Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH:14]([C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].[CH3:30][O:31][C:32]1[CH:37]=[CH:36][N:35]=[C:34]([CH2:38][CH2:39][C:40]2[NH:49][C:43]3=[N:44][CH:45]=[C:46](I)[CH:47]=[C:42]3[N:41]=2)[CH:33]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+]>O1CCOCC1.O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:17]([CH:14]1[CH2:15][CH2:16][N:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([C:46]3[CH:47]=[C:42]4[N:41]=[C:40]([CH2:39][CH2:38][C:34]5[CH:33]=[C:32]([O:31][CH3:30])[CH:37]=[CH:36][N:35]=5)[NH:49][C:43]4=[N:44][CH:45]=3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:12][CH2:13]1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1ccnc(CCc2nc3cc(I)cnc3[nH]2)c1
Reactant: O=C(c1ccccc1)C1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccnc(CCc2nc3cc(-c4ccc(S(=O)(=O)N5CCC(C(=O)c6ccccc6)CC5)cc4)cnc3[nH]2)c1
Temperature: 90 °C
Yield: 37 %

Procedure:
A mixture of 0.612 g of 1-(4-bromo-benzene-sulfonyl)-4-benzoyl-piperidine, 0.42 g of bis-(pinacolato)-diboron, 0.025 g of 1,1′-bis(diphenylphosphino)-ferrocene, 0.033 g of [1,1′-bis(diphenylphosphino)-ferrocene]palladium-dichloride (complex with CH2Cl2), 0.442 g of potassium acetate in 6 ml of degassed dioxane are heated to 90° C. in a sealed tube under N2 for 6 hours. To the resulting mixture 6 ml of degassed dioxane, 0.371 g of 2-[2-(4-methoxypyridin-2-yl)ethyl]-6-iodo-3H-imidazo[4,5-b]pyridine (starting material A1), 0.113 g of tetrakis(triphenylphosphine)-palladium(0) and a solution of 0.27 g of potassium carbonate and 0.083 g of lithium chloride in 6 ml of degassed water are added under N2. The tube is sealed again, the mixture is heated to 115° under N2 for 19 hours and, after cooling, addition of water and adjusting the pH to 7, it is extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate, concentrated and the residue is chromatographed on a silica gel column (dichloromethane/methanol 30-25:1). Concentration of the chromatographically pure fractions and crystallization of the residue from ethylacetate gives 0.21 g of the title compound as a solid of m.p. 174-175° C. The mass spectrum shows the molecular peak MH+ at 582.3 Da.
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][CH2:8][C@H:9]([OH:16])[CH2:10]OS(C)(=O)=O)=[CH:5][CH:4]=1)#[N:2].[CH2:19]([NH:21][CH2:22][CH2:23][CH2:24][S:25][CH2:26][CH2:27][CH3:28])[CH3:20].C(=O)([O-])[O-].[K+].[K+].Cl>CO.CO.ClCCl.CCOCC.C(#N)C>[CH2:19]([N:21]([CH2:22][CH2:23][CH2:24][S:25][CH2:26][CH2:27][CH3:28])[CH2:10][C@@H:9]([OH:16])[CH2:8][O:7][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:18][CH:17]=1)[CH3:20]
Reactant: CCCSCCCNCC
Reactant: CS(=O)(=O)OC[C@@H](O)COc1ccc(C#N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Solvent: CO
Product: CCCSCCCN(CC)C[C@@H](O)COc1ccc(C#N)cc1
Yield: 71 %

Procedure:
11.7 g of (2S)-1-(4-cyanophenoxy)-3-methanesulfonyloxy propane-2-ol, was stirred and refluxed overnight with ethyl (3-propylthio)propylamine (13.9 g), potassium carbonate (12.6 g) and acetonitrile (100 ml). Filtration and evaporation gave 21.5 g of crude product which was distributed between ether and 2 M hydrochloric acid. The aqueous layer was extracted three times with dichloromethane, in which it was present as an ion pair. Evaporation and distribution between ether and 1 M sodium hydroxide yielded the free base in the ether layer. Chromatography over silica using methanol-dichloromethane 5:95 as mobile phase gave 10.3 g of the title compound as a colourless oil, [α]D20 -24,2° (c 1.0, CH3OH).
Reaction SMILES: [F:1][C:2]1([F:7])[CH2:4][CH:3]1[CH2:5][OH:6].C(N(CC)CC)C.[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1)([O-:17])=[O:16].C(=O)([O-])O.[Na+]>C1COCC1>[N+:15]([C:18]1[CH:19]=[CH:20][C:21]([S:24]([O:6][CH2:5][CH:3]2[CH2:4][C:2]2([F:7])[F:1])(=[O:26])=[O:25])=[CH:22][CH:23]=1)([O-:17])=[O:16]
Reactant: OCC1CC1(F)F
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(S(=O)(=O)OCC2CC2(F)F)cc1
Reaction time: 4 h
Yield: 87 %

