Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[BH4-].C([O:5][C:6](=O)[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=1)C.CO>CCOCC>[OH:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]#[N:16])=[CH:13][CH:14]=1
Reactant: CCOC(=O)CCc1ccc(C#N)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CO
Product: N#Cc1ccc(CCCO)cc1

Procedure:
To a solution of LiBH4 (14 g, 0.65 mol) in dry ether (400 mL) was added 3-(4-cyanophenyl)propionic acid ethyl ester (50 g, 0.249 mol; see step (ii) above), followed by methanol (27 mL) dropwise. The reaction mixture was refluxed for 3 h. After completion (monitored by TLC), the reaction was quenched by adding cold, saturated ammonium chloride solution (100 mL), followed by water (300 mL). The layers were then separated. The aqueous layer was extracted with ether (2×100 mL) and the combined organic layers were washed with brine. After drying over anhydrous sodium sulfate, the organic layer was concentrated to give the crude product. This crude product was purified by column chromatography over silica gel, using ethyl acetate in petroleum ether as eluent. This yielded 16.5 g (42%) of the sub-title compound as a pale yellow liquid.
Reaction SMILES: [NH2:1][CH:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:3].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:3][CH:2]([NH:1][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCC(C)N
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCC(C)NS(C)(=O)=O
Reaction time: 0.17 h

Procedure:
To a solution of 10 g (50 mmol) 2-aminotridecane and 5 g triethylamine in 100 ml methylene chloride is added 6 g methanesulfonyl chloride while cooling and stirring for a period of 10 minutes. After one hour of additional stirring, it was allowed to stand over night. The reaction mixture was subsequently transferred to a separatory funnel, washed three times with water, dried over Na2SO4, evaporated to a white solid and dried in a vacuum oven.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Br:6][C:7]1[S:15][C:14]2[CH:13]=[CH:12][NH:11][C:10](=O)[C:9]=2[CH:8]=1>>[Br:6][C:7]1[S:15][C:14]2[CH:13]=[CH:12][N:11]=[C:10]([Cl:3])[C:9]=2[CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]ccc2sc(Br)cc12
Product: Clc1nccc2sc(Br)cc12
Temperature: 135 °C
Yield: 80.7 %

Procedure:
Phosphorus oxychloride (4.08 g, 26.6 mmol) was added dropwise to 2-bromothieno[3,2-c]pyridin-4 (5H)-one (2.04 g, 8.87 mmol) at 0° C. The mixture was heated at 135° C. for 2.5 h, then carefully poured over ice water. The precipitated was collected by filtration and dried to yield 1.78 g (80.7%) of title product. 1H NMR (270 MHz, CH3OH-d4) δ ppm 7.67 (d, 1H) 7.88 (dddd, J=6.33 Hz, 2H) 8.19 (d, J=5.54 Hz, 1H); MS 248.0 (M−H)+; Purity (HPLC) 100
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[C:12]([CH3:13])=[N:11][C:10]([CH3:14])=[N:9]2)[N:5]=[C:4]([CH3:15])[N:3]=1.[NH:16]1[CH2:19][CH:18]([C:20]2[N:24]([CH3:25])[C:23]3[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=3[N:21]=2)[CH2:17]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:14][C:10]1[N:11]=[C:12]([CH3:13])[N:8]([C:6]2[N:5]=[C:4]([CH3:15])[N:3]=[C:2]([N:16]3[CH2:19][CH:18]([C:20]4[N:24]([CH3:25])[C:23]5[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=5[N:21]=4)[CH2:17]3)[CH:7]=2)[N:9]=1
Reactant: Cn1c(C2CNC2)nc2ccccc21
Reactant: Cc1nc(Cl)cc(-n2nc(C)nc2C)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1nc(N2CC(c3nc4ccccc4n3C)C2)cc(-n2nc(C)nc2C)n1
Temperature: 100 °C
Yield: 67.8 %

