Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH2:24][CH3:25])[C:13]3[C:18]([C:19]=2[C:20]#[N:21])=[CH:17][CH:16]=[C:15]([O:22][CH3:23])[CH:14]=3)=[CH:7][CH:6]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>N1C=CC=CC=1>[C:20]([C:19]1[C:18]2[C:13](=[CH:14][C:15]([O:22][CH3:23])=[CH:16][CH:17]=2)[N:12]([CH2:24][CH3:25])[C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:1][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:6][CH:7]=1)#[N:21]
Reactant: CS(=O)(=O)Cl
Reactant: CCn1c(-c2ccc(OCCN)cc2)c(C#N)c2ccc(OC)cc21
Solvent: c1ccncc1
Product: CCn1c(-c2ccc(OCCNS(C)(=O)=O)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 86 %

Procedure:
2-[4-(2-Aminoethoxy)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (30 mg, 0.09 mmol), prepared in step B, above, is dissolved in pyridine (300 μL). Methanesulfonyl chloride (8 μL, 0.1 mmol) is added. This is stirred at room temperature for 45 minutes. More methansulfonyl chloride (4 μL, 0.05 mmol) is added. Stirring continues for another hour. The reaction mixture is partitioned between EtOAc and aqueous HCl. The organic layer is dried and concentrated. Purification by silica gel chromatography (1/1 CH2Cl2/EtOAc) yields N-{2-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)phenoxy]ethyl}methanesulfonamide, compound 268 (32 mg, 86%) as a white solid.
Reaction SMILES: CO.[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].[OH:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=CC=CC=2)[C:13]=1[CH:22]=O>C(O)C.ClCCl>[CH:22](=[N:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[C:13]1[C:12](=[CH:21][CH:20]=[CH:19][CH:14]=1)[OH:11]
Reactant: O=Cc1c(O)ccc2ccccc12
Reactant: Nc1ccccc1O
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: Oc1ccccc1C=Nc1ccccc1O

Procedure:
The preparations of compounds used in this invention are shown in detail below. In general [nBu4N][OsVI(N)Cl4] is reacted with the ligand in a suitable organic solvent, such as methanol, ethanol or dichloromethane. The Schiff base ligands 5-X—H2salpa (salpa=N-salicylidene-2-aminophenol dianions) are synthesized by condensation of the appropriate 2-hydroxybenzyaldehyde with the 2-aminophenol in refluxing ethanol. The Schiff base ligand nalph is synthesized by condensation of the 2-hydroxy-1-naphthaldehyde with the 2-aminophenol in refluxing ethanol. [NnBu4][OsVI(N)Cl4] were prepared by a literature procedure (Griffith, W. P. and Pawson, D. J. J. Chem. Soc., Dalton Trans. 1973, 1315.).
Reaction SMILES: N.C([O:5][C:6]1[CH:33]=[CH:32][C:9]2[N:10]=[C:11]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]3[C:19]([NH:21][CH2:22][CH2:23][N:24]3[C@H:29]([CH3:30])[CH2:28][CH2:27][CH2:26][C@@H:25]3[CH3:31])=[O:20])[O:12][C:8]=2[CH:7]=1)(=O)C>CC(C)=O>[NH3:10].[CH3:30][C@H:29]1[CH2:28][CH2:27][CH2:26][C@@H:25]([CH3:31])[N:24]1[CH2:23][CH2:22][NH:21][C:19]([C@@H:14]1[CH2:15][CH2:16][CH2:17][CH2:18][N:13]1[C:11]1[O:12][C:8]2[CH:7]=[C:6]([OH:5])[CH:33]=[CH:32][C:9]=2[N:10]=1)=[O:20]
Reactant: CC(=O)Oc1ccc2nc(N3CCCC[C@H]3C(=O)NCCN3[C@H](C)CCC[C@@H]3C)oc2c1
Agent: N
Solvent: CC(C)=O
Product: C[C@@H]1CCC[C@H](C)N1CCNC(=O)[C@@H]1CCCCN1c1nc2ccc(O)cc2o1
Reaction time: 18 h
Yield: 113.6 %

