Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH2:9][CH2:10][CH2:11][N:12](C(OC(C)(C)C)=O)[CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:21].CC(O)C>[Pd].CCO>[ClH:21].[ClH:21].[F:1][C:2]1[C:7]([CH:8]2[CH2:9][CH2:10][CH2:11][NH:12][CH2:13]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1C=C(c2cccnc2F)CCC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CC(C)O
Product: Fc1ncccc1C1CCCNC1
Reaction time: 0.08 h

Procedure:
To a N2 purged round bottomed flask containing tert-butyl 5-(2-fluoropyridin-3-yl)-3,4-dihydropyridine-1(2H)-carboxylate (673 mg, 2.418 mmol) was added 10% Pd/C (50 mg, 0.470 mmol) and EtOH (15 mL). After stirring for 5 minutes, 5N HCl in iPrOH (4.0 mL, 20.00 mmol) was added and the flask capped with a balloon of H2. After 16 hours, LC-MS shows ˜30% conversion. The balloon was refilled. After a further 5 days, LC-MS shows complete consumption of starting material. The reaction was filtered through a celite cartridge and the cartridge rinsed with DCM:10% EtOH (50 mL). The filtrate was concentrated in vacuo to give 2-fluoro-3-(piperidin-3-yl)pyridine dihydrochloride as a yellow foam. The material was carried forward without further purification.
Reaction SMILES: [C:1]([O:7][CH2:8][CH:9]([CH2:14][O:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])OCOC)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:22]([O:25][C:26](=[O:28])[CH3:27])(=[O:24])C.B(F)(F)F.CCOCC>C(Cl)Cl>[C:1]([O:7][CH2:8][CH:9]([CH2:14][O:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[O:24][CH2:22][O:25][C:26](=[O:28])[CH3:27])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: COCOC(COC(=O)C(C)(C)C)COC(=O)C(C)(C)C
Reactant: CC(=O)OC(C)=O
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)OCOC(COC(=O)C(C)(C)C)COC(=O)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
50 g of 1,3-dipivaloyl-2-methoxymethyl glycerol, 150 ml of methylene chloride, and 17 ml of acetic anhydride was cooled to about -5° C. Then 0.3 ml of boron trifluoride etherate was added and the mixture was stirred for an additional 1 hr at about 0° C. then allowed to warm to 25° C. over an additional 1.5 hr. After this period, 100 ml saturated aqueous Na2Cl3 was added to the mixture followed by 100 ml CH2Cl2. After vigorous stirring for 5 min, the organic layer was separated and washed once with 100 ml H2O, once with aqueous NaCl, dried over anhydrous magnesium sulfate and concentrated in vacuo to afford 1,3-dipivaloyl-2-acetoxymethyl glycerol as a faintly colored oil.
Reaction SMILES: [OH:1][C:2]([C:10]1[CH:11]=[C:12]([O:16][Si](C(C)(C)C)(C)C)[CH:13]=[CH:14][CH:15]=1)([C:5]1[S:6][CH:7]=[CH:8][N:9]=1)[CH2:3][CH3:4].[N+](CCCC)(CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[OH:1][C:2]([C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1)([C:5]1[S:6][CH:7]=[CH:8][N:9]=1)[CH2:3][CH3:4]
Reactant: CCC(O)(c1cccc(O[Si](C)(C)C(C)(C)C)c1)c1nccs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCC(O)(c1cccc(O)c1)c1nccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
To a solution of compound from Step 2 (5.57 g, 15.96 mmol) in THF (40 mL) them was added n-Bu4NF 1M in THF (18 mL); the mixture was stirred at r.t. for 30 min., then H2O (10 mL) was added. The mixture was concentrated to a small volume, the residue extracted with EtOAc, the extract washed twice with brine, dried and evaporated to a residue which was chromatographed on silica gel, eluting with a 1:1 mixture of EtOAc and hexane, to afford the title product as a white solid (2.59 g) m.p. 145°-146° C.
Reaction SMILES: FC(F)(F)C(O)=O.CC(C)(OC([NH:14][CH2:15][CH2:16][S:17][CH2:18][C@@:19]([CH3:24])([C:21]([OH:23])=[O:22])[NH2:20])=O)C.[ClH:26]>>[ClH:26].[NH2:14][CH2:15][CH2:16][S:17][CH2:18][C@@:19]([CH3:24])([C:21]([OH:23])=[O:22])[NH2:20]
Reactant: CC(C)(C)OC(=O)NCCSC[C@](C)(N)C(=O)O
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: C[C@](N)(CSCCN)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product of Example-1D, S-[2-[[(1,1-dimethylethoxy)carbonyl]amino]ethyl]-2-methyl-L-cysteine trifluoroacetate, (5.5 g, 14.0 mmol) was dissolved in 1 N HCl (100 mL) and stirred at room temperature under nitrogen overnight. The solution was removed by freeze-drying to give the title S-(2-aminoethyl)-2-methyl-L-cysteine hydrochloride, 1H NMR (DMSO-d6/D2O) δ1.43 (s, 3H), 2.72 (m, 2H), 2.85 (d, 1 H), 2.95 (t, 2H), 3.07 (d, 1H). m/z [M+H+] 179.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:18])[N:9]2[CH3:19])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:26](I)([CH3:28])[CH3:27]>O>[CH:26]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:18])[N:9]2[CH3:19])=[CH:6][CH:7]=1)([CH3:28])[CH3:27]
Reactant: CN1C(=O)c2ccccc2CC1c1ccc(O)cc1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)Oc1ccc(C2Cc3ccccc3C(=O)N2C)cc1

