Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5](=[O:15])[CH2:4]1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25].O>ClCCl>[CH3:23][S:24]([O:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5](=[O:15])[CH2:4]1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1CC(CO)CCN1c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OCC1CCN(c2ccccc2)C(=O)C1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
4-(Hydroxymethyl)-1-phenylpiperidin-2-one (0.27 g, 1.3 mmol) was dissolved in dichloromethane (15 mL), cooled to 0° C. and treated with triethylamine (1.0 mL, 7.2 mmol, 5.5 equiv). To the mixture was added methanesulfonyl chloride (0.10 mL, 1.3 mmol, 1 equiv), the mixture was warmed to ambient temperature and stirred for an additional 15 hours. The mixture was poured into water (25 mL) and extracted with dichloromethane (2×20 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:3]=1.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C([SiH](CC)CC)C.[C:44]1([S:50]([C:53]2[CH:60]=[CH:59][CH:58]=[CH:57][C:54]=2[CH:55]=O)(=[O:52])=[O:51])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(Cl)Cl>[CH3:1][C:2]1[N:6]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:4]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:3]=1[CH2:55][C:54]1[CH:57]=[CH:58][CH:59]=[CH:60][C:53]=1[S:50]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)(=[O:52])=[O:51]
Reactant: O=Cc1ccccc1S(=O)(=O)c1ccccc1
Reactant: CCOC(=O)Cn1c(C)cc(-c2ccccc2)c1-c1ccccc1
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
In a scintillation vial, ethyl 2-(5-methyl-2,3-diphenyl-1H-pyrrol-1-yl)acetate (0.3 g, 0.939 mmol) was dissolved in 10 mL of DCM and the mixture cooled to −78° C. Trimethylsilyl trifluoromethanesulfonate (0.382 ml, 2.113 mmol) was then added followed by triethylsilane (0.450 ml, 2.82 mmol). The resulting mixture was stirred at −78° C. for 30 minutes. At this time, 2-(phenylsulfonyl)benzaldehyde (0.231 g, 0.939 mmol) was added portionwise as a solution in 2.0 mL of DCM and the reaction evolution was monitored by LC/MS. Following addition of the aldehyde, the cold bath was removed and the reaction was stirred overnight (gradually warming to room temp). The reaction was quenched with a sodium bircarbonate solution and moved to a separatory funnel. Layers were separated and the aqueous portion was extracted 2 additional times with DCM. The organics were combined, dried, filtered, and concentrated. The crude oil was purified by column chromatography (SiO2) using a 0-40% EtOAc/hexane gradient to give ethyl 2-(2-methyl-4,5-diphenyl-3-(2-(phenylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate (294 mg, 0.535 mmol, 56.9% yield). 1H NMR (400 MHz, CDCl3) δ (ppm) 8.31-8.29 (m, 1H), 7.84-7.82 (m, 2H), 7.52-7.48 (m, 2H), 7.42-7.38 (m, 3H), 7.28-7.21 (m, 4H), 7.15-7.13 (m, 2H), 6.93-6.86 (m, 3H), 6.75-6.73 (m, 2H), 4.51 (s, 2H), 4.21 (q, 2H), 4.04 (s, 2H), 1.79 (s, 3H), 1.25 (t, 3H).
Reaction SMILES: [Si]([O:8][C@H:9]([C@@H:18]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH2:19][C@H:20]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH2:34][CH2:35][CH2:36][O:37][CH3:38])[CH:26]=1)[CH:21]([CH3:23])[CH3:22])[CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][NH:13][C:12]1=[O:17])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[OH:8][C@H:9]([C@@H:18]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:43])([CH3:45])[CH3:44])[CH2:19][C@H:20]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH2:34][CH2:35][CH2:36][O:37][CH3:38])[CH:26]=1)[CH:21]([CH3:23])[CH3:22])[CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][NH:13][C:12]1=[O:17]
Reactant: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@H](CN2CCCNC2=O)O[Si](C)(C)C(C)(C)C)C(C)C)ccc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CN2CCCNC2=O)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The solution of 0.035 g of tert-butyl {1(S)-[1(S)-(tert-butyldimethylsilanyloxy)-2-(2-oxotetrahydropyrimidin-1-yl)ethyl]-3(S)-[4-methoxy-3-(3-methoxypropoxy)benzyl]-4-methylpentyl}carbamate in 0.65 ml of tetrahydrofuran is admixed with 0.064 ml of 1M tetrabutylammonium fluoride (in tetrahydrofuran) and stirred at room temperature over 18 hours. The reaction solution is admixed with water and extracted with tert-butyl methyl ether (2×). The combined organic phases are washed with brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a colourless oil. Rf=0.36 (200:20:1 dichloromethane-methanol-25% conc. ammonia); Rt=4.44 (gradient I).