Procedure:
2N Aqueous ammonia solution (10 ml) and acetone (20 ml) were added to 2-[(2S)-2-[(2-[(cis)-2,6-dimethyl-1-piperidinyl]ethylamino)carbonyl]-1-piperidinyl]-1,3-benzoxazol-6-yl acetate (0.389 g) [see Preparation 38] at 0° C. The reaction mixture was then left in a refrigerator for 18 hours, after which time the solvent was removed under reduced pressure. The remaining aqueous layer was washed twice with ethyl acetate, the combined organic layers were then dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 99:1.75:0.25 changing to 97:3.5:0.5, by volume, dichloromethane:methanol:0.88 aqueous ammonia solution to afford (2S)-N-2-[(cis)-2,6-dimethyl-1-piperidinyl]ethyl-1-(6-hydroxy-1,3-benzoxazol-2-yl)-2-piperidinecarboxamide (0.2 g) as a white foam.
Reaction SMILES: [ClH:1].Cl.[CH3:3][C:4]1[NH:5][C:6]([CH3:37])=[C:7]([C:33]([O:35][CH3:36])=[O:34])[CH:8]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=2)[C:9]=1[C:10]([O:12][CH2:13][C:14]([CH3:23])([CH3:22])[CH2:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[O:11].C(N(CC)CC)C.[CH2:45]([Cl:48])[CH:46]=[CH2:47].Cl>O1CCCC1.C(OCC)C.C(O)C>[ClH:48].[ClH:1].[CH3:3][C:4]1[NH:5][C:6]([CH3:37])=[C:7]([C:33]([O:35][CH3:36])=[O:34])[CH:8]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=2)[C:9]=1[C:10]([O:12][CH2:13][C:14]([CH3:22])([CH3:23])[CH2:15][N:16]1[CH2:17][CH2:18][N:19]([CH2:47][CH:46]=[CH2:45])[CH2:20][CH2:21]1)=[O:11]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCC(C)(C)CN2CCNCC2)C1c1cccc([N+](=O)[O-])c1
Reactant: C=CCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: C1CCOC1
Product: C=CCN1CCN(CC(C)(C)COC(=O)C2=C(C)NC(C)=C(C(=O)OC)C2c2cccc([N+](=O)[O-])c2)CC1
Temperature: 50 °C
Reaction time: 12 h
Yield: 75 %

Procedure:
1.5 g of 3-(1-piperazinyl)-2,2-dimethylpropyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate dihydrochloride was dissolved in 10 ml of tetrahydrofuran, and 1.2 ml of triethylamine and 0.22 ml of allyl chloride were added. The mixture was then stirred at 50° C. for 12 hours. After evaporating the solvent, the residue was purified by the chromatography method [20 g silica gel, eluted with ethyl acetate] to give 1.1 g of an oily substance. This oily substance was dissolved in diethyl ether; a slightly excessive amount of a solution of hydrogen chloride in ethanol was added; the solid which separated was collected by filtration, after which it was recrystallized from ethanol to thereby give 1.1 g of the subject compound (yield: 75%). The IR and NMR data of the compound thus obtained are as follows: ##STR13##
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[CH3:20][C:21]1[O:25][N:24]=[C:23]([C:26]([OH:30])([C:28]#[CH:29])[CH3:27])[N:22]=1>>[F:19][C:3]1[C:2]([C:29]#[C:28][C:26]([OH:30])([C:23]2[N:22]=[C:21]([CH3:20])[O:25][N:24]=2)[CH3:27])=[CH:18][C:6]2[C:7]3[N:8]([CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: C#CC(C)(O)c1noc(C)n1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Product: Cc1nc(C(C)(O)C#Cc2cc3c(cc2F)OCCn2cc(C(N)=O)nc2-3)no1
Yield: 5 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol to give the titled compound as a brown solid (5.3 mg, 5%).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[Br:6][C:7]1[CH:8]=[C:9]([CH:13]([NH2:15])[CH3:14])[CH:10]=[N:11][CH:12]=1.CCN(CC)CC>C(Cl)Cl>[Br:6][C:7]1[CH:8]=[C:9]([CH:13]([NH:15][C:1](=[O:4])[CH2:2][CH3:3])[CH3:14])[CH:10]=[N:11][CH:12]=1
Reactant: CCC(=O)Cl
Reactant: CC(N)c1cncc(Br)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)NC(C)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
At 0° C., propionyl chloride (138 mg, 1.5 mmol) was added dropwise to a solution of (rac)-1-(5-bromo-pyridin-3-yl)-ethylamine (201 mg, 1 mmol) and Et3N (153 mg, 1.5 mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 1 hour before it was concentrated to dryness. The residue was redissolved in EtOAc and washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography to give the title compound (200 mg, 78%).
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([O:27][CH3:28])=[N:19]3)[N:16]=2)[N:11](COCC[Si](C)(C)C)[CH:10]=1)=[O:8])([CH3:5])[CH3:4].FC(F)(F)C(O)=O>ClCCl>[OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([O:27][CH3:28])=[N:19]3)[N:16]=2)[NH:11][CH:10]=1)=[O:8])([CH3:5])[CH3:4]
Reactant: COc1nn(-c2cnc3c(n2)c(C(=O)NC(C)(C)CO)cn3COCC[Si](C)(C)C)c2ccccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1nn(-c2cnc3[nH]cc(C(=O)NC(C)(C)CO)c3n2)c2ccccc12
Reaction time: 1 h
Yield: 0.1 %