Procedure:
To a solution of (2,2-difluorocyclopropyl)methanol (20.0 g) and triethylamine (32.2 mL) in THF (300 mL) was added 4-nitrobenzenesulfonyl chloride (41.0 g) at 0° C., and the mixture was stirred for 4 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (47.2 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH2:11][CH2:12][C:13]#[C:14][Si](C)(C)C)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C2C=1N(CCC#C[Si](C)(C)C)N=C2>>[CH2:11]([N:8]1[CH:7]=[C:6]2[C:10]([C:2]([Cl:1])=[CH:3][CH:4]=[CH:5]2)=[N:9]1)[CH2:12][C:13]#[CH:14]
Reactant: C[Si](C)(C)C#CCCn1cc2cccc(Cl)c2n1
Agent: C[Si](C)(C)C#CCCn1ncc2cccc(Cl)c21
Product: C#CCCn1cc2cccc(Cl)c2n1
Yield: 23 %

Procedure:
The title compound was prepared in accordance with the general method of Example 108(B), from 7-chloro-2-(4-trimethylsilanyl-but-3-ynyl)-2H-indazole and 7-chloro-1-(4-trimethylsilanyl-but-3-ynyl)-1H-indazole (250 mg, 0.90 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 44 mg (0.21 mmol, 23%) of 2-(but-3-ynyl)-7-chloro-2H-indazole as an orange oil.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([S:14]([NH:17][C:18]3([C:24]([O:26]C)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)(=[O:16])=[O:15])=[CH:11][CH:12]=2)[C:7]([NH:28][C:29]([NH2:31])=[NH:30])=[N:6][CH:5]=1.Cl>CO>[ClH:3].[Cl:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([S:14]([NH:17][C:18]3([C:24]([OH:26])=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)(=[O:15])=[O:16])=[CH:11][CH:12]=2)[C:7]([NH:28][C:29]([NH2:31])=[NH:30])=[N:6][CH:5]=1
Reactant: COC(=O)C1(NS(=O)(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)NC3(C(=O)O)CCCCC3)cc12
Temperature: 55 °C
Yield: 155.6 %

Procedure:
A solution of NaOH (1 mL, 2 M, 2 mmol) was added to a solution of methyl 1-{[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino}cyclohexanecarboxylate (12 mg, 0.027 mmol) in MeOH (4 mL) and the mixture was heated at 50-60° C. for 4 d. The cooled mixture was neutrilised with dilute HCl (1 mL, 2 M) to give a precipitate. The solid was collected by filtration, with copious water washing, and then triturated with EtOAc. The solid was dissolved in conc. HCl, the solvents were evaporated in vacuo azeptroping with PhMe, and then dried under high vacuum to give 1-{[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino}cyclohexanecarboxylic acid hydrochloride (11 mg, 0.021 mmol).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:16][C:17]([OH:19])=[O:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:28][CH2:29]O>OS(O)(=O)=O>[CH2:28]([O:18][C:17](=[O:19])[CH2:16][CH:15]([C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:8]=1)[C:20]#[C:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH3:29]
Reactant: CCO
Reactant: COc1ccc(C(C#Cc2ccccc2)CC(=O)O)cc1OC1CCCC1
Agent: O=S(=O)(O)O
Product: CCOC(=O)CC(C#Cc1ccccc1)c1ccc(OC)c(OC2CCCC2)c1

