Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:32]=[N:31][N:30]([CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][C:22]([CH3:29])([CH3:28])[NH:23][C:24]([CH3:27])([CH3:26])[CH:25]=2)[CH:19]=1)=[O:13].[C:39](Cl)(=[O:41])[CH3:40].O.CO.C(Cl)Cl>N1C=CC=CC=1>[C:39]([N:36]1[CH2:37][CH2:38][CH:33]([N:30]2[C:16]3[N:17]=[C:18]([C:20]4[CH2:21][C:22]([CH3:28])([CH3:29])[NH:23][C:24]([CH3:26])([CH3:27])[CH:25]=4)[CH:19]=[C:14]([C:12]([NH:11][CH2:10][C:3]4[C:4](=[O:9])[NH:5][C:6]([CH3:8])=[CH:7][C:2]=4[CH3:1])=[O:13])[C:15]=3[CH:32]=[N:31]2)[CH2:34][CH2:35]1)(=[O:41])[CH3:40]
Reactant: CC(=O)Cl
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CC(C)(C)NC(C)(C)C3)nc3c2cnn3C2CCNCC2)c(=O)[nH]1
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CC(=O)N1CCC(n2ncc3c(C(=O)NCc4c(C)cc(C)[nH]c4=O)cc(C4=CC(C)(C)NC(C)(C)C4)nc32)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 30 %

Procedure:
N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(piperidin-4-yl)-6-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.1 g, 0.2 mmol) was suspended in pyridine (1 mL) and acetyl chloride (0.016 g, 0.205 mmol) was added to it. The reaction mixture was stirred at room temperature for 5 h. On completion of reaction, water was added to it and extraction was carried out using 10% MeOH/DCM; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure. The residue was purified by prep HPLC to provide the desired compound (30% yield). LCMS: 560.00 (M+1)+; HPLC: 99.09% (@ 254 nm) (Rt; 4.685); 1H NMR (DMSO-d6, 400 MHz) δ 11.56 (s, 1H), 8.85 (t, 1H, J=5.2 Hz), 8.74 (s, 2H), 8.32 (s, 1H), 7.87 (s, 1H), 6.84 (s, 1H), 5.90 (s, 1H), 5.12-5.06 (m, 1H), 4.48 (d, 2H, J=12 Hz), 4.38 (d, 2H, J=5.2 Hz), 3.97 (m, 2H), 3.33-3.30 (m, 1H), 2.83 (s, 2H), 2.23 (s, 3H), 2.12 (s, 3H), 2.08 (s, 3H), 2.03-1.91 (m, 4H), 1.57 (s, 6H) 1.47 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([NH:13][CH:14]([CH:19]1CC1)[C:15]([O:17][CH3:18])=[O:16])=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22](NC(CC)C(O)=O)(OC(C)(C)C)=O.Cl.NC(CC)C(OC)=O>>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:10][CH3:22])[C:11]([NH:13][C@H:14]([C:15]([O:17][CH3:18])=[O:16])[CH3:19])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)C(NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C1CC1
Agent: CCC(N)C(=O)OC
Agent: Cl
Product: CCC(NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)OC

Procedure:
Following the procedure for the preparation of methyl {[N-(tert-butoxycarbonyl)-L-alanyl]amino}(cyclopropyl)acetate but substituting N-Boc-alpha-aminobutyric acid and methyl 2-aminobutanoate hydrochloride and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.82-0.91, 1.24-1.38, 1.52, 1.68-2.05, 3.75, 4.20, 4.52-4.59, 5.05, 6.69.
Reaction SMILES: CN1CCOCC1.ClC(OCC)=O.[NH:14]([C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44])[C@H:15]([C:40](O)=[O:41])[CH2:16][CH2:17][C:18](=[O:39])[NH:19][C:20]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[BH4-].[Na+]>C1COCC1.O>[CH2:46]([O:45][C:43](=[O:44])[NH:14][C@H:15]([CH2:40][OH:41])[CH2:16][CH2:17][C:18](=[O:39])[NH:19][C:20]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: O=C(CC[C@H](NC(=O)OCc1ccccc1)C(=O)O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: O
Solvent: C1CCOC1
Product: O=C(CC[C@@H](CO)NC(=O)OCc1ccccc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 23 °C
Reaction time: 0.33 h