Procedure:
To a stirred solution of N-(1-hydroxy-2-methylpropan-2-yl)-2-(3-methoxy-1H-indazol-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (101 mg, 198 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). After 15 h the mixture was concentrated in vacuo then 25 mL of a Jan. 10, 1960 mixture of ammonium hydroxide/methanol/dichloromethane solution was added. After 1 h, the mixture was concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-5% methanol containing 10% ammonium hydroxide in dichloromethane) gave 2-(3-methoxy-indazol-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)amide (45 mg, 60%). MS (M+H)+=381; 1H NMR (DMSO-d6) δ: 8.94 (s, 1H), 8.62 (d, J=8.7 Hz, 1H), 8.33 (s, 1H), 7.79 (d, J=7.9 Hz, 1H), 7.61 (s, 2H), 7.28-7.38 (m, 1H), 4.19 (s, 3H), 3.62 (d, J=5.7 Hz, 2H), 1.45 (s, 6H).
Reaction SMILES: O=[C:2]1C2C(=CC=CC=2)C(=O)N1C(CC1C=CC=CC=1)C(N[C@@H](CNCC=CC(=O)C(F)(F)F)C(OC)=O)=O.[CH2:39]([O:46][C:47]([NH:49][C@H:50]([C:53]([OH:55])=[O:54])[CH2:51][NH2:52])=[O:48])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.S(=O)(=O)(O)O>CO.C(OCC)C>[CH2:39]([O:46][C:47]([NH:49][C@H:50]([C:53]([O:55][CH3:2])=[O:54])[CH2:51][NH2:52])=[O:48])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: NC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@H](CNCC=CC(=O)C(F)(F)F)NC(=O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: CO
Product: COC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Temperature: 60 °C

Procedure:
N-[2-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-(S)-3-[(trifluoroacetyl-2-propenyl)amino]-2-amino-propionic acid, methyl ester Dissolve Nα -(benzyloxycarbonyl)-β-(amino)-L-alanine (47.6 g, 0.2 mol) in methanol (500 mL) and treat with concentrated sulfuric acid (0.5 mL). Heat to 60° C. for 16 hours, cool and reduce the solvent by 50% in vacuo. Dilute with ethyl ether (500 mL), wash with saturated sodium hydrogen carbonate, then brine. Dry (MgSO4) and evaporate the solvent in vacuo to give Nα -(benzyloxycarbonyl )-β-(amino)-L-alanine, methyl ester.
Reaction SMILES: C([O:8][C:9]([CH:11]1[CH2:15][CH:14]([CH2:16][CH:17]=[CH:18][CH2:19][CH3:20])[CH2:13][N:12]1[CH2:21][C:22]1[N:23]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:25][N:26]=1)=[O:10])C1C=CC=CC=1.C1COCC1.O.O.[OH-].[Li+]>O>[CH2:27]([N:23]1[CH:24]=[CH:25][N:26]=[C:22]1[CH2:21][N:12]1[CH2:13][CH:14]([CH2:16][CH:17]=[CH:18][CH2:19][CH3:20])[CH2:15][CH:11]1[C:9]([OH:10])=[O:8])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCC=CCC1CC(C(=O)OCc2ccccc2)N(Cc2nccn2Cc2ccccc2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCC=CCC1CC(C(=O)O)N(Cc2nccn2Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
To a stirred solution of 1-(1-benzyl-1H-imidazol-2-ylmethyl)-4-pent-2-enyl-pyrrolidine-2-carboxylic acid benzyl ester (257.2 mg, 0.6 mmol, 1 equiv) in a 4:1 THF/H2O (8 mL), at room temperature, was added lithium hydroxide monohydrate (250 mg, 5.96 mmol, 10 equiv). The resulting reaction mixture was stirred at room temperature overnight, and evaporated to dryness. The residue obtained was dissolved in water (10 mL), and the pH of the resulting solution was adjusted to between 3 and 4, and extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and evaporated to dryness, affording the acid product 1-(1-Benzyl-1H-imidazol-2-ylmethyl)-4-pent-2-enyl-pyrrolidine-2-carboxylic acid (202 mg, 98%): Rf=0.4 (7:2:1 CH2Cl2/hexanes/MeOH), KMnO4 visualization stain; MS (ESPOS): 355 [M+H]+; MS (ESNEG): 352 [M−H]−.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.S(Cl)([Cl:14])=O.[OH-].[Na+]>CCCCCC>[F:1][C:2]1[C:3]([C:9]([Cl:14])=[O:11])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ncc(Cl)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Product: O=C(Cl)c1ncc(Cl)cc1F
Temperature: 90 °C
Reaction time: 5 h

