Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][O:14]2)(=[O:10])=[O:9])=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:3]=1.[CH:22]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:22]1([NH:28][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH:13]3[CH2:17][CH2:16][CH2:15][O:14]3)(=[O:10])=[O:9])=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:3]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=S(=O)(NCC1CCCO1)c1ccc(Br)cc1C(F)(F)F
Reactant: NC1CCCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: O=S(=O)(NCC1CCCO1)c1ccc(NC2CCCCC2)cc1C(F)(F)F
Reaction time: 6 h
Yield: 29 %

Procedure:
Mixture of 4-bromo-N-(tetrahydrofuran-2-ylmethyl)-2-trifluoromethylbenzenesulfonamide (200 mg, 0.51 mmol), cyclohexylamine (193 mg, 1.94 mmol), Pd(OAc)2 (22 mg, 0.10 mmol), BINAP (70 mg, 0.11 mmol) and cesium carbonate (340 mg, 1.01 mmol) in 15 ml toluene was relaxed for 6 hours. Toluene was evaporated in vacuum and crude oil was purified twice by Combiflash (PE-THF). Yield 29%
Reaction SMILES: [C:1]([O:9][CH:10]1[C:19]2[C:14](=[C:15]([CH3:24])[CH:16]=[C:17]([C:21]([OH:23])=[O:22])[C:18]=2[CH3:20])[S:13](=[O:26])(=[O:25])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[C:33]1(=O)[CH2:38][CH2:37][CH2:36][CH2:35][C:34]1=[O:39].C(N(CC)CC)C>C(Cl)Cl.CN(C)C=O>[C:1]([O:9][CH:10]1[C:19]2[C:14](=[C:15]([CH3:24])[CH:16]=[C:17]([C:21]([O:23][C:38]3[CH2:37][CH2:36][CH2:35][C:34](=[O:39])[CH:33]=3)=[O:22])[C:18]=2[CH3:20])[S:13](=[O:25])(=[O:26])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCCC1=O
Reactant: Cc1cc(C(=O)O)c(C)c2c1S(=O)(=O)CCC2OC(=O)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)OC2=CC(=O)CCC2)c(C)c2c1S(=O)(=O)CCC2OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.80 g (2.1 mmol) of 4-benzoyloxy-5,8-dimethyl-1,1-dioxo-1,2,3,4-tetrahydro-1λ6-thiochromene-6-carboxylic acid in 30 ml of methylene chloride was admixed with 2 drops of N,N-dimethylformamide and 1.69 g (13.3 mmol) of oxalyl chloride, and the mixture was boiled under reflux for 3.5 h. The solvents were subsequently stripped off using a rotary evaporator, and the residue was taken up in 100 ml of methylene chloride and, at 0° C., admixed with 0.25 g (2.2 mmol) of cyclohexanedione and 0.44 g (7.4 mmol) of triethylamine. The mixture was stirred at room temperature for 4 h and subsequently concentrated using a rotary evaporator, and the residue was purified by chromatography (silica gel, ethyl acetate: hexane=1:1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH3:2].[S:42]1[CH:46]=[CH:45][C:44](B(O)O)=[CH:43]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:44]3[CH:45]=[CH:46][S:42][CH:43]=3)[CH:25]=[C:26]([S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])[CH:27]=2)[C:10]=1[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH3:2]
Reactant: OB(O)c1ccsc1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(S(=O)(=O)CC)c2)c1CCC(=O)OCC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccsc3)cc(S(=O)(=O)CC)c2)c1CCC(=O)OCC
Yield: 77.2 %