Reaction SMILES: [CH:1](=[O:10])[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C-]#N.[K+]>>[C:5]1([C:6](=[O:7])[C:6]([C:5]2[CH:8]=[CH:9][C:2]([C:1](=[O:10])[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:18])=[CH:3][CH:4]=2)=[O:7])[CH:8]=[CH:9][CH:2]=[CH:3][CH:4]=1
Reactant: O=Cc1ccc(C=O)cc1
Reactant: O=Cc1ccccc1
Agent: [C-]#N
Agent: [K+]
Product: O=C(C(=O)c1ccc(C(=O)C(=O)c2ccccc2)cc1)c1ccccc1

Procedure:
The benzoinic condensation of terephthalaldehyde (625 g) with benzaldehyde (2000 g) is effected in conditions strictly identical to those of example 1, while using 300 g of potassium cyanide, which represents 50% of the stoichiometrical proportion. The yield of pure bis-benzoin is 1516 g (94%). This product, when oxidized, yields 90% of very pure 1,4-bis (phenylglyoxyloyl) benzene. The tetraketone yield thus averages 85% with respect to the reacted terephthalic aldehyde.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]3=[N:10][C:9]=2[C:18]2[CH:19]=[C:20]([CH:32]=[CH:33][CH:34]=2)[C:21]([NH:23][C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])=[O:22])[CH:5]=[CH:4][N:3]=1.[N:35]1([CH:41]2[CH2:46][CH2:45][N:44]([C:47]3[CH:53]=[CH:52][C:50]([NH2:51])=[C:49]([O:54][CH3:55])[CH:48]=3)[CH2:43][CH2:42]2)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>FC(F)(F)CO.CO.C(Cl)Cl.CCCCCC>[N:35]1([CH:41]2[CH2:46][CH2:45][N:44]([C:47]3[CH:53]=[CH:52][C:50]([NH:51][C:2]4[N:7]=[C:6]([C:8]5[N:12]6[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]6=[N:10][C:9]=5[C:18]5[CH:19]=[C:20]([CH:32]=[CH:33][CH:34]=5)[C:21]([NH:23][C:24]5[C:25]([F:31])=[CH:26][CH:27]=[CH:28][C:29]=5[F:30])=[O:22])[CH:5]=[CH:4][N:3]=4)=[C:49]([O:54][CH3:55])[CH:48]=3)[CH2:43][CH2:42]2)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: COc1cc(N2CCC(N3CCCCC3)CC2)ccc1N
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3cc(F)ccn3c2-c2ccnc(Cl)n2)c1
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: OCC(F)(F)F
Product: COc1cc(N2CCC(N3CCCCC3)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3cc(F)ccn23)n1
Temperature: 150 °C
Yield: 57.9 %

Procedure:
To 3-[3-(2-chloro-4-pyrimidinyl)-7-fluoroimidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluoro-phenyl)benzamide (Example 194, step B) (100 mg, 0.21 mmol) and 4-(1,4′-bipiperidin-1′-yl)-2-(methyloxy)aniline (Example 22, step C) (54 mg, 0.19 mmol) in 2,2,2-trifluoroethanol (2 mL) was added p-toluenesulfonic acid monohydrate (95 mg, 0.50 mmol). The mixture was stirred and heated on a microwave at 150° C. for 30 min, then cooled to rt. The mixture was neutralized with 0.5M sodium methoxide in MeOH. The mixture was concentrated under vacuum and the residue purified by silica gel chromatography to give a yellow oil. The oil was dissolved in minimal DCM, then hexane was added until a precipitate was formed. The slurry was cooled at −10° C. for 30 min, then poured through a Teflon filter, washing the solids with cold hexanes. The solids were dried under vacuum to give the title compound (84 mg, 0.11 mmol, 62%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 9.48 (br s, 1H), 8.51 (s, 1H), 8.32 (s, 1H), 8.20 (d, 1H, J=5.13 Hz), 8.06 (d, 1H, J=7.88 Hz), 7.82 (d, 1H, J=7.88 Hz), 7.59-7.64 (m, 2H), 7.35-7.45 (m, 2H), 7.21 (t, 2H, J=8.06 HZ), 7.01-7.09 (m, 1H), 6.67-6.69 (m, 1H), 6.43-6.51 (m, 2H), 3.70-3.81 (m, 5H), 2.65 (t, 2H, J=11.36 Hz), 2.42-2.48 (m, 4H), 2.29-2.37 (m, 1H), 1.75-1.83 (m, 2H), 1.44-1.59 (m, 6H), 1.34-1.41 (m, 2H). MS (ESI): 733 [M+H]+.
