Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH3:28][S:29]([C:32]1[CH:33]=[C:34]([CH:42]([CH2:46][CH:47]2[CH2:51][CH2:50][CH2:49][CH2:48]2)[C:43](O)=[O:44])[CH:35]=[CH:36][C:37]=1[S:38]([CH3:41])(=[O:40])=[O:39])(=[O:31])=[O:30].[NH2:52][C:53]1[S:54][CH:55]=[CH:56][N:57]=1>C(Cl)Cl>[CH3:28][S:29]([C:32]1[CH:33]=[C:34]([CH:42]([CH2:46][CH:47]2[CH2:51][CH2:50][CH2:49][CH2:48]2)[C:43]([NH:52][C:53]2[S:54][CH:55]=[CH:56][N:57]=2)=[O:44])[CH:35]=[CH:36][C:37]=1[S:38]([CH3:41])(=[O:40])=[O:39])(=[O:31])=[O:30]
Reactant: Nc1nccs1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1S(C)(=O)=O
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 62 %

Procedure:
A solution of triphenylphosphine (154 mg, 0.59 mmol) in methylene chloride (2 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (105 mg, 0.59 mmol). The reaction mixture was stirred at 0° C. for 10 min and then treated with 2-(3,4-bis-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (200 mg, 0.53 mmol). The resulting reaction mixture was stirred at 0° C. for 5 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminothiazole (118 mg, 1.18 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was then directly purified by flash chromatography (Merck Silica gel 60, 230–400 mesh, 1/1 hexanes/ethyl acetate) to afford 2-(3,4-bis-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (150 mg, 61%) as a pale yellow foam: mp 104–107° C.; EI-HRMS m/e calcd for C19H24N2O5S3 (M+) 456.0847, found 456.0846.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]2=[O:25])[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.C([SiH](CC)CC)C.[CH:33]1([CH:36]=O)[CH2:35][CH2:34]1>C(#N)C.Br[Bi](Br)Br>[CH:33]1([CH2:36][O:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([N:15]3[C:16](=[O:25])[C:17]4[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:23]3=[O:24])[CH2:11][CH2:10]2)[CH2:35][CH2:34]1
Reactant: O=CC1CC1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N2C(=O)c3ccccc3C2=O)CC1
Agent: Br[Bi](Br)Br
Agent: CC[SiH](CC)CC
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@H](OCC2CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred solution of 12B (750 mg, 2.086 mmol) in acetonitrile (10 mL) was treated with triethylsilane (0.432 mL, 2.71 mmol) and tribromobismuthine (94 mg, 0.209 mmol), followed by slow addition of cyclopropanecarbaldehyde (175 mg, 2.503 mmol) (dissolved in acetonitrile (0.5 mL)). The reaction mixture was stirred at room temperature overnight. The dark solid was removed by filtration, the filtrate was concentrated, and the residue was purified by ISCO silica column (24 g), gradient elution with ethyl acetate:hexane (0%-100% ethyl acetate over 15 min). Concentration of the desired fractions yielded 12C (630 mg, 2.104 mmol, >quantitative yield) as a white solid. MS (ES): m/z=322 [M+Na]+. 1H NMR (400 MHz, CDCl3) δ ppm 7.56-7.65 (m, 2H); 7.46-7.53 (m, 2H); 3.89-3.99 (m, 1H); 3.13-3.22 (m, 1H); 3.12 (d, 2H, J=6.8 Hz); 2.04-2.16 (m, 2H); 1.92-2.00 (m, 2H); 1.52-1.61 (m, 2H); 1.14-1.27 (m, 2H); 0.80-0.92 (m, 1H); 0.30-0.39 (m, 2H); −0.02-0.05 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.[O:15]=[C:16]1[CH2:21][CH2:20][C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:22]#[N:23])[CH2:18][CH2:17]1.Cl>C1COCC1>[OH:15][C:16]1([C:2]2[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=2)[CH2:21][CH2:20][C:19]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:22]#[N:23])[CH2:18][CH2:17]1
Reactant: N#CC1(c2ccccc2)CCC(=O)CC1
Reactant: CSc1ccc(Br)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1ccc(C2(O)CCC(C#N)(c3ccccc3)CC2)cc1
Temperature: -70 °C
Reaction time: 3 h
Yield: 73.4 %

Procedure:
5.10 g of 4-bromothioanisole were dissolved in 50 ml of dry THF and 9.29 ml of an n-butyllithium solution (2.7 M in HEP) were added dropwise at a temperature between −65° C. and −70° C. The reaction mixture was stirred for 3 h at −70° C. Subsequently a solution of 5.00 g of 4-oxo-1-phenylcyclohexanecarbonitrile in 30 ml of THF was added dropwise at this temperature and the mixture was stirred for 10 min at −70° C. and 26 h at room temperature. The reaction mixture was then poured onto 400 g of ice, 100 ml of a 1 N hydrochloric acid were added and the mixture was extracted three times with 200 ml each of DCM. The combined extracts were dried over magnesium sulfate and the solvent was removed in vacuo. Chromatography of the residue on silica gel with EA/HEP (1:2) yielded 5.96 g of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Cl[CH2:10][CH:11]([OH:14])[CH2:12][OH:13]>C(O)C>[OH:14][CH:11]([CH2:12][OH:13])[CH2:10][N:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[N:6][C:5]1=[O:8]
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: OCC(O)CCl
Solvent: CCO
Product: O=c1ncc(Cl)cn1CC(O)CO
Yield: 32 %

Procedure:
A solution prepared from 5-chloropyrimid-2-one (0.02 mol) potassium hydroxide (0.02 mol), and 3-chloro-1,2-propanediol (0.02 mol) in abs. ethanol (160 ml) was heated under reflux until neutral pH. The warm reaction mixture was filtered before concentration to a small volume at reduced pressure. The syrupy precipitate was partially crystallised on standing in the cold. The oily material was removed from the crystalline material by suction on a filter and the crystalline material recrystallised from acetonitrile, yield 32% m.p. 136°-138° C.; (Found: C, 41.15; H, 4.55; Calc. for C7H9ClN2O3 : C, 41.09; H, 4.43).
Reaction SMILES: C([N:5]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[S:6]1(=[O:21])=[O:20])(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[N+:17]([C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:7]2[CH2:8][CH2:9][NH:5][S:6]2(=[O:21])=[O:20])=[CH:12][CH:13]=1)([O-:19])=[O:18]
Reactant: CC(C)(C)N1CCN(Cc2ccc([N+](=O)[O-])cc2)S1(=O)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CN2CCNS2(=O)=O)cc1
Reaction time: 48 h
Yield: 78.4 %

Procedure:
A solution of the product from Step 1 (1.5 g) in anhydrous dichloromethane (10 ml) and trifluoroacetic acid (10 ml) was allowed to stand at room temperature for 48 hours. Solvents were removed under vacuum and the remaining residue was azeotroped with methanol (1×25 ml) and crystallised from ethyl acetate-hexane to give 966 mg (78%) of the title compound as a pale yellow solid; mp 115°-117° C.; δH (250 MHz, CDCl3) 8.23 (2H, d, J=8.8 Hz, Ar--H), 7.57 (2H, d, J=8.8 Hz, Ar--H), 4.38 (1H, br t, --NH--), 4.29 (2H, s, Ar--CH2 --), 3.54 (2H, q, J=6.6 Hz, --CH2 --NH--), 3.34 (2H, t, J=6.6 Hz, --CH2 --).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:14])[C@H:10]([CH2:12][OH:13])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([O:24][C@H:25]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:26][C:27](O)=[O:28])(=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(Cl)CCl.CI>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:14])[C@H:10]([CH2:12][OH:13])[NH:11][C:27](=[O:28])[CH2:26][C@H:25]([O:24][C:15](=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCC[C@H](CC(=O)O)OC(=O)CCCCCCC
Reactant: N[C@@H](CO)C(=O)OCc1ccccc1
Solvent: CI
Solvent: ClCCl
Solvent: ClCCCl
Product: CCCCCCCCCCC[C@H](CC(=O)N[C@@H](CO)C(=O)OCc1ccccc1)OC(=O)CCCCCCC
Yield: 93.1 %

Procedure:
In the same manner as described in Example 2-(5), L-serine benzyl ester (390 mg, 2.0 mmol) was acylated with (R)-3-octanoyloxytetradecanoic acid (815 mg, 2.2 mmol) in the presence of EDC·MeI (745 mg, 2.5 mmol) in CH2Cl2 to afford 1.02 g (93%) of N-[(R)-3-octanoyloxytetradecanoyl]-L-serine benzyl ester: mp 50-51° C.; 1H NMR (CDCl3) δ 0.88 (t, 6H, J=6.8 Hz), 1.1-1.7 (m, 30H), 2.30 (t, 2 H, J=7.7 Hz), 2.51 (d, 2H, J=5.8 Hz), 2.60 (t, 1H, J=6.0 Hz), 3.97 (m, 2H), 4.65 (m, 1H), 5.22 (m, 3H), 6.61 (d, 1H, J=6.9 Hz), 7.35 (br s, 5H).
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[CH3:19][O:20][CH2:21][CH2:22]O.C(P(CCCC)CCCC)CCC.[C:37]([O:41][C:42]([N:44]1[CH2:49][C:48](=[O:50])[N:47]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=2[OH:57])[CH2:46][C:45]1([CH3:59])[CH3:58])=[O:43])([CH3:40])([CH3:39])[CH3:38]>C1(C)C=CC=CC=1.O>[C:37]([O:41][C:42]([N:44]1[CH2:49][C:48](=[O:50])[N:47]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=2[O:57][CH2:22][CH2:21][O:20][CH3:19])[CH2:46][C:45]1([CH3:59])[CH3:58])=[O:43])([CH3:40])([CH3:38])[CH3:39]
Reactant: COCCO
Reactant: CC(C)(C)OC(=O)N1CC(=O)N(c2ccccc2O)CC1(C)C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: COCCOc1ccccc1N1CC(C)(C)N(C(=O)OC(C)(C)C)CC1=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 86.3 %

Procedure:
518 mg of 1,1′-(azodicarbonyl)dipiperidine (2.05 mmol), 156 mg of 2-methoxyethanol (2.05 mmol) and 0.42 ml of tributylphosphine (2.05 mmol) were added to a solution of 400 mg of 4-(2-hydroxyphenyl)-2,2-dimethyl-5-oxopiperazine-1-carboxylic acid t-butyl ester obtained in Example (10d) (1.36 mmol) in toluene (14 ml), and the mixture was stirred at 100° C. for three hours. The reaction mixture was cooled and then water was added, followed by extraction with ethyl acetate. Then, the organic layer was washed with brine and then dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:n-hexane/ethyl acetate=1/2) to obtain 444 mg of 4-[2-(2-methoxyethoxy)phenyl]-2,2-dimethyl-5-oxopiperazine-1-carboxylic acid t-butyl ester (yield: 86%).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[CH2:3][O:4][C:5]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:17][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:8].[C:29]([OH:32])(=[O:31])[CH3:30].[H][H]>[Pt].CCCCCC>[C:29]([OH:32])(=[O:31])[CH3:30].[F:28][C:2]([F:1])([F:27])[CH2:3][O:4][C:5]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:17][C:6]=1[C:7]([NH:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][NH:12]1)=[O:8]
Reactant: O=C(NCc1ccccn1)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reactant: [H][H]
Agent: [Pt]
Solvent: CCCCCC
Solvent: CC(=O)O
Product: O=C(NCC1CCCCN1)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reaction time: 6.5 h
Yield: 71 %

Procedure:
A mixture of 0.33 mole (134.7 g.) of 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-pyridylmethyl)benzamide, 1.347 liters of glacial acetic acid and 13.5 g. of 5 percent platinum on carbon is reduced in a Parr apparatus at about 30 pounds of hydrogen at room temperature. The reaction is complete in 6-7 hours. The reaction mixture is filtered and the catalyst is washed with isopropyl alcohol. The solution and washings are evaporated to provide a residue. Hexane is added to the residue and the resulting white solid is collected and recrystallized from a mixture of acetone and hexane. A 71 percent yield of 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide acetate, m.p. 150° to 152° C., is obtained. By concentrating the residual liquid, an additional 18 percent of product is obtained as a second crop with a melting point of 148°-150° C.
Reaction SMILES: Cl[C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[CH3:18][C@H:19]1[O:24][C@@H:23]([CH3:25])[CH2:22][N:21]([CH2:26][CH2:27][NH:28][C:29]([NH:31][C:32]2[S:33][C:34]3[CH:40]=[C:39]([SH:41])[CH:38]=[CH:37][C:35]=3[N:36]=2)=[O:30])[CH2:20]1.[BH4-].[Na+]>C(N(CC)CC)C>[CH3:25][C@H:23]1[O:24][C@@H:19]([CH3:18])[CH2:20][N:21]([CH2:26][CH2:27][NH:28][C:29]([NH:31][C:32]2[S:33][C:34]3[CH:40]=[C:39]([S:41][C:2]4[N:6]5[N:7]=[C:8]([C:11]6[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=6)[CH:9]=[CH:10][C:5]5=[N:4][N:3]=4)[CH:38]=[CH:37][C:35]=3[N:36]=2)=[O:30])[CH2:22]1
Reactant: C[C@@H]1CN(CCNC(=O)Nc2nc3ccc(S)cc3s2)C[C@H](C)O1
Reactant: Fc1ccc(-c2ccc3nnc(Cl)n3n2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(CCNC(=O)Nc2nc3ccc(Sc4nnc5ccc(-c6ccc(F)cc6)nn45)cc3s2)C[C@H](C)O1
Yield: 16.9 %

Procedure:
The 1-{2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]ethyl}-3-(6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-1,3-benzothiazol-2-yl)urea was prepared according to the method described in Example 1a, but using 186 mg of 3-chloro-6-(4-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine, 366 mg of 1-{2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]ethyl}-3-(6-sulphanyl-1,3-benzothiazol-2-yl)urea, 0.14 cm3 of triethylamine and 38 mg of sodium borohydride. 73 mg of 1-{2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]ethyl}-3-(6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-1,3-benzothiazol-2-yl)urea are thus obtained in the form of a beige powder, the characteristics of which are as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:12]([OH:14])=O.[CH3:15][N:16]([CH3:34])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:12]([N:24]([CH2:23][C:20]1[CH:19]=[CH:18][C:17]([N:16]([CH3:34])[CH3:15])=[CH:22][CH:21]=1)[C:25]1[CH:26]=[CH:27][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:29][CH:30]=1)=[O:14]
Reactant: O=C(O)C1CCOc2ccc(Cl)cc21
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCOc3ccc(Cl)cc32)cc1
Yield: 25.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 6-chlorochroman-4-carboxylic acid (0.66 g) and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.83 g) as starting materials, 6-chloro-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)chroman-4-carboxamide (0.36 g) was obtained.
Reaction SMILES: CS(Cl)(=O)=O.[Si]([O:13][CH2:14][C:15]([CH3:45])([CH3:44])[CH2:16][N:17]1[CH:26]=[C:25]([CH2:27]O)[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:29]3[CH:30]=[C:31]([CH:38]=[C:39]([F:42])[C:40]=3[CH3:41])[C:32]([NH:34][CH:35]3[CH2:37][CH2:36]3)=[O:33])[CH:23]=2)[C:18]1=[O:43])(C(C)(C)C)(C)C.C(N(CC)CC)C.[CH3:53][C@H:54]1[NH:59][CH2:58][CH2:57][N:56](C(OC(C)(C)C)=O)[CH2:55]1>C(Cl)Cl>[CH:35]1([NH:34][C:32](=[O:33])[C:31]2[CH:30]=[C:29]([C:22]3[CH:23]=[C:24]4[C:19](=[CH:20][CH:21]=3)[C:18](=[O:43])[N:17]([CH2:16][C:15]([CH3:44])([CH3:45])[CH2:14][OH:13])[CH:26]=[C:25]4[CH2:27][N:59]3[CH2:58][CH2:57][NH:56][CH2:55][C@H:54]3[CH3:53])[C:40]([CH3:41])=[C:39]([F:42])[CH:38]=2)[CH2:37][CH2:36]1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO[Si](C)(C)C(C)(C)C)cc(CO)c2c1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO)cc(CN3CCNC[C@H]3C)c2c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 22.2 %

Procedure:
Methanesulfonyl chloride (0.55 mL) was added to a solution of 3-[2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-4-(hydroxymethyl)-1-oxo-1,2-dihydroisoquinolin-6-yl]-N-cyclopropyl-5-fluoro-4-methylbenzamide (Example 26 g, 3.65 g) and triethylamine (1.79 mL) in DCM (10 mL) at −20° C. After 30 min the solution was warmed to 0° C. and tert-butyl (3R)-3-methylpiperazine-1-carboxylate (2.58 g) was added. The reaction was stirred for 18 h at room temperature, evaporated and the residue purified (SiO2 chromatography, elution with 20 to 80% ethyl acetate in isohexane). Fractions containing product were evaporated, dissolved in THF (100 mL) and treated with 4 M HCl in dioxane (5 mL), stirred at room temperature for 60 h, evaporated to dryness and the residue purified (SiO2 chromatography, elution with 5 to 10% 7N NH3/methanol in DCM) to give the title compound (1.53 g) as a solid.
Reaction SMILES: C(C1CCCCC1=O)(=O)C(C)C.Cl.[CH3:14][O:15][C:16](=[O:19])[CH2:17][NH2:18].Br[C:21]1[C:30]([CH3:31])=[C:29]([Br:32])[C:28]2[C:23](=[CH:24][C:25]([F:34])=[CH:26][C:27]=2[F:33])[N:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O.[Cu]I>[Br:32][C:29]1[C:28]2[C:23](=[CH:24][C:25]([F:34])=[CH:26][C:27]=2[F:33])[N:22]=[C:21]([NH:18][CH2:17][C:16]([O:15][CH3:14])=[O:19])[C:30]=1[CH3:31]
Reactant: COC(=O)CN
Reactant: Cc1c(Br)nc2cc(F)cc(F)c2c1Br
Agent: [Cu]I
Agent: CC(C)C(=O)C1CCCCC1=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CNc1nc2cc(F)cc(F)c2c(Br)c1C
Temperature: 70 °C
Reaction time: 2 h

Procedure:
2-Isobutyrylcyclohexanone (0.086 mL, 0.51 mmol), glycine methyl ester hydrochloride (480 mg, 3.9 mmol), 2,4-dibromo-5,7-difluoro-3-methylquinoline (870 mg, 2.6 mmol), copper(I) iodide (24 mg, 0.13 mmol) and cesium carbonate (2.5 g, 7.70 mmol) were slurried in DMF (3.0 mL) and stirred in an oil bath at 70° C. for 2 h. Another aliquot of copper(I) iodide (24 mg, 0.13 mmol) and 2-isobutyryl-cyclohexanone (0.086 mL, 0.51 mmol) were added and heated for an additional 1.5 h. No further progress was observed. The reaction mixture was then diluted with water and extracted with EtOAc (2×100 mL). The combined organic layers were washed with 1N lithium chloride (1×50 mL) and brine (1×50 mL) and dried over magnesium sulfate. The residue was then purified by medium pressure chromatography (silica gel, 0 to 40% EtOAc:hexanes) to give methyl 2-(4-bromo-5,7-difluoro-3-methylquinolin-2-ylamino)acetate. Mass Spectrum (ESI) m/e=347.0 (M+1).
Reaction SMILES: Cl[Si](C)(C)C.C(N(CC)CC)C.C([O:16][C:17]([C:19]1[N:20]=[CH:21][C:22]2[NH:23][C:24]3[C:29]([C:30]=2[C:31]=1[CH2:32][O:33][CH3:34])=[CH:28][C:27]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[CH:26][CH:25]=3)=O)(C)C>C1(C)C=CC=CC=1>[CH2:36]([O:35][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22]1[CH:21]=[N:20][C:19]([CH:17]=[O:16])=[C:31]([CH2:32][O:33][CH3:34])[C:30]2=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc(OCc4ccccc4)cc3c12
Agent: C[Si](C)(C)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COCc1c(C=O)ncc2[nH]c3ccc(OCc4ccccc4)cc3c12
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
15 ml of chlorotrimethylsilane and 48 ml of triethylamine are added to a suspension of 24.3 g (60 mmol) of 6-benzyloxy-4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester in 250 ml of dry toluene. The reaction mixture is heated for one hour to 50° C. and then concentrated to half its volume. Thereafter the reaction mixture is cooled to -78° C. and, under nitrogen, 100 ml of DIBAL-H* (1-molar solution in toluene) is added within one-half hour; the mixture is stirred for another half hour at -78° C. Then the mixture is combined with 10 ml of ethanol and heated to room temperature; 200 ml of 0.5-molar sodium hydroxide solution and 200 ml of ethanol are added, and the mixture is stirred overnight. The precipitate is filtered off, washed with water, dried, and utilized in the subsequent reaction step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH:13]([CH2:15][O:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=3)[O:12][C:11]2=[O:27])=[CH:6][CH:5]=1)([O-])=O>[Zn].C(O)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH:13]([CH2:15][O:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=3)[O:12][C:11]2=[O:27])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(OCC2CN(c3ccc([N+](=O)[O-])cc3)C(=O)O2)cc1
Agent: [Zn]
Solvent: CC(=O)O
Product: COC(=O)c1ccc(OCC2CN(c3ccc(N)cc3)C(=O)O2)cc1
Reaction time: 3 h
Yield: 108.8 %

Procedure:
A 6.0 g quantity of zinc powder was added to an acetic acid (60 ml) solution of 3.0 g of methyl 4-[3-(4-nitrophenyl)-2-oxooxazolidin-5-yl]methoxybenzoate (compound 50) obtained in Example 3 at 60° C., and the mixture was stirred at the same temperature for 3 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Ethanol was added to the obtained residue to collect the crystals by filtration. Thus, 3.0 g of the title compound (compound 112) was obtained in a quantitative yield.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=O)[CH2:2]2.C1(C)C=CC(S([CH2:19][N+:20]#[C-])(=O)=O)=CC=1.COCCOC.CC(C)([O-])C.[K+]>C(O)C>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C:19]#[N:20])[CH2:2]2
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=C1CN2CCC1CC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Solvent: COCCOC
Product: N#CC1CN2CCC1CC2
Temperature: 40 °C

Procedure:
20.4 g (163 mmol) of 3-quinuclidinone and 41.4 g (212 mmol) of (4-toluenesulfonyl)methyl isocyanide are introduced into 435 ml of 1,2-dimethoxyethane and 16 ml of dry ethanol while cooling in ice. 45.7 g (407 mmol) of potassium tert-butoxide are slowly added in such a way that the temperature does not rise above 10° C. The mixture is then heated at 40° C. for 2.5 h. After cooling to RT, the resulting solid is filtered off. The filtrate is concentrated and chromatographed on neutral alumina (mobile phase: dichloromethane→ethyl acetate→ethyl acetate/methanol 50:1). 22.9 g (quant.) of the racemic product are obtained in slightly impure form.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:9]3[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:8]=3[S:7][C:6]=2[CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][O:37][C:36]1=[O:40]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH:10]([N:12]3[CH2:17][CH2:16][N:15]([CH2:33][CH2:34][N:35]4[CH2:39][CH2:38][O:37][C:36]4=[O:40])[CH2:14][CH2:13]3)[C:9]3[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:8]=3[S:7][C:6]=2[CH:23]=1
Reactant: Fc1ccc2c(c1)C(N1CCNCC1)Cc1ccc(Cl)cc1S2
Reactant: O=C1OCCN1CCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: c1ccccc1
Product: O=C1OCCN1CCN1CCN(C2Cc3ccc(Cl)cc3Sc3ccc(F)cc32)CC1

Procedure:
25 g. of 1-[3-chloro-8-fluoro-10,11-dihydro-dibenzo[b,f]-thiepin-10-yl]-piperazine are heated together with 20 g. of pulverized potassium carbonate, 0.4 g. of potassium iodide and 25.6 g. of N-(β-chloro-ethyl)oxazolidinone under reflux conditions over a period of 25 hours. The reaction mixture is poured onto water and equilibrated with benzene. The organic phase is washed with aqueous saturated sodium bicarbonate solution, dried over sodium sulfate and evaporated under reduced pressure. One obtains 3-{2-[4-(3-chloro-8-fluoro-10,11-dihydro-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl}-2-oxazolidinone which is treated with maleic acid to yield the corresponding maleate which after recrystallization from ethanol and ether melts at 143.5°-146° C.
Reaction SMILES: O.O=[C:3]([C:7]([OH:9])=[O:8])[C:4]([OH:6])=[O:5].[C:10]1([NH:16][NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)C.O>[C:10]1([NH:16][N:17]=[C:3]([C:7]([OH:9])=[O:8])[C:4]([OH:6])=[O:5])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NNc1ccccc1
Reactant: O=C(O)C(=O)C(=O)O
Solvent: O
Solvent: CCO
Product: O=C(O)C(=NNc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
To a vigorously stirred solution of ketomalonic acid monohydrate (29.33 g) in ethanol (140 ml) and water (300 ml) at ambient temperature was added phenylhydrazine (23.3 g) dropwise over a 40 minute period. The resultant slurry was stirred overnight at ambient temperature. The solid was separated by filtration, washed sucessively with cold water (100 ml) and ethanol (25 ml) and air dried. Subsequent drying was performed at 75° C. overnight in a vacuum oven to give the title compound as a yellow solid (42.38 g). 1H (300 MHz, DMSO-d6): d 7.12(t, 1H), 7.35-7.48(m, 4H); m.p.: 155°-157° C. (dec).