Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][C:7]1[C:8](=[O:19])[C:9]2[C:14]([C:15](=[O:18])[C:16]=1[CH3:17])=[CH:13][CH:12]=[CH:11][CH:10]=2)([OH:3])=O.ON1C(=O)CCC1=O.CCN=C=NCCCN(C)C.[CH2:39]([NH2:42])[CH2:40][NH2:41]>ClC(Cl)C.ClCCl>[NH2:41][CH2:40][CH2:39][NH:42][C:1]([CH2:4][CH2:5][CH2:6][C:7]1[C:8](=[O:19])[C:9]2[C:14]([C:15](=[O:18])[C:16]=1[CH3:17])=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:3]
Reactant: NCCN
Reactant: CC1=C(CCCC(=O)O)C(=O)c2ccccc2C1=O
Agent: CCN=C=NCCCN(C)C
Agent: O=C1CCC(=O)N1O
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CC1=C(CCCC(=O)NCCN)C(=O)c2ccccc2C1=O
Reaction time: 4 h
Yield: 58.7 %

Procedure:
2-(3-carboxypropyl)-3-methyl-1,4-naphthoquinone (1.00 g, 3.9 mmol) and N-hydroxysuccinimide (534 mg, 4.64 mmol) were dissolved in dichloroethane (80 ml). WSC (EDC) (890 mg, 4.64 mmol) was added to the mixture, and the mixture was stirred for 4 hours. 2.59 ml of ethylenediamine (2.33 g, 38.7 mmol) was dissolved in dichloromethane (10 ml), and the above reaction mixture was added thereto dropwise in 15 minutes. The mixture was stirred as it was at room temperature for 2 nights. Dichloromethane (300 ml) was added to the reaction mixture, and the reaction mixture was washed with water (500 ml×1). An organic layer was dried using sodium sulfate. A solvent was removed under reduced pressure, and the mixture was purified using a silica gel chromatography (silica gel: Fuji Silysia NH-DM1020; dichloromethane:methanol=96:4) and recrystallized (dichloromethane:hexane), to thereby obtain a yellow brown powder of 2-{3-[N-(2-aminoethyl)aminocarbonyl]propyl}-3-methyl-1,4-naphthoquinone (yield: 686 mg, 2.29 mmol, 58.9%).
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)[CH3:2].[S:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1.Cl>C(Cl)Cl>[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:7]([C:6]1[CH:10]=[CH:11][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1)=[O:8]
Reactant: c1ccsc1
Reactant: CCc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Product: CCc1ccc(C(=O)c2cccs2)cc1

Procedure:
To a stirred mixture of 26.7 parts of p-ethylbenzoyl chloride, 13.3 parts of thiophene in 80 parts of methylene chloride are added 41.1 parts of stannic chloride in 40 parts of methylene chloride at 30° C. Upon completion, stirring is continued for 3h.30 at reflux temperature. The reaction mixture is poured onto a mixture of crushed ice and hydrochloric acid. The layers are separated and the aqueous phase is extracted with methylene chloride. The combined organic layers are washed with water, dried, filtered and evaporated. The residue is evaporated once more from benzene. The latter residue is distilled, yielding p-ethylphenyl 2-thienyl ketone; bp. 200-205° C at 12 mm, pressure.
Reaction SMILES: Cl.[CH:2]([Si:5]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[O:6][CH2:7][CH2:8][C@@H:9]([CH3:24])[CH2:10][C@@H:11]1[N:16]=C(OC)[C@@H](C(C)C)N=[C:12]1[O:22][CH3:23])([CH3:4])[CH3:3].[OH-:31].[Na+]>O1CCCC1>[NH2:16][C@@H:11]([CH2:10][C@H:9]([CH3:24])[CH2:8][CH2:7][O:6][Si:5]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:2]([CH3:4])[CH3:3])[C:12]([O:22][CH3:23])=[O:31]
Reactant: [OH-]
Reactant: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1C[C@H](C)CCO[Si](C(C)C)(C(C)C)C(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)[C@@H](N)C[C@H](C)CCO[Si](C(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
100 ml of 0.5N hydrochloric acid are added to a solution of 10.0 g of 3,6-dihydro-3(S)-[4-triisoproylsilyloxy-2(S)-methylbutyl]-6(R)-isopropyl-2,5-dimethoxypyrazine in 100 ml of tetrahydrofuran and the mixture is stirred at room temperature for 40 min. The reaction mixture is brought to pH 9 by addition of 1N sodium hydroxide solution and then extracted with methylene chloride. The combined organic phase is filtered through cotton wool and concentrated. The crude product is purified by FC over 900 g of silica gel with a 500:10:1 mixture of methylene chloride, methanol and 25% ammonia solution. In addition to the re-isolated starting material, this gives the title compound: Rf (methylene chloride-methanol-concentrated ammonia: (140:10:1))=0.34.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:5]=[C:6]2[S:19][CH:18]=[CH:17][N:7]2[C:8](=[O:16])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:3].Br[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][NH:25]2.C(N(CC)C(C)C)(C)C>C(O)C>[C:10]1([C:9]2[C:8](=[O:16])[N:7]3[CH:17]=[CH:18][S:19][C:6]3=[N:5][C:4]=2[CH:2]([NH:1][C:21]2[N:29]=[CH:28][N:27]=[C:26]3[C:22]=2[N:23]=[CH:24][NH:25]3)[CH3:3])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(N)c1nc2sccn2c(=O)c1-c1ccccc1
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2[nH]cnc12)c1nc2sccn2c(=O)c1-c1ccccc1
Temperature: 110 °C