Procedure:
Intermediate 2 (0.15 g, 0.67 mmol), Intermediate 1 (0.13 g, 0.67 mmol), and Cs2CO3 (0.66 g, 2.01 mmol) were suspended in DMF (6.7 mL) in a microwave vial. The vial was then capped and heated in the microwave at 100° C. for 30 min. After cooling to room temperature, the reaction was filtered and the filtrate was purified by reverse phase chromatography (acetonitrile/water/0.1% TFA). The fractions containing the product were partitioned between EtOAc and saturated NaHCO3. The organic layer was washed with brine, dried over Na2SO4 and concentrated to provide Example 1 (0.17 g, 78%) as a white solid. 1H NMR: (500 MHz, CD3OD) δ 7.63 (d, J=8 Hz, 1H), 7.5 (d, J=8 Hz, 1H), 7.28 (m, 2H), 6.66 (s, 1H), 4.66 (m, 2H), 4.53 (m, 3H), 3.83 (s, 3H), 2.84 (s, 3H), 2.51 (s, 3H), 2.36 (s, 3H). MS: m/z=375.4 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11][C:12](OC)=[O:13].CO.O>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11][CH2:12][OH:13]
Reactant: COC(=O)Cc1cc([N+](=O)[O-])ccc1Br
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=[N+]([O-])c1ccc(Br)c(CCO)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
A solution of methyl 2-(2-bromo-5-nitrophenyl)acetate (14 g, 51 mmol) in THF (150 mL) was cooled to 0° C., then MeOH (15 ml) was added slowly, followed by stirring at room temperature overnight. Water was added to terminate the reaction. The aqueous layer was extracted with ethyl acetate 3 times. The combined organic phase was washed with brine, dried over sodium sulfate and concentrated to give 2-(2-bromo-5-nitrophenyl)ethanol (12 g, yield 96%). 1H NMR: 400 MHz CDCl3 δ 8.18-8.17 (m, 1H), 8.18-8.17 (m, 1H), 7.96-7.93 (m, 1H), 7.74-7.72 (m, 1H), 3.97-3.94 (m, 2H), 3.13-3.10 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[CH:22]=[C:21]([C:23]2[CH:28]=[C:27]([CH:29]=O)[CH:26]=[C:25]([CH:31]=[O:32])[CH:24]=2)[N:20]=[N:19][C:18]=1[O:33][CH3:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN.C(O)(=O)C.[C:41]([BH3-])#[N:42].[Na+]>CO.C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[CH:22]=[C:21]([C:23]2[CH:28]=[C:27]([CH2:29][NH:42][CH3:41])[CH:26]=[C:25]([CH2:31][OH:32])[CH:24]=2)[N:20]=[N:19][C:18]=1[O:33][CH3:34])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: [BH3-]C#N
Reactant: COc1nnc(-c2cc(C=O)cc(C=O)c2)cc1-c1cc2ccccc2n1C(=O)OC(C)(C)C
Agent: CN
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CNCc1cc(CO)cc(-c2cc(-c3cc4ccccc4n3C(=O)OC(C)(C)C)c(OC)nn2)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
170 mg of 2-[6-(3,5-diformyl-phenyl)-3-methoxy-pyridazin-4-yl]-indole-1-carboxylic acid tert-butyl ester is dissolved in 5 ml of methanol and 0.093 ml of methylamine solution in THF is added. The solution is stirred for 5 min at RT then 22 mg of acetic acid and 26 mg of sodium cyanoborohydride is added. The reaction is stirred for 4 h at 60° C. The product is purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid). Yield 19 mg. LC-MS (ES+) 475 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Br:21])=[O:13].[Sn](Cl)(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>C(O)C>[OH:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Br:21])=[O:13]
Reactant: O=C(Nc1ccccc1Br)Nc1cccc([N+](=O)[O-])c1O
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1cccc(NC(=O)Nc2ccccc2Br)c1O
Temperature: 25 °C
Yield: 100.1 %

Procedure:
To a solution of N-(2-hydroxy-3-nitrophenyl)-N′-(2-bromophenyl)urea (300 mg, 0.85 mmol) in ethanol (20 mL), Tin chloride (958 mg, 4.25 mmol) was added. The reaction mixture was stirred at reflux for 16 hours then cooled to room temperature. The reaction mixture was basified to pH 8 with aq. NaHCO3 then extracted with ethyl acetate (3×). The organic extracts were combined, dried over MgSO4, filtered and concentrated under reduced pressure to give product (274 mg, 99%). EI-MS m/z 323 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28].C([O-])([O-])=O.[K+].[K+].[CH:36](I)([CH3:38])[CH3:37]>C(#N)C>[CH:36]([N:14]1[CH2:15][CH2:16][C:11]2([CH2:10][C:9](=[O:28])[C:8]3[C:25](=[CH:26][CH:27]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:2])=[O:29])[CH:7]=3)[O:24]2)[CH2:12][CH2:13]1)([CH3:38])[CH3:37]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)N1CCC2(CC1)CC(=O)c1cc(/C=C/C(=O)O)ccc1O2
Temperature: 75 °C
Yield: 97.4 %