Reaction SMILES: C(O[C:6]([N:8](C)[C@H:9]([CH2:17][O:18][C:19](=[O:31])[NH:20][C:21]1[N:22]=[CH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=O)(C)(C)C.Cl>CO>[CH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=[C:21]([NH:20][C:19]([O:18][CH2:17][C@@H:9]([NH:8][CH3:6])[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:31])[N:22]=1
Reactant: COC(=O)CCC[C@@H](COC(=O)Nc1cc2ccccc2cn1)N(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CN[C@@H](CCCC(=O)OC)COC(=O)Nc1cc2ccccc2cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 115.8 %

Procedure:
To s solution of (S)-methyl 5-(tert-butoxycarbonyl(methyl)amino)-6-(isoquinolin-3-ylcarbamoyloxy)hexanoate (2.0 g, 4.5 mmol) in MeOH (10 mL) at 0° C. was added HCl (4 M in 1,4-dioxane, 10 mL) dropwise. The solution was stirred at RT for 2 h. The solvents were removed under high vacuum to give (S)-methyl 6-(isoquinolin-3-ylcarbamoyloxy)-5-(methylamino)hexanoate (1.8 g, 94%) as a yellow solid. LRMS (M+H+) m/z 346.2.
Reaction SMILES: [F:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N+:14]([O-])=O)[CH2:4][C@@H:3]1[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21]>C(O)C.C(OCC)(=O)C>[NH2:14][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[N:5]1[CH2:6][CH2:7][C@@H:2]([F:1])[C@H:3]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CN(c2ccncc2[N+](=O)[O-])CC[C@@H]1F
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H]1CN(c2ccncc2N)CC[C@H]1F
Yield: 99 %

Procedure:
Following Method 2 of Example 49, tert-butyl (3S,4S)-4-fluoro-1-(3-nitropyridin-4-yl)piperidin-3-ylcarbamate in ethanol and ethyl acetate (1:1, 0.1 M solution) was reduced yielding tert-butyl (3R,4R)-1-(3-aminopyridin-4-yl)-4-fluoropiperidin-3-ylcarbamate, (>99%). LCMS (m/z): 311.2 (MH+); LC Rt=2.14 min.