Procedure:
71.38 g of 3-fluoro-5-chloro-2-pyridinecarboxylic acid is initially introduced into a round-bottomed flask and heated up to 90° C. 59 ml of thionyl chloride are added dropwise from a dropping funnel in the course of 30 minutes, and the gas formed is passed into sodium hydroxide solution. The mixture is subsequently stirred at 100° C. for a further 5 hours. The thionyl chloride is then distilled off under normal pressure. After addition of 50 ml of dry toluene, 20 ml thereof are distilled off. The solution thus obtained is poured onto 200 ml of n-hexane and the mixture is stirred overnight. After cooling in an ice-bath, the mixture is filtered and the material on the filter is washed twice with n-hexane. 68.7 9 of the desired compound are obtained as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[C:11]1[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=3)[NH:13][C:12]1=[O:21])[O:6][CH2:5]2.[C:22](Cl)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>CN(C=O)C>[Cl:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:21])[C:11]2=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:10][CH:9]=2)[CH2:5][O:6]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Nc1ccc2c(c1)COC2=C1C(=O)Nc2ccc(Cl)cc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1Nc2ccc(Cl)cc2C1=C1OCc2cc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)ccc21
Yield: 44.9 %

Procedure:
A solution of 3-(5-Amino-3H-isobenzofuran-1-ylidene)-5-chloro-1,3-dihydro-indol-2-one (75 mg, 0.251 mmol), trityl chloride (84 mg, 0.301 mmol) and triethylamine (53 μμl, 0.377 mmol) in DMF (2.0 ml) was stirred at room temperature for 1.25 hours. The mixture was partitioned between EtOAc and water. The EtOAc layer was washed with brine, dried with Na2SO4 and rotary evaporated. The yellow solid was precipitated from CHCl3 to give 5-chloro-3-[5-(trityl-amino)-3H-isobenzofuran-1-ylidene]-1,3-dihydro-indol-2-one as a bright yellow solid (61 mg, 45%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][O:16][C:15]3=[O:24])[CH2:10][CH2:9]2)=[C:4]([Cl:25])[CH:3]=1.[CH3:26][N:27]1[CH2:34][CH2:33][CH2:32][C@H:28]1[C:29](O)=[O:30].C(N(CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:25][C:4]1[CH:3]=[C:2]([NH:1][C:29]([C@@H:28]2[CH2:32][CH2:33][CH2:34][N:27]2[CH3:26])=[O:30])[CH:7]=[CH:6][C:5]=1[N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][O:16][C:15]2=[O:24])[CH2:12][CH2:13]1
Reactant: Nc1ccc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c(Cl)c1
Reactant: CN1CCC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC[C@H]1C(=O)Nc1ccc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the product from example 120 step (ii) (0.1 g), N-methyl-L-proline (0.044 g), N,N-diisopropylethylamine (0.17 ml), 1-hydroxybenzotriazole (0.043 g), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (0.103 g) in N,N-dimethylformamide (3 ml) were stirred at room temperature overnight then partitioned between ethyl acetate and water. The organic layer was washed with water, dried and evaporated under reduced pressure. Purification was by chromatography eluting with 4% methanol/dichloromethane. Yield 0.038 g.
Reaction SMILES: O=C1CCC(=O)N1[C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:26]([O-:28])=O)=[C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[CH:15]=2)[N:10]([CH2:29][C:30]([F:33])([CH3:32])[CH3:31])[N:9]=1.[NH2:34][C@H:35]1[CH2:39][CH2:38][NH:37][C:36]1=[O:40]>ClCCl.C(OCC)(=O)C>[F:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[C:26]([NH:34][C@H:35]1[CH2:39][CH2:38][NH:37][C:36]1=[O:40])=[O:28])[N:10]([CH2:29][C:30]([F:33])([CH3:32])[CH3:31])[N:9]=[CH:8]2
Reactant: N[C@H]1CCNC1=O
Reactant: CC(C)(F)Cn1nc(N2C(=O)CCC2=O)c2cc(Oc3ccc(F)cc3F)c(C(=O)[O-])cc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(F)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)N[C@H]3CCNC3=O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 1032.3 %