Procedure:
4-Methylmorpholine (1.89 mL, 17.2 mmol, 1 equiv) and ethyl chloroformate (1.65 mL, 17.3 mmol, 1 equiv) were added to a mixture of commercially available Cbz-Gln(Trt)-OH (9.00 g, 17.2 mmol, 1 equiv) in THF (23 mL) at −10° C. After stirring 20 min, the reaction mixture was filtered and the filtrate was added dropwise to a suspension of NaBH4 (1.47 g, 38.9 mmol, 2.25 equiv) in H2O (10 mL) at 0° C. The resulting mixture was allowed to warm to 23° C. and stirred for 5 h. It was then cooled again to 0° C., quenched by the careful addition of 1 N HCl (30 mL) and then partitioned between MTBE (500 mL) and brine (2×100 mL). The organic phase was dried over Na2SO4 and evaporated to provide the title intermediate which was used without further purification.
Reaction SMILES: CC[CH2:3][CH:4]([C:7]1S[C:10]([C:12]2[S:13][C:14]([C:17]3[S:18][C:19](C4SC(C(CC)CCC)=CC=4)=[CH:20][CH:21]=3)=[CH:15][CH:16]=2)=[CH:9][CH:8]=1)CC.S1C=CC=C1C1SC=CC=1.C(OC(=O)CCCCC)(=[O:49])CCCCC.B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[C:10]([C:12]1[S:13][C:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)=[CH:15][CH:16]=1)(=[O:49])[CH2:9][CH2:8][CH2:7][CH2:4][CH3:3]
Reactant: CCCCCC(=O)OC(=O)CCCCC
Reactant: CCCC(CC)c1ccc(-c2ccc(-c3ccc(-c4ccc(C(CC)CCC)s4)s3)s2)s1
Agent: FB(F)F
Agent: c1csc(-c2cccs2)c1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCCCCC(=O)c1ccc(-c2cccs2)s1
Temperature: 100 °C

Procedure:
Preparation of 5,5′″-Bis(4-n-hexyl)-2,2′:5′,2″:5″,2′″-quaterthiophene (6TTTT6) is now discussed. A mixture of 6.2 g of bithiophene, 8.0 g of hexanoic anhydride, and 0.4 g boron trifluoride etherate is heated to about 100° C. and allowed to cool. The resulting mixture is dissolved in toluene, washed with aqueous sodium bicarbonate (allowing for venting of carbon dioxide gas), dried with magnesium sulfate, filtered, concentrated on a rotary evaporator, and chromatographed on 160 grams of silica gel eluting with hexane/methylene chloride mixtures. The product 5′-hexanoylbithiophene is isolated. The 5′-hexanoylbithiophene (3.9 g sample) is added to a stirred mixture of 3.0 g of aluminum chloride and 3.4 g of lithium aluminum hydride suspended in 300 mL of ethyl ether. After 1 hour, 50 mL ethyl acetate and 15 mL of concentrated hydrochloric acid are cautiously added, and the mixture is filtered, concentrated, and eluted through 30 g of silica gel with hexane. The product 5′-hexylbithiophene is isolated. A measured 2.4 g of this compound is dissolved in 150 mL of tetrahydrofuran. A measured 9.6 mmol of butyllithium as a hexane solution is added with stirring and cooling to −78° C. After 20 minutes, 2.6 g of cupric chloride is added. The mixture is allowed to warm to room temperature. After one day, dilute hydrochloric acid is added to dissolve the copper salts, and the mixture is dissolved in toluene, washed with concentrated hydrochloric acid and dilute aqueous ammonia, dried with magnesium sulfate, filtered, concentrated, and triturated with hexane, methanol, and petroleum ether.
Reaction SMILES: NC(N)=O.[CH:5]1([NH:8][S:9]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([NH2:19])[C:13]=2[OH:20])(=[O:11])=[O:10])[CH2:7][CH2:6]1.[Cl:21][C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[N:29]=[C:30]=[O:31]>>[Cl:18][C:17]1[CH:16]=[CH:15][C:14]([NH:19][C:30]([NH:29][C:23]2[CH:24]=[CH:25][CH:26]=[C:27]([Cl:28])[C:22]=2[Cl:21])=[O:31])=[C:13]([OH:20])[C:12]=1[S:9]([NH:8][CH:5]1[CH2:7][CH2:6]1)(=[O:11])=[O:10]
Reactant: Nc1ccc(Cl)c(S(=O)(=O)NC2CC2)c1O
Reactant: O=C=Nc1cccc(Cl)c1Cl
Agent: NC(N)=O
Product: O=C(Nc1ccc(Cl)c(S(=O)(=O)NC2CC2)c1O)Nc1cccc(Cl)c1Cl
Yield: 46.5 %

Procedure:
Following the general procedure for urea formation outlined in example 15, N-cyclopropyl -3-amino-6-chloro-2-hydroxybenzenesulfonamide (220 mg, 0.84 mmol) and 2,3-dichlorophenylisocyanate (190 mg, 1/01 mmol) were coupled to form the desired urea (176 mg, 46%). LC-MS (m/z) 452.0 (M+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[CH3:32][O:33][C:34](=[O:52])[C:35]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[CH:40][CH:39]=1)([OH:37])[CH3:36].[Cl:53][C:54]1[CH:59]=[CH:58][C:57](O)=[CH:56][CH:55]=1>C1COCC1>[CH3:32][O:33][C:34](=[O:52])[C:35]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)=[CH:40][CH:39]=1)([O:37][C:57]1[CH:58]=[CH:59][C:54]([Cl:53])=[CH:55][CH:56]=1)[CH3:36]
Reactant: COC(=O)C(C)(O)c1ccc(OCc2ccccc2)cc1
Reactant: Oc1ccc(Cl)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(C)(Oc1ccc(Cl)cc1)c1ccc(OCc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 59 %

Procedure:
A solution of triphenylphosphin(0.1 g, 0.38 mmol) in 5 ml of dry THF was treated at 0° C. with DEAD (0.066 g, 0.38 mmol) and stirred over 30 min. Then a solution of 4-Benzyloxyphenyl-2-hydroxypropanoic acid methyl ester (0.1 g, 0.35 mmol) and p-chlorophenol (0.048 g, 0.38 mmol) in 2 ml of THF was added to the solution and the mixture reaction was stirred at room temperature overnight. The mixture was concentrated to dryness and chromatographed in silicagel (hexanes/Ethyl acetate 3:1) to give 0.082 g of product (60%). 1H-NMR (200.15 MHz, CDCl3): δ 7.46–7.31 (m, 5H), 7.28–7.13 (m, 4H), 6.93 (d, 2H, J=8.8), 6.75 (d, 2H, J=8.8), 5.04 (s, 2H), 4.73(t, 1H, J=6.1), 3.71 s (s, 3H), 3.18 (d, 2H, J=6.4).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].N(CCO)CCO>C1COCC1.C(OCC)C>[C:4]1([C@@H:1]([OH:3])[CH3:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: OCCNCCO
Product: C[C@H](O)c1ccccc1
Reaction time: 7 h
Yield: 75.3 %