Procedure:
To 20 ml of a solution containing 1.50 g of 3-(4-hydroxyphenyl)-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline, 0.86 g of potassium carbonate and 1.24 ml of isopropyl iodide were added and the resulting mixture was heated to reflux for 21 hours. After allowing the mixture to cool, water was added thereto and the resultant was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography [hexane/ethyl acetate (2/1)] to obtain 1.53 g of 3-(4-isopropyloxyphenyl)-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](O)([C:13]1[C:22]([OH:23])=[CH:21][C:16]3[O:17][CH2:18][CH2:19][O:20][C:15]=3[CH:14]=1)[C:5](=[O:12])[N:6]2[CH3:11].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([C:13]1[C:22]([OH:23])=[CH:21][C:16]3[O:17][CH2:18][CH2:19][O:20][C:15]=3[CH:14]=1)[C:5](=[O:12])[N:6]2[CH3:11]
Reactant: CN1C(=O)C(O)(c2cc3c(cc2O)OCCO3)c2c(Br)cccc21
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)C(c2cc3c(cc2O)OCCO3)c2c(Br)cccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.8 %

Procedure:
To a stirred solution of 4-bromo-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1-methyl-1,3-dihydro-2H-indol-2-one (61.0 g; 155 mmol) and triethylsilane (75.0 mL, 456 mmol) in dichloromethane (300 mL) was added trifluoroacetic acid (48 mL, 623 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 20 h and concentrated in vacuo. The residue was triturated in methanol and washed with diethyl ether to afford 4-bromo-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1-methyl-1,3-dihydro-2H-indol-2-one (57.0 g, 97%): 1H NMR (300 MHz, CDCl3) δ 7.31-7.17 (m, 3H), 6.87-6.83 (m, 1H), 6.62 (s, 1H), 6.17 (s, 1H), 4.97 (s, 1H), 4.22-4.08 (m, 4H), 3.18 (s, 3H); MS (ES+) m/z 376.1 (M+1), 378.1 (M+1).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][O:18][CH:19]([CH3:25])[C:20]([O:22]CC)=[O:21])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.CCCCCC>CO>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][O:18][CH:19]([CH3:25])[C:20]([OH:22])=[O:21])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(C)OCCc1ccc(-c2ccc(Cl)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CO
Product: CC(OCCc1ccc(-c2ccc(Cl)cc2)cc1)C(=O)O
Yield: 60.8 %