Procedure:
A mixture of 7-(1-aminoethyl)-6-phenyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.025 g, 0.092 mmol), 6-bromo-9H-purine (0.033 g, 0.16 mmol), and N,N-diisopropylethylamine (0.029 mL, 0.16 mmol) in ethanol (0.5 mL) was heated at 110° C. overnight. The mixture was filtered, and the filtrate was purified on preparative-LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH) to give the desired product. LCMS calculated for C19H16N7OS (M+H)+: m/z=390.1. Found: 390.1. 1H NMR (DMSO-d6, 400 MHz) δ 8.08 (1H, s), 8.06 (1H, s), 7.97 (1H, d, J=4.8 Hz), 7.51 (1H, d, J=4.8 Hz), 7.44˜7.33 (6H, m), 5.15 (1H, m), 1.29 (3H, d, J=7.2 Hz) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].O>C(Cl)Cl.N1C=CC=CC=1.C(OCC)(=O)C>[C:14]([C:11]1[N:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:3][C:4]=2[C:16]([F:19])([F:17])[F:18])=[CH:9][CH:10]=1)#[N:15]
Reactant: Cn1c(C#N)ccc1-c1ccc(N)cc1C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1c(C#N)ccc1-c1ccc(NS(C)(=O)=O)cc1C(F)(F)F
Reaction time: 16 h
Yield: 70.4 %

Procedure:
5-[4-amino-2-(trifluoromethyl)phenyl]-1-methyl-1H-pyrrole-2-carbonitrile (0.34 g, 1.3 mmol) was dissolved in CH2Cl2 (5 mL) and pyridine (0.2 mL). Methanesulfonyl chloride (90 μL, 1.2 mmol) was added and the mixture was stirred for 16 hours followed by the addition of water. The mixture was then diluted with ethyl acetate, the mixture was washed with water, 2N HCl, brine, dried over MgSO4, and concentrated. The crude product was purified via Isco chromatography (the Redisep® column, silica, gradient 5-50% ethyl acetate in hexane) to afford 0.29 g of N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-3-(trifluoromethyl)phenyl]-methanesulfonamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][C:15](O)=[O:16])=[CH:9][CH:8]=1.S(Cl)(Cl)=O.[CH3:26][NH2:27]>ClCCl.C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][C:15]([NH:27][CH3:26])=[O:16])=[CH:9][CH:8]=1
Reactant: O=C(O)C=Cc1ccc(OCc2ccc(F)c(F)c2)cc1
Reactant: CN
Solvent: ClCCl
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: CNC(=O)C=Cc1ccc(OCc2ccc(F)c(F)c2)cc1
Temperature: 45 °C
Yield: 26 %

