Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([C:2]2[N:7]3[N:8]=[C:9]([NH2:11])[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1nc2cccc(Br)n2n1
Reactant: OB(O)c1ccccc1
Product: Nc1nc2cccc(-c3ccccc3)n2n1

Procedure:
5-Phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from 5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (3.00 g, 14.0 mmol) and phenyl boronic acid (1.8 g, 15.0 mmol), in a manner analogous to Step 73c. The product was isolated as a white powder (0.567 g, 19%) after chromatography on an Isco silica gel column (80 g) using methanol in dichloromethane as the eluent. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 7.94 (d, J=6.9 Hz, 2H), 7.52 (m, 4H), 7.37 (m, 1H), 7.02 (d, J=6.5 Hz, 1H), 6.02 (s, 2H). MS=210 (MH)+. 76b) (5-Phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine was prepared from 5-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (100.0 mg, 0.476 mmol) and 1-[2-(4-bromo-phenoxy)-ethyl]-pyrrolidine (119 μl, 0.571 mmol) in a manner analogous to Example 75. The title compound (5-Phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine was isolated as the TFA salt as a off white solid (0.0037 g, 2%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 10.05 (br s, 1H), 9.48 (s, 1H), 8.04 (d, J=8.5 Hz, 2H), 7.61 (m, 7H), 7.18 (d, J=7.5 Hz, 1H), 6.95 (d, J=8.5 Hz, 2H), 4.25 (m, 2H), 3.80-3.40 (m, 4H), 3.12 (m, 2H), 2.03 (m, 2H), 1.89 (m, 2H). MS=400 (MH)+.
Reaction SMILES: [CH3:1]/[CH:2]=[C:3](/[C:5]([O:7][C@@H:8]1[C@:16]23[C@H:20]([C@@:21]([C@:25]45[O:30][C@@:29]4([CH3:31])[C@H:28]4[C@:32]6([OH:38])[C@H:36]([O:37][C@@H:26]5[CH2:27]4)[O:35][CH:34]=[CH:33]6)([CH3:24])[C@H:22]([OH:23])[C@H:14]4[C@H:15]2[C@:11]([C:44]([O:46][CH3:47])=[O:45])([CH2:12][O:13]4)[C@H:10]([O:48][C:49]([CH3:51])=[O:50])[CH2:9]1)[C@@:19]([OH:43])([C:39]([O:41][CH3:42])=[O:40])[O:18][CH2:17]3)=[O:6])\[CH3:4].C/C=C(/C(O[C@H]1[C@@]2(C(OC)=O)CO[C@@H]3[C@@H]2[C@@]2([C@H]([C@@]([C@]45O[C@@]4(C)[C@@H]4[C@]6(O)[C@H](O[C@H]5C4)OC=C6)(C)[C@@H]3O)[C@@H](C(OC)=O)OC2)[C@@H](O)C1)=O)\C>>[CH3:1]/[CH:2]=[C:3](/[C:5]([O:7][C@@H:8]1[C@:16]23[C@H:20]([C@@:21]([C@:25]45[O:30][C@@:29]4([CH3:31])[C@@H:28]4[C@:32]6([OH:38])[C@H:36]([O:37][C@H:26]5[CH2:27]4)[O:35][CH:34]=[CH:33]6)([CH3:24])[C@H:22]([OH:23])[C@H:14]4[C@H:15]2[C@:11]([C:44]([O:46][CH3:47])=[O:45])([CH2:12][O:13]4)[C@H:10]([O:48][C:49]([CH3:51])=[O:50])[CH2:9]1)[C@@:19]([OH:43])([C:39]([O:41][CH3:42])=[O:40])[O:18][CH2:17]3)=[O:6])\[CH3:4]
Reactant: C/C=C(\C)C(=O)O[C@H]1C[C@@H](OC(C)=O)[C@@]2(C(=O)OC)CO[C@H]3[C@@H](O)[C@@](C)([C@]45O[C@@]4(C)[C@@H]4C[C@H]5O[C@@H]5OC=C[C@@]54O)[C@H]4[C@]1(CO[C@]4(O)C(=O)OC)[C@@H]32
Agent: C/C=C(\C)C(=O)O[C@@H]1C[C@H](O)[C@]23CO[C@H](C(=O)OC)[C@H]2[C@](C)([C@]24O[C@@]2(C)[C@H]2C[C@@H]4O[C@@H]4OC=C[C@@]42O)[C@H](O)[C@@H]2OC[C@@]1(C(=O)OC)[C@H]23
Product: C/C=C(\C)C(=O)O[C@H]1C[C@@H](OC(C)=O)[C@@]2(C(=O)OC)CO[C@H]3[C@@H](O)[C@@](C)([C@]45O[C@@]4(C)[C@H]4C[C@@H]5O[C@@H]5OC=C[C@@]54O)[C@H]4[C@]1(CO[C@]4(O)C(=O)OC)[C@@H]32
Reaction time: 6.62 h

Procedure:
The fractions around the two maxima were constituted by, in all, 8 portions. 15.5 g. azadirachtin A fraction, as well as 8.3 g. azadirachtin B fraction, were obtained. However, the azadirachtin A fraction still contained a large amount of azadirachtin B, whereas the azadirachtin B fraction still contained other substances in almost the same amount as azadirachtin B. Preparative HPLC was used in order to separate azadirachtin A and B. For this purpose, there was used a Latek column filled with silica gel-RP-18 material with a length of 540 mm. and an internal diameter of 54 mm. The separation was optimised. The flowthrough rate was 55 ml./minute with methanol/water (43:57 v/v) as elution agent. For each run, about 5 g. of the azadirachtin A fraction from the column chromatography on silica gel-RP-8 were applied to the column. Every 9 minutes, the receiver was changed at a volume of about 500 ml. The maximum of azadirachtin A was eluted after 284 minutes and the maximum of azadirachtin B appeared after 397 minutes. FIG. 2 of the accompanying drawings shows a preparative HPLC chromatography of the azadirachtin A fraction in the case of chromatography on RP-8. Pure azadirachtin A and azadirachtin B was only contained in the fractions round the peak maximum. Five further azadirachtins were also separated on a smaller scale in side fractions of the preparative HPLC with thin layer chromatography or semi-preparative HPLC. The various azadirachtin derivatives were prepared from azadirachtin A and azadirachtin B.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[Cl:7][CH2:8][CH2:9]O.OS(O)(=O)=O.O>C1(C)C=CC=CC=1>[C:1]([O:6][CH2:9][CH2:8][Cl:7])(=[O:5])[CH:2]([CH3:4])[OH:3]
Reactant: CC(O)C(=O)O
Reactant: OCCCl
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(O)C(=O)OCCCl
Temperature: 25 °C
Yield: 60 %

Procedure:
Lactic acid (74 mL of an 85% aqueous solution, 0.84 mol) and freshly distilled 2-chloroethanol (670 mL, 10.0 mol) were refluxed with 400 mL of toluene and 0.4 mL of conc. H2SO4 until one equivalent of H2O was collected in a Dean-Stark trap. The reaction mixture was cooled to room temperature, diluted with ethyl ether, and washed with a NaHCO3 /NaCl solution. The organic phase was dried with MgSO4, solvent was removed under reduced pressure, and the residue was distilled at 10 mm Hg. A fraction recovered at 95°-100° C./10 mm Hg was redistilled to give 2-chloroethyl lactate as a clear colorless liquid (76.7 g, 60%): b.p. 95° C./10 mm Hg; 1H NMR δ1.46 (d, 3H, J=6.9 Hz), δ2.95 (bs, 1H), δ3.72 (t, 2H, J=5.6 Hz), δ4.35 (q, 1H, J=6.9 Hz), δ4.44 (m, 2H); 13C NMR 20.4, 41.2, 64.8, 66.8, 175.2 ppm; HRMS calcd for C4H5ClO3Tms (M-CH3) 209.0401, obsd 209.0392.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][O:28]CC4C=CC(Cl)=CC=4Cl)[C@@H:14]([O:15]CC4C=CC(Cl)=CC=4Cl)[C@@:12]3([CH3:38])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1.B(Cl)(Cl)Cl>ClCCl>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][OH:28])[C@@H:14]([OH:15])[C@@:12]3([CH3:38])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C[C@@]1(O)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1ccc2c(Cl)ncnc21
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(Cl)ncnc21
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 65.6 %

Procedure:
To a solution of the compound from Step D (5.42 g, 8.8 mmol) in dichloromethane (175 mL) at −78° C. was added boron trichloride (1M in dichloromethane, 88 mL, 88 mmol) dropwise. The mixture was stirred at −78° C. for 2.5 h, then at −30° C. to −20° C. for 3 h. The reaction was quenched by addition of methanol/dichloromethane (1:1) (90 mL) and the resulting mixture stirred at −15° C. for 30 min., then neutralized with aqueous ammonia at 0° C. and stirred at room temperature for 15 min. The solid was filtered and washed with CH2Cl2/MeOH (1/1, 250 mL). The combined filtrate was evaporated, and the residue was purified by flash chromatography over silica gel using CH2Cl2 and CH2Cl2:MeOH (99:1, 98:2, 95:5 and 90:10) gradient as the eluent to furnish desired compound (1.73 g) as a colorless foam, which turned into an amorphous solid after treatment with MeCN.
Reaction SMILES: [CH2:1]1[O:6][C:4](=[O:5])[NH:3][CH:2]1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Li]CCCC.[Br:19][CH2:20][C:21](Br)=[O:22].CCOC(C)=O.CCCCCC>C1COCC1.C(OCC)(=O)C>[CH2:7]([C@H:2]1[CH2:1][O:6][C:4](=[O:5])[N:3]1[C:21](=[O:22])[CH2:20][Br:19])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1NC(Cc2ccccc2)CO1
Reactant: O=C(Br)CBr
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(CBr)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
To a solution of S-(−)-4-benzyl-2-oxazolidinone (20.0 g, 112.86 mmol) in THF (200 mL) was added nBuLi (2.5M in hexanes, 47.4 mL, 118.51 mmol) dropwise at −78° C. The solution was stirred at −78° C. for 30 min followed by the addition of bromo acetyl bromide (25.0 g, 10.81 mL, 124.15 mmol). The solution was allowed to warm to 25° C. overnight (19 h). An aliquot was taken and TLC (1:2 EtOAc-hexane) indicated that the reaction was complete. It was diluted with ethyl acetate (200 mL) and the organic layer was washed with saturated aqueous NaHCO3 (2×50 mL). The organic layer was dried over MgSO4, filtered and concentrated to obtain a crude brown oil (34 g). The crude product was purified by flash chromatography, eluent: 1:4 EtOAc-hexane, to furnish (4S)-4-benzyl-3-(bromoacetyl)-1,3-oxazolidin-2-one as a colorless oil (33.2 g, 98.6%). Mass Spectrum (−ESI): 297 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1.[CH3:25][N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27]1[CH:35]=O>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH:24][CH2:35][C:27]2[N:26]([CH3:25])[C:34]3[C:29]([CH:28]=2)=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:21]=[CH:22][CH:23]=1
Reactant: Nc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Reactant: Cn1c(C=O)cc2ccccc21
Product: Cn1c(CNc2cccc(-c3c(-c4ccccc4)nnc4c(Cl)cccc34)c2)cc2ccccc21

Procedure:
The title compound was prepared from 3-(8-chloro-3-phenyl-cinnolin-4-yl)-phenylamine and 1-methyl-1H-indole-2-carbaldehyde according to the procedure of Step 5 Example 6. MS (ES) m/z 474.9.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].N1C=CN=C1.O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
To a solution of (2S,4R)-1-t-butoxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine (20.0 g) and t-butyldimethylsilyl chloride (18.44 g) in dimethylformamide (60 ml) was added imidazole (11.1 g) under ice-cooling, and the mixture was stirred at 0°-10° C. for 1 hour and then at ambient temperature for 18 hours. The reaction mixture was poured into water (300 ml) and extracted with ethyl acetate (100 ml×3). The combined organic layer was washed with water (200 ml×2) and brine (150 ml) successively, dried over magnesium sulfate, and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (250 g) to give (2S,4R)-1-t-butoxycarbonyl-4-t-butyldimethylsilyloxy-2-methoxycarbonylpyrrolidine (27.95 g).
