Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]([C:21]([OH:23])=O)=[C:6]2[CH2:14][CH2:13][C:12]3[CH:11]=[C:10]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[S:9][C:8]=3[C:7]=12.O1C=C[N:26]=C1Cl>O1CCCC1.CN(C)C=O>[CH3:1][S:2][C:3]1[S:4][C:5]([C:21]([NH2:26])=[O:23])=[C:6]2[CH2:14][CH2:13][C:12]3[CH:11]=[C:10]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[S:9][C:8]=3[C:7]=12
Reactant: Clc1ncco1
Reactant: CSc1sc(C(=O)O)c2c1-c1sc(-c3ccccc3)cc1CC2
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CSc1sc(C(N)=O)c2c1-c1sc(-c3ccccc3)cc1CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
4,5-Dihydro-8-methylthio-2-phenylbenzo[2,1-c:3,4-b']dithiophene-6-carboxylic acid (0.50 g) was dissolved in tetrahydrofuran (10 ml); oxazolyl chloride (0.15 ml) and then N,N-dimethylformamide (one drop) were added. After the mixture was stirred at room temperature for 2 hours, it was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (30 ml); concentrated aqueous ammonia (5 ml) was added. After the reaction mixture was stirred at room temperature for one hour, it was poured over water and extracted with chloroform-methanol. The organic layer was washed with water and dried (MgSO4), after which the solvent was distilled off to yield 4,5-dihydro-8-methylthio-2-phenylbenzo[2,1-c:3,4-b']dithiophene-6-carboxamide (0.28 g, 56%), which was recrystallized from ethanol. Melting point 192-193° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10](COCC[Si](C)(C)C)[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31]C(C)(C)C)=[O:30])[C:26]([C:36]3[CH:37]=[N:38][NH:39][CH:40]=3)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12].Br[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[C:53]([Cl:57])[CH:52]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([OH:31])=[O:30])[C:26]([C:36]3[CH:40]=[N:39][N:38]([CH2:50][C:51]4[CH:56]=[CH:55][CH:54]=[C:53]([Cl:57])[CH:52]=4)[CH:37]=3)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)ccc1-c1cn[nH]c1
Reactant: Clc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1nc2ccccc2s1)c1cccc2c1CN(c1ccc(-c3cnn(Cc4cccc(Cl)c4)c3)c(C(=O)O)n1)CC2
Reaction time: 3 h

Procedure:
A solution of EXAMPLE 9B (0.178 g), 1-(bromomethyl)-3-chlorobenzene (0.080 g) and cesium carbonate (0.170 g) was stirred together in N,N-dimethylformamide (2 mL) at room temperature. After 3 hours, the reaction was diluted with ethyl acetate (25 mL) and washed with water (20 mL), brine (20 mL), dried over magnesium sulfate, filtered, and concentrated. The residue was dissolved in dichloromethane (1 mL) and treated with TFA (1 mL) and stirred overnight. The mixture was concentrated, dissolved in dichloromethane and loaded onto silica gel and eluted using a gradient of 0.5% to 4% methanol/dichloromethane to provide the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 12.84 (s, 1H), 8.04 (dd, 1H), 7.95 (d, 1H), 7.79 (d, 1H), 7.71 (d, 1H), 7.60 (dd, 2H), 7.53-7.28 (m, 7H), 7.22-7.16 (m, 1H), 6.95 (d, 1H), 5.35 (s, 2H), 4.95 (s, 2H), 3.87 (t, 2H), 3.00 (t, 2H).
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH3:4][C:5]1[O:9][C:8]2[CH:10]=[CH:11][C:12]([C:14](=[O:18])[C:15]([OH:17])=[O:16])=[CH:13][C:7]=2[CH:6]=1>C(OCC)C.C(O)(=O)C>[CH3:4][C:5]1[O:9][C:8]2[CH:10]=[CH:11][C:12]([C:14](=[O:18])[C:15]([O:17][CH3:3])=[O:16])=[CH:13][C:7]=2[CH:6]=1
Reactant: Cc1cc2cc(C(=O)C(=O)O)ccc2o1
Reactant: C=[N+]=[N-]
Solvent: CC(=O)O
Solvent: CCOCC
Product: COC(=O)C(=O)c1ccc2oc(C)cc2c1
Reaction time: 0.08 h

