Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[Mg].[Br-].Cl[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1([Mg]Br)C=CC=CC=1.C1C[O:30][CH2:29]C1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:29]([OH:30])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: Clc1ccccc1
Agent: Br[Mg]c1ccccc1
Agent: [Br-]
Agent: [Mg]
Product: O[C@@H](c1ccccc1)c1ccc(Cl)cc1

Procedure:
An operation was carried out in the same manner as in Example 14, except that 0.29 mL (0.375 mmol) of 4-chlorophenylmagnesium bromide (1.4 mol/L) prepared from magnesium and 4-chlorobenzene bromide was used instead of the anhydrous THF solution of phenylmagnesium bromide. Thus, (S)-4-chlorobenzhydrol was obtained. The conversion rate of the raw material was 96%, while the enantiomeric excess was 92% ee.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][O:12][C:13]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:14]=1[CH2:15][C:16]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:17]=1[O:18][CH2:19][C:20](O)=[O:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33]CN(C(C)C)C(C)C.CN(C(ON1N=[N:57][C:52]2C=[CH:54][CH:55]=[N:56][C:51]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCCCC1>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:10])[CH2:11][O:12][C:13]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:14]=1[CH2:15][C:16]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:17]=1[O:18][CH2:19][C:20]([N:56]1[CH2:51][CH2:52][N:57]([CH3:33])[CH2:54][CH2:55]1)=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)COc1ccc(Cl)cc1Cc1cc(Cl)ccc1OCC(=O)OCc1ccccc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCN(C(C)C)C(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN1CCCCC1
Product: CN1CCN(C(=O)COc2ccc(Cl)cc2Cc2cc(Cl)ccc2OCC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of [2-(2-benzyloxycarbonylmethoxy-5-chloro-benzyl)-4-chloro-phenoxy]-acetic acid (Intermediate C) (0.1 g, 0.211 mmol) in DCM (1 mL) is added DIPEA (37 μL, 0.211 mmol) and HATU (80 mg, 0.211 mmol). After stirring at RT for 1 hour, the reaction mixture is treated with 1-methyl piperidine (24 μL, 0.211 mmol) and allowed to stir at RT for 2 days. The resulting solution is purified by chromatography on silica eluting with EtOAc/MeOH (95:5) to yield the titled product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[C:11]([N:18]=[C:19]=S)[CH:12]=[CH:13][CH:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(OC1CC2C(CC=1)=CC=CC=2N=C=S)C.[N:38]([CH2:41][C:42]([C:44]1[CH:49]=[CH:48][C:47]([C:50]([F:53])([F:52])[F:51])=[CH:46][CH:45]=1)=[O:43])=[N+]=[N-]>>[C:1]([O:5][C:6](=[O:21])[NH:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[C:11]([NH:18][C:19]3[O:43][C:42]([C:44]4[CH:49]=[CH:48][C:47]([C:50]([F:51])([F:52])[F:53])=[CH:46][CH:45]=4)=[CH:41][N:38]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCc2cccc(N=C=S)c2C1
Reactant: [N-]=[N+]=NCC(=O)c1ccc(C(F)(F)F)cc1
Agent: CCOC1=CCc2cccc(N=C=S)c2C1
Product: CC(C)(C)OC(=O)NC1CCc2cccc(Nc3ncc(-c4ccc(C(F)(F)F)cc4)o3)c2C1
Yield: 36.8 %