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]3[C@@H:12](C(O)=O)[C@H:7]3[C:6]=2[C:5]([F:16])=[CH:4][CH:3]=1.C([N:19](CC)CC)C.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]3[C@@H:12]([NH2:19])[C@H:7]3[C:6]=2[C:5]([F:16])=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1[C@@H]2COc3c(F)ccc(F)c3[C@@H]21
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: N[C@@H]1[C@@H]2COc3c(F)ccc(F)c3[C@H]12
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 50 %

Procedure:
(1S,1aR,7bS)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-carboxylic acid (0.5 g, 2.2 mmol, ˜95% ee) was mixed with toluene (3 ml), triethylamine (0.34 ml, 1.1 eq), DPPA (0.52 ml, 1.1 eq) and bubbled with argon for about 5 min. The reaction mixture was then heated at stirring at 120° C. for 1.5 h under argon. The temperature was then decreased to 50° C. and a mixture of 3 ml of 10% hydrochloric acid in 10 ml dioxane was added. The reaction mixture was stirred for 2 h at 50° C. and then concentrated by rotary evaporation. The residue was mixed with water ant diethyl ether. Water phase was collected and basified with 28% aqueous ammonia to pH 11 and extracted into ether (3×20 ml). Combined organic phases were washed with water and brine and dried over magnesium sulfate. Concentration by rotary evaporation gave 310 mg of crude product as yellow orange oil. The product was purified by column chromatography on silica (30 g, EtOAc/hexane 1:2) to give 220 mg of colorless oil (50% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH:10]([O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][C:15]=1[O:21][CH3:22])([CH3:12])[CH3:11]>>[NH2:18][C:17]1[CH:16]=[C:15]([O:21][CH3:22])[C:14]([O:13][CH:10]([CH3:12])[CH3:11])=[CH:20][C:19]=1[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1])=[O:5]
Reactant: O=Cc1ccccc1Cl
Reactant: COc1cc(N)ccc1OC(C)C
Product: COc1cc(N)c(C(=O)c2ccccc2Cl)cc1OC(C)C

Procedure:
(2-amino-4-methoxy-5-(1-methylethoxy)phenyl)-(2-chlorophenyl)-methanone (Xjj) was prepared by reacting 2-chlorobenzaldehyde with 0.0267 moles of 4-isopropoxy-3-methoxy aniline in a manner analogous to Example 1. MH+/Z=320.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([N:18]([CH3:20])[CH3:19])[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.CN(C)C1(C2C=CC=CC=2)CCC2(CCNCC2)CC1>>[CH3:19][N:18]([CH3:20])[C:8]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:17][CH2:16][C:11](=[O:12])[CH2:10][CH2:9]1
Reactant: CN(C)C1(c2cccc(F)c2)CCC2(CC1)OCCO2
Agent: CN(C)C1(c2ccccc2)CCC2(CCNCC2)CC1
Product: CN(C)C1(c2cccc(F)c2)CCC(=O)CC1

Procedure:
The reaction was performed starting from 8-(3-fluorophenyl)-N,N-dimethyl-1,4-dioxaspiro[4.5]decan-8-amine in an analogous manner to stage 2 amine (A1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7](Cl)(=[O:9])=[O:8].[C:11]([O:15][C:16](=[O:27])[NH:17][C@@H:18]1[CH2:24][CH2:23][C@@H:22]([CH3:25])[NH:21][CH2:20][C@H:19]1[OH:26])([CH3:14])([CH3:13])[CH3:12].C(=O)(O)[O-].[Na+]>C(Cl)Cl.O.CCOC(C)=O>[C:11]([O:15][C:16](=[O:27])[NH:17][C@@H:18]1[CH2:24][CH2:23][C@@H:22]([CH3:25])[N:21]([S:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)(=[O:9])=[O:8])[CH2:20][C@H:19]1[OH:26])([CH3:13])([CH3:12])[CH3:14]
Reactant: C[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](O)CN1
Reactant: O=S(=O)(Cl)c1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](O)CN1S(=O)(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
Pyridine-2-sulfonyl chloride (0.55 g, 3.1 mmol) was added to a solution ((3R,4R,7R)-3-Hydroxy-7-methyl-azepan-4-yl)-carbamic acid tert-butyl ester (0.58 g, 0.2.4 mmol), sodium bicarbonate (0.84 g, 10 mmol) in CH2Cl2 (10 ml) and H2O (3 ml) and was stirred at RT for 30 minutes. The reaction mixture was diluted with EtOAc (100 ml), washed with H2O, brine, dried with magnesium sulfate, filtered, concentrated in vacuo by rotary evaporation, and chromatographed (silica gel, 45:55 EtOAC/hexanes) to yield the title compound (0.6 g, 65%): Electrospray mass spec: M+H+=386.27.
Reaction SMILES: [NH2:1][S:2]([C:5]1[C:46]([Cl:47])=[CH:45][C:8]2[NH:9][CH:10]([CH2:15][C:16]3[CH:44]=[CH:43][C:19]([O:20][CH:21]4[CH2:25][N:24]([C:26](=[O:39])[C@H:27]([CH3:38])[CH2:28][S:29]C(=O)C5C=CC=CC=5)[C@H:23]([C:40]([OH:42])=[O:41])[CH2:22]4)=[CH:18][CH:17]=3)[NH:11][S:12](=[O:14])(=[O:13])[C:7]=2[CH:6]=1)(=[O:4])=[O:3].CCOCC.SC[C@@H](C)C(N1CCC[C@H]1C(O)=O)=O>C(O)(=O)C.CO.C(Cl)Cl>[NH2:1][S:2]([C:5]1[C:46]([Cl:47])=[CH:45][C:8]2[NH:9][CH:10]([CH2:15][C:16]3[CH:44]=[CH:43][C:19]([O:20][CH:21]4[CH2:25][N:24]([C:26](=[O:39])[C@H:27]([CH3:38])[CH2:28][SH:29])[C@H:23]([C:40]([OH:42])=[O:41])[CH2:22]4)=[CH:18][CH:17]=3)[NH:11][S:12](=[O:14])(=[O:13])[C:7]=2[CH:6]=1)(=[O:3])=[O:4]
Reactant: C[C@H](CSC(=O)c1ccccc1)C(=O)N1CC(Oc2ccc(CC3Nc4cc(Cl)c(S(N)(=O)=O)cc4S(=O)(=O)N3)cc2)C[C@H]1C(=O)O
Agent: C[C@H](CS)C(=O)N1CCC[C@H]1C(=O)O
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: CO
Product: C[C@H](CS)C(=O)N1CC(Oc2ccc(CC3Nc4cc(Cl)c(S(N)(=O)=O)cc4S(=O)(=O)N3)cc2)C[C@H]1C(=O)O
Reaction time: 3 h

Procedure:
The product from Example 1 (0.3 g., 0.4 mmole) is dissolved in 50 ml. of argon purged sodium hydroxide (2.5%) and stirred at 25° for 3 hours. The solution is acidified with 10% potassium bisulfate and extracted with ethyl acetate. The organics are dried (Na2SO4) and evaporated. Trituration with ether gives a solid. Chromatography on 50 g. of LH-20 in methanol and pooling and evaporation of the product containing fractions gives a glass. Trituration with ether gives 0.2 g. of (S)-4-[[7-(aminosulfonyl)-6-chloro-3,4-dihydro-1,1-dioxo-2H-1,2,4-benzothiadiazin-3-yl]methyl]phenoxy]-1-[(S)-3-mercapto-2-methyl-1-oxopropyl]-L-proline as a white crystalline solid; m.p. 175°-185°; [α]D =-22° (c=0.1%, methanol). TLC (silica, methylene chloride:methanol:acetic acid; 8:1:1) Rf =0.32.
Reaction SMILES: [CH2:1]([N:9]=[C:10]=[O:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N+:12](=[C:14]1[N:18]=[CH:17][N:16]=[C:15]1[C:19]([NH2:21])=[O:20])=[N-:13]>CS(C)=O>[O:11]=[C:10]1[N:9]([CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:13]=[N:12][C:14]2=[C:15]([C:19]([NH2:21])=[O:20])[N:16]=[CH:17][N:18]12
Reactant: [N-]=[N+]=C1N=CN=C1C(N)=O
Reactant: O=C=NCCc1ccccc1
Solvent: CS(C)=O
Product: NC(=O)c1ncn2c(=O)n(CCc3ccccc3)nnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Phenethyl isocyanate (0.441 g, 3 mmol) was added drop wise to a suspension of 5-diazoimidazole-4-carboxamide (0.274 g, 2 mmol) in dry dimethylsulfoxide (2.5 mL) at room temperature under nitrogen. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by the addition of ice and the solid product (pale pink) was removed by filtration, washed with water and ethyl acetate, and recrystallised from chloroform to give the title compound. Yield: 0.259 g, 46%. IR vmax/cm−1 3132, 1743, 1668. 1H NMR δH (DMSO-d6) 3.14 (2H, t, J 7.4, CH2), 4.53 (2H, t, J 7.4, CH2), 7.21-7.33 (5H, m, ArH), 7.68 (1H, br s, NH), 7.81 (1H, br s, NH), 8.83 (1H, s, 6-H). δC 31.1, 34.6, 50.4, 127.1, 129.0, 129.2, 129.3, 131.2, 134.7, 138.2, 139.4, 162.0. MS Found 285.1161. Calc for (M+H): 285.1100. Found C, 55.0; H, 4.3; N, 29.4. Calc. for C13H12N6O3C 54.9; H 4.3; N, 29.6%.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[NH2:23][C@H:24]([C:32]([OH:34])=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>C(#N)C.O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([NH:23][C@H:24]([C:32]([OH:34])=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:16])[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Solvent: O
Solvent: CC#N
Solvent: c1ccncc1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Yield: 91.8 %

Procedure:
A solution of 0.223 g (0.001 mol) of N-benzyloxycarbonyl alanine (Z-Ala), 0.08 g (0.001 mol) of pyridine and 0.256 g (0.001 mol) of DSC in 10 ml of acetonitrile was stirred at ambient temperature. After silica gel TLC. showed that Z-Ala (the free acid form) disappeared in the solution, the reaction solution was concentrated to a small volume, and the concentrated solution was admixed with ethyl acetate and then washed with aqueous 4% NaHCO3, with 1 N-HCl and finally with a saturated aqueous solution of sodium chloride to remove the liberated N-hydroxysuccinimide. The solution so treated was distilled to remove the ethyl acetate. The resultant solid residue was admixed with a solution of 0.165 g (0.001 mol) of phenylalanine (Phe-OH) and 0.101 g (0.001 mol) of triethylamine in 20 ml of a mixed solvent of acetonitrile and water (4:6 by volume). 24 Hours later, the reaction solution was concentrated to a small volume, and the concentrated solution was admixed with ethyl acetate, washed with aqueous 4% NaHCO3, with 1 N-HCl and with a saturated aqueous solution of sodium chloride, followed by drying over anhydrous sodium sulfate. The dried solution was then filtered and the filtrate was distilled, affording a colorless crystalline substance. Recrystallization of this crystalline substance from methylene chloride-ethyl ether gave 0.34 g of N-benzyloxycarbonylalanyl-phenylalanine (Z-Ala-Phe-OH) as a colorless crystalline substance. Yield 90%.
Reaction SMILES: [CH3:1][C:2]1(Br)[CH2:4][CH2:3]1.[S:6]([C:10]1[CH:16]=[CH:15][C:13]([CH3:14])=[CH:12][CH:11]=1)([O-:9])(=[O:8])=[S:7].[K+]>C(O)C>[CH:4]1([CH2:3][O:9][S:6]([C:10]2[CH:16]=[CH:15][C:13]([CH3:14])=[CH:12][CH:11]=2)(=[S:7])=[O:8])[CH2:2][CH2:1]1
Reactant: Cc1ccc(S(=O)([O-])=S)cc1
Reactant: CC1(Br)CC1
Agent: [K+]
Solvent: CCO
Product: Cc1ccc(S(=O)(=S)OCC2CC2)cc1
Temperature: 90 °C
Yield: 72.5 %

Procedure:
To a solution of methylcyclopropyl bromide (4.00 g, 29.6 mmol) in ethanol (20.0 mL) was added potassium thiotosylate (10.0 g, 44.4 mmol) and the mixture heated to 90° C. for 10 h. The mixture was then quenched into a 1:1 mixture of H2O (50.0 mL) and diethyl ether (50.0 mL). The layers were separated and the organic layer washed with brine (50.0 mL). The organic layer was then dried with MgSO4 and concentrated in vacuo to yield the title compound as a solid (5.2 g, m.p. 46°-48° C.). 'H NMR (400 MHz, CDCl3) δ 7.816 (d, 2H, J=8.8 Hz), 7.308 (d, 2H, J =8.8 Hz), 2.945 (d, 2H, J=7.6 Hz), 2.451 (s, 3H), 1.010-0.933 (m, 1H), 0.592-0.545 (m, 2H), 0.236-0.197 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7](C)=[C:6](I)[C:5]=1[O:13][CH3:14].[N+:16]([C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)([O-:18])=[O:17].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.CCOCC>[CH3:1][O:2][C:3]([C:4]1[C:5]([O:13][CH3:14])=[C:6]([C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:16]([O-:18])=[O:17])[CH:24]=2)[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:15]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: COC(=O)c1cc(Cl)c(C)c(I)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Cl)cc(-c2cccc([N+](=O)[O-])c2)c1OC

Procedure:
To a solution of methyl,5-chloro-3-iodo-2-methoxybenzoic acid methyl ester (0.80 g, 2.5 mmol) and tetrakis (triphenylphosphine)palladium(0) (0.085 g, 0.074 mmol) in toluene (12 mL) was added 3-nitrobenzene-boronic acid (0.45 g, 2.7 mmol) dissolved in 1 mL of ethanol. Aqueous 2 N K2CO3 (2.7 mL, 5.4 mmol) was added and the mixture was heated to reflux for 18 h. The mixture was diluted with ether, washed with 3:1 saturated NaHCO3/conc. ammonium hydroxide, 0.1 M EDTA, saturated NaCl, and dried (Na2SO4). The solvent was removed under reduced pressure, and the crude material was purified by silica gel chromatography employing a gradient elution of 60 to 75% CH2Cl2/hexane. 5-Chloro-2-methoxy-3′-nitro-biphenyl-3-carboxylic acid methyl ester 43 was obtained as an amber waxy solid (0.59 g, 75% yield).