Procedure:
Under a nitrogen atmosphere, with stirring, acetophenone (3.05 mL, 25 mmol) was added to a solution of diisopinocampheylchloroborane (9.0 g, 28 mmol) in THF (20 mL0 at -25° C. A yellow color developed immediately. The reaction was complete after 7 h at -25° C. (followed by 11B NMR after methanolysis of an aliquot). The volatiles were pumped off at aspirator pressure and the α-pinene was removed under reduced pressure (0.1 mm Hg, 8 h). The residue was dissolved in ethyl ether (100 mL0 and diethanolamine (2.2 equiv) was added. The separated solid was filtered off after 2 h and washed twice with pentane (~30 mL). The combined ether and pentane filtrates were concentrated. The residue, upon distillation (bp 118° C., 22 mm Hg) provided [S]-1-phenylethanol (2.3 g, 72% yield) [α]20D -42.6° (neat) after purification by preparative gas liquid chromotagraphy on Carbowax 20 M; 98% ee based on -43.5° for maximum reported rotation. Gas chromotagraphy analysis of its α-methoxy-α-(trifuloromethyl)phenylacetate (made from (+)-MTPA chloride, Aldrich) on Supelcowax glass capillary column (15 m) showed a composition of 98.7% S+1.3% R (i.e., 97.4% ee), in good agreement with the optical rotation measurement.
Reaction SMILES: [Cl:1][C:2]1[S:19][C:5]2[NH:6][C:7](=S)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.[C:20]([NH:25][NH2:26])(=O)[CH:21]([CH3:23])[OH:22]>CO>[Cl:1][C:2]1[S:19][C:5]2[N:6]3[C:20]([CH:21]([OH:22])[CH3:23])=[N:25][N:26]=[C:7]3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: CC(O)C(=O)NN
Reactant: S=C1CN=C(c2ccccc2Cl)c2cc(Cl)sc2N1
Solvent: CO
Product: CC(O)c1nnc2n1-c1sc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
1 g of 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepine-2-thione is refluxed for 1.5 hours in 50 ml of absolute methanol with 2 g of lactic acid hydrazide. The precipitated 7-chloro-5-(o-chlorophenyl)-2-(2-lactoylhydrazino)-3H-thieno[2,3-e]-1,4-diazepine is dried and refluxed for 4 hours in 120 ml of absolute xylene. The solution is evaporated and the product recrystallized from ethyl acetate containing active carbon to yield 2-chloro-4-(o-chlorophenyl)-9-(α-hydroxyethyl)-6H-thieno[3,2-f]-s- triazolo[4,3-a][1,4]diazepine of melting point 118°-120° C.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:8]([O:10]C(C)(C)C)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])O.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:34][C:35]1[CH:36]=[CH:37][C:38]([OH:45])=[C:39]([S:41]([O-:44])(=[O:43])=[O:42])[CH:40]=1.[Na+]>C(Cl)Cl.C1COCC1>[OH:45][C:38]1[CH:37]=[CH:36][C:35]([NH:34][C:5](=[O:7])[CH2:4][CH2:3][C@@H:2]([C:8]([OH:10])=[O:9])[NH2:1])=[CH:40][C:39]=1[S:41]([OH:44])(=[O:42])=[O:43]
Reactant: Nc1ccc(O)c(S(=O)(=O)[O-])c1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: N[C@@H](CCC(=O)Nc1ccc(O)c(S(=O)(=O)O)c1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Boc-Glu-OtBu (100 mg, 0.33 mmol) was dissolved in methylene chloride (1 ml) and THF (1 ml), and CDI (65 mg, 1.1 mmol) was added to the solution. The mixture was stirred for 30 minutes at room temperature. Sodium 5-amino-2-hydroxybenzenesulfonate (77 mg, 0.33 mmol) was added to the mixture and stirred overnight at room temperature. After the solvent was removed by distillation, the mixture was purified in accordance with the purification step A. The resulting intermediate was dissolved in 2 ml of TFA. After stirring for 3 hours at room temperature, the solvent was distilled off. The mixture was purified according to the purification step A to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:29]=[N:30][C:31](F)=[CH:32][CH:33]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.[CH3:35][O:36][CH2:37][CH2:38][NH2:39]>CN1C(=O)CCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:33]=[CH:32][C:31]([NH:39][CH2:38][CH2:37][O:36][CH3:35])=[N:30][CH:29]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: COCCN
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(-c4ccc(F)nc4)ccc2OCC3)c(F)c1
Solvent: CN1CCCC1=O
Product: COCCNc1ccc(-c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)cn1
Temperature: 150 °C
Yield: 19.8 %

Procedure:
2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(6-fluoro-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (470 mg, 1.0 mmol), from the procedure for 249, 2-Methoxy-ethylamine (90 mg, 1.2 mmol) DIPEA (340 mg, 3 mmol) and NMP (4 mL) were added in a 10 mL of sealed tube, and the mixture was heated by microwave at 150° C. for 120 min under N2. The reaction mixture was filtered to gather the solution and water was added. The mixture was extracted by DCM (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and purified by preparative HPLC to give 341 (105.5 mg, yield: 20%). 1HNMR (DMSO-d6, 400 MHz): δ8.63 (s, 1H), 8.31 (s, 1H), 7.94-7.88 (m, 2H), 7.76-7.68 (m, 2H), 7.46-7.38 (m, 2H), 7.21 (s, 2H), 6.99 (s, 1H), 6.63 (d, J=8.8 Hz, 1H), 4.31 (s, 2H), 3.49 (s, 4H), 3.29 (s, 3H), 3.15 (s, 2H). ESI-MS: m/z=533 [M+H+]
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[C:7]([C:9]1[CH:23]=[C:22](I)[C:12]2[N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:14]=[N:15][C:11]=2[CH:10]=1)#[N:8].C(N(CC)CC)C>C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(#N)C>[CH3:6][O:5][C:1](=[O:4])[CH:2]=[CH:3][C:22]1[C:12]2[N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:14]=[N:15][C:11]=2[CH:10]=[C:9]([C:7]#[N:8])[CH:23]=1
Reactant: C=CC(=O)OC
Reactant: N#Cc1cc(I)c2c(c1)ncn2-c1ccccc1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)C=Cc1cc(C#N)cc2ncn(-c3ccccc3)c12
Yield: 82.4 %