Procedure:
A similar procedure as described in Example 41, step 1 was used, starting from 4-[3-[6-(3-bromo-5-ethanesulfonyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (154 mg, 0.23 mmol), 3-thiopheneboronic acid (60.2 mg, 0.47 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (26 mg, 0.035 mmol), and cesium carbonate (155 mg, 0.47 mmol) to afford 4-[3-[6-(3-ethanesulfonyl-5-thiophen-3-yl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (117 mg, 76%) as a colorless viscous oil: ES(+)-HRMS m/e calcd for C35H46O8S2 (M+Na)+ 681.2526, found 681.2526.
Reaction SMILES: [F:1][C:2]1[C:28]([F:29])=[C:27]([F:30])[C:5]2[N:6]([C@@H:13]3[O:25][C@H:24]([CH3:26])[C@@H:19]([O:20]C(=O)C)[C@H:14]3[O:15]C(=O)C)[C:7]([NH:9][CH:10]([CH3:12])[CH3:11])=[N:8][C:4]=2[CH:3]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].O>CO>[F:1][C:2]1[C:28]([F:29])=[C:27]([F:30])[C:5]2[N:6]([C@@H:13]3[O:25][C@H:24]([CH3:26])[C@@H:19]([OH:20])[C@H:14]3[OH:15])[C:7]([NH:9][CH:10]([CH3:11])[CH3:12])=[N:8][C:4]=2[CH:3]=1
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1c(NC(C)C)nc2cc(F)c(F)c(F)c21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CO
Product: CC(C)Nc1nc2cc(F)c(F)c(F)c2n1[C@@H]1O[C@H](C)[C@@H](O)[C@H]1O
Yield: 46.8 %

Procedure:
5,6,7-Trifluoro-1-(2,3-di-O-acetyl-5-deoxy-beta-D-ribofuranosyl)-N-(1-methylethyl)-1H-benzimidazol-2-amine (0.41 g, 0.99 mmol), ethanol (10 mL), sodium carbonate (0.19 g, 1.79 mmol), water (2 mL), and methanol (5 mL) were used according to general procedure III. The title compound was purified by silica gel chromatography using 10:1 dichlormethane-methanol as eluant to provide a white solid (0.16 g, 47%); m.p. 175-178° C.: 1H NMR (DMSO-d6) δ: 7.17 (m, 1H, Ar—H), 6.78 (d, J=7.4, Hz, 1H, NH), 5.69 (dd, J=6.3, 1.8 Hz, 1H, CH), 5.26 (d, J=6.5 Hz, 1H, OH), 5.21 (d, J=5.2 Hz, 1H, OH), 4.15 (m, 1H, CH), 4.07 (m, 1H, CH), 3.86-3.74 (m, 2H, overlapping CH), 1.34 (d, J=6.3 Hz, 3H, CH3), 1.23 (d, J=6.5 Hz, 6H, overlapping CH3).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.Cl.[NH2:12][CH2:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22](=[O:33])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]([F:32])([F:31])[F:30])[CH2:18][CH2:17]1)=[O:15].C(N(CC)CC)C.O>C(Cl)Cl>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:12][CH2:13][C:14](=[O:15])[N:16]2[CH2:17][CH2:18][N:19]([C:22](=[O:33])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([F:30])([F:32])[F:31])[CH2:20][CH2:21]2)=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)NCC(=O)N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)cc1
Reaction time: 3 h
Yield: 73.98 %

Procedure:
4-Methyl benzoyl chloride (44 mg, 0.03 ml, 1.8 mmol) was added to a stirred a cold (0° C.) solution of 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (prepared by the method described above)(100 mg, 0.28 mmol) and triethylamine (72 mg, 0.1 ml, 0.71 mmol) in DCM (5 mL) and stirring continued at room temperature for 3 hrs. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 50% EtOAc in Hexane as eluent) to afford 91 mg (73.98% yield 4-methyl-N-{2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-benzamide. LCMS Purity: 98.52%. 1H NMR (DMSO-d6): δ 8.54-8.42 (bs, 1H), 7.88-7.62 (m, 5H), 7.58-7.5 (bs, 1H), 7.3-7.22 (d, 2H), 4.2-4.1 (d, 2H), 3.8-3.5 (m, 4H), 3.5-3.4 (bs, 2H), 3.3-3.0 (bd, 2H), 2.3 (s, 3H)
Reaction SMILES: [OH:1][N:2]1C(=O)C2=CC=CC=C2C1=O.Cl[CH2:14][C:15]1[CH:19]=[C:18]([CH3:20])[O:17][N:16]=1>>[CH3:20][C:18]1[O:17][N:16]=[C:15]([CH2:14][O:1][NH2:2])[CH:19]=1
Reactant: Cc1cc(CCl)no1
Reactant: O=C1c2ccccc2C(=O)N1O
Product: Cc1cc(CON)no1

Procedure:
Prepared by a similar procedure as described for preparation 15. Starting materials: N-hydroxyphthalimide and 3-chloromethyl-5-methylisoxazole (Maybridge).
Reaction SMILES: [OH:1][C:2]1[C:7]([C@@H:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][C@H:9]2[OH:15])=[C:6]([O:16][CH3:17])[CH:5]=[C:4]([O:18][CH3:19])[C:3]=1[C:20](=[O:22])[CH3:21].[Cl:23][C:24]1[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=1[C:26](OC)=O.[H-].[Na+]>CN(C=O)C>[Cl:23][C:24]1[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=1[C:26]1[O:1][C:2]2[C:3]([C:20](=[O:22])[CH:21]=1)=[C:4]([O:18][CH3:19])[CH:5]=[C:6]([O:16][CH3:17])[C:7]=2[C@@H:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][C@H:9]1[OH:15]
Reactant: COC(=O)c1ccccc1Cl
Reactant: COc1cc(OC)c([C@@H]2CCN(C)C[C@H]2O)c(O)c1C(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)cc(-c3ccccc3Cl)oc2c1[C@@H]1CCN(C)C[C@H]1O

Procedure:
Compound of example 105 (9 g, 29 mmol) in dry DMF (50 mL) was reacted methyl 2-chlorobenzoate (16.5 g, 96.7 mmol) in the presence of NaH (50%, 6.99 g, 145.6 mmol) as described in example 16 to obtain the title compound.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][CH2:7][C:8](=[O:20])[C:9](=[N:13][O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:10]([OH:12])=O.[NH2:21][CH:22]1[C:34](=[O:35])[N:24]2[C:25]([C:31]([OH:33])=[O:32])=[C:26]([CH:29]=[CH2:30])[CH2:27][S:28][C@H:23]12.C[Si](CC(N)=O)(C)C>O1CCCC1.C(OCC)(=O)C.O.CN(C)C=O>[Cl:6][CH2:7][C:8](=[O:20])[C:9](=[N:13][O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:10]([NH:21][CH:22]1[C:34](=[O:35])[N:24]2[C:25]([C:31]([OH:33])=[O:32])=[C:26]([CH:29]=[CH2:30])[CH2:27][S:28][C@H:23]12)=[O:12]
Reactant: COC(=O)CON=C(C(=O)O)C(=O)CCl
Reactant: C=CC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: C[Si](C)(C)CC(N)=O
Solvent: O
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)OC)C(=O)CCl)[C@H]2SC1
Yield: 85 %