Procedure:
An ethereal solution of diazomethane is added in portions to a solution of 2-methyl-5-benzo(b)furanylglyoxylic acid in dry ethyl ether until the yellow color of diazomethane persists. The resulting mixture is stirred five minutes and a few drops of ethereal acetic acid added to consume the excess reagent. The ether solution is washed with water, dilute sodium bicarbonate solution, water again and dried over anhydrous magnesium sulfate. The ether is evaporated to obtain methyl 2-methyl-5-benzo(b)furanylglyoxylate.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:41])[C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([O:20][CH3:21])[C:14]=2[NH:22][C:23]([C:25]2[S:26][CH:27]=[C:28]([CH2:31][C:32]3[N:36]=[C:35](C(Cl)(Cl)Cl)[O:34][N:33]=3)[C:29]=2[Cl:30])=[O:24])=[N:9][CH:10]=1.O>CN(C=O)C>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:41])[C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([O:20][CH3:21])[C:14]=2[NH:22][C:23]([C:25]2[S:26][CH:27]=[C:28]([CH2:31][C:32]3[N:36]=[C:35]([N:2]([CH3:3])[CH3:1])[O:34][N:33]=3)[C:29]=2[Cl:30])=[O:24])=[N:9][CH:10]=1
Reactant: CNC
Reactant: COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cn2)c1NC(=O)c1scc(Cc2noc(C(Cl)(Cl)Cl)n2)c1Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cn2)c1NC(=O)c1scc(Cc2noc(N(C)C)n2)c1Cl
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Dimethylamine (40% aqueous, 0.51 mL, 4.1 mmol) was dissolved in DMF (2 mL) under nitrogen, and N-(5-chloropyridin-2-yl)-2-[((4-((5-trichloromethyl-1,2,4-oxadiazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide (0.151 g, 0.23 mmol) was added. The reaction mixture was stirred for 40 minutes at ambient temperature, then poured into water (40 mL). The aqueous layer was extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with water (3×25 mL), brine (25 mL), dried over magnesium sulfate, concentrated in vacuo, and dried under vacuum. The crude product was purified by flash chromatography on silica gel, eluting with 75% ethyl acetate/hexanes to afford N-(5-chloropyridin-2-yl)-2-[((4-((5-(dimethylamino)-1,2,4-oxadiazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide; NMR (DMSO-d6) 10.9 (br, 1), 9.4 (br, 1), 8.4 (d, 1), 8.1 (d, 1), 7.9 (dd, 1), 7.8 (s, 1), 7.4 (d, 1), 3.9 (s, 3), 3.8 (s, 2), 3.0 (s, 6) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[N+:10]([CH3:13])([O-:12])=[O:11].[OH-].[Na+].C(O)(=O)C>CCO>[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH2:13][N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: Cc1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccc(C(O)C[N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
A stirred solution of 4-methylbenzaldehyde (325 mg, 319 μL, 2.71 mmol) and nitromethane (531 μL, 9.89 mmol) in absolute EtOH (20 mL) at 0° C. was treated with 10% aq. NaOH (m/v) (1.14 mL, 2.84 mmol), stirred for 1 h and treated with 2% aq. acetic acid (m/v) (8.54 mL, 2.84 mmol). The reaction was stirred for 1 h at room temperature then partitioned between water (50 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (2×50 mL) and the combined organic extracts were washed with saturated NaHCO3 (50 mL) and brine (50 mL), dried (Na2SO4) and concentrated in vacuo to afford 1-(4-methylphenyl)-2-nitroethanol as a colorless oil. 1H NMR (CDCl3, 500 MHz) δ 7.28 (d, J=8.1 Hz, 2H), 7.21 (d, J=8.1 Hz, 2H), 5.42 (dt, J=9.6, 3.3 Hz, 1H), 4.60 (dd, J=13.3, 9.7 Hz, 1H), 4.49 (dd, J=13.3, 3.1 Hz, 1H), 2.79 (d, J=3.7, 1H), 2.36 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:4].[NH:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:14][C:15]([OH:17])=[O:16].C(N(CCC)C(COC(=O)CCNC(OC(C)(C)C)=O)=O)CC.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH:6]1([O:5][C:3]([CH2:2][O:17][C:15](=[O:16])[CH2:14][CH2:13][NH:12][C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])=[O:4])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=C(CCl)OC1CCCCC1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CCCN(CCC)C(=O)COC(=O)CCNC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)(C)OC(=O)NCCC(=O)OCC(=O)OC1CCCCC1

Procedure:
This compound was prepared from cyclohexyl 2-chloroacetate and Boc-Beta-Ala-OH by an analogous method to 3-tert-butoxycarbonylamino-propionic acid dipropylcarbamoylmethyl ester (Int. AA step 1). Cesium carbonate was used in place of potassium carbonate; 1H NMR (400 MHz, DMSO-d6) δ 6.83 (1H, br s), 4.76-4.70 (1H, m), 4.62 (2H, s), 3.20-3.12 (2H, m), 2.53 (2H, under DMSO peak), 1.28-1.72 (2H, m), 1.68-1.60 (2H, m), 1.53-1.18 (15H, m).
Reaction SMILES: [CH2:1]([CH2:8][NH:9][C:10]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[C:13]([C:23](O)=[O:24])=[CH:12][N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][NH:27][CH2:28][C@H:29]([OH:37])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=1.Cl>>[OH:37][CH:29]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=1)[CH2:28][N:27]([CH3:26])[C:23]([C:13]1[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[N:15][C:10]([NH:9][CH2:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:11][CH:12]=1)=[O:24]
Reactant: O=C(O)c1cnc(NCCc2ccccc2)nc1-c1ccccc1Cl
Reactant: CNC[C@H](O)c1cccc(O)c1
Agent: Cl
Product: CN(CC(O)c1cccc(O)c1)C(=O)c1cnc(NCCc2ccccc2)nc1-c1ccccc1Cl

Procedure:
The material is prepared according to the method described in Example 17. starting from 2-(Benzylmethylamino)-4-(2-chlorophenyl)pyrimidine-5-carboxylic acid and L-phenylephrine hydrochloride. M.p.: 139° C.
Reaction SMILES: [N+](=[C:3]([C:17](=[O:28])[C@@H:18]([C@@H:20]1[C@@H:23]([C@H:24]([OH:26])[CH3:25])[C:22](=[O:27])[NH:21]1)[CH3:19])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])=[N-]>ClC(Cl)C.C1C=CC=CC=1.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[OH:26][C@@H:24]([C@H:23]1[C:22](=[O:27])[N:21]2[C@@H:20]1[C@@H:18]([CH3:19])[C:17](=[O:28])[CH:3]2[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])[CH3:25]
Reactant: C[C@@H](O)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: c1ccccc1
Solvent: CC(Cl)Cl
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12

Procedure:
To a solution of 4-nitrobenzyl (4R)-2-diazo-4-[(2R, 3S)-3-{(1R)-1-hydroxyethyl}-4-oxoazetidin-2-yl]-3-oxopentanoate (1.0 g) in dichloroethane (50 ml) was added rhodium (II) acetate (2 mg) under refluxing. After refluxing for 1 hour, the reaction mixture was evaporated in vacuo to give a residue. The residue was dissolved in anhydrous benzene (10 ml) and then evaporated. This operation was repeated once again to give 4-nitrobenzyl (4R,5R,6S)-6-[(1R)-1-hydroxyethyl]4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate. The compound obtained above was dissolved in anhydrous acetonitrile (20 ml) and cooled to 0° C. under an atmosphere of nitrogen. To this solution were added N,N-diisopropyl-N-ethylamine (0.59 ml) and diphenyl phosphorochloridate (0.61 ml) successively, and the solution was stirred at 0°-5° C. for 40 minutes. To the resulting solution were added a solution of (2S,4S)-2-(2-aminothiazol-4-yl)-4-mercapto-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.07 g) in acetonitrile and N,N-diisopropyl-N-ethylamine (0.59 ml) and the stirring was continued at the same temperature for 2 hours. The reaction mixture was poured into ethyl acetate (60 ml) and washed with 0.1N hydrochloric acid, saturated aqueous sodium bicarbonate and brine successively. The dried organic layer was evaporated and the oily residue was chromatographed on silica gel (60 g) eluting with a mixture of dichloromethane and acetone (5:2 V/V) to give 4-nitrobenzyl (4R,5S,6S)-3-[(2S,4S)-2-(2-aminothiazol-4-yl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (900 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10](=[O:25])[CH2:11][C:12](=[O:24])/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([O:22][CH3:23])[CH:16]=2)=[CH:4][C:3]=1[O:26][CH3:27].[CH3:28][N:29]([CH3:33])[C:30](Cl)=[O:31]>C(Cl)Cl>[CH3:28][N:29]([CH3:33])[C:30](=[O:31])[O:21][C:18]1[CH:19]=[CH:20][C:15](/[CH:14]=[CH:13]/[C:12](=[O:24])[CH2:11][C:10](=[O:25])/[CH:9]=[CH:8]/[C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([O:26][CH3:27])[CH:4]=2)=[CH:16][C:17]=1[O:22][CH3:23]
Reactant: CN(C)C(=O)Cl
Reactant: COc1cc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)c(OC)c2)ccc1O
Solvent: ClCCl
Product: COc1cc(/C=C/C(=O)CC(=O)/C=C/c2ccc(OC(=O)N(C)C)c(OC)c2)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.4 %

Procedure:
To the solution of (1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione (150 mg, 0.4 mmol, 1.0 eq.) in dry DCM (15 mL) were added TEA (81 mg, 0.8 mmol, 2.0 eq.) and dimethylcarbamic chloride (43.8 mg, 0.4 mmol, 1.0 eq.). The reaction mixture was stirred at rt overnight, then washed with water and extracted with CH2Cl2 (30 mL×2). The combined organic layers werewashed with H2O, dried over anhydrous Na2SO4 and concentrated. The resulting residue was separated by Prep-HPLC to provide 4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl dimethylcarbamate (50 mg, 28% yield). LRMS (M+H+) m/z calculated 440.2. found 440.2. 1H NMR (CDCl3, 400 MHz) δ 7.56 (s, 1H), 7.52 (s, 1H), 6.98-7.07 (m, 6H), 6.87 (d, 1H), 6.40-6.49 (m, 2H), 5.76 (s, 1H), 3.88 (s, 3H), 3.82 (s, 3H), 3.06 (s, 3H), 2.95 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.Br[CH2:13][C:14]1[CH:15]=[C:16]([C:20]2[N:24]=[C:23]([CH3:25])[O:22][N:21]=2)[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]4[N:24]=[C:23]([CH3:25])[O:22][N:21]=4)[CH:15]=3)[C:6]=2[CH:11]=1
Reactant: O=c1[nH]c2cc(Cl)ccc2s1
Reactant: Cc1nc(-c2cccc(CBr)c2)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1nc(-c2cccc(Cn3c(=O)sc4ccc(Cl)cc43)c2)no1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A suspension of 100 mg (0.54 mmol) of 5-chloro-3H-benzothiazol-2-one, 153 mg (0.59 mmol) of 3-(3-bromomethylphenyl)-5-methyl-1,2,4-oxadiazole and 303 mg (2.16 mmol) of potassium carbonate in 20 ml of acetonitrile are stirred at 80° C. for 1 h. 30 ml of water are added to the reaction mixture, which is then extracted with MTBE, dried and evaporated to dryness. The crude product is purified by column chromatography on silica gel and stirred with ether, giving “A12”: ESI: 358 (M+H); Rt.=3.25 min (method A);
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH3:55][O:56][C:57]1[CH:62]=[CH:61][C:60]([S:63](Cl)(=[O:65])=[O:64])=[CH:59][CH:58]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([S:63]([C:60]2[CH:59]=[CH:58][C:57]([O:56][CH3:55])=[CH:62][CH:61]=2)(=[O:65])=[O:64])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(S(=O)(=O)N2CCC(CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)CC2)cc1
Yield: 41 %

Procedure:
The desired compound was prepared according to the procedure of Example A42 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 4-methoxybenzenesulfonyl chloride as starting materials in 41% yield. LCMS for C31H33ClN7O4S (M+H)+: m/z=634.2.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].N1C=CN=C1.[C:18]([Si:22]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)Cl)([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C.C(OCC)(=O)C>[C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([O:12][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2]
Reactant: N#Cc1nc2ccc(O)cc2s1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](Oc1ccc2nc(C#N)sc2c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 112 %

Procedure:
A solution of 2-cyano-6-hydroxybenzothiazole (5.0 g, 28 mmol) in 100 ml of anhydrous DMF under inert atmosphere was treated with 2.9 g of imidazole (4.2 mmol) followed by t-butyldiphenylchlorosilane (9.34 g, 34 mmol). The reaction was stirred at room temperature for 3 h and then diluted with 200 ml of ethyl acetate and washed with water (4×400 ml). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography, eluting with 5-10% ethyl acetate/hexanes to afford 13.0 g of the desired product containing ~10% silyl impurity in quantitative yield. The product was taken on without further purification. 1H NMR (CDCl3): δ 1.12 (s, 9H) ; 7.13-7.46 (m, 8H); 7.70-7.72 (m, 4H); 7.92-7.95 (d, 1H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[CH2:18]([O:25][C:26](=[O:34])[CH2:27][C@@H:28]([NH2:33])[CH2:29][N:30]([CH3:32])[CH3:31])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:25][C:26](=[O:34])[CH2:27][C@@H:28]([NH:33][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:29][N:30]([CH3:31])[CH3:32])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)CCCCCCc1ccccc1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Agent: Cl
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCc1ccccc1

Procedure:
The title compound, m/e=335.4 ([M+H]+), was produced in analogy with intermediate 1, steps 3 and 4. Thus, commercially available 7-phenylheptanoic acid was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (R)-4-dimethylamino-3-(7-phenyl-heptanoylamino)-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: [OH-].[Na+].[S:3]1[CH:7]=[CH:6][C:5]([CH:8]=O)=[CH:4]1.[CH:10](=[O:12])[CH3:11]>C(O)C.O>[S:3]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:11][CH:10]=[O:12])=[CH:4]1
Reactant: CC=O
Reactant: O=Cc1ccsc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=CC=Cc1ccsc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 64.6 %

Procedure:
To a solution of sodium hydroxide (1.0 g, 25 mmol) in a mixture of ethanol (6 ml) and water (12 ml) was added thiophen-3-carbaldehyde (4.5 g, 40.1 mmol), and the mixture was stirred at 0° C. for 10 minute. To the mixture was dropwise added 40% acetaldehyde (10 g, 90.8 mmol) over 3 hours at the same temperature, and the mixture was further stirred for 30 minutes. The reaction mixture was treated in a similar manner to that in Reference 6 to give compound B4 (3.58 g, 64.6%) as oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([Cl:22])[C:7]([CH3:21])=[C:8]([C:18]([NH2:20])=[O:19])[C:9]=1[C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:29].[Na+]>CO.C(#N)C>[NH2:29][CH:1]([C:4]1[CH:5]=[C:6]([Cl:22])[C:7]([CH3:21])=[C:8]([C:18]([NH2:20])=[O:19])[C:9]=1[C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1)[CH3:2]
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c(C)c(C(N)=O)c1-c1cc(F)cc(F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: Cc1c(Cl)cc(C(C)N)c(-c2cc(F)cc(F)c2)c1C(N)=O
Temperature: 65 °C

Procedure:
A mixture of 6-acetyl-4-chloro-3′,5′-difluoro-3-methylbiphenyl-2-carboxamide (61 mg, 0.19 mmol), ammonium acetate (150 mg, 1.9 mmol) and sodium cyanoborohydride (24 mg, 0.38 mmol) in methanol (0.7 mL) and acetonitrile (0.7 mL) was heated at 65° C. overnight in a sealed tube. The mixture was then cooled to room temperature, quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The crude product was used directly in next step (61 mg, 99%). LCMS calculated for C16H13ClF2NO (M−NH2)+: m/z=308.1. found: 308.0.
Reaction SMILES: [I-].[F:2][CH2:3][CH2:4][N:5]([N:21]=[O:22])[C:6]([NH:8][CH2:9][CH2:10][O:11][C:12](C1[CH2+]=CC=CN1C)=[O:13])=[O:7].[CH2:23]([N:30]1[CH:38]=[CH:37][C:33](C(N)=O)=[CH:32][CH2:31]1)C1C=CC=CC=1>CO>[F:2][CH2:3][CH2:4][N:5]([N:21]=[O:22])[C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]([C:37]1[CH2:33][CH:32]=[CH:31][N:30]([CH3:23])[CH:38]=1)=[O:13])=[O:7]
Reactant: CN1C=CC=[CH2+]C1C(=O)OCCNC(=O)N(CCF)N=O
Reactant: NC(=O)C1=CCN(Cc2ccccc2)C=C1
Agent: [I-]
Solvent: CO
Product: CN1C=CCC(C(=O)OCCNC(=O)N(CCF)N=O)=C1
Yield: 55 %

Procedure:
A solution of the quaternary nitrosourea prepared in Example 126 (0.426 g, 1 mmol) and 1-benzyl-1,2-dihydroisonicotinamide (0.21 g, 1 mmol) in 25 mL of anhydrous methanol was stirred at 0° C. for 4 hours under nitrogen. The solvent was evaporated in vacuo at about 30° C. and the residue was suspended in chloroform, filtered and flash chromatographed on a short column of neutral alumina. The title compound was obtained in 55% yield after elution with chloroform and was assigned the structure ##STR154## consistent with UV analysis.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=1.[Li]CCCC.CN([CH:24]=[O:25])C>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[C:3]=1[CH:24]=[O:25]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)ccn1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1nccc(F)c1C=O
Reaction time: 0.5 h
Yield: 57 %

Procedure:
To a stirred solution of tert-butyl 4-fluoropyridin-2-ylcarbamate (1 g, 4.72 mmol) in THF (20 mL) was added dropwise n-BuLi (4.7 mL, 11.8 mmol) at −78° C. After stirring for 0.5 h, a solution of DMF (2 mL) in THF (2 mL) was added dropwise at −78° C. TLC indicated the reaction was completed. The reaction was quenched with 1N HCl at −78° C. to pH=4. Then water (20 mL) was added and extracted with ethyl acetate (3×20 mL). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc:PE=1:2) to give the title compound (0.65 g, 57%) as a white solid. 1H-NMR (600 MHz, DMSO-d6) δ 10.35 (s, 1H), 9.99 (s, 1H), 8.58-8.56 (m, 1H), 7.23-7.21 (m, 1H), 1.46 (s, 9H) ppm.