Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C@@H:27]([CH2:28][OH:29])[CH2:26][CH2:25][C:24]4=[O:30])=[CH:19][C:18]=3[S:31]([CH3:34])(=[O:33])=[O:32])=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.S(C1C=CC(C)=CC=1)(O[CH3:39])(=O)=O>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C@@H:27]([CH2:28][O:29][CH3:39])[CH2:26][CH2:25][C:24]4=[O:30])=[CH:19][C:18]=3[S:31]([CH3:34])(=[O:33])=[O:32])=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CC[C@@H]4CO)cc3S(C)(=O)=O)CC2)c(C)c1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Product: COC[C@H]1CCC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)c(S(C)(=O)=O)c1

Procedure:
Using (R)-5-hydroxymethylpyrrolidin-2-one (409 mg) and (4-bromo-2-methanesulfonylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (1.53 g) described in Preparation Example 112 and by the reaction and treatment in the same manner as in Example 1, (R)-1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-methanesulfonylphenyl}-5-hydroxymethylpyrrolidin-2-one (700 mg) was obtained. Using the obtained (R)-1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-methanesulfonylphenyl}-5-hydroxymethylpyrrolidin-2-one (700 mg) and methyl tosylate (0.21 mL) and by the reaction and treatment in the same manner as in Example 36, the title compound (319 mg) was obtained.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]([C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[C:10]([F:16])[CH:9]=1)[C:5](Cl)=[O:6].[C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])[NH:18][NH2:19].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C1COCC1>[Cl:1][CH2:2][CH2:3][CH:4]([C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[C:10]([F:16])[CH:9]=1)[C:5]([NH:19][NH:18][C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:6]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(Cl)C(CCCl)c1cc(F)c(F)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NNC(=O)C(CCCl)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
oxalyl chloride (0.63 mL) and DMF (1 drop) were added to a solution of 4-chloro-2-(3,4,5-trifluorophenyl)butyric acid (1.17 g) in methylene chloride (30 mL) at 0° C., and the reaction solution was stirred at room temperature for one hour. The reaction solution was concentrated under reduced pressure to obtain 4-chloro-2-(3,4,5-trifluorophenyl)butyryl chloride. A solution of 4-chloro-2-(3,4,5-trifluorophenyl)butyryl chloride in THF (5 mL) was added to a solution of tert-butyl carbazate (600 mg) and triethylamine (3.1 mL) in THF (20 mL) at 0° C., and the reaction solution was stirred at room temperature for one hour. The reaction solution was added to a saturated sodium bicarbonate solution, followed by extraction with ethyl acetate. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 1.35 g of the title compound. The property value of the compound is as follows.
Reaction SMILES: C(OC(C[N:9]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)(=[O:20])=[O:19])[C@@H:10]([C:15]([OH:17])=[O:16])[C:11]([SH:14])([CH3:13])[CH3:12])=O)(C)(C)C.F[C:36](F)(F)[C:37]([OH:39])=[O:38]>ClCCl>[C:37]([CH2:36][S:14][C:11]([CH3:13])([CH3:12])[C@H:10]([C:15]([OH:17])=[O:16])[NH:9][S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)(=[O:19])=[O:20])([OH:39])=[O:38]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)CN([C@@H](C(=O)O)C(C)(C)S)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Solvent: ClCCl
Product: CC(C)(SCC(=O)O)[C@@H](NS(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1)C(=O)O
Reaction time: 16 h
Yield: 40 %

Procedure:
To a solution of S--(t-Butoxycarbonyl)methyl--N--[4-(4-fluorophenoxy)benzenesulfonyl]-D-penicillamine (188.8 mg, 0.367 mmol) in 3.4 mL of dichloromethane at 20° C. was added trifluoroacetic acid (0.85 mL). The solution was stirred for 16 h and concentrated in vacuo. The residue was partitioned between ethyl acetate (25 mL) and 1 M aq. phosphate buffer (pH 7). The aqueous layer was extracted with two additional portions of ethyl acetate (25 mL), and the combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was triturated with diethyl ether (5 mL) to give 67 mg (40%) of S-Carboxymethyl--N--[4-(4-fluorophenoxy)benzenesulfonyl]-D-penicillamine as an off-white solid: mp 69° C.; 1H--NMR (DMSO-d6) δ 1.32 (br s, 6H), 3.25-3.5 (br m, 3H), 7.12 (d, J=8 Hz, 2H), 7.2-7.5 (m, 4H), 7.82 (d, J=8 Hz, 2H), 8.00-8.40 (br s, 1H), 12.5-13.2 (v br s, 1H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH2:11].[O:12]=[C:13](C(OCC)=O)[C:14](OCC)=[O:15].[OH-].[K+]>C(O)(=O)C.O>[C:14]1(=[O:15])[C:1]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[CH:4]=[CH:3][C:2]=2[NH:11][C:13]1=[O:12]
Reactant: Nc1ccc2ccccc2c1
Reactant: CCOC(=O)C(=O)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=C1Nc2ccc3ccccc3c2C1=O
Temperature: 120 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
A mixture of 2-naphthylamine (8.0 g, 56 mmol) in glacial acetic acid (500 mL) was treated with diethyl ketomalonate (9.2 mL, 62 mmol), heated to 120° C. for 4 hours, and concentrated. The concentrate was suspended in a solution of KOH (36.8 g, 690 mmol) in water (736 mL) and stirred overnight with a stream of air blowing into the solution. The resulting mixture was filtered and the filtrate was adjusted to approximately pH 3 with concentrated HCl. The resulting suspension was cooled to 0° C. and filtered. The filter cake was dried under vacuum to provide the desired product (8.76 g, 79%). MS (DCI) m/e 198 (M+H)+, 215 (M+NH4)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:8]([C:12]([NH:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:13])=[C:7]([Cl:22])[CH:6]=[CH:5][C:4]=2[N:3]=1.[NH:23]1[CH2:34][CH2:33][CH2:32][C@@H:24]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>>[CH3:31][C:28]([O:27][C:25](=[O:26])[C@H:24]1[CH2:32][CH2:33][CH2:34][N:23]1[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=2[C:12]([NH:14][CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:13])[N:3]=1)([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1
Reactant: O=C(NCC1CCCCC1)c1c(Cl)ccc2nc(Cl)ccc12
Product: CC(C)(C)OC(=O)[C@H]1CCCN1c1ccc2c(C(=O)NCC3CCCCC3)c(Cl)ccc2n1
Yield: 89.3 %

Procedure:
Prepared according to the method of example 30, using 2,6-dichloro-N-(cyclohexylmethyl)-5-quinolinecarboxamide (Example 43(a)) (200 mg) and D-proline, 1,1-dimethylethyl ester (310 mg). Purification (SiO2, ethyl acetate:isohexane 30:70 as eluant) gave the sub-title compound as an oil (250 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:20][CH2:21][CH3:22])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.I.[C:26]1([NH:32][C:33](SC)=[N:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>CN(C)C=O.[Hg](Cl)Cl>[NH:34]([C:33]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:20][CH2:21][CH3:22])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)=[CH:23][CH:24]=1)=[N:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CSC(=Nc1ccccc1)Nc1ccccc1
Reactant: CCOC(Cc1ccc(OCCc2ccc(N)cc2)cc1)C(=O)O
Agent: Cl[Hg]Cl
Agent: I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(Cc1ccc(OCCc2ccc(NC(=Nc3ccccc3)Nc3ccccc3)cc2)cc1)C(=O)O
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
3-{4-[(4-Aminophenethyl)oxy]phenyl}-2-ethoxypropanoic acid (20 mg, 0.061 mmol) and methyl N,N′-diphenylcarbamimidothioate hydroiodide (23.7 mg, 0.064 mmol) were mixed in 0.3 ml N,N-dimethylformamide. Triethylamine (34 ml, 0.244 mmol) was added. The mixture was then cooled in an ice-bath. Mercury (II)chloride (18 mg, 0.066 mmol) was added. After 30 minutes, the cooling bath was removed. The reaction mixture was stirred overnight. Water (1 ml) and ethyl acetate (0.5 ml) were added and then hydromatrix (ca. 0.5 g) was added. After a while, the mixture was filtered. The filtrate was evaporated to dryness. Chromatography of the residue on an ISOLUTE column (SI, 500 mg/3 ml) using ethyl acetate/heptane (10:90, then 25:75, and then 50:50) as eluant gave 16 mg, yield 50% of the desired product.
Reaction SMILES: [C:1]([C:3]1[CH:36]=[CH:35][C:6]([CH2:7][C@@:8]2([CH3:34])[N:12]3[C:13]([S:16]([NH:19][C@@H:20]([CH3:24])[C:21]([OH:23])=O)(=[O:18])=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=3)[C:9]2=[O:33])=[CH:5][CH:4]=1)#[N:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[NH2:60][C@@H:61]([C:63]([NH2:65])=[O:64])[CH3:62].C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[C:63]([C@H:61]([NH:60][C:21](=[O:23])[C@@H:20]([NH:19][S:16]([C:13]1[N:12]2[C@@:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:36][CH:35]=3)([CH3:34])[C:9](=[O:33])[N:10]([C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=3)[C:11]2=[N:15][CH:14]=1)(=[O:17])=[O:18])[CH3:24])[CH3:62])(=[O:64])[NH2:65]
Reactant: C[C@@H](N)C(N)=O
Reactant: C[C@H](NS(=O)(=O)c1cnc2n1[C@](C)(Cc1ccc(C#N)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H](NS(=O)(=O)c1cnc2n1[C@](C)(Cc1ccc(C#N)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)N[C@H](C)C(N)=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.2 %

Procedure:
(S)-2-[(R)-5-(4-Cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-sulfonylamino]-propionic acid (see Example 14) (0.05 g, 0.091 mmol) was dissolved in anhydrous DMF (2 mL) and TBTU (0.044 g, 0.137 mmol) was added to the reaction solution. The reaction mixture was stirred at room temperature for 10 min and D-alaninamide hydrochloride (0.017 g, 0.137 mmol) was added to the mixture followed by N,N-diisopropylethylamine (0.039 mL, 0.227 mmol). The reaction mixture was stirred at room temperature for another 15 min. The mixture was then diluted with EtOAc (10 mL) and washed with water, 1 N HCl, saturated NaHCO3 and then water. The organic phase was dried over Na2SO4 and concentrated. The crude product was purified by silica gel preparative thin layer chromatography to afford 0.035 g of the title compound as a white foam (M+1, 618.2).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH-:15].[O:16]=[C:17]1[C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([C:30](O)=O)[C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2>C(O)(=O)C>[CH3:14][N:11]1[CH2:12][CH2:13][N:8]([C:6]2[CH:5]=[CH:4][C:3]3[N:15]=[C:30]([C:25]4[C:24]5[C:23]6[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=6)[C:17](=[O:16])[C:29]=5[CH:28]=[CH:27][CH:26]=4)[NH:1][C:2]=3[CH:7]=2)[CH2:9][CH2:10]1
Reactant: O=C(O)c1cccc2c1-c1ccccc1C2=O
Reactant: CN1CCN(c2ccc([NH-])c(N)c2)CC1
Solvent: CC(=O)O
Product: CN1CCN(c2ccc3nc(-c4cccc5c4-c4ccccc4C5=O)[nH]c3c2)CC1

Procedure:
The procedure used in Example 68 is followed. In a 250 ml round-bottomed flask under an argon atmosphere, reflux, for 6 hours, a suspension of 4 g of [2-amino-4-(4-methylpiperazin-1-yl)phenyl]amide of 9-oxo-9H-fluorene-4-carboxylic acid, obtained in the previous stage, in 64 ml of acetic acid. After purification by formation of a paste with diisopropyl ether, in this way we obtained 2.5 g of 4-[6-(4-methylpiperazin-1-yl)-1H -benzimidazol-2-yl]-9H-fluoren-9-one, in the form of an orange powder, which is used as it is in the following stage, with the following characteristics:
Reaction SMILES: Br[CH2:2][C:3]([C:5]([CH3:8])([CH3:7])[CH3:6])=[O:4].C(=O)([O-])[O-].[K+].[K+].[O:15]=[C:16]1[NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[N:19]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:18][C@H:17]1[NH:33][C:34]([NH:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH:38]=1)=[O:35]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CS(C)=O.[I-].[K+]>[C:5]([C:3]([CH2:2][N:22]1[C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[N:19]([CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)[CH2:18][C@@H:17]([NH:33][C:34]([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([O:45][C:46]([CH3:48])([CH3:47])[CH3:49])=[O:44])[CH:38]=2)=[O:35])[C:16]1=[O:15])=[O:4])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)c1cccc(NC(=O)N[C@@H]2CN(C3CCCCC3)c3ccccc3NC2=O)c1
Reactant: CC(C)(C)C(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)c1cccc(NC(=O)N[C@@H]2CN(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
Bromomethyl tert-butylketone (2.95 g), potassium iodide (125 mg), tetra n-butylammonium bromide (145 mg) and potassium carbonate (2.07 g) were added to a solution of (R)-(−)-1-(2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonylphenyl)urea (7.18 g) in dimethylsulfoxide (100ml), the mixture was stirred for 2hours at room temperature. The reaction mixture was poured into ice-water, extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography(ethyl acetate:n-hexane=1:2), to thereby obtain 8.22 g of the titled compound (Yield 95%).
Reaction SMILES: [N+](C1C=CC(C[O:9][C:10]([CH2:12][S:13][C:14]2[CH2:15][C@@H:16]3[CH:33]([CH:34]([OH:36])[CH3:35])[C:32](=[O:37])[N:17]3[C:18]=2[C:19]([O:21]CC2C=CC([N+]([O-])=O)=CC=2)=[O:20])=[O:11])=CC=1)([O-])=O.C(=O)(O)[O-].[Na+:44]>O1CCOCC1.C(O)C.O.[Pd]>[C:10]([CH2:12][S:13][C:14]1[CH2:15][C@@H:16]2[CH:33]([CH:34]([OH:36])[CH3:35])[C:32](=[O:37])[N:17]2[C:18]=1[C:19]([O-:21])=[O:20])([OH:11])=[O:9].[Na+:44].[Na+:44].[C:10]([CH2:12][S:13][C:14]1[CH2:15][C@@H:16]2[CH:33]([CH:34]([OH:36])[CH3:35])[C:32](=[O:37])[N:17]2[C:18]=1[C:19]([O-:21])=[O:20])([OH:11])=[O:9]
Reactant: CC(O)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SCC(=O)OCc3ccc([N+](=O)[O-])cc3)C[C@H]12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCO
Product: CC(O)C1C(=O)N2C(C(=O)[O-])=C(SCC(=O)O)C[C@H]12

Procedure:
A solution of crude p-nitrobenzyl 2-(p-nitrobenzyloxycarbonyl)methylthio-6-(1-hydroxy)ethyl-carbapen-2-em-3-carboxylate (8.7 mg) in dioxane (1.20 ml) is diluted with ethanol (0.10 ml) and water (0.70 ml) containing sodium bicarbonate (2.3 mg). The resulting solution is treated with 10% palladium on charcoal (15 mg) and hydrogenated at 40 psi for 60 minutes. The mixture is diluted with water to 5 ml and centrifuged to remove the catalyst which is washed with more water (2×1 ml). The combined aqueous solution is washed with ethyl acetate (4×3 ml), filtered through a cotton plug, concentrated in vacuo to ca. 1 ml, and lyophilized to provide the title compound as a solid: UV (pH 7 phosphate buffer) 301 nm; electrophoresis (0.05 M pH 7 phosphate buffer 2 KV, 20 ma, 20 mins) gives a biactive zone migrating 9.3 cm toward the anode (dicarboxylate).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:13]3[CH:14]=[C:15]([C:18]4[CH:23]=[CH:22][N:21]=[C:20]5[NH:24][C:25]([CH:27]6[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]6)=[CH:26][C:19]=45)[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)[CH:5]=[N:6][CH:7]=1.FC(F)(F)C([O-])=O.C(N(CC)CC)C.C(O)(=O)C.[OH:51][CH:52]([CH2:55]O)[CH:53]=[O:54].C([BH3-])#N>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:13]3[CH:14]=[C:15]([C:18]4[CH:23]=[CH:22][N:21]=[C:20]5[NH:24][C:25]([CH:27]6[CH2:32][CH2:31][N:30]([CH2:55][CH:52]([OH:51])[CH2:53][OH:54])[CH2:29][CH2:28]6)=[CH:26][C:19]=45)[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)[CH:5]=[N:6][CH:7]=1
Reactant: Fc1cncc(Cn2cnc3ccc(-c4ccnc5[nH]c(C6CCNCC6)cc45)cc32)c1
Reactant: O=CC(O)CO
Agent: O=C([O-])C(F)(F)F
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: OCC(O)CN1CCC(c2cc3c(-c4ccc5ncn(Cc6cncc(F)c6)c5c4)ccnc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of Example 12D trifluoroacetate salt (60 mg), triethylamine (0.06 mL, 0.422 mmol) and acetic acid (42 mg, 0.703 mmol) in dichloromethane (2 mL) was added 2,3-dihydroxypropanal (25.3 mg, 0.281 mmol) and MP-cyanoborohydride (224 mg, 0.563 mmol) and the mixture was stirred at room temperature for 2 days. The solid was filtered and rinsed with 10 mL 50% methanol/dichloromethane. The filtrate was concentrated and purified by reverse-phase HPLC (Phenomenex Luna C8 AXIA column, 100 Å), eluting with a gradient of 10-95% acetonitrile/0.1% trifluoroacetic acid in water with 10 mM ammonium acetate to afford the title compound. 1H NMR (400 MHz, dimethylsulfoxide-d6) δ 1.65-1.79 (m, 2 H) 1.91-1.98 (m, 2 H) 2.12-2.25 (m, 2 H) 2.29-2.43 (m, 2 H) 2.65-2.76 (m, 1 H) 2.95-3.05 (m, 2 H) 3.33-3.46 (m, 2 H) 3.60-3.71 (m, 1 H) 5.67 (s, 2 H) 6.11 (s, 1 H) 7.09 (d, J=4.88 Hz, 1 H) 7.57 (dd, J=8.54, 1.53 Hz, 1 H) 7.61-7.68 (m, 1 H) 7.75-7.86 (m, 2 H) 8.15 (d, J=4.88 Hz, 1 H) 8.42 (s, 1 H) 8.46-8.51 (m, 2 H) 11.29 (s, 1 H). MS (ESI) m/e 501 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:31][C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)[C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]3[CH:26]=[C:25]([C:27]([O:29]C)=[O:28])[CH:24]=[CH:23][C:21]=3[N:22]=2)[CH2:14][CH2:13]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:31][C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)[C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]3[CH:26]=[C:25]([C:27]([OH:29])=[O:28])[CH:24]=[CH:23][C:21]=3[N:22]=2)[CH2:14][CH2:13]1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc2nc(N3CCN(C(=O)[C@H](Cc4cccs4)NC(=O)OC(C)(C)C)CC3)sc2c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)N1CCN(c2nc3ccc(C(=O)O)cc3s2)CC1
Temperature: 50 °C

Procedure:
(S)-methyl 2-(4-(2-(tert-butoxycarbonylamino)-3-(thiophen-2-yl)propanoyl)piperazin-1-yl)benzo[d]thiazole-6-carboxylate (0.61 g, 1.15 mmol) was dissolved in methanol (6 ml) followed by the addition of 1N NaOH (1.26 ml, 1.26 mmol) and the resulting mixture heated to 50° C. overnight. The resulting mixture was then cooled to room temperature, acidified with 10% citric acid and extracted with ethyl acetate. The organic layer was dried (MgSO4) and concentrated in vacuo to yield (S)-2-(4-(2-(tert-butoxycarbonylamino)-3-(thiophen-2-yl)propanoyl)piperazin-1-yl)benzo[d]thiazole-6-carboxylic acid.
Reaction SMILES: [CH:1](NC(C)C)(C)C.CN(P(N(C)C)(N(C)C)=O)C.[CH3:19][N:20]1[CH2:25][C:24]([N+:32]([O-:34])=[O:33])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:23][CH:22]([CH3:35])[C:21]1=[O:36].CI>C1COCC1.CCCCCC>[CH3:19][N:20]1[CH2:25][C:24]([N+:32]([O-:34])=[O:33])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:23][C:22]([CH3:1])([CH3:35])[C:21]1=[O:36]
Reactant: CC1CC(c2ccccc2)([N+](=O)[O-])CN(C)C1=O
Reactant: CC(C)NC(C)C
Solvent: CI
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN1CC(c2ccccc2)([N+](=O)[O-])CC(C)(C)C1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 62 %

Procedure:
To a solution of 170.7 ul (1.208 mmol) diisopropylamine in 4 ml THF were added 755 ul (1.208 mmol) of a 1.6M n-Buli solution in hexane at −5° C. The solution was stirred for 15 minutes at 0° C. and then cooled to −70° C. Then 300 ul HMPA was added. A solution of 200 mg (0.805 mmol) (3SR,5RS)-1,3-dimethyl-5-nitro-5-phenyl-piperidin-2-one (example A.20, step a) in 2 ml THF was added dropwise. The brown solution was stirred at −70° C. for 45 minutes. 151 ul (2.415 mmol) methyliodide in THF (1 ml) were added dropwise at −70° C. The mixture was stirred at −70° C. for 1 hour and then allowed to warm to 0° C. After 1 hour at 0° C., the mixture was quenched with 7 ml of a 20% NH4Cl solution. Water and ethyl acetate were added. The aqueous layer was extracted once with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified on silica gel (Eluent: Heptane/ethyl acetate 0 to 100%) to provide 131 mg (62%) of the title compound as a yellow oil. MS (m/e): 263.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]2[CH2:17][CH2:16][CH:15]([OH:18])[O:14]2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[C:39]1(=[O:53])[N:43]([CH2:44][CH2:45][CH2:46]O)[C:42](=[O:48])[C:41]2=[CH:49][CH:50]=[CH:51][CH:52]=[C:40]12>ClCCl>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C@H:13]2[CH2:17][CH2:16][C@@H:15]([O:18][CH2:46][CH2:45][CH2:44][N:43]3[C:39](=[O:53])[C:40]4=[CH:52][CH:51]=[CH:50][CH:49]=[C:41]4[C:42]3=[O:48])[O:14]2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(C2CCC(O)O2)cc(OC)c1OC
Reactant: O=C1c2ccccc2C(=O)N1CCCO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc([C@H]2CC[C@@H](OCCCN3C(=O)c4ccccc4C3=O)O2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
Compound 105 (1.14 g, 4.49 mmol) was dissolved in 4 mL dichloromethane. Triethylamine (681.4 mg, 6.73 mmol) was added to this solution. The reaction mixture was cooled with an ice bath and trifluoroacetic anhydride (1.41 g, 6.73 mmol) was added in a dropwise manner. The reaction mixture was stirred at 0° C. for 30 minutes and then 3-phthalimidylpropanol (106) (2.4 g, 13.26 mmol) was added. The reaction mixture was warmed to room temperature and stirred at room temperature for 2 hours. The reaction was quenched with saturated aqueous NaHCO3 solution and extracted with ethyl acetate. The organic layer was washed with water and saturated NaCl solution, dried over MgSO4, filtered and evaporated in vacuo to an oil which was purified by column chromatography (silica, 2:1 hexane/ethyl acetate) (107: 522 mg (trans); 108: 271 mg (cis); 1:1 mixture of 107 and 108: 110 mg; total yield 46%) . 1H NMR (CDCl3): 107: 1.70 (m,1H); 1.82 (m,1H); 2.00(m,2H); 2.02(m,1H); 2.28(m,1H); 3.46(m,1H); 3.83(s,3H); 3.84(m,3H); 3.88(s,6H); 4.99(t,1H); 5.30(dd,1H); 6.56(s,2H); 7.72(m,2H); 7.85(m,2H). 108: 1.95(m,3H); 2.00(m,2H); 2.20(m,1H); 3.51(m,1H); 3.83(s,3H); 3.85(m,2H); 3.88(s,6H); 3.92(m,1H); 4.90(m,1H); 5.16(dd,1H); 6.60(s,2H); 7.72(m,2H); 7.84(m,2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9](O)=[O:10])=[N:6][CH:7]=1.B.O1CCCC1.O.C(O)(=O)C>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][OH:10])=[N:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Br)cn1
Agent: B
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: OCCc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 19 h
Yield: 80.1 %

Procedure:
To a solution of (5-bromopyridin-2-yl)acetic acid (60.0 mg, 0.278 mmol) in dry tetrahydrofuran (1.4 mL) was added dropwise borane-tetrahydrofuran complex (1.06M in tetrahydrofuran, 0.34 mL, 0.361 mmol) under N2. The mixture was stirred at room temperature for 19 hours and water (5 mL)-acetic acid (5 mL) was added slowly. The mixture was concentrated under reduced pressure, the residue was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/3→ethyl acetate) to give the title compound as a yellow oil (45 mg, yield 80%).