Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[CH2:20]([C:24]1[CH:29]=[CH:28][C:27]([CH:30]([CH3:34])[C:31](Cl)=[O:32])=[CH:26][CH:25]=1)[CH:21]([CH3:23])[CH3:22]>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:31](=[O:32])[CH:30]([C:27]3[CH:28]=[CH:29][C:24]([CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:25][CH:26]=3)[CH3:34])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Reactant: CC(C)Cc1ccc(C(C)C(=O)Cl)cc1
Product: CC(C)Cc1ccc(C(C)C(=O)NCCCCn2cnc3c(N)nc4ccccc4c32)cc1

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and 4-isobutyl-α-methylphenylacetyl chloride were combined to provide N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-(4-isobutylphenyl)propanamide as a white powder, m.p. 172.0-173.0° C. 1H NMR (300 MHz, DMSO-d6) δ 8.14 (s, 1H), 8.01 (d, J=7.6 Hz, 1H), 7.90 (t, J=5.6 Hz, 1H), 7.63 (dd, J=8.1, 1.0 Hz, 1H), 7.44 (dt, J=7.0, 1.0 Hz, 1H), 7.25 (dt, J=7.0 Hz, 1H), 7.14 (d, J=8.0 Hz, 2H), 6.97 (d, J=8.0 Hz, 2H), 6.58 (broad s, 2H), 4.55 (t, J=7.0 Hz, 2H), 3.47 (q, J=7.1 Hz, 1H), 3.06 (m, 2H), 2.34 (d, J=7.11 Hz, 2H), 1.80-1.69 (m, 3H), 1.44 (m, 2H), 1.24 (d, J=7.0 Hz, 3H), 0.82 (d, J=6.6 Hz, 6H); MS (EI) m/e 443.2687 (443.2685 calcd for C27H33N5O).
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:26][C:27]1[CH:28]=[C:29]([S:34]([NH2:37])(=[O:36])=[O:35])[CH:30]=[CH:31][C:32]=1[CH3:33]>>[CH3:33][C:32]1[CH:31]=[CH:30][C:29]([S:34](=[O:36])(=[O:35])[NH2:37])=[CH:28][C:27]=1[NH:26][C:12]([C:11]1[CH:10]=[N:9][N:8]2[C:3]([CH:2]([F:1])[F:25])=[CH:4][C:5]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=3)=[N:6][C:7]=12)=[O:14]
Reactant: Cc1ccc(S(N)(=O)=O)cc1N
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Cc1ccc(S(N)(=O)=O)cc1NC(=O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-amino-4-methyl-benzenesulfonamide [CAS-No. 6274-28-8; commercially available] according to general procedure II. Light brown solid. MS (ISP) 524.0 [(M−H−]; mp 293° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1)[O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:16]=2[CH3:24])=[CH:11][CH:10]=1)[CH:2]=[CH2:3].[F:32][C:33]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:34]=1[CH2:35]Br>>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1)[O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]([CH2:35][C:34]2[CH:37]=[CH:38][C:39]([F:41])=[CH:40][C:33]=2[F:32])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:16]=2[CH3:24])=[CH:25][CH:26]=1)[CH:2]=[CH2:3]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: C=CCOc1cc(OC)cc(Oc2ccc(CNc3cccc([N+](=O)[O-])c3C)cc2)c1
Product: C=CCOc1cc(OC)cc(Oc2ccc(CN(Cc3ccc(F)cc3F)c3cccc([N+](=O)[O-])c3C)cc2)c1

Procedure:
The product from Example 90C and 2,4-difluorobenzyl bromide were processed as described in Example 6B to provide the title compound. MS (APCI+) m/z 547 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[N:5]=1)(=[O:3])[CH3:2].Cl.S(Cl)([Cl:15])(=O)=O>O1CCOCC1>[Cl:10][C:6]1[N:5]=[C:4]([C:1]([CH2:2][Cl:15])=[O:3])[CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)c1cccc(Cl)n1
Reactant: O=S(=O)(Cl)Cl
Agent: Cl
Solvent: C1COCCO1
Product: O=C(CCl)c1cccc(Cl)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-acetyl-6-chloropyridine (7.48 g) in 1,4-dioxane (112 ml) was added 4N hydrogen chloride in 1,4-dioxane (12.6 ml). To the solution, sulfuryl chloride (13.51 ml) was added dropwise at 30° C. After stirring for 0.5 hour, ice water (150 ml) was added to the solution and the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of n-hexane and toluene (1:1) as an eluent to give chloromethyl 6-chloro-2-pyridyl ketone (7.05 g) as a powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2Br)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(OC)[C:21](=[O:30])[C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[NH2:29].C([Li])CCC.O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[C:21]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[NH2:29])=[O:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CON(C)C(=O)c1cc(Cl)ccc1N
Reactant: CC(C)(C)OC(=O)N1CCc2c(Br)cccc2C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2c(cccc2C(=O)c2cc(Cl)ccc2N)C1
Temperature: -78 °C
Yield: 23.3 %