Procedure:
Potassium hydroxide (5.5 g.) was added to a solution of ethyl 2-{2-[4-(4-chlorophenyl)phenyl]-ethoxy}propionate (7.0 g.) in methanol (50 ml.), and the resultant solution was heated under reflux for 2 hours. The mixture was cooled and solvent removed by evaporation, the residue was mixed with water (50 ml.) and the solution obtained was extracted with ether (2×50 ml.) to remove non-acidic material. The aqueous phase was acidified with 4 N-hydrochloric acid to pH 2-3 and extracted with ethyl acetate (3×50 ml.). The extracts were washed with water, dried (MgSO4) and evaporated. The oil obtained, solidified on trituration with hexane to give 2-{2-[4-(4-chlorophenyl)phenyl]-ethoxy}propionic acid (3.9 g., 57%), m.p. 90°-92° C. (after recrystallisation from a mixture of hexane and toluene), molecular ion: M+ 304.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:23])[N:9]([CH2:11][CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=2)[CH:7]=1.C([Sn](CCCC)(CCCC)[C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)CCC>CN(C=O)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[N:31]1[CH:32]=[CH:33][CH:34]=[C:29]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8](=[O:23])[N:9]([CH2:11][CH2:12][C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[N:10]=3)[CH:7]=2)[CH:30]=1
Reactant: O=c1n(CCc2ccc3ccccc3n2)nc2ccc(Br)cn12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: CN(C)C=O
Product: O=c1n(CCc2ccc3ccccc3n2)nc2ccc(-c3cccnc3)cn12
Temperature: 135 °C
Yield: 33.2 %

Procedure:
In a 2 mL microwave vial were placed 3-4 (15 mg, 0.041 mmol), 3-(tributylstannyl)pyridine (16 mg, 0.045 mmol), and bis(tri-tert-butylphosphine)palladium (2 mg, 0.004 mmol) in anhydrous DMF (0.4 mL). The vial was sealed and the reaction was heated at 135° C. under microwave irradiation for 15 min. The reaction mixture was filtered, and the filtrate was directly purified by reversed phase HPLC to give 5.0 mg (35%) of 9-1. 1H NMR (500 MHz, DMSO-d6): δ 9.03 (s, 1H), 8.67 (d, J=5.0 Hz, 1H), 8.51 (d, J=8.4 Hz, 1H), 8.34 (d, J=8.0 Hz, 1H), 8.29 (s, 1H), 8.04 (d, J=8.1 Hz, 1H), 7.98 (d, J=8.5 Hz, 1H), 7.83 (t, J=7.6 Hz, 1H), 7.69-7.61 (m, 4H), 7.38 (d, J=9.8 Hz, 1H), 4.47 (t, J=6.9 Hz, 2H), 2.54 (t, J=6.9 Hz, 2H). HRMS (ES) 368.1502 (M+H) found, 368.1509 required.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[N:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH:21]1([CH2:24][C@H:25]([NH2:32])[C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)[CH2:23][CH2:22]1>>[CH:21]1([CH2:24][C@H:25]([NH:32][C:12]([C:10]2[CH:9]=[N:8][C:7]([N:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])[C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)[CH2:23][CH2:22]1
Reactant: O=C(O)c1cnc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: Cc1nc([C@@H](N)CC2CC2)no1
Product: Cc1nc([C@H](CC2CC2)NC(=O)c2cnc(N3CC(F)(F)C3)c(OCC3CC3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 15, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid (Example 8d, 100 mg, 0.35 mmol) and (S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (88.51 mg, 0.53 mmol) as starting materials, and isolated (12 mg, 7.8%) as white solid, LC-MS (UV peak area, ESI) 97.53%, 435.51 (M+H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH2:15][CH2:14][C:9]2([CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:8][CH:7]=1)=O)C.C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[CH2:13]1[C:9]2([CH2:14][CH2:15][C:6]([CH2:4][OH:3])=[CH:7][CH2:8]2)[CH2:10][CH2:11][CH2:12]1
Reactant: CCOC(=O)C1=CCC2(CCCC2)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OCC1=CCC2(CCCC2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
To a solution of spiro[4.5]dec-7-ene-8-carboxylic acid ethyl ester (2.8 g) obtained in Step 3 in tetrahydrofuran (40 mL) was added dropwise a toluene solution of diisobutylaluminum hydride (0.99 M, 41 mL) under argon atmosphere at −78° C., followed by stirring the reaction mixture at −78° C. for 1 hour. Then, after adding 2N aqueous hydrochloric acid solution and raising the temperature to room temperature, the reaction mixture was extracted with ethyl acetate twice. The organic layer was washed with saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:4) to give spiro[4.5]dec-7-en-8-yl-methanol (1.95 g).
Reaction SMILES: C[O:2][C:3](=[O:38])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]([CH:27]3[CH2:32][CH2:31][N:30]([CH:33]([CH3:37])[CH2:34][CH2:35][NH2:36])[CH2:29][CH2:28]3)[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[N:26])[CH:20]=3)=[CH:13][CH:12]=2)=[CH:6][CH:5]=1.[Cl:39][C:40]1[CH:48]=[CH:47][CH:46]=[C:45]([CH3:49])[C:41]=1[C:42](O)=[O:43]>>[Cl:39][C:40]1[CH:48]=[CH:47][CH:46]=[C:45]([CH3:49])[C:41]=1[C:42]([NH:36][CH2:35][CH2:34][CH:33]([N:30]1[CH2:29][CH2:28][CH:27]([N:17]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[N:26])[CH:20]=2)[C:14]2[CH:13]=[CH:12][C:11]([O:10][C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:2])=[O:38])=[CH:9][CH:8]=3)=[CH:16][CH:15]=2)[CH2:32][CH2:31]1)[CH3:37])=[O:43]
Reactant: Cc1cccc(Cl)c1C(=O)O
Reactant: COC(=O)c1ccc(Oc2ccc(N(Cc3cccc(C#N)c3)C3CCN(C(C)CCN)CC3)cc2)cc1
Product: Cc1cccc(Cl)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(Oc3ccc(C(=O)O)cc3)cc2)CC1
Yield: 40.3 %