Procedure:
Methyl acrylate (0.27 ml, 3 mmol), 5-cyano-7-iodo-1-phenylbenzimidazole (346 mg, 1.0 mmol), triethylamine (0.28 ml, 2 mmol) palladium acetate (4.5 mg, 0.02 mmol), tri-o-tolylphosphine (16.1 mg, 0.05 mmol) and acetonitrile (5 ml) were combined in Reactivial™. The mixture was heated under reflux under an argon atmosphere for 17 h. The mixture was cooled, filtered through Dicalite and the filtrate was concentrated under reduced pressure. Crystals formed and were isolated by filtration and dried to give the title compound (250 mg, 83%), m/z 304.2 (M+H)+.
Reaction SMILES: [C:1]([NH:9][C:10](=[CH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)[C:11]([O:13]C)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26]O>[Pd]>[CH3:26][N:9]([C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@H:10]([C:11]([OH:13])=[O:12])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1
Reactant: COC(=O)C(=Cc1ccc(OC)c(OC)c1)NC(=O)c1ccccc1
Reactant: CO
Agent: [Pd]
Product: COc1ccc(C[C@@H](C(=O)O)N(C)C(=O)c2ccccc2)cc1OC
Yield: 95 %

Procedure:
Methyl α-benzoylamino-3,4-dimethoxycinnamate (20 g) was treated with 10% palladium on carbon (2 g) in methanol (400 mL) under a hydrogen atmosphere (1 atm.) for 3 days. The reaction mixture was then filtered and the solvent stripped to yield the title compound (18.90 g, 95%); MP 106°-107° C.
Reaction SMILES: [CH3:1][C@@:2]1(/[CH:28]=[CH:29]/[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[S:8](=[O:10])(=[O:9])[C@H:7]2[N:4]([C:5](=[O:11])[CH2:6]2)[C@H:3]1[C:12]([O:14]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:13].[K+].[Br-]>>[CH3:1][C@@:2]1(/[CH:28]=[CH:29]/[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[S:8](=[O:9])(=[O:10])[C@H:7]2[N:4]([C:5](=[O:11])[CH2:6]2)[C@H:3]1[C:12]([OH:14])=[O:13]
Reactant: C[C@]1(/C=C/c2ccccn2)[C@H](C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C[C@H]2S1(=O)=O
Agent: [Br-]
Agent: [K+]
Product: C[C@]1(/C=C/c2ccccn2)[C@H](C(=O)O)N2C(=O)C[C@H]2S1(=O)=O

Procedure:
200 mg (0.41 mmol) of benzhydryl (E)-(2S,3S,5R)-3-methyl-3-(2- pyridin-2-yl-vinyl)-4,4,7-trioxo-4-thia-1-aza-bicyclo[3.2.0]-heptane-2-carboxylate were deprotected analogously to Example 10. Yield: 85 mg (65%) of pale beige crystal powder MS: (M+H)+ 323.3 IR (KBr): 2700(br), 1790, 1720, 1621, 1318, 1140, 978 cm-1
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)=[C:19]([O:30][CH2:31][CH2:32][O:33][C:34]3[N:39]=[CH:38][C:37]([C:40]([O:42]CC)=[CH2:41])=[CH:36][N:35]=3)[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C(=O)([O-])O.[Na+]>CC(C)=O>[C:40]([C:37]1[CH:38]=[N:39][C:34]([O:33][CH2:32][CH2:31][O:30][C:19]2[N:18]=[CH:17][N:16]=[C:15]([NH:14][S:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][CH:9]=3)(=[O:13])=[O:12])[C:20]=2[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=2)=[N:35][CH:36]=1)(=[O:42])[CH3:41]
Reactant: C=C(OCC)c1cnc(OCCOc2ncnc(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)c2Oc2cccc(OC)c2)nc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ncc(C(C)=O)cn2)c1
Yield: 87 %