Procedure:
In tetrahydrofuran (15 ml) were dissolved N-tert-butoxycarbonyl-5-bromo-1,2,3,4-tetrahydroisoquinoline (0.9 g) and N-methyl-N-methyloxy-2-amino-5-chlorobenzamide (0.68 g). The solution was cooled to −78° C., to which was added dropwise, while stirring, n-butyl lithium (1.6 mol, hexane solution) (9 ml) over 30 minutes. To the reaction mixture was added water (50 ml) to decompose, followed by extraction with ethyl acetate (80 ml). The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by means of a silica gel column chromatography to give 2-(N-tert-butoxycarbonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)carbonyl-4-chloro-aniline (0.26 g) as a yellow crystalline product. m.p.: 159-160° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:15][CH2:16][C:17]2[CH:26]=[CH:25][C:20]([C:21](OC)=[O:22])=[CH:19][CH:18]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[CH2:28]([CH2:30][NH2:31])[OH:29]>>[OH:29][CH2:28][CH2:30][NH:31][C:21](=[O:22])[C:20]1[CH:19]=[CH:18][C:17]([CH2:16][CH2:15][C:10]2[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:26][CH:25]=1
Reactant: NCCO
Reactant: COC(=O)c1ccc(CCc2ncccc2OCc2ccccc2)cc1
Solvent: O
Product: O=C(NCCO)c1ccc(CCc2ncccc2OCc2ccccc2)cc1
Temperature: 160 °C
Yield: 29 %

Procedure:
Methyl 4-[2-(3-benzyloxy-2-pyridyl)ethyl]benzoate (0.20 g, 0.576 mmol) was dissolved in ethanolamine (3 ml) and heated to 160° C. under argon for 2 hours. Water was added (3 ml) and the aqueous layers were extracted with ethyl acetate and the organic phase was dried (MgSO4) and evaporated. The residue was recrystallised from EtOAc/hexane and washed with ether to give the title product (0.064 g, 29%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH:14]([O:30][CH:31]([CH3:33])[CH3:32])[C:15]([N:17]2[CH:21]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:20][O:19][C:18]2=[O:29])=[O:16])[CH:8]=1)(=O)=O.[CH2:36]([OH:39])[C:37]#[CH:38].C(N(CC)CC)C>CN(C)C=O.[Cu](I)I.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:22]([CH:21]1[CH2:20][O:19][C:18](=[O:29])[N:17]1[C:15](=[O:16])[CH:14]([O:30][CH:31]([CH3:32])[CH3:33])[CH2:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:38]#[C:37][CH2:36][OH:39])[CH:8]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)OC(Cc1cccc(OS(=O)(=O)C(F)(F)F)c1)C(=O)N1C(=O)OCC1Cc1ccccc1
Reactant: C#CCO
Agent: I[Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)OC(Cc1cccc(C#CCO)c1)C(=O)N1C(=O)OCC1Cc1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
390 mg of 3-[3-(4-Benzyl-2-(oxo)-oxazolidin-3-yl)-2-isopropoxy-3-oxo-propyl]-phenyl trifluoromethanesulfonate was dissolved in 2 ml of N,N-dimethylformamide, 85 mg of propargyl alcohol, 8 mg of copper iodide, 45 mg of tetrakis (triphenylphosphine) palladium and 0.3 ml of triethylamine were added in succession, and the mixture was stirred overnight at 50° C. under a nitrogen atmosphere. The reaction solution was filtered through silica gel, and the filtrate was dissolved in ethyl acetate, washed with water, 1N hydrochloric acid and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography, to give 207 mg of the title compound as a colorless oil in the 3:2 hexane-ethyl acetate fraction.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][CH2:8][N:9]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]2[CH:16]=[C:17]([NH2:20])[CH:18]=[CH:19][C:10]1=2.CN(CCN1C2C(=CC=C([NH:44][C:45]([C:47]3[S:48][CH:49]=[CH:50][CH:51]=3)=N)C=2)CCC1)C(=O)OC1C=CC=CC=1>C(O)C.C([O-])(O)=O.[Na+]>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][CH2:8][N:9]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]2[CH:16]=[C:17]([NH:20][C:45]([C:47]3[S:48][CH:49]=[CH:50][CH:51]=3)=[NH:44])[CH:18]=[CH:19][C:10]1=2
Reactant: CN(CCN1CCCc2ccc(NC(=N)c3cccs3)cc21)C(=O)Oc1ccccc1
Reactant: CN1CCCC1CCN1CCCCc2cc(N)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CN1CCCC1CCN1CCCCc2cc(NC(=N)c3cccs3)ccc21
Temperature: 25 °C
Reaction time: 17 h
Yield: 74.6 %

Procedure:
A solution of 4 (170 mg, 0.62 mmol) in dry ethanol (15 mL) was treated with 5 (0.355 g, 1.24 mmol) and stirred for overnight (17 h) at room temperature. The reaction mixture was diluted with saturated NaHCO3 solution (100 mL) and extracted with CH2Cl2 (2×50 mL). The combined organic fractions were washed with brine (50 mL), dried (Na2SO4) and concentrated. The crude product was purified by dry column chromatography (MeOH:CH2Cl2, 2:98 followed by 2 N NH3 in MeOH:CH2Cl2 3:97) to give compound 45 (177 mg, 74%) as a yellow solid. 1H-NMR (DMSO-d6) δ: 1.38-1.69 (m, 8H), 1.83-1.89 (m, 2H), 2.02-2.12 (m, 2H), 2.19 (s, 3H), 2.65-2.68 (m, 2H), 2.80-3.12 (m, 5H), 6.32 (brs, 2H), 6.62-6.64 (m, 2H), 6.85-6.88 (d, 1H, J=8.9 Hz), 7.06-7.09 (t, 1H, J=3.8 Hz), 7.56-7.58 (d, 1H, J=5.0 Hz), 7.69-7.71 (d, 1H, J=3.6 Hz); ESI-MS (m/z, %): 383 (MH+, 33), 192 (100), 142 (51). ESI-HRMS calculated for C22H30N4S (MH+), calculated: 383.2253; observed: 383.2263; HPLC-purity: 93.49% by area.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:4]([CH3:12])[N:3]=1.[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][O:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:4]([CH3:12])[N:3]=1
Reactant: CN(C)CCO
Reactant: CCOC(=O)c1cc(O)nn1C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(OCCN(C)C)nn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.5 %

Procedure:
To a stirred solution of ethyl 3-hydroxy-1-methyl-1H-pyrazole-5-carboxylate (10 g, 58.8 mmol), 2-(dimethylamino)ethanol (5.76 g, 64.7 mmol) and PPh3 (21.6 g, 82.3 mmol) in anhydrous THF (200 mL) was added dropwise DIAD (16.6 g, 82.3 mmol) at 0° C. After the addition, the reaction mixture was stirred at rt overnight. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (CH2Cl2/MeOH 30:1) to give the title compound (5.6 g, 40% yield) as a brown oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:17][C:6]2=[C:7]([C:12]3[CH:16]=[CH:15][NH:14][N:13]=3)[S:8][C:9]([S:10][CH3:11])=[C:5]2[C:4](=[O:18])[CH2:3]1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl.C1COCC1.CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][C:2]1([CH3:19])[CH2:17][C:6]2=[C:7]([C:12]3[CH:16]=[CH:15][N:14]([S:21]([CH3:20])(=[O:23])=[O:22])[N:13]=3)[S:8][C:9]([S:10][CH3:11])=[C:5]2[C:4](=[O:18])[CH2:3]1
Reactant: CSc1sc(-c2cc[nH]n2)c2c1C(=O)CC(C)(C)C2
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CSc1sc(-c2ccn(S(C)(=O)=O)n2)c2c1C(=O)CC(C)(C)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
To a solution of 6,6-dimethyl-3-methylthio-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (70 mg, 0.24 mmol) in CH2Cl2:THF (5:1, 6 mL), was added methanesulphonyl chloride (36 μL, 0.48 mmol) and 4-dimethylaminopyridine (58 mg, 0.48 mmol). The mixture was stirred at room temperature overnight then diluted with CH2Cl2 (10 mL) and washed with water (2×10 mL). The organic layer was separated, dried (Na2SO1) and evaporated. The residue was chromatographed on silica gel, eluting with CH2Cl2:MeOH (95:5), to give the title compound (38 mg, 43%) as a pale yellow solid. mp 193-195° C. Found: C, 47.72; H, 4,71; N, 7.16%. C15H18N2S3O3.0.3 (H2O) requires: C, 47.93, H, 4.99; N, 7.45%. 1HNMR (360 Hz, d6-DMSO) δ 1.02 (6H, s), 2.41 (2H, s), 2.64 (3H, s), 2.90 (2H, s), 3.61 (3H, s), 6.91 (1H, d, J=2.8 Hz). MS (ES+) 371 (M+1).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][C:8]=1[CH:9]=[N:10]O>C1C=CC=CC=1>[CH3:5][O:6][C:7]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][C:8]=1[C:9]#[N:10]
Reactant: COc1ccc(Oc2ccccc2)cc1C=NO
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: COc1ccc(Oc2ccccc2)cc1C#N

Procedure:
Thionyl chloride (11.9 ml, 163 mmol) was added under a nitrogen atmosphere to a suspension of 2-methoxy-5-phenoxybenzaldehyde oxime (3.96 g, 16.3 mmol) in 75 ml of benzene. There was a slight exotherm and the mixture turned yellow. The reaction was heated to reflux temperature over 1 hour and at reflux temperature for an additional hour. The solvent and excess thionyl chloride were removed under reduced pressure to give 2-methoxy-5-phenoxybenzonitrile as a light tan crystalline solid (3.66 g, 100% ), mp 88°-89° C.
Reaction SMILES: [NH2:1][C@H:2]([CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=1)[CH2:3][N:4]([C@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]([NH:12][CH3:13])=[O:11])[C:5](=[O:8])[CH2:6]Cl.C(=O)([O-])O.[Na+].O>CO>[CH3:13][NH:12][C:10](=[O:11])[C@H:9]([N:4]1[CH2:3][C@@H:2]([CH2:21][C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)[NH:1][CH2:6][C:5]1=[O:8])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C[C@H](N)Cc1ccc2ccccc2c1)C(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNC(=O)[C@@H](Cc1ccccc1)N1C[C@@H](Cc2ccc3ccccc3c2)NCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
(2R)-2-(N-((2R)-2-Amino-3-(2-naphthyl)propyl)-N-chloroacetyl-amino)-N-methyl-3-phenylpropionamide (0.69 g, 1.58 mmol) was dissolved in methanol (14 ml) and sodium hydrogen carbonate (0.40 g, 4.73 mmol) and water (7 ml) were added. The mixture was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was dissolved in a mixture of ethyl acetate (30 ml) and saturated aqueous sodium hydrogen carbonate (20 ml). The mixture was extracted with ethyl acetate (4×20 ml). The combined organic phases were dried (magnesium sulfate) and the solvent was removed in vacuo. The residue was chromatographed on silica (2×20 cm) using methylene chloride/methanol/25% aqueous ammonia (100:10:1) to afford 0.19 g of (2R)-N-methyl-2-((5R)-5-((2-naphthyl)methyl)-2-oxopiperazin-1-yl)-3-phenylpropionamide
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:12][C:13](=[O:15])[CH3:14])([CH3:11])[CH3:10])=[CH:5][CH:4]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[CH3:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:25]2[CH2:26][CH2:27][N:22]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=3)[CH2:23][CH2:24]2)=[CH:4][CH:5]=1)[CH3:11]
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: CC(=O)NC(C)(C)c1ccc(CCl)cc1
Product: CC(=O)NC(C)(C)c1ccc(CN2CCN(c3ccccn3)CC2)cc1

Procedure:
By similar reaction and treatment to that in Example 1(5) using N-(1-(4-chloromethylphenyl)-1-methylethyl)acetamide obtained in Example 95(4) instead of N-(4-chloromethylphenylmethyl)acetamide and 1-(2-pyridyl)piperazine instead of phenylpiperazine, the title compound was obtained as white crystals, m.p.=129-130° C.
Reaction SMILES: [C:1]([CH:4]=[N:5][C:6]1[C:7](=[CH:11][CH:12]=[C:13]([Cl:15])[CH:14]=1)[C:8]([OH:10])=[O:9])([OH:3])=[O:2].S(=O)(=O)(O)O.[CH2:21](O)[CH3:22]>>[C:1]([CH:4]=[N:5][C:6]1[C:7](=[CH:11][CH:12]=[C:13]([Cl:15])[CH:14]=1)[C:8]([OH:10])=[O:9])([O:3][CH2:21][CH3:22])=[O:2]
Reactant: O=C(O)C=Nc1cc(Cl)ccc1C(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C=Nc1cc(Cl)ccc1C(=O)O
Reaction time: 10 h
Yield: 67.7 %

Procedure:
74.5 g (324.8 mmol) of N-carboxymethylene-4-chloroanthranilic acid are suspended in 1660 g of ethanol, 2.9 g (2.96 mmol) of concentrated sulfuric acid are added and the mixture is heated at the boiling point for 10 hours. After a reaction time of 5 hours, the same amount of sulfuric acid is again added. After 10 hours, the ethanol is distilled off and the product which precipitates out is filtered off in the cold and washed with cold ethanol. 55.5 g (0.22 mol, 73%) of N-carboethoxymethylene-4-chloro-anthranilic acid are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][Si](C(C)(C)C)(C)C)[CH2:14][C@H:13]([O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]([O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H](OC(=O)c2ccccc2)CN(C(=O)OCc2ccccc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O[C@H]1C[C@@H](O)CN(C(=O)OCc2ccccc2)C1)c1ccccc1
Temperature: 25 °C
Yield: 95.7 %

Procedure:
To a solution of 2.3 g (5.0 mmol) (3S,5R)-3-benzoyloxy-5-(tert-butyl-dimethyl-silanyloxy)-piperidine-1-carboxylic acid benzyl ester in 20 ml dry THF were added 5.5 ml (5.5 mmol) of a 1M solution of tetrabutyl ammoniumfluoride in THF at 0° C. After completed addition, the mixture was allowed to warm to room temperature over 30 min. Addition of water was followed by extraction with three portions of tert-butyl methyl ether. The combined organic extracts were dried over sodium sulfate. Kugelrohr distillation gave 1.7 g (95%) of the title compound as a light yellow oil.
Reaction SMILES: [C:1]1(=[O:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:10](Cl)[C:11](=[CH2:13])[CH3:12]>>[CH2:12]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:1]1=[O:9])[C:11](=[CH2:10])[CH3:13]
Reactant: O=C1CCCCCCC1
Reactant: C=C(C)CCl
Product: C=C(C)CC1CCCCCCC1=O

Procedure:
2-Methallylcyclooctanone was prepared starting from cyclooctanone and methallyl chloride, analogously as described in example 1 in the allylation section.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[N:32]1([CH2:38][C:39]([NH:41][CH:42]([CH3:44])[CH3:43])=[O:40])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:29])([F:31])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([N:35]3[CH2:34][CH2:33][N:32]([CH2:38][C:39]([NH:41][CH:42]([CH3:44])[CH3:43])=[O:40])[CH2:37][CH2:36]3)=[O:23])=[CH:17][C:9]1=2
Reactant: CC(C)NC(=O)CN1CCNCC1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: CC(C)NC(=O)CN1CCN(C(=O)c2cccc(-c3cnc4c(c3)N(Cc3cc(Cl)ccc3C(F)(F)F)CCN4)c2)CC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 2-piperazinyl-N-isopropylacetamide as in General Procedure 10 to give the title compound. LCMS: m/z=615.01 (M+H+); retention time=0.61 minutes.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3].[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.O>[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:1][CH:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3]
Reactant: Oc1ccccc1F
Reactant: COC(=O)c1ccc(C(C)O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(C(C)Oc2ccccc2F)cc1
Temperature: 20 °C
Reaction time: 12 h
Yield: 32.8 %

Procedure:
To a solution of methyl 4-(1-hydroxyethyl)benzoate (0.9 g, 5 mmol), 2-fluorophenol (627 mg, 5.6 mmol), triphenylphosphine (2.2 g, 8.4 mmol) in tetrahydrofuran (30 mL) was added diisopropyl azodicarboxylate (1.7 g, 8.4 mmol) at 0° C. The mixture was stirred at 20° C. for 12 hours. Water (15 mL) was added to the mixture and then extracted with ethyl acetate (35 mL×3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated in vacuo and purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1) to give methyl 4-(1-(2-fluorophenoxy)ethyl)benzoate (450 mg, 33%).
Reaction SMILES: Br[CH:2]1[CH2:6][N:5]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:4][C:3]1=[O:17].[C:18](=[S:21])([NH2:20])[CH3:19]>CN(C)C=O.C(OCC)(=O)C>[CH3:19][C:18]1[S:21][CH:2]2[CH2:6][N:5]([S:7]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)(=[O:9])=[O:8])[CH2:4][C:3]2([OH:17])[N:20]=1
Reactant: CC(N)=S
Reactant: Cc1ccc(S(=O)(=O)N2CC(=O)C(Br)C2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1=NC2(O)CN(S(=O)(=O)c3ccc(C)cc3)CC2S1
Temperature: 50 °C

Procedure:
To 4-bromo-1-[(4-methylphenyl)sulfonyl]pyrrolidin-3-one (159 mg) (W.-J Kim, et al., Heterocycles, 1995, 41, 1389-1398) in 2 mL of N,N-dimethylformamide was added ethanethioamide (38 mg) and the reaction mixture heated to 50° C. for 2 h. The mixture was cooled to ambient temperature and diluted with a mixture of ethyl acetate/saturated aqueous sodium bicarbonate solution (1:1, 20 mL). The layers were separated and the aqueous phase extracted with ethyl acetate (3×10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, evaporated in vacuo The product was used without further purification. LC/MS 313.1 (M+1).
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH:12]2[CH2:15][N:14]([CH3:16])[CH2:13]2)=[O:11])=[CH:6][CH:5]=1.[CH2:17](Cl)Cl>>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH:12]2[CH2:17][CH2:13][N:14]([CH3:16])[CH2:15]2)[OH:11])=[CH:8][CH:9]=1
Reactant: ClCCl
Reactant: CN1CC(C(=O)c2ccc(Br)cc2)C1
Agent: [BH4-]
Agent: [Na+]
Product: CN1CCC(C(O)c2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
Add sodium tetrahydroborate (0.36 g, 9.52 mmol) in portions to a solution of (4-bromo-phenyl)-(1-methyl-azetidin-3-yl)-methanone (0.64 g, 2.38 mmol) in CH2Cl2 at 0° C. Stir the mixture at RT overnight and quench with water. Adjust the aqueous to pH=10 by using 1 N NaOH and extract with ethylacetate (2×150 mL). Dry the combined organic layers over Na2SO4, filter, and concentrate. Purify the crude material by flash chromatography, collecting all the fractions as the product does not show by UV. Elute with 10% MeOH (2 N NH3)/CH2Cl2 to give 0.22 g (34%) of the title compound. LC-MS/ES m/z (79Br) 270.0 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([CH2:13][Br:14])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[P:15]([O:20]C)([O:18][CH3:19])[O:16][CH3:17]>C1(C)C=CC=CC=1>[Br:14][CH2:13][C:12]1[C:3]([CH2:2][P:15]([O:18][CH3:19])([O:16][CH3:17])=[O:20])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: BrCc1cc2ccccc2nc1CBr
Reactant: COP(OC)OC
Solvent: Cc1ccccc1
Product: COP(=O)(Cc1nc2ccccc2cc1CBr)OC
Yield: 72.6 %

Procedure:
A mixture of 2,3-di(bromomethyl)quinoline (0.50 g, 1.4 mmol) and trimethyl phosphite (0.18 ml, 1.4 mmol) was refluxed in toluene for 4 hours. The reaction mixture was then concentrated in vacuo and the residue was flash chromatographed on silica gel. Elution with ethyl acetate afforded 0.35 g of 3-bromomethyl-2-(dimethylphosphonomethyl)quinoline.