Procedure:
Vilsmeir reagent prepared from N,N-dimethylformamide (3.76 ml) and phosphorus oxychloride (4.46 ml) was suspended in dry tetrahydrofuran (50 ml). To the suspension was added 4-chloro-2-methoxycarbonylmethoxyimino-3-oxobutyric acid (syn isomer) (10.5 g), and the mixture was stirred under ice-cooling to prepare the activated acid solution. This solution was added at a time to a solution of 7-amino-3-vinyl-3-cephem-4-carboxylic acid (10 g) and trimethylsilylacetamide (35 g) in ethyl acetate (110 ml) at -30° C. After the reaction mixture was stirred at -15° C. for an hour, the resultant solution was poured into water (100 ml) and then extracted with ethyl acetate (200 ml). The extract was washed with a saturated aqueous sodium chloride and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was triturated with diisopropyl ether to give 7-(4-chloro-2-methoxycarbonylmethoxyimino-3-oxobutyramido)-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (16.75 g).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH3:8])[S:6][CH:7]=1)[CH3:2].C([Li])CCC.[C:14](OCC)(=[O:16])[CH3:15]>C1COCC1>[CH2:1]([C:3]1[N:4]=[C:5]([CH2:8][C:14]([CH3:15])=[O:16])[S:6][CH:7]=1)[CH3:2]
Reactant: CCc1csc(C)n1
Reactant: CCOC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1csc(CC(C)=O)n1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
1.70 g (13.4 mmol) of the compound from example 16A are dissolved in 15 ml of abs. THF and, at −78° C., 5.88 ml (14.7 mmol) of n-butyllithium (2.5 M solution in hexane) are added dropwise. After stirring at −78° C. for 2 hours, 2.00 g (22.7 mmol) of ethyl acetate are added as a solution in 10 ml of abs. THF. The mixture is stirred at −78° C. for 1 h and then warmed to room temperature. It is then hydrolyzed with sodium bicarbonate solution, and the mixture is extracted three times with diethyl ether. The combined organic phases are dried with magnesium sulfate, and the solvent is removed in a rotary evaporator. 1.89 g (84% of theory) of the title compound are obtained. GC-MS (Method 2): Rt=4.20 min; MS (Elpos): m/z=169 [M]+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl[C:11]1[C:16]([N+:17]([O-])=O)=[CH:15][CH:14]=[CH:13][N:12]=1.C[O:21][C:22]([CH2:24][CH:25]1[NH:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]1)=O.C[O-].[Na+]>CS(C)=O.O=[Pt]=O>[O:21]=[C:22]1[NH:17][C:16]2[CH:15]=[CH:14][CH:13]=[N:12][C:11]=2[N:30]2[CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26][CH:25]2[CH2:24]1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: COC(=O)CC1CN(C(=O)OC(C)(C)C)CCN1
Agent: O=[Pt]=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN2c3ncccc3NC(=O)CC2C1
Temperature: 95 °C
Reaction time: 54 h

Procedure:
Diisopropylethylamine (3.03 mL, 17.34 mmol) was added to a mixture of 2-chloro-3-nitropyridine (2.75 g, 17.34 mmol) and the product of Example 22B (4.48 g, 17.34 mmol) in dimethyl sulfoxide (20 mL). The mixture was heated at 95° C. under nitrogen for 7 hours and then cooled to room temperature. Ice water (200 mL) was added, and the mixture was extracted with ethyl acetate (2×100 mL). The organic phase was washed with saturated brine (60 mL), dried (MgSO4) and concentrated under vacuum to an oil (6.81 g). This material was dissolved in methanol (400 mL), and PtO2 (25 mg, 0.11 mmol) was added. The flask was evacuated and purged with nitrogen (3 cycles) and then with hydrogen (3 cycles). The suspension was stirred under hydrogen (1 atm) for 54 hours. The flask was evacuated and purged with nitrogen (3 cycles) and the black suspension was filtered through diatomaceous earth with a methanol (2×10 mL) rinse. Sodium methoxide (Aldrich, 25% in methanol, 12.01 g, 55.6 mmol) was added to the filtrate, and the mixture was heated at reflux for 41 hours. After cooling to room temperature, the reaction mixture was concentrated under vacuum. The residue was purified by chromatography (SiO2, eluted with methanol-CH2Cl2 (0:100-5:95), followed by crystallization from ethanol (10 mL) to provide the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 1.48 (s, 9H), 2.27-2.40 (m, 1H), 2.78 (dd, J=13.5, 5.9 Hz, 1H), 2.91-3.20 (m, 3H), 3.55-3.68 (m, 1H), 3.69-3.80 (m, 1H), 3.99-4.19 (m, 2H), 6.95 (dd, J=7.7, 5.0 Hz, 1H), 7.23 (dd, J=7.7, 1.4 Hz, 1H), 7.61 (s, 1H), 8.18 (dd, J=5.0, 1.8 Hz, 1H); MS (ESI) m/z 319 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](Br)=[CH:13][C:12]([CH:16]2[O:20][CH2:19][CH2:18][O:17]2)=[C:11]([CH3:21])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[CH2:33]([O:40][C@@H:41]1[C@@H:47]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C@H:46]([O:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[C@@H:45]([CH2:64][O:65][CH2:66][C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[O:44][C:42]1=[O:43])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:33]([O:40][C@@H:41]1[C@@H:47]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C@H:46]([O:56][CH2:57][C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=2)[C@@H:45]([CH2:64][O:65][CH2:66][C:67]2[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=2)[O:44][C:42]1([C:14]1[CH:13]=[C:12]([CH:16]2[O:20][CH2:19][CH2:18][O:17]2)[C:11]([CH3:21])=[CH:10][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[OH:43])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: Cc1cc(OCc2ccccc2)c(Br)cc1C1OCCO1
Reactant: O=C1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(OCc2ccccc2)c(C2(O)O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1C1OCCO1
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
To a tetrahydrofuran solution (36 mL) of 2-[4-(benzyloxy)-5-bromo-2-methylphenyl]-1,3-dioxolane (5.82 g, 16.6 mmol) was added dropwise under nitrogen atmosphere at −78° C. a 2.67 M n-butyllithium solution in hexane (6.40 mL, 16.6 mmol), and the mixture was stirred for 30 minutes at the same temperature. Then a tetrahydrofuran solution (18 mL) of 2,3,4,6-tetra-O-benzyl-D-glucono-1,5-lactone (8.16 g, 15.1 mmol) was added dropwise, and the mixture was stirred for 20 minutes at the same temperature. To the reaction solution was added a saturated aqueous solution of ammonium chloride, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine, and dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure. Thus obtained residue was purified with silica gel column chromatography (hexane:ethyl acetate=3:1 to 2:1) to obtain the title compound (10.7 g, 87%) as a yellow oily compound.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[N:10](C)[C:11](=[O:13])[CH3:12].[Cl:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>>[Cl:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[CH2:1][CH:2]([NH:10][C:11](=[O:13])[CH3:12])[CH2:3]2)=[O:21]
Reactant: O=C(Cl)CCCCCl
Reactant: CC(=O)N(C)C1Cc2ccccc2C1
Product: CC(=O)NC1Cc2ccc(C(=O)CCCCCl)cc2C1

Procedure:
Using N-(2,3-dihydro-1H-inden-2-yl)-N-methylacetamide and 5-chlorovaleryl chloride according to the same method as that of Example 1, the title compound was obtained as colorless crystals.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([O:9]CC)=O.[Cl:12][C:13]1[S:14][C:15]2[C:21]([N:22]=[C:23]=[O:24])=[C:20]([F:25])[CH:19]=[C:18]([Cl:26])[C:16]=2[N:17]=1>O1CCCC1>[Cl:12][C:13]1[S:14][C:15]2[C:21]([N:22]3[C:7](=[O:9])[CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][N:1]4[C:23]3=[O:24])=[C:20]([F:25])[CH:19]=[C:18]([Cl:26])[C:16]=2[N:17]=1
Reactant: CCOC(=O)C1CCCCN1
Reactant: O=C=Nc1c(F)cc(Cl)c2nc(Cl)sc12
Solvent: C1CCOC1
Product: O=C1C2CCCCN2C(=O)N1c1c(F)cc(Cl)c2nc(Cl)sc12

Procedure:
2.6 g Ethyl piperidine-2-carboxylate was added to a solution of 4.2 g 2,4-dichloro-6-fluoro-7-isocyanato-benzothiazole in 50 ml tetrahydrofuran. The mixture was heated for 5 hours under reflux. After cooling, the solvent was removed in vacuo and the residue recrystallised several times from ethyl acetate. Yield: 2.5 g=42% of theory m.p.: 168°-170° C.
Reaction SMILES: [Br:1][CH2:2][C:3](Cl)=[O:4].[CH:6]1[C:19]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[O:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[CH:6]1[C:19]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:3](=[O:4])[CH2:2][Br:1])[CH:16]=3)[O:11][C:10]=2[CH:9]=[CH:8][C:7]=1[C:3](=[O:4])[CH2:2][Br:1]
Reactant: c1ccc2c(c1)Cc1ccccc1O2
Reactant: O=C(Cl)CBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CBr)c1ccc2c(c1)Cc1cc(C(=O)CBr)ccc1O2
Temperature: 25 °C
Reaction time: 72 h
Yield: 36.7 %