Procedure:
The title compound was prepared using the procedure as described in Example 1H, substituting the product of Example 20F (215 mg, 0.706 mmol) for the product of Example 1F, and the product of Example 1G (194 mg, 0.848 mmol). The crude product was purified by flash chromatography eluting with 20% EtOAc/hexane which gave 123 mg (37%) of the title compound as a white solid. 1H NMR (DMSO-d6) δ 9.32 (br s, 1H), 7.75 (m, 4H), 7.60 (s, 1H), 7.55 (d, J=7.8 Hz, 1H), 7.12 (t, J=7.8 Hz, 1H), 6.98 (br d, 1H), 6.88 (d, J=7.5 Hz, 1H), 3.64 (m, 1H), 3.02 (m, 1H), 2.84 (m, 2H), 2.42 (m, 1H), 1.87 (m, 1H), 1.60 (m, 1H), 1.39 (s, 9H); MS (ESI+) m/z 474 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.BrCC1C=CC(C2C=CC=CC=2C(C2C=CC=CC=2)=O)=CC=1>C(#N)C>[Br:16][CH2:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)c2ccccc2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C(c1ccccc1)c1ccccc1-c1ccc(CBr)cc1
Solvent: CC#N
Product: O=C(c1ccccc1)c1ccc(CBr)cc1
Temperature: 80 °C

Procedure:
To a 200-mL flask equipped with a reflux condenser were added 25.1 g of 4-methylbenzophenone (Aldrich), 22.8 g of N-bromosuccinimide (Wako Pure Chemical Industries, Ltd.), 0.54 g of benzoyl peroxide (containing 20% water, Wako Pure Chemical Industries, Ltd.), and 80 g of acetonitrile, which were heated to 80° C. and were made react under reflux for 2 hours. After cooling, the solvent was distilled away and the residue was recrystallized from 160 g of methanol, so that 26 g of intermediate (H10) (white crystals) was obtained. As a result of an analysis by 1H-NMR {300 MHz, CDCl3, δ (ppm): 7.9-7.7 (m, 4H), 7.6 (t, 1H), 7.55-7.4 (m, 4H), 4.5 (s, 2H)}, it was confirmed that this intermediate (H10) was 4-bromomethylphenylbenzophenone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12](=O)[CH3:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:15][C:16]1[CH:20]=[C:19]([NH2:21])[NH:18][N:17]=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH:26]=O>C1COCC1.N1CCCCC1>[Cl:22][C:23]1[CH:24]=[C:25]([CH:26]2[N:18]3[N:17]=[C:16]([CH3:15])[CH:20]=[C:19]3[NH:21][C:12]([CH3:13])=[C:11]2[S:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH:28]=[CH:29][C:30]=1[Cl:31]
Reactant: Cc1cc(N)[nH]n1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: CC(=O)CS(=O)(=O)c1ccc(F)cc1
Solvent: C1CCOC1
Solvent: C1CCNCC1
Product: CC1=C(S(=O)(=O)c2ccc(F)cc2)C(c2ccc(Cl)c(Cl)c2)n2nc(C)cc2N1
Temperature: 70 °C
Reaction time: 48 h

Procedure:
1-(4-Fluorophenylsulfonyl)propan-2-one (150 mg, 0.69 mmol), 3-methyl-1H-pyrazol-5-amine (67 mg, 0.69 mmol) and 3,4-dichlorobenzaldehyde (121 mg, 0.69 mmol) were dissolved in THF (5 mL), to which was added a catalytic amount of piperidine (3 drops). The reaction in a sealed tube was stirred at 70° C. for about 48 hrs. After cooling to rt., solvent was removed and crude product was purified by HPLC (acetonitrile-water, 5% to 95% gradient) to provide pure Step B product 7-(3,4-dichlorophenyl)-6-(4-fluorophenylsulfonyl)-2,5-dimethyl-4,7-dihydropyrazolo[1,5-a]pyrimidine as a solid. LC-MS found: (M+1)+=452.17. The two enantiomers were readily separated on Chiral PAK AS using 15% EtOH-MeOH in heptane.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:44])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([C@@H:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:23][OH:24])[CH:17]=[C:16]([C:29]([O:31]CC)=[O:30])[C:15]3=[O:34])=[C:8]([C:35]2[S:36][CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[N:39]=2)[CH:7]=1)[CH3:2].[OH-].[Li+].Cl>O1CCCC1.CO.O>[CH2:1]([NH:3][C:4](=[O:44])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([C@@H:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:23][OH:24])[CH:17]=[C:16]([C:29]([OH:31])=[O:30])[C:15]3=[O:34])=[C:8]([C:35]2[S:36][CH:37]=[C:38]([C:40]([F:41])([F:43])[F:42])[N:39]=2)[CH:7]=1)[CH3:2]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3[C@H](CO)C(C)(C)C)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)O)cn3[C@H](CO)C(C)(C)C)cn1
Temperature: 100 °C
Yield: 35.2 %

