Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][C@@H:5]1[CH2:9][NH:10][C:11]1[NH:12][C:13]2[C:18]([C:19](=[O:21])[CH:20]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH:26]=O.C([O-])(=O)C.[Na+].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:26][NH:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][C@@H:5]1[CH2:9][NH:10][C:11]1[NH:12][C:13]2[C:18]([C:19](=[O:21])[CH:20]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: N[C@@H]1CCC[C@@H]1CNc1cc(=O)c2ccccc2[nH]1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CO
Product: O=c1cc(NC[C@H]2CCC[C@H]2NCc2ccc(Cl)c(Cl)c2)[nH]c2ccccc12

Procedure:
The title compound was prepared from 2-[((1R,2R)-2-aminocyclopentylmethyl)amino]-1H-quinolin-4-one dihydrochloride(0.059 g, 0.18 mmol), 3,4-dichlorobenzaldehyde (0.031 g, 0.18 mmol), sodium acetate (0.045 g, 0.54 mmol) and sodium cyanoborohydride (0.02 g, 0.32 mmol) in a 1% solution of acetic acid in methanol (2 mL) according to the procedure described in Example 61d. δH (CD3OD) 1.61-1.72 (3H, m), 1.79-1.96 (3H, m), 2.27-2.37 (1H, m), 3.18 (1H, q, J=6.44 Hz), 3.30 (1H, d×d, J=6.67 & 13.34 Hz), 3.49 (1H, d×d, J=6.95 & 13.28 Hz), 3.75 (1H, d, J=13.82 Hz), 3.88 (1H, d, J=13.76 Hz), 5.70 (1H, s), 7.18-7.32 (4H, m), 7.42 (1H, d, J=8.26 Hz), 7.51 (1H, t, J=7.84 Hz), 8.10 (1H, d, J=8.02 Hz). MS (ES+) 833 (5%) [2M]H+, 416 (87%) MH+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12]4.Br[C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1>>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)[C:6]3[CH:11]4[CH2:12][CH2:13][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:16][CH2:17]4
Reactant: Brc1ccc2ccccc2n1
Reactant: Fc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Product: Fc1ccc2c(c1)c1c(n2-c2ccc3ccccc3n2)C2CCN(CC2)C1

Procedure:
The reaction of 9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (230 mg, 1.0 mmol; Example 161) and 2-bromoquinoline (312 mg, 1.5 mmol; Alfa Aesar) was performed as described in Example 68 to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.98-2.11 (m, 2H) 2.17-2.31 (m, 2H) 3.09-3.28 (m, 5H) 4.31 (s, 2H) 6.90 (td, J=9, 3 Hz, 1H) 7.13 (dd, J=9, 2 Hz, 1H) 7.42 (dd, J=9, 4 Hz, 1H) 7.57 (d, J=8 Hz, 1H) 7.67 (t, J=8 Hz, 1H) 7.79-7.87 (m, 1H) 7.98-8.08 (m, 2H) 8.55 (d, J=8 Hz, 1H); MS (DCI/NH3) m/z 358 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([S:16]([C:19]1[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=1)(=[O:18])=[O:17])[CH2:3][CH2:4]OS(C1C=C(C)C=CC=1)(=O)=O.[CH3:26][C:27]1[NH:28][C:29]2[C:34]([C:35]=1[C:36]1[CH2:37][CH2:38][NH:39][CH2:40][CH:41]=1)=[CH:33][CH:32]=[CH:31][CH:30]=2>>[CH3:25][C:21]1[CH:20]=[C:19]([S:16]([N:2]([CH3:1])[CH2:3][CH2:4][N:39]2[CH2:40][CH:41]=[C:36]([C:35]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[NH:28][C:27]=3[CH3:26])[CH2:37][CH2:38]2)(=[O:17])=[O:18])[CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cccc(S(=O)(=O)OCCN(C)S(=O)(=O)c2cccc(C)c2)c1
Reactant: Cc1[nH]c2ccccc2c1C1=CCNCC1
Product: Cc1cccc(S(=O)(=O)N(C)CCN2CC=C(c3c(C)[nH]c4ccccc34)CC2)c1

Procedure:
The title compound was prepared using the procedure described in Example 1 using toluene-3-sulfonic acid 2-(methyl-(toluene-3-sulfonyl)-amino)-ethyl ester (D1) and 2-methyl-3-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H indole. MH+ 424.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].ClCCCl.[O:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.[O-]S([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>>[O:13]1[CH2:18][CH2:17][CH:16]([N:1]2[CH2:8][CH2:7][CH2:6][C@H:2]2[C:3]([OH:5])=[O:4])[CH2:15][CH2:14]1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(O)[C@@H]1CCCN1C1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To L-proline (1.00 g; 8.69 mmol) in 1,2-dichloroethane (10 mL) acetic acid (1.98 mL; 33.0 mmol)) is added tetrahydro-pyran-4-one (0.87 g; 8.69 mmol) and Na2SO4 (˜10 equivalents). After 45 minutes of agitation on an orbital shaker, Mp-triacetoxyborohydride resin (4.27 g; 10.42 mmol) is added. The mixture is agitated at RT overnight and filtered and the resin washed with DCM. The combined filtrate is washed with aq. sat. NaHCO3 solution and brine, dried (Na2SO4), filtered and concentrated in vacuo. Excess acetic acid is removed by successive azeotropic distillation with toluene on the rotary evaporator to afford (S)-1-(tetrahydro-pyran-4-yl)pyrrolidine-2-carboxylic acid. ESI-MS: 200 [M+H]+
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:8]=2[O:7][C:6]1=[O:17].[CH3:18][O:19][CH2:20][CH2:21][OH:22]>>[CH3:18][O:19][CH2:20][CH2:21][O:22][C:6]([N:5]1[C:9]2[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:8]=2[O:7][CH2:2][CH2:3][CH2:4]1)=[O:17]
Reactant: O=c1oc2cc([N+](=O)[O-])ccc2n1CCCCl
Reactant: COCCO
Product: COCCOC(=O)N1CCCOc2cc([N+](=O)[O-])ccc21

Procedure:
3-Nitro-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid 2-methoxy-ethyl ester was prepared from 3-(3-chloro-propyl)-6-nitro-3H-benzoxazol-2-one and 2-methoxyethanol in an analogous manner to Example 1426a. Product isolated as a yellow oil (175 mg, 25%). LCMS (m/e) 297 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 7.89-7.83 (m, 2H), 7.57-7.42 (m, 1H), 4.43-4.20 (m, 4H), 3.95-3.81 (m, 2H), 3.70-3.54 (m, 2H), 3.38 (s, 3H), 2.23-2.12 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>>[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:21]
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Reactant: O=C(Cl)c1ccccc1Cl
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3ccccc3Cl)c2)CC1
Yield: 97.8 %

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (50 mg, 0.229 mmol) and 2-chlorobenzoyl chloride (87 μl, 0.687 mmol), 79.9 mg (98%) of the title compound were recovered.
Reaction SMILES: O1CC[CH2:3][CH2:2]1.[CH2:6]([O:8][C:9]([C:11]1[O:12][C:13]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][CH2:24][N:25]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:26]([CH3:29])([CH3:28])[CH3:27])[C:14]=2[C:15]=1[CH3:16])=[O:10])[CH3:7].C([N-]C(C)C)(C)C.[Li+].C(I)C>C(OCC)(=O)C>[CH2:6]([O:8][C:9]([C:11]1[O:12][C:13]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][CH2:24][N:25]([C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[C:26]([CH3:27])([CH3:28])[CH3:29])[C:14]=2[C:15]=1[CH2:16][CH2:2][CH3:3])=[O:10])[CH3:7]
Reactant: CCOC(=O)c1oc2cccc(OCCCN(C(=O)OC(C)(C)C)C(C)(C)C)c2c1C
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCI
Product: CCCc1c(C(=O)OCC)oc2cccc(OCCCN(C(=O)OC(C)(C)C)C(C)(C)C)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a dry tetrahydrofuran (3 ml) solution of 4-[3-(tert-butoxycarbonyl-tert-butyl-amino)-propoxy]-3-methyl-benzofuran-2-carboxylic acid ethyl ester (50 mg) was added lithium diisopropylamide (1.2 ml, 0.5N in THF) at −78° C. After 30 minutes ethyl iodide (160 μl) was added at the same temperature. Then reaction mixture was allowed to warm to ambient temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated ammonium chloride solution and dried over anhydrous sodium sulfate then concentrated in vacuo to dryness. The residue was purified by silica gel column chromatography developed by dichloromethane-methanol to give 4-[3-(tert-butoxycarbonyl-tert-butyl-amino)-propoxy]-3-propyl-benzofuran-2-carboxylic acid ethyl ester as a pale yellow oil (5.1 mg). FAB-MS: m/z 462 (MH+); 1H-NMR (CDCl3): δ 1.12-1.54 (21H, m), 2.09 (2H, m), 2.75 (3H, s), 3.52 (2H, dd, J=7.6 Hz, 9.9 Hz), 4.09 (2H, t, J=5.9 Hz), 4.43 (2H, q, J=7.3 Hz), 6.61 (1H, d, J=7.9 Hz), 7.12 (1H, d, J=8.6 Hz), 7.31 (1H, dd, J=8.6 Hz, 7.9 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27]Br)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:29][C@H:30]1[C@@H:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:33][C:32](=[O:41])[NH:31]1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][N:31]4[C@@H:30]([CH3:29])[C@@H:34]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[O:33][C:32]4=[O:41])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CBr)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CN4C(=O)O[C@H](c5ccccc5)[C@@H]4C)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 5, Step 3, using 1-[4′-(4-bromomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and (4S,5R)-4-methyl-5-phenyl-oxazolidin-2-one.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CN(C=O)C>[N:16]1([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C1CCNCC1
Reactant: O=Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccccc1N1CCCCC1
Yield: 95.1 %

Procedure:
A mixture of o-fluorobenzaldehyde (1.24 gm, 10 mmol), potassium carbonate (2.76 gm, 20 mmol), and piperidine (1.7 gm, 20 mmol) was refluxed in dry DMF for 6 hrs. After the completion of reaction DMF was distilled out at vaccum and 5 ml of water was added to the residue and extracted the product with ethyl acetate (10 ml×2). Organic layer was dried over sodium sulphate and evaporated the solvent to afford 1.8 gm of product (8) (90.5%) 1HNMR CDCl3 (Spectrum 9): 1.68(m, 6H), 3.05(m, 4H), 7.05(m, 2H), 7.45(dd, 1H), 7.75(dd, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[OH:55])[C:5]([OH:47])=[C:6]([CH:46]=1)[CH2:7][C:8]1[C:9]([OH:45])=[C:10]([CH:42]=[CH:43][CH:44]=1)[C:11]([O:13][CH2:14][C:15]1[CH2:16][S:17][C@@H:18]2[CH:29]([NH:30][C:31](=[O:40])[CH2:32][O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28](=[O:41])[N:19]2[C:20]=1[C:21]([O:23]C(C)(C)C)=[O:22])=[O:12].C(Cl)(Cl)(Cl)Cl>C(C(O)=O)(F)(F)F.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[OH:55])[C:5]([OH:47])=[C:6]([CH:46]=1)[CH2:7][C:8]1[C:9]([OH:45])=[C:10]([CH:42]=[CH:43][CH:44]=1)[C:11]([O:13][CH2:14][C:15]1[CH2:16][S:17][C@@H:18]2[CH:29]([NH:30][C:31](=[O:40])[CH2:32][O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28](=[O:41])[N:19]2[C:20]=1[C:21]([OH:23])=[O:22])=[O:12]
Reactant: CC(C)(C)OC(=O)C1=C(COC(=O)c2cccc(Cc3cc(Cl)cc(Cc4ccccc4O)c3O)c2O)CS[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N12
Solvent: ClC(Cl)(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)O)=C(COC(=O)c3cccc(Cc4cc(Cl)cc(Cc5ccccc5O)c4O)c3O)CS[C@H]12
Yield: 90 %

Procedure:
A solution of 17 (3.93 g, 4.99 mmol) in CF3CO2H (35%) in CH2Cl2 (45 mL) was stirred at room temperature for 13 h. The solution was condensed under reduced pressure and then CCl4 (30 mL) was added to the residue and evaporated. The resultant solid was crystallized from a mixture of EtOH and ether (2:1) to afford pure 19 (3.28 g, 4.49 mmol) as a white crystal in 90% yield: mp 196-198° C.; 1H NMR (DMSO-d6 /D2O) d 3.60 (br s, 4H, 2×CH2), 3.68, 3.79 (AB, Jgem =19 Hz, 2H, CH2S), 4.65 (s, 2H, OCH2CO), 4.95, 5.21 (AB, Jgem =14 Hz, 2H, CH2O), 5.15 (d, J=5.1 Hz, 1H, HC(6)), 5.76 (d, J=5.1 Hz, 1H, HC(7)), 6.80-7.35 (m, 14H, 4×ArH); IR (nujol): 3300-3450 (OH, NH, CO2H), 1785 (β-lactam), 1720 (ester), 1685 (amide), 1610 (C=O) cm-1. Anal. (C37H31N2O10SCl) C, H, N, S Cl.
Reaction SMILES: C([CH2:4][O:5][C:6]1[C:14]([CH3:15])=[CH:13][C:12]([O:16][CH3:17])=[CH:11][C:7]=1[C:8]([OH:10])=O)(O)=O.C(O)(=O)C.C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+]>CCCCCC.C(OCC)(=O)C.C(OCC)(=O)C>[CH3:17][O:16][C:12]1[CH:13]=[C:14]([CH3:15])[C:6]2[O:5][CH2:4][C:8](=[O:10])[C:7]=2[CH:11]=1
Reactant: COc1cc(C)c(OCC(=O)O)c(C(=O)O)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: CC(=O)OC(C)=O
Product: COc1cc(C)c2c(c1)C(=O)CO2
Temperature: 120 °C
Reaction time: 4 h
Yield: 8.8 %

Procedure:
The synthesis was performed with reference to the known literature (Bioorganic & Medicinal Chemistry Letters, Vol. 17, p. 6354, 2007). 2-(Carboxymethoxy)-5-methoxy-3-methylbenzoic acid (3.9 g, 16 mmol) was successively added with acetic acid (12 mL), acetic anhydride (20 mL), and sodium acetate (4.0 g), and the mixture was stirred at 120° C. for 4 hours. The reaction mixture was added with ethyl acetate, and the organic layer was successively washed with water, saturated aqueous sodium hydrogencarbonate, and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was successively added with methanol (40 mL), water (10 mL), and concentrated hydrochloric acid (1.0 mL), and the mixture was refluxed for 1 hour by heating. The solvent was evaporated under reduced pressure, then the residue was dissolved in ethyl acetate, and the solution was washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the solid formed was suspended in hexane/ethyl acetate (90:10) and thereby washed to obtain 5-methoxy-7-methylbenzofuran-3(2H)-one (0.25 g, 8%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C([Mg]Br)C.[Br:15][C:16]1[C:17]([N:19]([CH3:24])[C:20](=[O:23])[C:21]=1Br)=[O:18].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Br:15][C:16]1[C:17]([N:19]([CH3:24])[C:20](=[O:23])[C:21]=1[C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([CH3:1])[CH:3]=2)[NH:7][CH:6]=1)=[O:18]
Reactant: CN1C(=O)C(Br)=C(Br)C1=O
Reactant: Cc1ccc2[nH]ccc2c1
Agent: CC[Mg]Br
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Product: Cc1ccc2[nH]cc(C3=C(Br)C(=O)N(C)C3=O)c2c1
Temperature: 40 °C
Reaction time: 0.75 h
Yield: 86.8 %

Procedure:
To a solution of 5-methylindole (90 mg, 0.78 mmol) dissolved in THF (3 mL) was added 0.95M ethylmagnesium bromide (0.83 mL, 0.78 mmol) at 40° C., and the whole was stirred at 40° C. for 45 minutes. Successively, thereto was added a solution of 2,3-dibromo-N-methylmaleimide (100 mg, 0.39 mmol) dissolved in THF (5 mL), followed by stirring under heating and refluxing for 3 hours. After 20% aqueous citric acid solution (1 mL) was added thereto under ice cooling and the whole was stirred, THF was removed by concentration under reduced pressure and the resulting concentrate was extracted with ethyl acetate. The extract was dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (ethyl acetate:n-hexane=1:1) to obtain 2-bromo-3-(5-methyl-1H-indol-3-yl)-N-methylmaleimide (108 mg, 86.3%) as red solids.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:16][C:17]2[CH:27]=[CH:26][C:20]3[NH:21][C:22](=[O:25])[CH2:23][S:24][C:19]=3[CH:18]=2)[CH:5]=[C:6]([C:8]2([O:14][CH3:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.[CH3:28]I>>[F:1][C:2]1[CH:3]=[C:4]([S:16][C:17]2[CH:27]=[CH:26][C:20]3[N:21]([CH3:28])[C:22](=[O:25])[CH2:23][S:24][C:19]=3[CH:18]=2)[CH:5]=[C:6]([C:8]2([O:14][CH3:15])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[CH:7]=1
Reactant: COC1(c2cc(F)cc(Sc3ccc4c(c3)SCC(=O)N4)c2)CCOCC1
Reactant: CI
Product: COC1(c2cc(F)cc(Sc3ccc4c(c3)SCC(=O)N4C)c2)CCOCC1
Yield: 41 %

Procedure:
Using the procedure described in Example 12, 4-[5-fluoro-3-(3-oxo-2,3-dihydro-4H-1,4-benzothiazin-7-ylthio)phenyl]-4-methoxytetrahydropyran was reacted with methyl iodide to give 4-[5-fluoro-3-(4-methyl-3-oxo-2,3-dihydro-4H-1,4-benzothiazin-7-ylthio)phenyl]-4-methoxytetrahydropyran in 41% yield, m.p. 131°-133° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].Br[CH:13]1[CH2:18][CH2:17][O:16][C:14]1=[O:15]>C1COCC1>[N:1]1([CH:13]2[CH2:18][CH2:17][O:16][C:14]2=[O:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C1OCCC1Br
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1OCCC1n1ccc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
An ice cooled solution of indole (9 g, 78 mmol) in dry THF (80 mL) was treated with oil free sodium hydride (2.25 g, 94 mmol). After 1 hour, a solution of 2-bromobutyrolactone (14.6 mL, 78 mmol) in dry THF (20 mL) was added dropwise. After stirring overnight at ambient temperature, the mixture was poured on crushed ice, extracted with ethyl acetate (3×), dried, and evaporated. The residue was purified by flash chromatography on silica gel with a hexane/ethyl acetate gradient (9:1 to 7:3). Evaporation of the eluting solvent gave 8 g of a yellowish oil (52% of theory).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5](=[O:20])[CH:6]=[C:7]([S:14][CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[C:8]2=[O:13].O.[O:22]1CCOCC1>O>[OH:22][CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5](=[O:20])[CH:6]=[C:7]([S:14][CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[C:8]2=[O:13]
Reactant: CC(SC1=CC(=O)c2c(CBr)cccc2C1=O)C(=O)O
Reactant: C1COCCO1
Solvent: O
Product: CC(SC1=CC(=O)c2c(CO)cccc2C1=O)C(=O)O
Reaction time: 1 h

Procedure:
The bromomethyl acid 1b (6 mmol) is mixed in 50 mL of water-dioxane (3:2, v/v) and refluxed with stirring for 1 hour. The solution is then diluted with water (300 mL) and extracted with CHCl3 (3×300 mL). The CHCl3 solution is dried (Na2SO4), concentrated, and chromatographed on a silica gel column (CHCl3 -EtOAc, 7:3 v/v) to yield (5-hydroxymethyl-1,4-naphthoquinonyl thio)-propionic acid, designated 1d.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9](C)[C:10]([N:12]([CH2:16][CH:17]([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[CH:13]([CH3:15])[CH3:14])=[O:11])=[CH:4][CH:3]=1.C([NH:27]CC)C.C(Cl)Cl>>[NH2:27][CH:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:10]([N:12]([CH2:16][CH:17]([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[CH:13]([CH3:15])[CH3:14])=[O:11]
Reactant: CCOC(CN(C(=O)C(C)Cc1ccc(Cl)cc1)C(C)C)OCC
Reactant: CCNCC
Solvent: ClCCl
Product: CCOC(CN(C(=O)C(N)Cc1ccc(Cl)cc1)C(C)C)OCC

Procedure:
A solution of 530 mg (0.915 mmol) of 3-(4-chlorophenyl)-N-(2,2-diethoxyethyl)-N-isopropyl-2-methylpropionamide in 15 ml of a 20% diethylamine DCM solution is stirred at room temperature overnight. The reaction mixture is concentrated in vacuo and purified by chromatography on 5 g of SiO2 (eluent DCM followed by 20% EtOAc/DCM followed by 20% MeOH/DCM). 320 mg of the desired product are obtained as an oil. MW=356.19 (calculated, monoisotopic); measured value (M+H)+=357
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:7]=1.[CH3:16][S-:17].[Na+]>CS(C)=O>[CH3:16][S:17][C:2]1[CH:3]=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:7]=1
Reactant: C[S-]
Reactant: COC(=O)Cc1cc(F)ccc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)Cc1cc(SC)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.3 %

Procedure:
A solution of methyl 5-fluoro-2-nitrophenylacetate (3 g, 14 mmol), (Synthesis 1993, 51), in DMSO (10 ml) was added to a suspension of sodium thiomethoxide (1.08 g, 15.5 mmol) in anhydrous DMSO (10 ml). The mixture was stirred for 10 minutes at ambient temperature and further sodium thiomethoxide (100 mg, 1.5 mmol) was added. The mixture was stirred for 15 minutes at ambient temperature and was then partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (15/85) to give methyl 5-methylthio-2-nitrophenylacetate (2.68 g, 81%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)[CH3:2].C(N(CC)C(C)C)(C)C.Cl.[NH2:27][CH2:28][C:29]1([C:35]2[CH:40]=[CH:39][C:38]([S:41]([NH:44][C:45]3[S:46][C:47]([CH:50]([CH3:52])[CH3:51])=[N:48][N:49]=3)(=[O:43])=[O:42])=[CH:37][CH:36]=2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:5]=1[C:6]([NH:27][CH2:28][C:29]1([C:35]2[CH:36]=[CH:37][C:38]([S:41](=[O:43])(=[O:42])[NH:44][C:45]3[S:46][C:47]([CH:50]([CH3:52])[CH3:51])=[N:48][N:49]=3)=[CH:39][CH:40]=2)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1)=[O:8])[CH3:2]
Reactant: CC(C)c1nnc(NS(=O)(=O)c2ccc(C3(CN)CCCCC3)cc2)s1
Reactant: CCOc1cc(C(F)(F)F)ccc1C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(C(F)(F)F)ccc1C(=O)NCC1(c2ccc(S(=O)(=O)Nc3nnc(C(C)C)s3)cc2)CCCCC1
Yield: 94.6 %

Procedure:
55 mg of 2-ethoxy-4-trifluoromethyl-benzoic acid (example 1g), 85 mg Totu and 100 mg N,N-diisopropylethylamine were dissolved in cold dimethylformamide. After 30 minutes 100 mg of 4-(1-aminomethyl-cyclohexyl)-N-(5-isopropyl-[1,3,4]thiadiazol-2-yl)-benzenesulfonamide hydrochloride were added and the mixture stirred over night. After evaporation of the solvent the residue was purified by chromatography on silica gel with the eluents dichloromethane:methanol=98:2 to obtain 134 mg of an oily product.
Reaction SMILES: [Cl:1][CH2:2][CH:3]([OH:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]([CH3:18])([CH3:17])[C:13]([O:15][CH3:16])=[O:14].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.S(=O)(=O)(O)O.O>CC(C)=O.C(O)(C)C>[Cl:1][CH2:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]([CH3:17])([CH3:18])[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)C(C)(C)OCCCCCCCC(O)CCl
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Solvent: CC(C)O
Product: COC(=O)C(C)(C)OCCCCCCCC(=O)CCl
Yield: 59 %

Procedure:
Methyl 2-(9-chloro-8-hydroxynonyloxy)-2-methylpropionate (31 g) was dissolved in 465 ml of acetone, and 46 ml of Jones reagent prepared by adding 10.2 ml of conc. sulfuric acid and 12 g of chromic (VI) oxide to 45 ml of water was added dropwise with stirring under ice-cooling. After 3-hour-stirring at room temperature, an excess amount of Jones reagent was decomposed by adding isopropyl alcohol, The reaction mixture was poured into ice-cold water, extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane: ethyl acetate=7.5:1) to provide 18.16 g of the objective compound as oil.