Reaction SMILES: Cl(O)(=O)(=O)=O.[CH3:6][O:7][N:8]=[C:9]([C:25](OCC)([O:28]CC)[CH2:26][Br:27])[C:10]([NH:12][CH:13]1[C:23](=[O:24])[N:15]2[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]12)=[O:11].O>C(C(C)=O)C(C)C>[CH3:6][O:7][N:8]=[C:9]([C:25](=[O:28])[CH2:26][Br:27])[C:10]([NH:12][CH:13]1[C:23](=[O:24])[N:15]2[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]12)=[O:11]
Reactant: CCOC(CBr)(OCC)C(=NOC)C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)CC(C)C
Solvent: O
Product: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Reaction time: 0.33 h
Yield: 59.4 %

Procedure:
70% Perchloric acid (0.54 ml) was added to a solution of 7-(2-methoxyimino-3,3-diethoxy-4-bromobutyramido)-3-cephem-4-carboxylic acid (syn isomer, 1 g) in methyl isobutyl ketone (4 ml) under ice-cooling, and stirred at the same temperature for 20 minutes. Water (4 ml) was added to the resultant mixture and stirred for 5 minutes. The precipiates were collected by filtration, washed with water and dried over phosphorus pentachloride in vacuo to give 7-(2-methoxyimino-3-oxo-4-bromobutyramido)-3-cephem-4-carboxylic acid (syn isomer, 502 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[NH2:11][CH2:12][C:13]([N:15]1[C@H:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][S:17][C@@H:16]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:14]>O1CCCC1.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:10])[NH:11][CH2:12][C:13]([N:15]2[C@H:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][S:17][C@@H:16]2[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CS[C@H](c2ccccc2)N1C(=O)CN
Reactant: Cc1cccc(N=C=O)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cccc(NC(=O)NCC(=O)N2[C@@H](c3ccccc3)SC[C@H]2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
0.8 cm3 of 3-methylphenyl isocyanate is added to a solution of 2.0 g of tert-butyl (2R,4R)-3-(2-aminoacetyl)-2-phenyl-4-thiazolidinecarboxylate in 25 cm3 of anhydrous tetrahydrofuran. The reaction mixture is stirred for 12 hours at a temperature in the vicinity of 25° C., then diluted with 100 cm3 of ethyl acetate. The organic phase is washed with 2 times 40 cm3 of water, dried over magnesium sulphate and concentrated to dryness under reduced pressure at 40° C. The crude product obtained is purified by chromatography on silica [eluent: methylene chloride/methanol (98/2 by volume)]. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure at 40° C. After vigorous stirring in heptane, 0.5 g of tert-butyl (2R,4R)-3-{2-[3-(3-methylphenyl)ureido]acetyl}-2-phenyl-4-thiazolidinecarboxylate is thus obtained in the form of a white amorphous powder ([α]D20 =+70.0°±1.3° (C=1.02%; CHCl3)) [proton NMR (200 MHz, CDCl3, δ in ppm), 2 rotamers at room temperature, description for the preponderant rotamer at 25° C.: 1.45 (bs, 9H, (CH3)3); 2.2 (s, 3H, CH3); 3.2 (A2X, 2H, CH2S); 3.2 and 4.3 (ABX, 2H, CH2N); 4.9 (t, 1H, CHN); 6.1 (bdd, 1H, NH); 6.2 (s, 1H, SCHN); 6.8 to 7,7 (m, 9H, aromatic). Infrared spectrum (KBr), characteristic bands in cm-1 : 3375, 2975, 2930, 1735, 1650, 1610, 1595, 1560, 1490, 1455, 1370, 1150, 780, 730, 695].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([S:10][CH2:11][CH3:12])=[C:8]([C:13]([NH2:15])=[O:14])[CH:7]=[N:6][N:5]2[CH:16]=1.[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:11]([S:10][C:9]1[C:4]2[N:5]([CH:16]=[C:2]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:3]=2)[N:6]=[CH:7][C:8]=1[C:13]([NH2:15])=[O:14])[CH3:12]
Reactant: CCSc1c(C(N)=O)cnn2cc(Br)cc12
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: CCSc1c(C(N)=O)cnn2cc(-c3ccccc3)cc12
Temperature: 125 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