Procedure:
A solution of (+/-)-3-(3-cyclopentyloxy-4-methoxyphenyl)-3-phenylethynylpropionic acid (250 mg, 0.69 mmol) in EtOH (20 ml) and H2SO4 (1 drop) was refluxed for 6 hr. The solvent was evaporated, the residue taken up in Et2O, washed with aqueous Na2CO3, dried, and the solvent evaporated. The residue was crystallized from hexane, and gave the titled compound, 180 mg (67%). 1H NMR (400 MHz, CDCl3) δ 7.40 (m, 2 H), 7.28 (m, 3 H), 6.98 (m, 2 H), 6.82 (d, 1 H), 4.80 (m, 1 H), 4.32 (t, 1 H), 4.14 (q, 2 H), 3.80 (s, 3 H), 2.86 (d of d, 1 H), 2.76 (d of d, 1 H), 1.76-1.98 (m, 6 H), 1.62 (m, 2 H), 1.22 (t, 3 H).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)(=[O:16])=[O:15])[CH2:11][NH:10]2)=[O:8])[CH2:5][CH2:4]1)#[N:2].[CH2:27]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([N:38]2[CH2:41][CH2:40][CH:39]2[C:42]([O-])=[O:43])[CH2:34][CH2:33]1)=[O:31])[CH3:28].[Li+]>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[CH:18]=3)(=[O:16])=[O:15])[CH2:11][N:10]2[C:42]([CH:39]2[CH2:40][CH2:41][N:38]2[CH:35]2[CH2:34][CH2:33][N:32]([C:30]([O:29][CH2:27][CH3:28])=[O:31])[CH2:37][CH2:36]2)=[O:43])=[O:8])[CH2:4][CH2:5]1)#[N:2]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3cccc(C(F)(F)F)c3)CN2)CC1
Reactant: CCOC(=O)N1CCC(N2CCC2C(=O)[O-])CC1
Agent: [Li+]
Product: CCOC(=O)N1CCC(N2CCC2C(=O)N2C[C@H](S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]2C(=O)NC2(C#N)CC2)CC1

Procedure:
The reaction of (2S,4R)-N-(1-cyanocyclopropyl)-4-(3-(trifluoromethyl)phenylsulfonyl)pyrrolidine-2-carboxamide 7E and lithium 1-(1-(ethoxycarbonyl)piperidin-4-yl)azetidine-2-carboxylate 20J carried out according to the general procedure L yielded ethyl 4-(2-((2S,4R)-2-(1-cyanocyclopropylcarbamoyl)-4-(3-(trifluoromethyl)phenylsulfonyl)pyrrolidine-1-carbonyl)azetidin-1-yl)piperidine-1-carboxylate 1:1 epimers as a white solid (77%). MS ISP (m/e): 626.3 (100) [(M+H)]+.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].C([O-])([O-])=O.[Cs+].[Cs+].S(O[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(C1C=CC(C)=CC=1)(=O)=O.O>CN(C=O)C>[C:33]([NH:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][N:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3])([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCNC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=c1cc[nH]c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1ccn(CCCCCCNC(c2ccccc2)(c2ccccc2)c2ccccc2)c(=O)[nH]1
Temperature: 40 °C
Yield: 70 %

Procedure:
Uracil (0.087 g, 0.776 mmol) was stirred with Cs2CO3 (0.169 g, 0.519 mmol) in DMF (4 mL) at room temperature for 1 h. A solution of O-tosyl-6-tritylaminohexanol (0.250 g, 0.487 mmol) in DMF (2 mL) was then added dropwise. The reaction mixture was heated at 40° C. for 64 h, left to cool to room temperature, poured into cold water (15 mL) and extracted with EtOAc (25 mL). The organic extracts were washed with brine (10 mL), dried over Na2SO4 and concentrated in vacuo. Further purification was carried out by flash column chromatography (ISOLUTE SI column) using a gradient elution of 20→50% EtOAc in hexane. The fractions with Rf=0.49 (10% CH3OH/CHCl3) gave the title compound slightly contaminated with DMF as a white solid (0.111 g, ca 50%). Remaining traces of DMF could be removed by recrystallisation from CH3OH or alternatively by water wash with a purification yield of 70-80%.
Reaction SMILES: CC(C[AlH]CC(C)C)C.COC1C=CC(/C=C/C=O)=CC=1.[CH3:22][O:23][C:24]1[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=1/[CH:26]=[CH:27]/[CH:28]=[O:29]>N1C=CC=CC=1>[CH3:22][O:23][C:24]1[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=1/[CH:26]=[CH:27]/[CH2:28][OH:29]
Reactant: COc1ccccc1/C=C/C=O
Agent: CC(C)C[AlH]CC(C)C
Agent: COc1ccc(/C=C/C=O)cc1
Solvent: c1ccncc1
Product: COc1ccccc1/C=C/CO