Procedure:
To a solution of (S)-ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-(1-hydroxy-3,3-dimethylbutan-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (Example 104, 212.7 mg, 0.34 mmol) in tetrahydrofuran (1 mL) and methanol (1 mL) was added 2 M lithium hydroxide (0.253 mL, 0.51 mmol). The reaction mixture was heated at 100° C. for 15 min in a microwave reactor. The reaction mixture was cooled to room temperature and diluted with water. 1 N HCl was added until pH 3-4 was reached. The precipitate that formed was collected by filtration, washed with water and hexanes. Purification via column chromatography (silica, 95:5 methylene chloride/methanol) provided (S)-6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-(1-hydroxy-3,3-dimethylbutan-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid as a light yellow solid (72.3 mg, 35%).
Reaction SMILES: [O:1]1[C:5]2=[CH:6][CH:7]=[CH:8][C:9]([OH:10])=[C:4]2[CH:3]=[CH:2]1.[F:11][C:12]1[CH:13]=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[CH:16][C:17]=1F.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[F:11][C:12]1[CH:13]=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[CH:16][C:17]=1[O:10][C:9]1[C:4]2[CH:3]=[CH:2][O:1][C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: Oc1cccc2occc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2cccc3occc23)c(F)c1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
2.40 g (5.37 mmol) of 1-benzofuran-4-ol (from example XXI), 0.90 g (5.64 mmol) of 3,4-difluoronitrobenzene and 1.48 g (10.7 mmol) of potassium carbonate are suspended in 20 ml of anhydrous dimethylformamide, and the mixture is stirred at 50° C. for 5 hours. The reaction solution is then diluted with water and extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate. The solvent is removed under reduced pressure. The crude product is purified on a silica gel column (mobile phase: cyclohexane:ethyl acetate (10:1)).
Reaction SMILES: [S:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([CH2:18][N:19]=[N+:20]=[N-:21])[O:15][C:14]3=[O:22])=[CH:9][C:8]=2[F:23])[CH2:3][CH2:2]1.[CH:24]12CC(C=C1)C=[CH:25]2>O1CCOCC1>[S:1]1[CH2:2][CH:3]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([CH2:18][N:19]4[CH:25]=[CH:24][N:21]=[N:20]4)[O:15][C:14]3=[O:22])=[CH:9][C:8]=2[F:23])[CH2:5][CH2:6]1
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(C3=CCSCC3)c(F)c2)C(=O)O1
Reactant: C1=CC2C=CC1C2
Solvent: C1COCCO1
Product: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(C2=CCSCC2)c(F)c1
Yield: 73.5 %

Procedure:
(5R)-3-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-azidomethyloxazolidin-2-one (2 g, 5.7 mmol) was dissolved in dioxane (10 ml). Bicyclo[2.2.1]hepta-2,5-diene (3.1 ml, 28.7 mmol) was added and it was refluxed under nitrogen for 18 hours. The solvent was evaporated in vacuo and the residue subjected to chromatography on silica gel eluting with 25% ethylacetate in dichloromethane to give the title compound (1.51 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14](O)[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([CH:14]2[C:15]3[C:10](=[N:9][C:8]4[C:3]([C:2]=3[NH2:1])=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:11][CH2:12][CH2:13]2)[CH2:20][CH2:19]1
Reactant: CN1CCNCC1
Reactant: Nc1c2c(nc3ccccc13)CCCC2O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CN1CCN(C2CCCc3nc4ccccc4c(N)c32)CC1