Procedure:
A mixture of 4-tert-butyl-N-[6-{2-(5-(1 -ethoxyethenyl)pyrimidin-2-yloxy)ethoxy}-5-(3-methoxyphenoxy)pyrimidin-4-yl]benzenesulfonamide (1.022 g), 10% hydrochloric acid (1 ml) and acetone (20 ml) is reacted at room temperature for four hours. The pH value of the reaction solution is adjusted to pH 6 with aqueous sodium hydrogen carbonate solution, and the mixture is evaporated to remove the solvent. To the residue are added aqueous ammonium chloride solution and ethyl acetate, and the ethyl acetate layer is collected. The ethyl acetate layer is washed, dried, and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; ethyl acetate/n-hexane=1:1~ethyl acetate), and recrystallized from ethyl acetate/n-hexane to give N-[6-{2-(5-acetylpyrimidin-2-yloxy)ethoxy}-5-(3-methoxyphenoxy)pyrimidin-4-yl]-4-tert-butylbenzenesulfonamide (849 mg).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[N:5][S:6][C:7]=1[NH:8][C:9](=[O:17])OC1C=CC=CC=1)#[N:2].[O:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][NH2:36])[CH2:29][CH2:28]1>O1CCOCC1>[C:1]([C:3]1[C:4]([C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)=[N:5][S:6][C:7]=1[NH:8][C:9]([NH:36][CH2:35][CH2:34][CH2:33][N:30]1[CH2:31][CH2:32][O:27][CH2:28][CH2:29]1)=[O:17])#[N:2]
Reactant: N#Cc1c(-c2ccc([N+](=O)[O-])cc2)nsc1NC(=O)Oc1ccccc1
Reactant: NCCCN1CCOCC1
Solvent: C1COCCO1
Product: N#Cc1c(-c2ccc([N+](=O)[O-])cc2)nsc1NC(=O)NCCCN1CCOCC1
Temperature: 80 °C
Yield: 79.2 %

Procedure:
A mixture of phenyl (4-cyano-3-(4-nitrophenyl)isothiazol-5-yl)carbamate (37 mg, 0.10 mmol) and 3-morpholinopropylamine (0.021 mL, 0.14 mmol) in 0.8 mL dioxane was heated at 80° C. After 2 hours the reaction mixture was evaporated to a yellowish oily film. This material was then chromatographed eluting with EtOAc, then gradient 2% to 6% MeOH in EtOAc to give the title compound as a pale yellow solid (33 mg, 80%). 1H NMR (acetone) δ: 8.38-8.44 (m, 2H), 8.22-8.27 (m, 2H), 6.91 (t, J=5.4 Hz, 1H), 3.59-3.64 (m, 4H), 3.38-3.45 (m, 2H), 2.37-2.45 (m, 6H), 1.77 (quin, J=6.8 Hz, 2H)
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]([C:23]([OH:25])=[O:24])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C@H](C(O)=O)[CH2:28][C:29]1[C:37]2C(=CC=CC=2)N[CH:30]=1.C(Cl)(OCC1C=CC=CC=1)=O.[OH-].[Na+].C([O-])([O-])=O.[K+].[K+].C(Br)(C)(C)C>O.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.CC(N(C)C)=O>[CH3:28][C:29]([O:24][C:23](=[O:25])[C@H:12]([CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)[NH:11][C:9]([O:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:10])([CH3:37])[CH3:30]
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)OCc1ccccc1
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: CC(C)(C)Br
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C(Cl)OCc1ccccc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1
Temperature: 55 °C
Reaction time: 19 h
Yield: 99 %

Procedure:
To a suspension of N-[(phenylmethoxy)carbonyl]-L-tryptophan (33.27 g; 98.32 mol) (previously prepared by reacting L-tryptophan with CBZCl, in H2O and 1N NaOH), benzyltriethylammonium chloride (BTEAC) (22.4 g; 98.32 mol) and K2CO3 (176.91 g; 1.28 mol) in dimethylacetamide (750 mL) is added tert-butyl bromide (265 mL; 2.36 mol). The solution is heated to 55° C. and vigorously stirred for 19 hours. The mixture is then cooled to room temperature, diluted with H2O (3L) and then extracted with EtOAc (2×1L). The organic phases are evaporated to dryness to obtain the title product as a pale yellow oil (36 g; 98 mol)
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([NH:7][CH:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[O:12][CH2:11][CH2:10][CH2:9]1)=[O:6].[O:19]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH2:33][CH2:34][NH:35][CH2:36][CH:37]=2)=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[O:19]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH2:37][CH2:36][N:35]([CH2:2][CH2:3][CH2:4][C:5]([NH:7][CH:8]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[O:12][CH2:11][CH2:10][CH2:9]3)=[O:6])[CH2:34][CH:33]=2)=[CH:28][CH:27]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(CCCCl)NC1CCCOc2ccccc21
Reactant: C1=C(c2ccc(Oc3ccccc3)cc2)CCNC1
Product: O=C(CCCN1CC=C(c2ccc(Oc3ccccc3)cc2)CC1)NC1CCCOc2ccccc21

Procedure:
The compound (9) synthesized in Reference Example 9 and the compound (3) synthesized in Reference Example 3 were used to produce the above compound in the same way as Example 1.