Procedure:
[Ir(cod)Cl]2, O,O′-(R)-(1,1′-Dinaphthyl-2,2′-diyl)-N,N′-di-(R,R)-phenylethylphosphoramidite were prepared according to published procedures (Herde, J. L.; Lambert, J. C.; Senoff, C. V. Inorg. Synth. 1974, 15, 18; Alexakis, A.; Rosset, S.; Allamand, J.; March, S.; Guillen, F.; Benhaim, C. Synlett 2001, 1375). Lithium aryloxides were prepared by reaction of the corresponding phenols with n-BuLi in THF at 0° C. After being stirred for 10 min at room temperature, the solution was concentrated under vacuum to afford the corresponding lithium aryloxides as white powders, which were stored under inert atmosphere. All allylic carbonates were synthesized by the reaction of the corresponding allylic alcohols with the corresponding alkylchloroformate in the presence of pyridine. (E)-4-Methoxycinnamamyl alcohol and (E)-2-methoxycinnamyl alcohol were prepared by the reduction of the corresponding aldehydes with DIBAL-H (Nung Min, Y.; Young Soo, G. J. Org. Chem. 1985, 50, 2443). Phenols, (E)-4-methoxycinnamaldehyde, and (E)-2-methoxycinnamaldehyde were purchased from Aldrich Chemicals Co. and used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2.[Br-].[C:13]([O:17][C:18](=[O:21])[CH2:19][Zn+])([CH3:16])([CH3:15])[CH3:14]>C1COCC1.CC(P(C(C)(C)C)[C-]1C=CC=C1)(C)C.C1C=CC([C-]2C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C(C3C=CC=CC=3)=C2C2C=CC=CC=2)=CC=1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[CH2:19][C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:21])[CH:7]=[CH:8][N:9]=1
Reactant: CC(C)(C)OC(=O)C[Zn+]
Reactant: Brc1cccc2ccncc12
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cc1cccc2ccncc12
Temperature: 80 °C
Yield: 78 %

Procedure:
To a suspension of 8-bromoisoquinoline (2.0 g, 9.7 mmol), Q-phos (68 mg, 0.096 mmol) and Pd(dba)2 (132 mg, 0.14 mmol) in dry THF (30 mL) was added 40 mL of (2-tert-butoxy-2-oxoethyl)zinc(II) bromide solution under N2 protection. The resulting mixture was heated at 80° C. overnight. The solvent was evaporated under vacuum and the crude residue was diluted with ethyl acetate (100 mL) and washed with water (3×50 mL). The combined organic layer was washed with brine, dried over Na2SO4 and the solvent was evaporated under vacuum to give a residue which was purified with silica gel chromatography to give tert-butyl 2-(isoquinolin-8-yl)acetate (1.85 g, 78%).
Reaction SMILES: [OH:1]C1C=CC=CC=1C(O)=O.C(OO)(C)(C)C.[CH3:17][CH:18]([C:20](=[CH:23][CH:24]=[C:25]([CH3:37])[CH2:26][CH2:27][CH:28]=[C:29]([CH3:36])[CH2:30][CH2:31][CH:32]=[C:33]([CH3:35])[CH3:34])[C:21]#[N:22])[CH3:19]>C(Cl)Cl.[Se](=O)=O>[OH:1][CH2:34][C:33]([CH3:35])=[CH:32][CH2:31][CH2:30][C:29]([CH3:36])=[CH:28][CH2:27][CH2:26][C:25]([CH3:37])=[CH:24][CH:23]=[C:20]([CH:18]([CH3:17])[CH3:19])[C:21]#[N:22]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CC=C(C#N)C(C)C
Reactant: O=C(O)c1ccccc1O
Agent: CC(C)(C)OO
Agent: O=[Se]=O
Solvent: ClCCl
Product: CC(=CCCC(C)=CCCC(C)=CC=C(C#N)C(C)C)CO
Reaction time: 0.5 h
Yield: 317.6 %