Procedure:
(E)-3-{4-Oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (500 mg, 1.48 mmol, Intermediate 1, hydrochloride salt) was suspended in acetonitrile (65 ml). K2CO3 (818 mg, 5.92 mmol) and isopropyl iodide (523 mg, 3.07 mmol) were subsequently added and the mixture was heated at 75° C. for 14 h. The solvent was evaporated and the residue was diluted with water and extracted with ethyl acetate. The combined organic phases were dried, evaporated, and the crude oily residue (575 mg) was hydrolyzed as described in Example 55, Step B, giving (E)-3-{1′-isopropyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid (475 mg) as an orange solid (hydrochloride salt). The resulting acid was suspended in DCM (16 ml), TEA (0.30 ml) was added, and the resulting clear solution was treated with NH2OTHP following the procedure described in Example 1, Step B, giving (E)-3-{1′-isopropyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide as an orange solid (314 mg). The compound was dissolved in DCM (4 ml) and treated with 1 M HCl in diethyl ether (6 ml, 6 mmol) as described in Example 2, Step D, giving a light pink solid (192 mg, trifluoroacetate salt) after purification by preparative HPLC.
Reaction SMILES: [CH3:1][N:2]1[C:15]2[CH:14]=[C:13]([CH2:16][C:17](OCC)=[O:18])[CH:12]=[CH:11][C:10]=2[S:9](=[O:23])(=[O:22])[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.I[CH2:25][C@H:26]1[CH2:34][CH2:33][C:28]2([O:32]CCO2)[CH2:27]1.O=C1CC[C@H](C(OC)=O)C1.[CH3:45][O:46][C:47]1[N:52]=[C:51]2[S:53][C:54]([NH2:56])=[N:55][C:50]2=[CH:49][CH:48]=1>>[CH3:45][O:46][C:47]1[N:52]=[C:51]2[S:53][C:54]([NH:56][C:17](=[O:18])[CH:16]([C:13]3[CH:12]=[CH:11][C:10]4[S:9](=[O:22])(=[O:23])[C:8]5[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=5)[N:2]([CH3:1])[C:15]=4[CH:14]=3)[CH2:25][C@H:26]3[CH2:34][CH2:33][C:28](=[O:32])[CH2:27]3)=[N:55][C:50]2=[CH:49][CH:48]=1
Reactant: IC[C@H]1CCC2(C1)OCCO2
Reactant: CCOC(=O)Cc1ccc2c(c1)N(C)c1ccccc1S2(=O)=O
Reactant: COc1ccc2nc(N)sc2n1
Agent: COC(=O)[C@H]1CCC(=O)C1
Product: COc1ccc2nc(NC(=O)C(C[C@H]3CCC(=O)C3)c3ccc4c(c3)N(C)c3ccccc3S4(=O)=O)sc2n1

Procedure:
Analogously to Example 1 and Example 36, ethyl (10-methyl-5,5-dioxo-5,10-dihydrophenothiazin-2-yl)acetate, (S)-7-iodomethyl-1,4-d ioxaspiro[4.4]nonane (prepared analogously to Example 40 from commercially available methyl (S)-3-oxo-cyclopentanecarboxylate) and 5-methoxy-thiazolo[5,4-b]pyridin-2-ylamine give N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)-2-(10-methyl-5,5-dioxo-5,10-dihydrophenothiazin-2-yl)-3-((R)-3-oxocyclopentyl)propionamide.
Reaction SMILES: [ClH:1].[C:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][N:21]=2)[C:15]([O:17][CH3:18])=[O:16])=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3]>CO.[Pt](=O)=O>[ClH:1].[C:2]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:13][CH:14]([C:15]([O:17][CH3:18])=[O:16])[CH2:19][CH2:20][NH:21]2)=[CH:8][CH:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccnc(-c2ccc(C(C)(C)C)cc2)c1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: COC(=O)C1CCNC(c2ccc(C(C)(C)C)cc2)C1
Yield: 98.7 %

Procedure:
To a solution of methyl 2-(4-tert-butylphenyl)isonicotinate hydrochloride (9.6 g, 31.39 mmol) in MeOH (100 mL) was added platinum(IV) oxide (0.713 g, 3.14 mmol). The resulting mixture was hydrogenated in a Büchi hydrogenator at 5 bar. After 8 h the reaction mixture was filtered through a diatomeous earth filter carton, the residue washed with methanol, and the filtrate evaporated. Methyl 2-(4-tert-butylphenyl)piperidine-4-carboxylate hydrochloride (9.66 g, 99%) was isolated as a brown solid. 1H NMR (400 MHz, dmso) δ 1.26 (s, 9H), 1.88-2.15 (m, 4H), 2.82-2.92 (m, 1H), 3.03-3.16 (m, 1H), 3.27-3.38 (m, 1H), 3.61 (s, 3H), 4.22-4.29 (m, 1H), 7.42-7.53 (m, 4H), 9.43 (br, 2H). MS m/z 276 (M+H)+
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)[O:3]1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(N(CC)CC)C>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([O:15][C:11]2[CH:10]=[C:9]([B:4]3[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)[CH:14]=[CH:13][CH:12]=2)=[CH:20][CH:19]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC1(C)OB(c2cccc(O)c2)OC1(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Product: CC1(C)OB(c2cccc(Oc3ccc(Cl)cc3)c2)OC1(C)C

Procedure:
3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (0.23 g), copper(II) acetate (0.19 g), triethylamine (0.218 g) and 4-chlorophenylboronic acid (0.237 g) were stirred at room temperature overnight. The solid was filtered off, and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (Varian, Superflash SF25-40 g column), eluting with 0-25% ethyl acetate/hexane, to provide the title compound.
Reaction SMILES: [N+]([C@@H:4]1[CH2:9][CH2:8][C:7](=[O:10])[NH:6][C@H:5]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O-])=O.ClCCl.CC(C)([O-:23])C.[K+].CSC>CO>[O:10]=[C:7]1[CH2:8][CH2:9][C:4](=[O:23])[CH:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:6]1
Reactant: CC(C)(C)[O-]
Reactant: O=C1CC[C@@H]([N+](=O)[O-])[C@H](c2ccccc2)N1
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: CSC
Product: O=C1CCC(=O)C(c2ccccc2)N1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 78.4 %

Procedure:
trans-3 -Nitro-6-oxo-2-phenylpiperidine (80 g, 0.364 mol) was suspended in methanol:dichloromethane (Example 1a, 1:1, 500 ml) under nitrogen. The suspension was cooled to 0° C. and potassium t-butoxide (44.8 g, 0.4 mol) was added in portions over 30 mins. The cooling bath was then removed and the solution stirred for a further 15 mins to afford a clear yellow solution. The solution was then cooled to -78° C. and ozone bubbled through the reaction mixture for 4.5 hrs, the flow of ozone was then stopped and the mixture purged with a stream of nitrogen. Anhydrous dimethyl sulphide (53 ml, 0.73 mol) was then added dropwise and the reaction mixture allowed to warm to room temperature. The solvent was then removed at reduced pressure and the residual orange solid dissolved in dichloromethane (800 ml), washed with water (2×200 ml), dried (MgSO4), the solvent was then removed at reduced pressure. The residue was suspended in ether, filtered, and the pale yellow crystalline solid washed with ether (3×100ml) and dried under vacuum to afford 2,5-dioxo-6-phenylpiperidine (54 g, 78%): m.p. 160°-164° C.; 1H NMR (360 MHz, DMSO-d6) δ2.55-2.58 (2H, m, CH2), 2.63-2.70 (2H, m, CH2), 2.5-2.9 (4H, m, CH2CH2), 4.96 (1H, d, J=2.4 Hz, PhCH), 7.4-7.7 (5H, m, Ar), 8.2 (1H, brs, NH); m/z (CI+) 207 (M+NH4 +), 190 (M+H); Calculated for C11H11NO2C; 69.83; H, 5.86; N, 7.40%. Found C, 70.04; H, 5.77; N, 7.60%.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[C:19]([S:21][C:22]#N)[CH:18]=[CH:17][C:5]=1[NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8])([O-:3])=[O:2].[BH4-].[Na+].CI.O>CO>[N+:1]([C:4]1[CH:20]=[C:19]([S:21][CH3:22])[CH:18]=[CH:17][C:5]=1[NH:6][S:7]([C:10]1[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=1)(=[O:9])=[O:8])([O-:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(SC#N)cc2[N+](=O)[O-])cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: CO
Product: CSc1ccc(NS(=O)(=O)c2ccc(C)cc2)c([N+](=O)[O-])c1
Yield: 47 %