Procedure:
Using general procedure E with 4-{4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(3-cyano-benzyl)-amino]-phenoxy}-benzoic acid methyl ester (see EXAMPLE 162) (80 mg, 0.16 mmol) and 2-chloro-6-methyl benzoic acid (29 mg, 0.17 mmol) followed by general procedure K afforded COMPOUND 163 as a white solid (42 mg, 41% over 2 steps). 1H NMR (CD3OD) δ 1.39 (d, 3H, J=6.6 Hz), 1.79-2.07 (m, 3H), 2.08-2.21 (m, 3H), 2.34 (s, 3H), 3.06-3.26 (m, 2H), 3.34-3.64 (m, 5H), 3.98-4.10 (m, 1H), 4.48 (s, 2H), 6.86 (d, 2H, J=8.4 Hz), 6.92 (s, 4H), 7.19-7.30 (m, 3H), 7.44-7.51 (m, 1H), 7.55-7.65 (m, 3H), 7.91 (d, 2H, J=8.4 Hz). 13C NMR (CD3OD) δ 14.26, 19.87, 28.36, 28.48, 32.53, 37.62, 51.11, 56.02, 61.37, 113.82, 117.65, 119.02, 120.25, 122.79, 128.23, 128.90, 130.28, 131.07, 131.75, 131.85, 131.92, 132.11, 133.03, 133.18, 138.02, 138.59, 143.83, 146.92, 149.84, 163.81, 171.08, 172.17. ES-MS m/z 651 (M+H). Anal. Calcd. for C38H39N4ClO4.0.5CH2Cl2.1.7H2O: C, 63.84; H, 6.04; N, 7.74; Cl, 9.79. Found. C, 63.70; H, 6.08; N, 7.64; Cl, 9.92.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[N:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[N:12]=2)[CH:8]=[CH:9][CH:10]=1)=[C:2]=[O:3].[CH:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH:36][C:37]([NH2:39])=[S:38])([CH3:29])[CH3:28]>>[CH:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH:36][C:37]([NH:39][C:2]([NH:1][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[N:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:25])([F:24])[F:26])=[CH:18][CH:17]=3)[N:12]=2)[CH:6]=1)=[O:3])=[S:38])([CH3:29])[CH3:28]
Reactant: CC(C)c1ccccc1NC(N)=S
Reactant: O=C=NCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1
Product: CC(C)c1ccccc1NC(=S)NC(=O)NCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1

Procedure:
The title compound was prepared as described in Example 75 using 3-(3-(isocyanatomethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (CB34) and 1-(2-isopropylphenyl)thiourea and isolated as an off-white solid (0.213 g, 47%).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.[F:6][C:7]1[CH:14]=[CH:13][C:10](CO)=[CH:9][C:8]=1[CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[F:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:1][Br:5])=[CH:9][C:8]=1[CH3:15]
Reactant: Cc1cc(CO)ccc1F
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(CBr)ccc1F
Reaction time: 1 h
Yield: 68 %