Procedure:
Referring to Scheme 5, bromoacetyl chloride (4.59 ml, 54.9 mmol) was added dropwise to a solution of 9H-xanthene (5 g, 27.4 mmol) and AlCl3 (8.05 g, 60.4 mmol), DCM (100 mL) at 0° C. The reaction mixture was allowed to warm up to rt and left to stir for 72 hrs. The reaction mixture was poured onto ice (400 mL), extracted with DCM (2×200 mL). The combined organic phase was washed with brine (400 mL), dried over MgSO4, filtered and evaporated to dryness. The crude material was precipitated in EtOAc and filtered to give 1,1′-(9H-xanthene-2,7-diyl)bis(2-bromoethanone) (5-2) as a white solid (4.27 g, 36.7% yield). LC-MS (ESI): m/z 425.9 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9]O)[CH:2]=1.[N:11]1C=CC=C[CH:12]=1.CS(Cl)(=O)=O.[C-]#N.[Na+]>C(Cl)Cl.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][C:12]#[N:11])[CH:2]=1
Reactant: c1ccncc1
Reactant: OCCCc1cccnc1
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: N#CCCCc1cccnc1
Reaction time: 4 h
Yield: 56.9 %

Procedure:
To a solution of 0.66 mL (5.11 mmol) 3-pyridine propanol in 5 mL CH2Cl2 at 0° C. was added 0.62 mL (7.67 mmol) pyridine and 0.47 mL (6.14 mmol) methanesulfonyl chloride and the reaction stirred for 4 h. The solution was concentrated under reduced pressure and the crude mesylate dissolved in 10 mL DMF. To this solution was added 902 mg (18.41 mmol) sodium cyanide and the reaction stirred at 60° C. for 3 days. Then the solution was cooled, diluted with H2O (30 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with H2O, dried over MgSO4, and the solvent removed under reduced pressure to give a dark red oil. The crude nitrile was purified by dissolving in EtOAc, washing with H2O, concentrating, and filtering through a silica gel plug (5% MeOH in CH2Cl2) to yield 425 mg (57%) of the nitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2([C:23]([OH:25])=[O:24])[CH2:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1.CC(=CC)C.Cl([O-])=[O:32].[Na+].OP([O-])(O)=O.[Na+]>C(#N)C.C(O)(C)(C)C.O>[C:23]([C:19]1([C:16]2[CH:17]=[CH:18][C:13]([C:3]3[CH:4]=[C:5]4[C:9](=[CH:10][C:2]=3[Cl:1])[NH:8][CH:7]=[C:6]4[C:11]([OH:32])=[O:12])=[CH:14][CH:15]=2)[CH2:22][CH2:21][CH2:20]1)([OH:25])=[O:24]
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1c[nH]c2cc(Cl)c(-c3ccc(C4(C(=O)O)CCC4)cc3)cc12
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CC(C)(C)O
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(C4(C(=O)O)CCC4)cc3)cc12
Temperature: 0 °C
Reaction time: 18 h
Yield: 31.5 %

Procedure:
To a mixture of 1-[4-(6-chloro-3-formyl-1H-indol-5-yl)phenyl]cyclobutane carboxylic acid (120 mg, 0.30 mmol) in acetonitrile (3 mL) and tert-butanol (3 mL) was added 2-methyl-2-butene (3 mL). The reaction mixture was cooled to 0° C. and treated with a solution of sodium chlorite (550 mg, 6.00 mmol) and sodium phosphate monobasic (800 mg, 6.00 mmol) in water (3 mL) dropwise via additional funnel. The ice water bath was removed, and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo to give a residue, which was purified by prep-HPLC (Column: Boston Symmetrix ODS-H 150*30 mm*5 μm Mobile phase: from 39% MeCN in water (0.1% TFA) to 39% MeCN in water (0.1% TFA); Wavelength: 220 nm Flow rate: 30 mL/min;) to give the title compound (35 mg, 27% yield) as a white solid. MS (ES+) 392.0 (M+Na)+. 1H NMR (400 MHz, CD3OD) δ 8.03 (s, 1H), 7.99 (s, 1H), 7.58 (s, 1H), 7.44-7.38 (m, 4H), 2.90-2.84 (m, 2H), 2.62-2.54 (m, 2H), 2.11-1.97 (m, 1H), 1.95-1.91 (m, 1H).