Procedure:
To a solution of 2′-Nitro-4′-thiocyano-p-toluenesulfonanilide (5.0 g (14.3 mmol) in methanol (20 ml), sodium borohydride (2.80 g (66.7 mmol)) was added under cooling with ice and with stirring. After 30 minutes' stirring, to the resulting mixture, methyl iodide (3.67 ml (59.0 mmol)) was added dropwise under cooling with ice and the mixture was then stirred at room temperature for 20 hours. Then, water was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was then subjected to silica gel column chromatography with ethyl acetate-hexane (1:4) as eluent. The resulting crystals were recrystallized from ethyl acetate to give 2.27 g (47%) of 2′-nitro-4′-methylthio-p-toluenesulfonanilide as orange crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[C:5]([N:7]([CH3:20])[C@@H:8]([C:17](O)=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)=[O:6].N[C@@H](C(O)=O)CC1C=CC(O)=CC=1.Cl.C[O:40][C:41](=[O:54])[C@H:42]([CH2:44][C:45]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[NH:47][CH:46]=1)[NH2:43]>>[CH3:24][C:22]1[CH:21]=[C:4]([CH:3]=[C:2]([CH3:1])[CH:23]=1)[C:5]([N:7]([CH3:20])[C@@H:8]([C:17]([NH:43][C@H:42]([C:41]([OH:40])=[O:54])[CH2:44][C:45]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[NH:47][CH:46]=1)=[O:18])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1)=[O:6]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: Cc1cc(C)cc(C(=O)N(C)[C@H](Cc2ccc(O)cc2)C(=O)O)c1
Agent: Cl
Agent: N[C@H](Cc1ccc(O)cc1)C(=O)O
Product: Cc1cc(C)cc(C(=O)N(C)[C@H](Cc2ccc(O)cc2)C(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)O)c1

Procedure:
Coupling of N-(3,5-dimethylbenzoyl)-N-methyl-(D)-tyrosine (prepared from (D)-tyrosine following the procedure described in example 55) with (L)-tryptophan methyl ester hydrochloride according to example 1 followed by hydrolysis of the methyl ester moiety according to example 12 gives N-(3,5-dimethylbenzoyl)-N-methyl-(D)-tyrosyl-(L)-tryptophan; FAB-MS m/e 512 (M-H)-.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[C:19]([N:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])=[N:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:25]([O:27]C)=[O:26])[CH:16]=3)[N:11]=2)=[CH:2]1.[OH-].[Na+].Cl>O1CCCC1.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[C:19]([N:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])=[N:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:25]([OH:27])=[O:26])[CH:16]=3)[N:11]=2)=[CH:2]1
Reactant: COC(=O)c1ccc2nc(-c3coc4ccccc34)c(N(C)C(C)C)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1coc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.6 %

Procedure:
To a solution of methyl 2-(benzofuran-3-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (100 mg, 0.27 mmol) in tetrahydrofuran (20 mL) and water (1 mL) was added sodium hydroxide (105 mg, 2.62 mmol). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (10 mL), the pH was adjusted to 6 with HCl (3N) and filtered to give 2-(benzofuran-3-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid as a light yellow solid (35.7 mg, 37%).
Reaction SMILES: [CH3:1][O:2][C:3]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH2:12][CH2:11][C:6]2(OCC[O:7]2)[CH2:5][CH2:4]1.O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH3:1][O:2][C:3]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH2:12][CH2:11][C:6](=[O:7])[CH2:5][CH2:4]1
Reactant: COC1(Cc2ccccc2C)CCC2(CC1)OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: COC1(Cc2ccccc2C)CCC(=O)CC1
Reaction time: 8 h
Yield: 100.4 %

Procedure:
A solution of EXAMPLE 15B (0.51 g, 1.80 mmol) in acetone (10 mL) was treated with water (5 mL) and p-toluenesulfonic acid monohydrate (0.20 g), heated to reflux, stirred overnight, and concentrated to remove the acetone. The remaining aqueous solution was extracted with ethyl acetate (3×100 mL) and the combined extracts were washed sequentially with 1N NaOH, water, and brine, dried (Na2SO4), filtered, and concentrated to provide the desired product (0.42 g, 100%). MS (ESI) m/e 233 (M+H)+.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([NH:13][C:14]([C:16]1[N:17]=[C:18]([N:21]2[CH2:24][CH:23]([S:25][C:26]3[C@H:27]([CH3:50])[C@@H:28]4[C@@H:45]([C@H:46]([OH:48])[CH3:47])[C:44](=[O:49])[N:29]4[C:30]=3[C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[CH2:22]2)[S:19][CH:20]=1)=[O:15])[CH2:11][CH3:12])(C(C)(C)C)(C)C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][CH2:9][C@@H:10]([NH:13][C:14]([C:16]1[N:17]=[C:18]([N:21]2[CH2:24][CH:23]([S:25][C:26]3[C@H:27]([CH3:50])[C@@H:28]4[C@@H:45]([C@H:46]([OH:48])[CH3:47])[C:44](=[O:49])[N:29]4[C:30]=3[C:31]([O:33][CH2:34][C:35]3[CH:36]=[CH:37][C:38]([N+:41]([O-:43])=[O:42])=[CH:39][CH:40]=3)=[O:32])[CH2:22]2)[S:19][CH:20]=1)=[O:15])[CH2:11][CH3:12]
Reactant: CC[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)C2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC[C@@H](CO)NC(=O)c1csc(N2CC(SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)C2)n1
Yield: 56.2 %

Procedure:
To a solution of p-nitrobenzyl (1R,5S,6S)-2-(1-{4-[(1S)-1-(t-butyldimethylsilyloxymethyl)-propylcarbamoyl]-1,3-thiazol-2-yl}azetidin-3-yl)thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (920 mg, 1.23 mmol) (obtained as described in Example 39(1)) in tetrahydrofuran (46 ml) were added acetic acid (208 μl, 3.63 mmol) and a solution of 1 M tetrabutylammonium fluoride in tetrahydrofuran (3.63 ml, 3.63 mmol) in an ice bath and the mixture was stirred for 2 days at room temperature. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate and ethyl acetate:methanol (95:5) as the eluant to afford p-nitrobenzyl (1R,5S,6S)-2-{1-[4-((1S)-1-hydroxymethyl-propylcarbamoyl)-1,3-thiazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (437 mg, yield 56%) as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[NH:17]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21](B(O)O)[C:20]=2[CH:19]=[CH:18]1.C(=O)([O-])O.[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH:17]1[C:25]2[C:20](=[C:21]([C:2]3[N:3]=[C:4]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)[C:5]4[S:10][CH:9]=[CH:8][C:6]=4[N:7]=3)[CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18]1
Reactant: OB(O)c1cccc2[nH]ccc12
Reactant: Clc1nc(N2CCOCC2)c2sccc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: c1cc(-c2nc(N3CCOCC3)c3sccc3n2)c2cc[nH]c2c1
Yield: 25.3 %

Procedure:
2-Chloro-4-morpholin-4-yl-thieno-[3.2-d]pyrimidine 4 (120 mg), 4-indole-boronic acid (110 mg), sodium hydrogen carbonate (120 mg) and PdCl2(PPh3)2 (30 mg) in DME (3 ml) and water (1 ml) were heated in a microwave for 90 min at 130° C. Dichloromethane/water extraction and purification on silica gave 199 (40 mg). NMR: (400 MHz, CDCl3): 3.95 (4H, t, J=4.5), 4.13 (4H, t, J=4.5), 7.30-7.38 (2H, m), 7.52 (1H, d, J=8.1), 7.55-7.59 (2H, m), 7.75 (1H, d, J=5.5), 8.22 (1H, d, J=7.4), 8.30 (1H, br) MS: (ESI+): MH+ 337