Procedure:
500 mg (1.72 mmol) 3-[4-(3,4-difluoro-benzyloxy)-phenyl]-acrylic acid is suspended in 5 ml dichloromethane. 0.62 ml (8.6 mmol) thionyl chloride is added and the reaction mixture heated overnight to 45° C. Concentration leaves a yellowish tar which is dissolved again in 10 ml dichloromethane and treated with 1.1 ml of a 33% solution of methylamine in ethanol. After heating at 45° C. for 3 hours, the reaction mixture is filtered and the filtrate concentrated. Chromatography (silica gel, dichloromethane/methanol) yields 136 mg (26%) of a colorless solid. MS: m/e=304.1 (M++H).
Reaction SMILES: Br[C:2]1[S:3][C:4]([S:17]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)(=[O:19])=[O:18])=[CH:5][C:6]=1[C:7]1[S:11][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[N:9][C:8]=1[CH3:16].C([Li])CCC.O>C1COCC1>[CH3:16][C:8]1[N:9]=[C:10]([NH:12][C:13](=[O:15])[CH3:14])[S:11][C:7]=1[C:6]1[CH:5]=[C:4]([S:17]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)(=[O:19])=[O:18])[S:3][CH:2]=1
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)N3CCOCC3)sc2Br)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1nc(C)c(-c2csc(S(=O)(=O)N3CCOCC3)c2)s1
Temperature: -70 °C
Reaction time: 0.42 h
Yield: 64.5 %

Procedure:
N-{ 5-[2-bromo-5-(morpholin-4-ylsulfonyl)-3-thienyl]-4-methyl-1,3-thiazol-2-yl}acetamide (54 mg; 0.12 mmol; 1 eq) is dissolved in dry THF (5 ml) at −70° C. under an inert atmosphere. n-Butyllithium (0.16 ml; 1.6 M; 0.26 mmol; 2.20 eq) is added slowly and reaction stirred at −70° C. for 25 minutes before being hydrolyzed with water (0.3 ml). Crude material is warmed up to room temperature before being concentrated to dryness. Residue is then taken up with water (2 ml) and EtOAc (10 ml). The organic phases are decanted, dried over MgSO4, filtrated and evaporated. Crude material is purified by flash chromatography on silica gel using cyclohexane/EtOAc (10/90) as eluent, affording expected Compound (46) as an oil (30 mg; 67%).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]([NH:12][C:13]2[O:14][C:15]([C:18]3[N:19](C(OC(C)(C)C)=O)[C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:16][N:17]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:4])=[O:3].C(=O)([O-])[O-].[K+].[K+]>CO.CC(C)=O.CCCCCC>[NH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:26]=[C:18]1[C:15]1[O:14][C:13]([NH:12][C:8]2[CH:7]=[C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])[CH:11]=[CH:10][CH:9]=2)=[N:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2cnc(Nc3cccc(NS(C)(=O)=O)c3)o2)cc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCCCCC
Solvent: CC(C)=O
Product: CS(=O)(=O)Nc1cccc(Nc2ncc(-c3cc4ccccc4[nH]3)o2)c1
Yield: 63.3 %

Procedure:
To a stirred solution of tert-butyl 2-(2-((3-(methylsulfonamido) phenyl)amino)oxazol-5-yl)-1H-indole-1-carboxylate 24 (0.221 g, 0.472 mmol) in methanol (30 mL) was added potassium carbonate (0.652 g, 4.71 mmol) at room temperature. Reaction mixture was refluxed for 2 hours. After completion of the reaction (as judged by TLC) it was concentrated using rotavapour and the crude product was purified by MPLC column chromatography (Biotage; Acetone/hexane as an eluent) to provide N-(3-((5-(1H-indol-2-yl)oxazol-2-yl)amino)phenyl)methanesulfonamide 25 (0.11 g, 63% yield) as a solid. MS (ES) m/z 369 (M+H+).
Reaction SMILES: [N:1]1[C:9]2[CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5][C:4]=2[NH:3][CH:2]=1.CN(C=O)C.[H-].[Na+].[S:24](Cl)([C:27]1[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=1)(=[O:26])=[O:25]>O.C(Cl)Cl>[S:24]([N:3]1[C:4]2[CH2:5][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][CH2:8][C:9]=2[N:1]=[CH:2]1)([C:27]1[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=1)(=[O:26])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2nc[nH]c2C1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cnc3c2CN(C(=O)OC(C)(C)C)CC3)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 27.8 %