Procedure:
Carbon tetrabromide (3.08 g) was added portion wisely to a solution of 4-fluoro-3-methylbenzylalcohol (1.3 g) and triphenylphosphine (2.9 g) in methylene chloride (50 ml) and the mixture was stirred for 1 hour. The solution was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, dried over sodium sulfate, and evaporated in vacuo. The residue was triturated with hexane and the resulting precipitate was removed by filtration. The filtrate was evaporated in vacuo and the residue was purified by column chromatography on silica gel with hexane as eluent to give 4-fluoro-3-methylbenzylbromide (1.28 g) as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[CH:6]=1.[Li]CCCC.CN([CH:21]=[O:22])C.O>C1COCC1>[O:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]1[N:5]1[CH:6]=[C:2]([CH:21]=[O:22])[CH:3]=[N:4]1
Reactant: Brc1cnn(C2CCCCO2)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cnn(C2CCCCO2)c1
Reaction time: 0.75 h
Yield: 61 %

Procedure:
4-Bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (61 g, 0.264 mol) was dissolved in THF (400 mL). Then 1.6 M n-BuLi (181 mL) was added to the solution which was at −95° C. The reaction mixture was stirred over a period of 45 minutes at the same temperature. Then DMF (22.4 mL, 0.29 mol) was added (the same temperature was maintained). The mixture was allowed to heat up to room temperature before addition of water (100 mL). The organic layer was separated, and the aqueous phase was extracted with ether (3×50 mL). The combined organic extracts were dried over Na2SO4, filtered and evaporated. The residue was purified by chromatography (EtOAc/hexane, 1:4) to afford 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carbaldehyde (29 g, 57%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].[CH3:14][NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:14][N:15]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24])[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6]
Reactant: CNCc1ccc(Cl)cc1Cl
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(Cc1ccc(Cl)cc1Cl)c1cc(C(=O)O)ccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 14 h
Yield: 44.3 %

Procedure:
A solution of 10 ml N,N-dimethylformamide containing 3-fluoro-4-nitrobenzoic acid (1.00 g), N-methyl-2,4-dichlorobenzylamine (1.54 g) and sodium carbonate (1.15 g) was stirred at 100° C. for 14 hours. The reaction mixture was extracted using water and ethyl acetate with stirring. The organic layer was separated and concentrated, and then methanol was added to the resulting residue. After removal of an insoluble material, the solvent was evaporated. The resulting residue was purified by silica-gel column chromatography to give 0.85 g of 3-(N-methyl-2,4-dichlorobenzylamino)-4-nitrobenzoic acid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][CH2:4][O:3]1.[CH3:9][C:10](=[CH2:14])[CH2:11][CH2:12]O>CCCCCC>[CH3:14][C:10](=[CH2:9])[CH2:11][CH2:12][O:1][CH:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][CH2:4][O:3]1
Reactant: CC1CCOC(O)C1
Reactant: C=C(C)CCO
Solvent: CCCCCC
Product: C=C(C)CCOC1CC(C)CCO1
Temperature: 60 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
A 300-ml three-necked flask equipped with condensor, stirrer and thermometer was charged with 70 g (0.60 mole) of 2-hydroxy-4-methyltetrahydropyran, 52.46 g (0.61 mole) of 3-methyl-3-buten-1-ol, 150 ml of hexane and 3 g of active clay, and the mixture was stirred at 60° C. for 1 hour. Thereafter, the reaction mixture was analyzed by gas chromatography. The chromatogram showed no peak for 2-hydroxy-4-methyltetrahydropyran but showed a new peak. The active clay was filtered off from the reaction mixture, then, the hexane was distilled off and the residue was distilled under reduced pressure to give 105 g (98% yield) of tetrahydro-2-(3-methyl-3-butenoxy)-4-methyl-2H-pyran as a fraction boiling at 89.5°-90.0° C./10 mm Hg. A nuclear magnetic resonance (NMR) spectrum (in CDCl3) and an infrared absorption spectrum (liquid film-NaCl method) each obtained with the above product are shown in FIG. 1 and FIG. 2, respectively. The NMR spectrum suggested this product was a mixture of 70% of ##STR16## and 30% of ##STR17## Field desorption ionization (FD) mass spectrometry of this product gave M+ =184.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[OH-].[Na+].[CH3:8][O:9][CH2:10][CH2:11][NH2:12]>ClCCl.O>[Cl:1][CH2:2][C:3]([NH:12][CH2:11][CH2:10][O:9][CH3:8])=[O:4]
Reactant: COCCN
Reactant: O=C(Cl)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COCCNC(=O)CCl
Temperature: 0 °C
Reaction time: 8 h

