.[NH2:27][CH:28]1[CH2:34][CH2:33][NH:32][C:30](=[O:31])[CH2:29]1.C(=O)(O)[O-].[Na+]>S(Cl)(Cl)=O.O1CCCC1>[CH2:2]([N:4]1[CH:8]=[C:7]([CH:9]=[CH:10][C:11]([NH:27][CH:28]2[CH2:34][CH2:33][NH:32][C:30](=[O:31])[CH2:29]2)=[O:13])[N:6]=[C:5]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:3]
Reactant: CCn1cc(C=CC(=O)O)nc1-c1ccccc1
Reactant: NC1CCNC(=O)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCn1cc(C=CC(=O)NC2CCNC(=O)C2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 422.2 %

Procedure:
β-(1-Ethyl-2-phenylimidazole-4-yl)acrylate hydrochloride (5.49 g, 20.3 mmole) was heated with stirring in thionyl chloride (50 ml) for 50 minutes. After excessive thionyl chloride was completely distilled off under reduced pressure, tetrahydrofuran (50 ml) and triethylamine (4.12 g, 40.7 mmole) were added and then 3-amino-δ-valerolactam (2.79 g, 24.4 mmole) was added to the mixture with cooling, followed by stirring at room temperature overnight. A sodium bicarbonate solution was added to the reaction mixture which was extracted with a chlorofolm-methanol mixed solvent. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel flash chromatography to obtain the titled compound (29 g, 62.3%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:10][C@@H:11]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]2)=[N:4][CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=1>CCOC(C)=O.O=[Mn]=O>[Cl:1][C:2]1[C:3]([NH:10][C@@H:11]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]2)=[N:4][CH:5]=[C:6]([CH:8]=[O:9])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Nc2ncc(CO)cc2Cl)C1
Agent: O=[Mn]=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](Nc2ncc(C=O)cc2Cl)C1
Reaction time: 1.5 h
Yield: 100.6 %

Procedure:
A mixture of tert-butyl (3R)-3-{[3-chloro-5-(hydroxymethyl)-2-pyridinyl]amino}-1-pyrrolidinecarboxylate (0.95 g) and MnO2 (3.02 g) in AcOEt (30 ml) was refluxed under stirring for 1.5 hours. After removal of the insoluble material, and the solvent was evaporated in vacuo to give tert-butyl (3R)-3-[(3-chloro-5-formyl-2-pyridinyl)amino]-1-pyrrolidinecarboxylate (0.95 g).
Reaction SMILES: [CH3:1][C:2]([CH3:31])([O:4][C:5]([NH:7][C@@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:17][CH2:16]1)[C:9]([OH:11])=O)=[O:6])[CH3:3].Cl.[CH2:33]([CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)[CH3:34].C(N(CC)C(C)C)(C)C>ClCCl.C(OCC)(=O)C>[CH3:31][C:2]([CH3:1])([O:4][C:5]([NH:7][C@H:8]([C:9]([N:38]1[CH2:39][CH2:40][CH:35]([CH2:33][CH3:34])[CH2:36][CH2:37]1)=[O:11])[CH2:12][CH2:13][CH2:14][CH:15]1[CH2:16][CH2:17][N:18]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:19][CH2:20]1)=[O:6])[CH3:3]
Reactant: CCC1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCC1CCN(C(=O)OCc2ccccc2)CC1)C(=O)O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCC1CCN(C(=O)[C@H](CCCC2CCN(C(=O)OCc3ccccc3)CC2)NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.4 %