Procedure:
9-Amino-1,2,3,4-tetrahydroacridin-1-ol (5.36 g) was refluxed for 48 h in 300 ml of toluene that contained 1-methylpiperazine (5.06 g) and p-toluenesulfonic acid monohydrate (9.5 g). At the end of this time the reaction mixture was distributed between EtOAc and aqueous K2CO3 and then the combined organic phase was concentrated and the residue purified by flash chromatography (5% Et3N/EtOAc) to give, after concentration of the product-containing fractions and recrystallization from EtOAc, 2.30 g of analytically pure product, m.p. 200°-202°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[OH:15].[C:16]1(O)C=CC=C[CH:17]=1.[Cl:23][C:24]1[CH:25]=[C:26](O)[CH:27]=[CH:28][C:29]=1OCC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[O:15][CH2:16][CH2:17][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([Cl:23])[CH:25]=1
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: CCOc1ccc(O)cc1Cl
Reactant: Oc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: ClC(Cl)=CCOc1cc(Cl)c(OCCc2cccc(Cl)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 81 %

Procedure:
To a solution of 0.30 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol, phenol, 0.16 g of 3-chlorophenetyl alcohol and 0.27 g of triphenylphosphine dissolved in 10 ml of tetrahydrofuran was added dropwise a solution of 0.21 g of diisopropylazodicarboxylate dissolved in 5 ml of tetrahydrofuran, while stirring at room temperature. After siring at room temperature for 24 hours, the reaction mixture was concentrated to obtain a residue. The residue was subjected to silica gel chromatography, which afforded 0.36 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(2-(3-chlorophenyl)ethoxy)benzene (81% yield), nD26.0 1.5897.
Reaction SMILES: ClC(O[C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:12])=O.[FH:13]>>[CH3:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:5]=1[F:13]
Reactant: Cc1cccc(C)c1OC(=O)Cl
Reactant: F
Product: Cc1cccc(C)c1F
Temperature: 140 °C
Yield: 68.4 %

Procedure:
500 ml of anhydrous hydrogen fluoride were placed at 0° C. in a stainless steel laboratory autoclave and 150 g of 2,6-dimethylphenyl chloroformate were added dropwise. The autoclave was sealed and heated at a maximum temperature of 140° C. for 1.5 hours, the pressure of the gases formed being released at 26 bar. The reaction mixture was worked up as described in Example 9. 2,6-Dimethylfluorobenzene was obtained in a yield of 68.4%.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[C:5]([N:14]=[C:15]=[O:16])=[C:4]([F:17])[CH:3]=1.[H-].[Na+].[NH2:20]/[C:21](/[C:28]([F:31])([F:30])[F:29])=[CH:22]\[C:23](OCC)=[O:24].CI.[C:34](=O)([O-])[O-].[K+].[K+]>O1CCCC1>[Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[C:5]([N:14]2[C:23](=[O:24])[CH:22]=[C:21]([C:28]([F:31])([F:30])[F:29])[N:20]([CH3:34])[C:15]2=[O:16])=[C:4]([F:17])[CH:3]=1
Reactant: CC1(C)CCc2c(Cl)cc(F)c(N=C=O)c2O1
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3c2OC(C)(C)CC3)c1=O
Yield: 36.9 %