Procedure:
To a suspension of selenium dioxide (58 mg) and 2-hydroxybenzoic acid (365 mg) in methylene chloride (10.5 ml) was gradually added an aqueous solution of 80% t-butyl hydroperoxide (11.6 ml) with stirring on a water bath. After 30 minutes, 2-(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-tetradecatetraenenitrile (7.56 g, 26.8 mmol) was added to the mixture, which was then allowed to stand at room temperature for 30 hours. Most of the solvent was removed by evaporation in vacuo, and the residue was dissolved in ether. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over MgSO4, and concentrated. The resultant residue was subjected to silica gel column chromatography to give the aimed 14-hydroxy-2-(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-tetradecatetraenenitrile (2.53 g, 31%). The starting material was also recovered (3.10 g, 40%) in the column chromatography. The yield of the aimed product based on the consumed starting material was 52%.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]([NH:13][CH2:14][CH2:15]Cl)=[O:12])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[H-].[Na+].C(OCC)(=O)C>CN(C=O)C.C1COCC1>[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:15][CH2:14][NH:13][C:11]3=[O:12])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(NCCCl)Nc1ccc2ncsc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C1NCCN1c1ccc2ncsc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
1-Benzothiazol-6-yl-3-(2-chloro-ethyl)-urea (I-84a: 2.7 g, 10.58 mmol) in dry DMF (80 mL) was added dropwise to a stirred mixture of sodium hydride (0.76 g, 31.74 mmol) in THF (100 mL) over a period of 20 minutes at 0° C. under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC (100% ethyl acetate). The reaction mixture was quenched with MeOH (6 mL), concentrated under reduced pressure, followed by the addition of ice. The precipitate was collected and dried under reduced pressure to afford 2.3 g (85.18% yield) of 1-benzothiazol-6-yl-imidazolidin-2-one as the required product.
Reaction SMILES: [CH:1]([C:3]1[N:7]([CH3:8])[CH:6]=[C:5]([C:9]([O:11]C)=[O:10])[CH:4]=1)=[O:2].[CH3:13]O.[OH-].[Na+]>O>[CH3:13][C:6]1[N:7]([CH3:8])[C:3]([CH:1]=[O:2])=[CH:4][C:5]=1[C:9]([OH:11])=[O:10]
Reactant: COC(=O)c1cc(C=O)n(C)c1
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1c(C(=O)O)cc(C=O)n1C
Temperature: 40 °C
Yield: 85 %

Procedure:
To a solution of methyl 5-formyl-1-methyl-1H-pyrrole-3-carboxylate (90.0 g, 0.540 mol), MeOH (1000 mL) and water (500 mL) was added sodium hydroxide solution (1000 mL, 1.0 M in water). The mixture was heated at 40° C. overnight. Solvent was then evaporated, and the aqueous residue was neutralized with 1 N HCl and extracted with EtOAc (3×500 mL) to give methyl 5-formyl-1-methyl-1H-pyrrole-3-carboxylic acid (70.0 g, 85%). 1H NMR (CDCl3, 400 MHz) δ 9.54 (s, 1H), 7.45 (s, 1H), 7.32 (s, 1H), 3.93 (s, 3H).
Reaction SMILES: COC1C=C2C(CCC(=O)N2)=CC=1.[H-].[Na+].CS(OCCN1CCC(NC(OC(C)(C)C)=O)CC1)(=O)=O.[CH3:37][O:38][C:39]1[CH:48]=[C:47]2[C:42]([CH:43]=[CH:44][C:45](=[O:65])[N:46]2[CH2:49][CH2:50][N:51]2[CH2:56][CH2:55][CH:54]([NH:57][C:58](=[O:64])[O:59][C:60]([CH3:63])([CH3:62])[CH3:61])[CH2:53][CH2:52]2)=[CH:41][CH:40]=1>CC(C)=O.ClCCl.C(OCC)(=O)C>[CH3:37][O:38][C:39]1[CH:48]=[C:47]2[C:42]([CH2:43][CH2:44][C:45](=[O:65])[N:46]2[CH2:49][CH2:50][N:51]2[CH2:52][CH2:53][CH:54]([NH:57][C:58](=[O:64])[O:59][C:60]([CH3:61])([CH3:63])[CH3:62])[CH2:55][CH2:56]2)=[CH:41][CH:40]=1
Reactant: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Agent: COc1ccc2c(c1)NC(=O)CC2
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: COc1ccc2c(c1)N(CCN1CCC(NC(=O)OC(C)(C)C)CC1)C(=O)CC2