Procedure:
1.7 g (4.4 mmol) of O-(benzotriazol-1-yl)-N,N,N,N′-tetramethyluronium hexafluorophosphate (HBTU) are added portionwise, at 0° C. under nitrogen, to a solution of 1.73 g (4.0 mmol) of (S)-α-[[(1,1-dimethylethoxy)carbonyl]amino]-1-[(phenylmethoxy)carbonyl]-piperidine-4-pentanoic acid, 0.66 g (4.4 mmol) of 4-ethylpiperidine hydrochloride and 1.8 ml (10.4 mmol) of N,N-diisopropylethylamine (DIEA) in dichloromethane. The reaction mixture is allowed to warm slowly to room temperature and the reaction is continued for 18 hours. The reaction mixture is then taken up in 200 ml of ethyl acetate and is washed with 100 ml of 1N hydrochloric acid solution and then with 100 ml of saturated sodium hydrogen carbonate solution and with 100 ml of saturated sodium chloride solution. The resulting product is dried over sodium sulphate and is filtered and then concentrated. The residue obtained is purified by chromatography on a column of silica gel, eluting under pressure with a 4/6 ethyl acetate/cyclohexane mixture. 2 g of phenylmethyl (S)-4-[4-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(4-ethylpiperid-1-yl)-5-oxopentyl]piperidine-1-carboxylate are obtained in the form of a viscous oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH2:30][C:31]2[CH:32]=[C:33]3[C:37](=[C:38]([CH3:40])[CH:39]=2)[NH:36][N:35]=[CH:34]3)[CH2:10][C:11]([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:21][C:20]3=[O:29])[CH2:15][CH2:14]2)=[O:12])=[N:7][CH:8]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH3:40][C:38]1[CH:39]=[C:31]([CH2:30][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([CH:2]=[O:1])=[CH:8][N:7]=2)[CH2:10][C:11](=[O:12])[N:13]2[CH2:14][CH2:15][CH:16]([N:19]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:21][C:20]3=[O:29])[CH2:17][CH2:18]2)[CH:32]=[C:33]2[C:37]=1[NH:36][N:35]=[CH:34]2
Reactant: Cc1cc(CC(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2ccc(CO)cn2)cc2cn[nH]c12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cc1cc(CC(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2ccc(C=O)cn2)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
Solid (±)-3-(1-(3-(5-(hydroxymethyl)pyridin-2-yl)-4-(7-methyl-1H-indazol-5-yl)butanoyl)piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one (20.9 mg, 0.025 mmol, 1.0 equiv) and Dess-Martin reagent (21.8 mg, 2.0 equiv) were dissolved in anhydrous methylene chloride (2 mL). The cloudy solution was stirred at room temperature for 1 h. The reaction was quenched with 0.5 N sodium hydroxide. The layers were separated and the organic layer was washed with brine, dried over sodium sulfate and concentrated to give an off-white solid. Purification by flash column chromatography (10% MeOH in methylene chloride) afforded the desired product (9.5 mg, 69%) as a colorless oily solid. 1H-NMR (400 MHz, CDCl3) δ 10.02 (d, J=8.0 Hz, 1H), 9.06 (d, J=16.4 Hz, 1H), 7.94-7.82 (m, 2H), 7.18-7.08 (m, 4H), 7.08-6.84 (m, 3H), 6.65 (d, J=7.6 Hz, 1H), 4.68-4.44 (m, 2H), 4.24, 4.16 (2s, 1H), 4.05-3.95 (m, 1H), 3.88-3.76 (br. 1H), 3.30-2.92 (m, 4H), 2.72-2.47 (m, 2H), 2.47 (s, 3H), 1.84-1.35 (m, 6H).
Reaction SMILES: [C:1]([NH:7][C:8]1[C:9]2[N:10]([C:14]([CH3:18])=[C:15]([CH3:17])[N:16]=2)[CH:11]=[CH:12][CH:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C([Li])(C)(C)C.[CH:24](=[O:33])[CH:25]=[CH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CCCCC.C(OCC)C>[CH3:17][C:15]1[N:16]=[C:9]2[C:8]([NH:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[C:13]([CH:24]([OH:33])[CH:25]=[CH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:12]=[CH:11][N:10]2[C:14]=1[CH3:18]
Reactant: Cc1nc2c(NC(=O)C(C)(C)C)cccn2c1C
Reactant: O=CC=Cc1ccccc1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Product: Cc1nc2c(NC(=O)C(C)(C)C)c(C(O)C=Cc3ccccc3)ccn2c1C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 47.6 %

Procedure:
A vigorously stirred solution of 41 g of 8-pivaloylamino-2,3-dimethylimidazo[1,2-a]pyridine is treated dropwise at −78° C. under argon protective gas with 320 ml of a commercially available, 1.5 molar solution of t-butyllithium in n-pentane such that the temperature does not exceed −70° C. After stirring at −78° C. for a further 15 min, a solution of 61 g of cinnamaldehyde in 50 ml of dry diethyl ether is added dropwise (internal temperature <−68° C.). The mixture is then allowed to warm to room temperature, and is poured cautiously onto ice water and extracted three times with a total of 500 ml of ethyl acetate, the reddish-colored, organic phase is washed with distilled water and dried over sodium sulfate, and the solvent is stripped off in vacuo. The residual, yellowish suspension is treated with diethyl ether. The crystals obtained are filtered off with suction. 30 g of 2,3-dimethyl-7-(3-phenyl-1-hydroxy-2-propenyl)-8-pivaloylaminoimidazo[1,2-a]pyridine of melting point 194-5° C. are obtained.
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[OH:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br-:13].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)(Cl)Cl>[Br:13][C:10]1[CH:9]=[CH:8][C:7]([OH:12])=[C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:11]=1
Reactant: Oc1ccccc1C1CCCC1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClC(Cl)Cl
Product: Oc1ccc(Br)cc1C1CCCC1
Temperature: 25 °C

Procedure:
2-cyclopentyl phenol (3.0 g, 0.0185 mol) was dissolved in CHCl3 (100 mL) and magnetically stirred at room temperature. To this solution was added a solution of Tetrabutyl ammonium tribromide (8.92 g, 0.0185 mol) in CHCl3 (100 mL). The resulting yellow solution was allowed to stir at room temperature for 1 hour. The reaction was quenched with a 5% solution of sodium thiosulfate (200 mL). The biphasic mixture was stirred for 15 min. The organics were separated and concentrated. The residue was dissolved in EtOAc (100 mL) and washed with water (2×100 mL) and brine (1×100 mL). The organics were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel) eluting with 3% EtOAc in Hexanes. The result was a yellow oil (3.70 g).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][OH:27].C(O)CC>O.C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][OH:27])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: OCCCBr
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCO
Solvent: CC#N
Product: OCCCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2benzisoxazole (10.0 g, 0.045 mol), K2CO3 (10.0 g), 3-bromo-1-propanol (7.3 g, propanol (7.3 g, 0.046 mol) and acetonitrile (200 ml) was refluxed for 3 hours. The reaction was poured into H2O and 7.1 g of a beige solid was collected. The filtrate was extracted with dichloromethane, and after concentration an additional 6.7 g of crude solid was harvested. The solids were combined and triturated with refluxing ethyl acetate to afford 8.0 g of 6-fluoro-3-[1-(3-hydroxypropyl)-4-piperidinyl]-1,2-benzisoxazole as an off-white solid. A sample (4.0 g) was recrystallized from ethanol-water (with charcoal treatment) to yield 2.4 g (40%) of the alcohol as a white solid, m.p.=140°-142° C.