Procedure:
By the method of Example 1, Step G, 4.0 grams (0.016 mole) of 5-chloro-3,4-dihydro-2,2-dimethyl-7-fluoro-2H-1-benzopyran-8-yl isocyanate was reacted with 1.0 gram (0.023 mole) of sodium hydride and 3.0 grams (0.017 mole) of ethyl 3-amino-4,4,4-trifluorocrotonate in 150 mL of tetrahydrofuran. Subsequently, 4.5 grams (0.032 mole) of methyl iodide and 4.4 grams (0.032 mole) of potassium carbonate were reacted with the product of the first reaction, yielding 2.4 grams of 3-(5-chloro-3,4-dihydro-2,2-dimethyl- 7-fluoro-2H-1-benzopyran-8-yl)-1-methyl-6-trifluoromethyluracil, mp 132°-135° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH2:18])=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[CH2:4][CH2:3]1.N1C=CC=CC=1.[C:25]1([S:31]([Cl:34])(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[ClH:34].[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:18][S:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:33])=[O:32])=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2ccc(N)c3cccnc23)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN1CCN(c2ccc(NS(=O)(=O)c3ccccc3)c3cccnc23)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 8-(4-methyl-1-piperazinyl)-5-nitroquinoline (0.379 g, 1.39 mmol) in THF:EtOH 1:4 solvent system was added Raney-Ni (1.0 mL suspension in EtOH) followed by hydrazine hydrate (0.348 g, 6.95 mmol). The mixture was stirred vigorously at room temperature for 16 hours and then filtered through celite pretreated with water. The filtrate was concentrated, and the residue was purified by column chromatography (SiO2, CHCl3/MeOH/NH3 9:1:0.4%) to give 0.337 g of 8-(4-methyl-1-piperazinyl)-5-quinolinylamine. The amine was dissolved in CH2Cl2 (6.0 mL) and pyridine (0.785 mL, 9.73 mmol) and benzenesulfonyl chloride (0.178 mL, 1.39 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours and then washed with saturated aqueous NaHCO3. The organic phase was dried with Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (SiO2, CHCl3/MeOH/NH3 9:1:0.4%) to give 0.130 g of the free base which was converted to its HCl-salt: 1H NMR (DMSO-d6) δ; 11.09 (br s, 1H), 10.32 (s, 1H), 8.94–8.89 (m, 1H), 8.55–8.48 (m, 1H), 7.68–7.65 (m, 2H), 7.64–7.57 (m, 2H), 7.54–7.49 (m, 2H), 7.27–7.22 (m, 1H), 7.12–7.08 (m, 1H), 3.95–3.84 (m, 2H), 3.55–3.49 (m, 2H), 3.45–3.35 (m, 2H), 3.26–3.16 (m, 2H), 2.85–2.82 (m, 3); MS (posESI) m/z 383 (M+H).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:58][C:59]1[CH:68]=[CH:67][C:66]2[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=2)[N:60]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=2)[C:8]([NH:58][C:59]2[CH:68]=[CH:67][C:66]3[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=3)[N:60]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1[N+](=O)[O-]
Reactant: Nc1ccc2ccccc2n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccc3ccccc3n2)cc1[N+](=O)[O-]
Yield: 13.6 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid (prepared as in Example 32, 150 mg, 0.439 mmol), triethylamine (0.184 mL, 1.32 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (291 mg, 0.659 mmol), and 2-aminoquinoline (95 mg, 0.659 mmol) in methylene chloride (4 mL) was stirred at 25° C. overnight. The crude reaction mixture was directly purified by Biotage chromatography (FLASH 40M, Silica, 1/1 hexanes/ethyl acetate) to afford 3-cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-N-quinolin-2-yl-propionamide (28 mg, 13.6%) as a white foam: mp 102-106° C. (foam to gel); EI-HRMS m/e calcd for C24H25N3O5S (M+) 467.1515, found 467.1513.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:18])[C@@H:6]([CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)[NH2:7])[CH:2]=[CH2:3].C(N(CC)CC)C.[CH2:26]([O:33][C:34]([NH:36][C:37]([CH3:42])([C:39](O)=[O:40])[CH3:38])=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.C(OCC)(=O)C>[CH2:26]([O:33][C:34]([NH:36][C:37]([CH3:42])([CH3:38])[C:39]([NH:7][C@H:6]([CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)[C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:18])=[O:40])=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Reactant: C=CCOC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CCOC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)C(C)(C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.5 %