Procedure:
In a three-necked 2L round bottom flask fitted with two 500 mL addition funnels, containing 56.4 g (39.8 mL, 0.50 mole) chloroacetyl chloride in 400 mL dichloromethane and 20 g (0.50 mole) sodium hydroxide in 400 mL water, respectively, and a water-oooled condenser, was placed 35.7 g (41.3 mL, 0.48 mole) 2-methoxyethylamine, 100 mL water, 100 mL dichloro-methane. The reaction vessel was cooled to 0° C. by a salt-ice bath. The organic and aqueous solutions were allowed to add slowly, ~0.25mL per minute, to the reaction mixture. During the addition the pH of the water phase of the reaction was monitored and the rate of addition of the alkali solution adjusted so as to maintain pH=12. When the addition was complete, the mixture was allowed to warm to room temperature and stir overnight. The organic layer was removed by siphon and dried with magnesium sulfate for four hours. The mixture was filtered through #4 filter paper on a large Buchner funnel and the sulfate washed with 2×100 mL fresh dichloromethane. The combined filtrates were then placed in 2L round bottomed flask and the mixture distilled at 1 torr. Fractions collected from 55° C. to 60° C. were combined and analyzed by NMR. Yield 31.1 g (43% based on starting 2-methoxyethylamine). TLC (silica on glass, 2% methanol in dichloromethane) Rf =0.40. 1H(δ,CDCl,) 3.28(s,3H), 3.40(m,4H), 3.97(s,2H), 6.92(br, 1H). 13C{1H} (δ, CDCl3) 39.27, 42.32, 58.60, 70.54, 166.22.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[CH:15]=[C:14]([O:17][CH2:18][CH2:19][CH2:20][C:21](OCC)=[O:22])[CH:13]=[CH:12]2)(=[O:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[OH:22][CH2:21][CH2:20][CH2:19][CH2:18][O:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[CH:9][CH:8]=[C:7]2[CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])=[CH:12][CH:13]=1
Reactant: CCOC(=O)CCCOc1ccc2cccc(CCNC(C)=O)c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(=O)NCCc1cccc2ccc(OCCCCO)cc12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In a 250 ml round-bottomed flask, the ester obtained in Step A (0.009 mol) is dissolved in 100 ml of anhydrous ether. 0.009 mol of lithium aluminium hydride is added in portions, and the reaction mixture is stirred for 6 hours at room temperature. The reaction mixture is then hydrolysed with a few drops of 1M NaOH, and the precipitate that forms is filtered off. The filtrate is dried over MgSO4 and evaporated under reduced pressure. The resulting residue is precipitated from an Et2O/petroleum ether mixture (1/1), suctioned off and recrystallised. White solid.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(N(CC)CC)C>ClCCl>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([S:15]([CH3:14])(=[O:17])=[O:16])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(S(C)(=O)=O)CC1

Procedure:
N—BOC-piperazine and methanesulfonyl chloride were reacted together in dichloromethane and triethylamine to yield 4-methanesulfonyl-piperazine-1-carboxylic acid tert-butyl ester. Cleavage of the BOC protecting group using HCl (2M) in dichloromethane yielded 1-methanesulfonyl-piperazine. HCl salt.
Reaction SMILES: C([Li])CCC.[CH:6](=[O:15])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23]>>[F:16][C:17]1[C:18]([F:23])=[CH:19][CH:20]=[CH:21][C:22]=1[CH:6]([OH:15])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCC=O
Reactant: Fc1ccccc1F
Agent: [Li]CCCC
Product: CCCCCCCCC(O)c1cccc(F)c1F

Procedure:
Quantities: n-butyllithium (50 cm3, 10.0M in hexanes, 0.5 mol), nonanal (71 g, 0.5 mol) and 1,2-difluorobenzene (57 g, 0.5 mol). The experimental procedure was as described in Example 16.