Procedure:
7-Methoxy-3,4-dihydroquinolin-2(1H)-one (Intermediate 33) (300 mg, 1.78 mmol) was deprotonated with sodium hydride (75 mg, 60% in oil, 1.86 mmol) and alkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate (Intermediate 6) (2.03 mmol) as described for Intermediate 2. Chromatography on silica gel eluting with ethyl acetate and then acetone/dichloromethane (4:1) gave the product as a colorless oil, 559 mg (82%).
Reaction SMILES: [CH2:1]([CH:4]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:5][C@@H:6]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[NH:7][C:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:2]=[CH2:3].[OH-:41].[Na+].OO.O>C1COCC1>[OH:41][CH2:3][CH2:2][CH2:1][CH:4]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:5][C@@H:6]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[NH:7][C:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C=CCC(C[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(CCCO)C[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 16 h
Yield: 44 %

Procedure:
Borane tetrahydrofuran complex (1M, 2.8 mL, 2.8 mmol) was added drop wise to a solution of di-tert-butyl 4-allyl-N-trityl-L-glutamate (1.00 g, 1.85 mmol) in THF (10 mL) at 0° C. The resulting mixture was stirred for 2 h at 0° C. and for 16 h at room temperature. The solution was cooled to 0° C. NaOH (1M, 3 mL) and H2O2 (30% in water, 3 mL) were added drop wise. The mixture was stirred at 0° C. for 1 h. Water (5 mL) was added and the mixture was concentrated under reduced pressure. The aqueous residue was extracted with ethyl acetate. The combined organic fraction was washed with brine, dried over sodium sulfate, filtrated and concentrated. The crude product was purified by flash chromatography (silica, ethyl acetate/hexane) to afford di-tert-butyl 4-(3-hydroxypropyl)-N-trityl-L-glutamate (0.46 g, 44%) as a mixture of (4S,4S)/(2S,4R) diastereoisomers.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]([C:16]3[CH:31]=[CH:30][C:19]([NH:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)=[C:18]([N+:32]([O-])=O)[CH:17]=3)[CH2:14][CH2:13][CH:12]2[C:35]2[CH:50]=[CH:49][C:38]([NH:39][CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)=[C:37]([N+:51]([O-])=O)[CH:36]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>C1COCC1.C(O)C.C(OCC)(=O)C.[Pt]=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:12]([C:35]3[CH:36]=[C:37]([NH2:51])[C:38]([NH:39][CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=4)=[CH:49][CH:50]=3)[CH2:13][CH2:14][CH:15]2[C:16]2[CH:17]=[C:18]([NH2:32])[C:19]([NH:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)=[CH:30][CH:31]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CNc2ccc(C3CCC(c4ccc(NCc5ccc(OC)cc5)c([N+](=O)[O-])c4)N3c3ccc(C(C)(C)C)cc3)cc2[N+](=O)[O-])cc1
Agent: O=[Pt]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(CNc2ccc(C3CCC(c4ccc(NCc5ccc(OC)cc5)c(N)c4)N3c3ccc(C(C)(C)C)cc3)cc2N)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 27.8 %

Procedure:
The product from Example 28E (2 g, 2.79 mmol) was dissolved in a mixture of THF (15 mL), ethanol (15 mL), and ethyl acetate (5 mL) then platinum oxide (0.254 g, 1.12 mmol) was added via THF slurry. The flask was evacuated and purged with nitrogen twice, then evacuated and opened to hydrogen balloon. The mixture was stirred at room temperature for 20 h, then filtered through celite, concentrated, and purified by chromatography on silica gel with an 80 g column, eluting with 0-40% ethyl acetate/dichloromethane to give the first peak of trans product 0.508 g (28%).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:18][CH3:19])=[N:4][N:5]([CH3:17])[C:6]=1[CH2:7][N:8](C)[C:9](=O)OC(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[Br:1][C:2]1[C:3]([O:18][CH3:19])=[N:4][N:5]([CH3:17])[C:6]=1[CH2:7][NH:8][CH3:9]
Reactant: COc1nn(C)c(CN(C)C(=O)OC(C)(C)C)c1Br
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CNCc1c(Br)c(OC)nn1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 120.1 %

Procedure:
To a solution of compound 91 (1613 mg, 4.826 mmol) in DCM (10 ml) was added 4N HCl in dioxane.(10 ml). The solution was allowed to stir at room temperature for 2 hours, then the reaction mixture was concentrated to give compound 196 (1357 mg, 104%) as a yellow solid.