Procedure:
To a solution of 2,5-dioxopyrrolidin-1-yl-5-(2,4-difluorophenoxy)-1-(2-fluoro-2-methylpropyl)-1H-indazole-6-carboxylate (prepared according to Example 26; 100 mg, 0.217 mmol) in dichloromethane (1 mL) was added (S)-3-aminopyrrolidin-2-one (4a) 521 mg, 4.56 mmol), and the reaction mixture was allowed to stir overnight at ambient temperature. The reaction mixture was diluted with ethyl acetate and washed with 1M hydrochloric acid, 1M sodium hydroxide, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on a silica gel column, eluting with 50% acetone/hexanes to yield (S)-5-(2,4-difluorophenoxy)-1-(2-fluoro-2-methylpropyl)-N-(2-oxopyrrolidin-3-yl)-1H-indazole-6-carboxamide (Ik) (1.00 g, 99%). Mass spec: 447 (M+1). 1H NMR (CDCl3) δ 8.42 (s, 1H), 8.21 (br, 1H), 7.15 (m, 1H), 7.03 (s, 1H), 7.01 (m, 1H), 6.91 (m, 1H), 6.59 (br, 1H), 4.58 (m, 1H), 4.55 (d, 2H), 3.43 (m, 2H), 2.84 (m, 1H), 2.06 (m, 1H), 1.40 (d, 3H), 1.39 (d, 3H).
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].OC(N)(C)CN.[Mn+2:15]>O>[Mn:15].[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5]
Reactant: [Mn+2]
Agent: CC(N)(O)CN
Agent: O=C(O)/C=C/C(=O)O
Solvent: O
Product: [Mn]

Procedure:
A reaction mixture was prepared by using the recovered precipitate according to the procedures of (2). The concentrations of the respective components at the initiation of the reaction were 1,139 mM of fumaric acid, 570 mM of 2-hydroxypropylenediamine, 570 mM of the recovered manganese (II) (concentration in terms of manganese), 56 mM of S,S-HPDDS and 10 g/l of strain cells (in terms of dry weight), and the reaction mixture was subjected to a reaction in the same manner as in (2) above. At the time of the reaction mixture preparation, to a brown (due presumably to an oxidation of manganese) suspension resulting from an addition of recovered manganese and fumaric acid to water, was added sodium sulfite powder (about 5% by mole relative to manganese) until a color turned pink, then 2-hydroxypropylenediamine and 7.5N NaOH were added, the resulting mixture was adjusted to pH 7.5 and was allowed to react in the same manner as in (2) above.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([NH:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[C:13]([OH:15])[CH:14]=1>O1CCOCC1>[C:1]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([NH:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[C:13]([OH:15])[CH:14]=1)(=[O:3])[CH3:2]
Reactant: Nc1ccc(NC(=O)OCc2ccccc2)c(O)c1
Reactant: CC(=O)OC(C)=O
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(NC(=O)OCc2ccccc2)c(O)c1
Temperature: 70 °C

Procedure:
0.6 mole (57 ml) of acetic anhydride is added dropwise to a solution of 0.6 mole (172 g) of 5-amino-2-(benzyloxycarbonylamino)phenol in 465 ml of dioxane heated to 70° C. After the reaction medium is cooled, the expected product precipitates. When recrystallized in 96° ethanol, it melts at 205° C.
Reaction SMILES: C([O:4][C:5](=[O:36])[CH2:6][C@@H:7]([N:20]1[CH:24]=[CH:23][C:22]([C:25](=[O:35])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=2)=[CH:21]1)[C:8]([NH:10][C@H:11]([C:16](=[O:19])[NH:17][CH3:18])[C:12]([CH3:15])([CH3:14])[CH3:13])=[O:9])C=C.N1CCOCC1>C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:33]([C:30]1[CH:31]=[CH:32][C:27]([CH2:26][C:25]([C:22]2[CH:23]=[CH:24][N:20]([C@@H:7]([C:8]([NH:10][C@H:11]([C:16](=[O:19])[NH:17][CH3:18])[C:12]([CH3:15])([CH3:13])[CH3:14])=[O:9])[CH2:6][C:5]([OH:36])=[O:4])[CH:21]=2)=[O:35])=[CH:28][CH:29]=1)#[N:34]
Reactant: C=CCOC(=O)C[C@H](C(=O)N[C@H](C(=O)NC)C(C)(C)C)n1ccc(C(=O)Cc2ccc(C#N)cc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: C1COCCN1
Product: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)O)n1ccc(C(=O)Cc2ccc(C#N)cc2)c1)C(C)(C)C
Reaction time: 0.5 h
Yield: 107.2 %

Procedure:
Routine allyl ester cleavage conditions were previously described by Friedrich-Bochnitschek, S.; Waidmann, H.; Kunz, H. J. Org. Chem. 1989, 54, 751-756. To a solution of 3(R)-[3-[(4-cyanophenyl)acetyl]-1H-pyrrol-1-yl]-N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]succinamic acid allyl ester (247 mg, 0.501 mmol) in acetonitrile (2 mL) was added in succession Pd(PPh3)4 (29 mg, 0.026 mmol) and morpholine (226 μL, 2.60 mmol). The resultant mixture was carefully purged with argon. After 30 min, the resultant green mixture was stirred with 10% aqueous KHSO4 (20 mL) and extracted with CHCl3 (35 mL). The organic layer was washed with 10% aqueous KHSO4 (20 mL), dried over Na2SO4, and concentrated. Flash column chromatography with 1% HOAc/3% MeOH/CHCl3 and drying via azeotrope with n-heptane gave 243 mg (94%) of 3(R)-[3-[(4-cyanophenyl)acetyl]-1H-pyrrol-1-yl]-N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]succinamic acid as a yellow solid. 1H NMR (CD3OD): δ 8.09 (d, 1H, J=8.7 Hz), 8.05 (dd, 1H, J=2.8, 6.9 Hz), 7.78 (dd, 1H, J=1.9, 1.9 Hz), 7.66 (d, 2H, J=8.4 Hz), 7.46 (d, 2H, J=8.4 Hz), 6.90 (dd, 1H, J=2.2, 2.2 Hz), 6.59 (dd, J=1.9, 3.1 Hz), 5.33 (t, 1H, J=7.5 Hz), 4.22-4.15 (m, 3H), 3.24 (t, 1H, J=8.7 Hz), 2.98 (dd, 1H, J=5.3, 17.4 Hz), 2.66 (d, 3H, J=4.7 Hz), 0.99 (s, 9H). IR (KBr): 3332, 2696, 2230, 1719, 1654, 1532, 1412, 1177 cm−1. HRFABMS: Calculated for C24H29N4O5 (M+H+): 453.2125. Found: 453.2125. Anal. Calculated for C24H28N4O5•0.5 HOAc•0.3 CHCl3: C, 58.62; H, 5.89; N, 10.81. Found: C, 58.41; H, 5.72; N, 10.50.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([O-])([O-])=O.[K+].[K+].I[CH2:27][CH3:28]>CN(C=O)C>[CH2:27]([O:1][C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[CH3:28]
Reactant: CCI
Reactant: N#Cc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(Oc2ccc([N+](=O)[O-])cc2)ccc1C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.8 %

Procedure:
2-hydroxy-4-[(4-nitrophenyl)oxy]benzonitrile (Intermediate 127, 87.2 mg) was dissolved in DMF (5 mL). K2CO3 (92.2 mg, 0.67 mmol) and iodoethane (32 μL, 0.40 mmol) were added. The reaction mixture was stirred at r.t. After 16 h, the reaction mixture was evaporated to dryness to give the crude product that was purified by silica gel chromatography (from 100:0 to 50:50 Cyclohexane/EtOAc in 10 CV; then 50:50 Cyclohexane/EtOAc for 10 CV) to obtain 84.9 mg of the title compound as a yellow solid.