A mixture of 6-bromo-4-(ethylthio)pyrrolo[1,2-b]pyridazine-3-carboxamide (1.2 g, 4.00 mmol), phenylboronic acid (0.731 g, 6.00 mmol), palladium (II) acetate (0.090 g, 0.400 mmol), 2M potassium phosphate, tribasic (7.60 mL, 15.19 mmol) and 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbyphenyl (0.381 g, 0.800 mmol) in dioxane (volume: 30 mL) was heated to 125° C. in a pressure vessel, behind a blast shield for 4 hr. Additional phenylboronic acid (0.366 g, 3.00 mmol), palladium (II) acetate (0.045 g, 0.200 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (0.191 g, 0.400 mmol) and 2M potassium phosphate, tribasic (7.60 mL, 15.19 mmol) were added and heating was continued for 1 hr. The reaction mixture was partitioned between EtOAc (250 ml) and water (250 ml). The organic layer was washed with brine (100 ml), dried (MgSO4) and concentrated to a yellow solid that was triturated with ethyl ether. Filtration, washing with ethyl ether/hexane, 1:1 and drying afforded the title compound (0.91 g, 3.06 mmol, 77% yield) as a yellow solid that was used in the next step without further purification. 1H NMR (400 MHz, MeOD) δ ppm 1.28 (t, J=7.4 Hz, 3 H) 3.19 (q, J=7.5 Hz, 2 H) 7.23 (d, J=1.8 Hz, 1 H) 7.28 (d, J=7.5 Hz, 1 H) 7.40 (t, J=7.7 Hz, 2 H) 7.74 (d, J=7.3 Hz, 2 H) 8.16 (s, 1 H) 8.21 (d, J=1.8 Hz, 1 H). LCMS (M+H)=298.07.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:16](=[C:17]4[CH:25]=[CH:24][CH:23]=[CH:22][C:18]4=[CH:19][CH:20]=3)[O:15][C:14]([NH2:26])=[C:13]2[C:27]2[N:31]=[C:30]([CH2:32]Cl)[O:29][N:28]=2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9].[CH2:34]([N:36](CC)CC)C.CN>C(#N)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:16](=[C:17]4[CH:25]=[CH:24][CH:23]=[CH:22][C:18]4=[CH:19][CH:20]=3)[O:15][C:14]([NH2:26])=[C:13]2[C:27]2[N:31]=[C:30]([CH2:32][NH:36][CH3:34])[O:29][N:28]=2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9]
Reactant: COc1cc(C2C(c3noc(CCl)n3)=C(N)Oc3c2ccc2ccccc32)cc(Br)c1OC
Reactant: CCN(CC)CC
Agent: CN
Solvent: O
Solvent: CC#N
Product: CNCc1nc(C2=C(N)Oc3c(ccc4ccccc34)C2c2cc(Br)c(OC)c(OC)c2)no1
Temperature: 25 °C

Procedure:
4-(3-Bromo-4,5-dimethoxy-phenyl)-3-(5-chloromethyl-[1,2,4]oxadiazol-3-yl)-4H-benzo[h]chromen-2-ylamine (24) (528 mg, 1 mmol) and triethylamine (140 μl, 1 mmol) and 2M methanolic solution of methylamine (600 μl, 1.2 mmol) is taken in acetonitril (10 ml) and stirred at room temperature under LC-MS control till the reaction is complete. The reaction mixture is diluted with water to about 50 ml and stirred for 2 h at room temperature. Thus resulting precipitates are separated by filtration, washed well with water and is dried under high vacuum to get solids of the title compound.
Reaction SMILES: [C:1]1([CH:7]([O:16][C:17]2[CH:27]=[CH:26][C:20]([C:21](OCC)=[O:22])=[CH:19][CH:18]=2)[CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>CCOCC>[C:1]1([CH:7]([O:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:21][OH:22])=[CH:26][CH:27]=2)[CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1ccc(OC(CCc2ccccc2)c2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: OCc1ccc(OC(CCc2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 6-4 (2.46 g, 6.8 mmol) in ether (30 ml) was added dropwise under nitrogen atmosphere to a stirred cold suspension of lithium aluminum hydride (0.285 g, 7.5 mmol) in ether (5 ml). The mixture was stirred for 3 hrs at ambient temperature and was decomposed by carefully adding water and sodium hydroxide. This mixture was extracted with ethyl acetate. The extract was washed with water, dried, filtered and concentrated in vacuo to yield 6-5 as a colorless viscious oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=1.CC(C)([O-])C.[K+].[CH2:23]([O:30][C@H:31]1[CH2:35][N:34]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[C@H:33]([CH2:41][CH2:42]Cl)[CH2:32]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C(=O)C>[CH2:39]([O:38][C:36]([N:34]1[CH2:35][C@H:31]([O:30][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:32][C@H:33]1[CH2:41][CH2:42][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:37])[CH3:40]