Procedure:
D-Tryptophan allyl ester (250 mg; 0.822 mmol), triethylamine (230 μl; 1.650 mmol) and N-benzyloxycarbonyl-α-methylalanine (167.9 mg; 0.826 mmol) were dissolved in dry methylene chloride (5 ml) and BOP (363.7 mg; 0.822 mmol) added. The reaction mixture was stirred at room temperature for 16 h and then the reaction quenched with saturated brine (5 ml). The methylene chloride layer was separated, dried with magnesium sulfate and filtered then the volatiles removed under reduced pressure to leave a dark brown oil. Chromatography of this oil on silica gel using ethyl acetate and hexanes 2:1 v/v afforded 322 mg (84.5%) of the desired product. FAB-MS:- calculated for C26H29N3O5 463.2; found 464.5 (M+1).
Reaction SMILES: [CH:1]1([CH2:6][C:7]([N:9]2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:16]([C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][CH:20]=1)([CH3:18])[CH3:17].CO>C1COCC1>[CH:16]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([N:12]2[CH2:13][CH2:14][CH2:15][N:9]([C:7](=[O:8])[CH2:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:10][CH2:11]2)=[S:27])=[CH:21][CH:20]=1)([CH3:18])[CH3:17]
Reactant: O=C(CC1CCCC1)N1CCCNCC1
Reactant: CC(C)c1ccc(N=C=S)cc1
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1ccc(NC(=S)N2CCCN(C(=O)CC3CCCC3)CC2)cc1
Reaction time: 8 h
Yield: 71 %

Procedure:
The 1-(2-cyclopentyl-acetyl)-1,4-diazepane (100 mg; 0.475 mmol) and 4-isopropylphenyl isothiocyanate (80 mg; 0.45 mmol) were mixed together at room temperature in 5 mL anhydrous THF. The reaction mixture was left stirring overnight, then 1 mL methanol was added and the solvents were evaporated in vacuo. The crude mixture was purified by flash column chromatography on SiO2 using 0-50% EtOAc in hexanes mixtures as eluent, followed by 1-4% methanol in DCM mixtures. The desired product was isolated as a colorless foam, 180 mg (71% yield). ES+MS: 388 amu (MH+).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH:7]1[O:12][CH2:11][CH2:10][N:9](CC2C=CC=CC=2)[CH2:8]1)(=[O:3])[CH3:2].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>C(#N)C>[C:1]([O:4][CH2:5][CH2:6][CH:7]1[O:12][CH2:11][CH2:10][N:9]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:8]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCC1CN(Cc2ccccc2)CCO1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CC#N
Product: CC(=O)OCCC1CN(C(=O)OCc2ccccc2)CCO1
Yield: 72.1 %

Procedure:
To a solution of 2-(2-acetoxyethyl)-4-benzylmorpholine (29.1 g) in acetonitrile (200 ml) is dropwise added benzyl chloroformate (24.4 g). The reaction mixture is refluxed for 30 minutes, cooled and evaporated under reduced pressure. The residue is chromatographed on silica gel. The eluate with hexane is discarded, and the subsequent eluates with hexane-chloroform (1:1) are pooled and evaporated to give the title compound (24.5 g) as an oil.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[F:28][C:29]([F:40])([F:39])[C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:34](=[O:35])[C:33]5[CH:37]=[CH:38][C:30]([C:29]([F:28])([F:39])[F:40])=[CH:31][CH:32]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)c1ccc(C(F)(F)F)cc1

Procedure:
The title compound, white solid (117 mg, 93%), MS (ISP) m/z=503.3 [(M+H)+], mp 242.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 4-trifluoromethyl-benzoic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:11]=[CH:10][C:9](F)=[CH:8][CH:7]=1.[CH3:16]C1C=CC(C=O)=CC=1.FC1C=CC(C=O)=CC=1>>[CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:11]=[CH:10][C:9]([CH3:16])=[CH:8][CH:7]=1
Reactant: COC(=O)C(=O)C(Cl)c1ccc(F)cc1
Reactant: Cc1ccc(C=O)cc1
Agent: O=Cc1ccc(F)cc1
Product: COC(=O)C(=O)C(Cl)c1ccc(C)cc1

Procedure:
This compound was synthesised as 3-chloro-3-(4-fluoro-phenyl)-2-oxo-propionic acid methyl ester but using 4-methylbenzaldehyde instead 4-fluorobenzaldehyde. 1H-NMR (CDCl3): δ=2.35 (s, 3H); 3.83 (s, 3H); 6.13 (s, 1H); 7.21 (d, 2H); 7.28 (d, 2H).