Procedure:
A flask was charged with tert-butyl 6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate (0.44 g, 2.0 mmol, WO2009158394, Example M-In-1) and DMF (10 mL). The mixture was cooled to about 0° C. and NaH (60% dispersion in mineral oil, 0.095 g, 2.4 mmol) was added. The mixture was stirred at about 0° C. for about 20 min followed by the addition of TsCl (0.41 g, 2.2 mmol). The resulting mixture was stirred at about 0° C. for about 90 min and then at about rt for about 3.5 h. The mixture was poured into DCM (40 mL) and water (20 mL) was added. The layers were separated and the organic solution was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 0 to 50% EtOAc in DCM to give tert-butyl 3-tosyl-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate (0.21 g, 28%): LC/MS (Table 2, Method n) Rt=2.53 min; MS m/z: 378 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=3)[C:12]([C:20]([OH:22])=O)=[CH:11]2)[C:4]=1[CH3:23].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.[F:49][CH:50]([F:53])[CH2:51][NH2:52]>C(Cl)Cl>[F:49][CH:50]([F:53])[CH2:51][NH:52][C:20]([C:12]1[C:13]2=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=[C:18]2[N:10]([CH2:9][C:5]2[C:4]([CH3:23])=[C:3]([O:2][CH3:1])[N:8]=[CH:7][N:6]=2)[CH:11]=1)=[O:22]
Reactant: COc1ncnc(Cn2cc(C(=O)O)c3ncc(C)cc32)c1C
Reactant: NCC(F)F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ncnc(Cn2cc(C(=O)NCC(F)F)c3ncc(C)cc32)c1C
Temperature: 25 °C
Yield: 16.7 %

Procedure:
See FIG. 24(a). 1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (100 mg, 0.32 mmol) was taken in a thermal reactor. DCM (3 mL) was added to get a suspension. Triethyl amine (0.089 mL, 0.64 mmol) was added followed by the addition of 1-Propanephosphonic acid cyclic anhydride (0.381 mL, 0.64 mmol). 2,2-difluoroethanamine (26.0 mg, 0.32 mmol) was added and stirred at RT for ON. After the completion of the reaction, reaction mixture was concentrated and dissolved in DCM:MeOH. This crude compound was subjected for reverse phase purification to obtain N-(2,2-difluoroethyl)-1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (20.00 mg, 16.64%) as a off white solid. ES+MS m/z: 376 (M−1). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.24 (s, 4 H ) 2.40 (s, 3 H ) 3.77-3.89 (m, 2 H ) 3.93 (s, 4 H) 5.65 (s, 2 H ) 7.77 (s, 1 H ) 8.20 (s, 1 H ) 8.40 (s, 1 H ) 8.36 (s, 1 H ) 8.91 (br. s., 1 H ).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>ClCCl>[O:10]=[C:8]1[NH:9][CH:3]([CH:2]=[O:1])[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C1CCCCC(CO)N1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=CC1CCCCC(=O)N1
Reaction time: 3 h
Yield: 36.8 %

Procedure:
750 mg of 7-hydroxymethyl-azepan-2-on (compound F1) are dissolved in 85 ml of dichloromethane under an atmosphere of dry nitrogen. Subsequently, 2.22 g of triacetoxy periodinane (Dess-Martin reagent) are added at room temperature and stirring is continued for further 3 hours. Thereafter, the suspension is evaporated to dryness to yield 2.65 g of crude material. The crude product is purified by chromatography (eluent gradient: cyclohexane/50-100 vol. % ethyl acetate) to afford 272 mg of the title compound as a colorless, waxy solid. ESI-MS: 140.1 (MH+). TLC: Rf=0.60 (dichloromethane/ethanol 10:1 parts by volume).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]([C:18]2[CH:27]=[C:26]3[C:21]([C:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][S:25]3)=[CH:20][CH:19]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:6][CH:5]=1.[OH-].[K+].C1COCC1.Cl>C(O)C.O>[CH3:28][C:22]1([CH3:29])[C:21]2[C:26](=[CH:27][C:18]([CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:11][O:10][C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:30])=[O:2])=[CH:9][CH:8]=3)=[CH:19][CH:20]=2)[S:25][CH2:24][CH2:23]1
Reactant: CCCCCC(COc1ccc(C(=O)OC)cc1)c1ccc2c(c1)SCCC2(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CCCCCC(COc1ccc(C(=O)O)cc1)c1ccc2c(c1)SCCC2(C)C
Temperature: 45 °C
Yield: 89 %

Procedure:
A solution of 4-[2-(4,4-dimethyl-thiochroman-7-yl)-heptyloxy]-benzoic acid methyl ester (0.715 g, 1.68 mmole) in 12 mL of ethanol was treated with a solution of potassium hydroxide (1.9 g) in 7.5 mL of water. THF (5 mL) was added and the mixture was heated at 45° C. for two hours, diluted with 30 mL of water and the pH adjusted to 2.0 with concentrated HCl. The mixture was extracted with three portions of 30 mL of ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give a pale yellow foam. The product was purified by trituration in pentane, to yield 0.617 g of 4-[2-(4,4-dimethyl-thiochroman-7-yl)-heptyloxy]-benzoic acid as an off-white solid. M.p.: 123.0-123.5° C.
Reaction SMILES: [Li].[CH3:2][Cu]C.[CH2:5]([CH:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]=[CH:9]1)[CH:6]=[CH2:7]>O1CCCC1>[CH3:2][C@H:9]1[C@H:8]([CH2:5][CH:6]=[CH2:7])[CH2:13][CH2:12][C:11](=[O:14])[CH2:10]1
Reactant: C[Cu]C
Reactant: C=CCC1C=CC(=O)CC1
Agent: [Li]
Solvent: C1CCOC1
Product: C=CC[C@@H]1CCC(=O)C[C@H]1C
Reaction time: 0.25 h
Yield: 55 %

Procedure:
To a 0° C. solution of 0.282 mole of dimethyl copper lithium in 200 ml. of tetrahydrofuran was slowly added a solution of 25.6 g. (0.188 mole) of 4-(2-propenyl)cyclohex-2-en-1-one in 50 ml. of tetrahydrofuran. The reaction was stirred 15 minutes and then quenched by addition to a 0° C. saturated solution (500 ml.) of ammonium chloride. The quenched reaction was extracted with 500 ml. ether. The ether extract was washed with 500 ml. saturated ammonium chloride, dried over magnesium sulfate and evaporated to an oil which was purified via distillation to yield 15.5 g. (55%) of the title compound.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH2:15])=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1.CC1(C)C(C)(C)OB([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O1CCOCC1>[F:14][C:10]1[CH:9]=[C:8]([C:7]2[N:6]=[C:5]([NH2:15])[CH:4]=[N:3][C:2]=2[C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Nc1cnc(Br)c(-c2cccc(F)c2)n1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Nc1cnc(-c2ccncc2)c(-c2cccc(F)c2)n1
Reaction time: 20 h
Yield: 60.2 %

Procedure:
An oven dried resealable Schlenk tube was charged with 5-bromo-6-(3-fluorophenyl)pyrazin-2-amine (Preparation 1, 0.3 g, 1.11 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine (459 mg, 2.23 mmol), dioxane (35 mL) and a 2M aqueous solution of cesium carbonate (3.3 mL, 6.66 mmol) were added. The Schienk tube was subjected to three cycles of evacuation-backfilling with argon, and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex [PdCl2dppf.DCM] (45 mg, 0.055 mmol) was added. After three new cycles of evacuation-backfilling with argon, the Schlenk tube was capped and placed in a 100° C. oil bath. After 20 h, the mixture was cooled, partitioned between water and ethyl acetate, the aqueous phase extracted twice with ethyl acetate the organic layers washed with brine, dried (MgSO4) and evaporated. Flash chromatography (dichloromethane/methanol 98:2 to dichloromethane/methanol 95:5) provided the title compound as a yellowish solid (178 mg, 60%)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][N:8]=2)[CH2:3][CH2:2]1.[N:16]#[C:17]Br.C(=O)(O)[O-].[Na+].[I-].[K+]>C(Cl)(Cl)Cl>[C:17]([N:1]1[CH2:2][CH2:3][CH:4]([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][N:8]=2)[CH2:5][CH2:6]1)#[N:16]
Reactant: N#CBr
Reactant: c1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: N#CN1CCC(c2noc3ccccc23)CC1
Temperature: 25 °C
Yield: 63 %

Procedure:
A suspension of 4.8 g of 3-(4-piperidyl)-1,2-benzisoxazole, 2.7 g of cyanogen bromide, 5.0 g of sodium bicarbonate and 3.0 g of potassium iodide in 100 ml of chloroform was heated under reflux overnight. The reaction was cooled to room temperature, filtered and concentrated in vacuo to give a solid. The benzisoxazole was purified on 120 g of silica gel, eluted with chloroform and recrystallized twice from acetone-hexane to give 3.4 g (62.3%) of product, mp, 115°-117°.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[CH2:19][C@H:20]2[CH2:24][CH2:23][CH2:22][N:21]2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)C.C(O)(=O)C.[OH-].[OH-].[Pd+2]>[NH2:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[CH2:19][C@H:20]2[CH2:24][CH2:23][CH2:22][N:21]2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1Cc1cccc2ccc(N(Cc3ccccc3)Cc3ccccc3)cc12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1Cc1cccc2ccc(N)cc12
Reaction time: 8 h
Yield: 84.1 %

Procedure:
A mixture of 7-dibenzylamino-1-(1-t-butoxycarbonyl-pyrrolidin-2-(R)-ylmethyl)-naphthalene (0.68 g, 1.34 mmol) and 20% palladium hydroxide on carbon (0.25 g) in ethanol (20 mL) and acetic acid (20 mL) was hydrogenated at 50 psi for 8 hours. Additional 20% palladium hydroxide on carbon (0.25 g) was added and hydrogenation was continued overnight. The catalyst (0.3 g) was added a third time and hydrogenation was continued 24 hours more. The reaction was filtered through celite and the pad was washed with ethanol. The filtrate was concentrated and the residue was taken up in ether. This organic phase was extracted with saturated aqueous sodium bicarbonate, water and brine, then it was dried and concentrated to give 0.368 g (84%) of the title compound as a tan foam. A sample recrystallized from ether/hexane as a light tan solid had mp 157°-158.5° C. Analysis calculated for C20H26N2O2 : C, 73.59; H, 8.03; N, 8.58. Found: C, 73.47; H, 7.93; N, 8.37.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:8][OH:9])[C@H:4]([CH2:5][CH2:6][CH3:7])[O:3]1.[Si:10](OS(C(F)(F)F)(=O)=O)([CH2:15][CH3:16])([CH2:13][CH3:14])[CH2:11][CH3:12].N1C(C)=CC(C)=CC=1C.[Si](O[C@H](CCC)[C@@H](C)C=O)(C(C)(C)C)(C)C>>[CH2:11]([Si:10]([CH2:15][CH3:16])([CH2:13][CH3:14])[O:3][C@@H:4]([CH2:5][CH2:6][CH3:7])[C@H:2]([CH3:1])[CH:8]=[O:9])[CH3:12]
Reactant: CCC[C@@H]1O[C@]1(C)CO
Reactant: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Agent: CCC[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C=O
Solvent: Cc1cc(C)nc(C)c1
Product: CCC[C@H](O[Si](CC)(CC)CC)[C@H](C)C=O

Procedure:
Epoxy alcohol 13, 1.4 eq TESOTf, and 1.5 eq of collidine were reacted as in the preparation of 16 to give 95%+yield (<20:1 de) of crude aldehyde 22 which was chromatographed (SiO2, 3% EtOAc/96% Hex/1% TEA) to give 85% of 22. 1H NMR (CDCl3, 500.135 MHz) δ:9.68 (1H, d, J=2.37 Hz), 3.89 (1H, q, J=5.03 Hz), 2.43 (1H, qdd, J=6.95, 5.03, 2.30 Hz), 1.5-1.2 (4H, m), 1.02 (3H, d, J=6.95 Hz), 0.89 (6H, t J=8.0 Hz), 0.85 (3H, t, J=7.14 Hz), and 0.54 (9H, q, J=7.80 Hz). 13C NMR (CDCl3, 90.55 MHz) δ:205.1, 73.3, 51.3, 37.2, 18.1, 14.1, 10.3, 6.4, and 5.1. IR (thin film): 2957 (s), 2938 (s), 2912 (s), 2877 (s), 1726 (s), 1459 (s), 1415 (w), 1379 (w), 1239 (m), 1155 (w), 1074 (s), 1038 (m), 1005 (w), and 741 (s) cm-1. high resolution MS (m/z): 215. 1467, calcd for C11H23O2Si 215.1467 (M-C2H5). [α]D =+14.7° (c=1.89, CH2Cl2). 1H NMR integration of δ 9.69 to δ 9.72 indicated a 90.3:9.7 ratio.