Reactant: CCOC(=O)N1C[C@H](OCc2ccccc2)C[C@H]1CCCl
Reactant: Cc1ccc(O)c(CCc2ccccc2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)N1C[C@H](OCc2ccccc2)C[C@H]1CCOc1ccc(C)cc1CCc1ccccc1
Yield: 72.7 %

Procedure:
1200 mg of 4-methyl-2-(2-phenylethyl)phenol were dissolved in 10 ml of N,N-dimethylacetamide, allowed to react with 700 mg of potassium t-butoxide and 1600 mg of (2S,4R)-4-benzyloxy-2-(2-chloroethyl)-1-ethoxycarbonylpyrrolidine and extracted in the same manner as described in step (a) of Example 2. The resulting oily substance was purified by silica gel column chromatography, using a 3:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1820 mg (yield 73%) of the title compound as an oily substance.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([S:8]([OH:11])(=[O:10])=[O:9])[CH2:4][C:5]([OH:7])=[O:6].[C:12]1(=[O:18])[O:17][C:15](=[O:16])[CH:14]=[CH:13]1>CC(N(C)C)=O>[C:5]([CH2:4][CH:3]([S:8]([OH:11])(=[O:9])=[O:10])[CH2:2][NH:1][C:12](=[O:18])/[CH:13]=[CH:14]\[C:15]([OH:17])=[O:16])([OH:7])=[O:6]
Reactant: O=C1C=CC(=O)O1
Reactant: NCC(CC(=O)O)S(=O)(=O)O
Solvent: CC(=O)N(C)C
Product: O=C(O)/C=C\C(=O)NCC(CC(=O)O)S(=O)(=O)O
Yield: 86.9 %

Procedure:
To the solution of 4-amino-3-sulfobutanoic acid (˜2.50 g, 13.66 mmol) in 100 ml of DMA was added maleic anhydride (1.48 g, 15.10 mmol) and the mixture was stirred over night, evaporated, purified on C-18 column (2×30 cm) eluted with 1% HAc in water and crystallized with MeOH/Acetone/toluene to afford 3.34 g (83%) of (Z)-4-(3-carboxy-2-sulfopropylamino)-4-oxobut-2-enoic acid. 1H NMR (CD3OD) 6.33 (d, 1H, J=12.6 Hz), 6.10 (d, 1H, J=12.6 Hz), 3.64 (dd, 1H, J=5.8, 14.0 Hz), 3.54 (m, 1H), 3.30 (m, 1H), 2.78 (dd, 1H, J=4.9, 16.8 Hz), 2.39 (m, 1H); 13C NMR 173.52, 168.68, 167.98, 135.59, 127.79, 57.31, 40.56, 34.52; ESI MS m/z−279.7 (M−H).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH3:51])[CH:46]([OH:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([O:55][Si:56]([CH:63]([CH3:65])[CH3:64])([CH:60]([CH3:62])[CH3:61])[CH:57]([CH3:59])[CH3:58])[CH2:5][C:4]1=[O:66])[CH3:2].[N+:67]([C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][C:71]=1[S:76](Cl)(=[O:78])=[O:77])([O-:69])=[O:68]>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH3:51])[CH:46]([O:52][S:76]([C:71]3[CH:72]=[CH:73][CH:74]=[CH:75][C:70]=3[N+:67]([O-:69])=[O:68])(=[O:77])=[O:78])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([O:55][Si:56]([CH:60]([CH3:62])[CH3:61])([CH:57]([CH3:59])[CH3:58])[CH:63]([CH3:65])[CH3:64])[CH2:5][C:4]1=[O:66])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OC)C(O)C3)C(C)C(O[Si](C(C)C)(C(C)C)C(C)C)CC1=O)C(C)CC2OC
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OC)C(OS(=O)(=O)c4ccccc4[N+](=O)[O-])C3)C(C)C(O[Si](C(C)C)(C(C)C)C(C)C)CC1=O)C(C)CC2OC

Procedure:
The reaction of 17-ethyl-1-hydroxy-14-triisopropylsilyloxy-12-[2'-(3"-hydroxy-4"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]-octacos-18-ene-2,3,10,16-tetraone with o-nitrobenzenesulfonyl chloride as in Example 34 yields 17-ethyl-1-hydroxy-14-triisopropylsilyloxy-12-[2'-(3"-o-nitrobenzenesulfonyloxy-4"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone