Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:18]([O:19]C(=O)C)[C@H:17]([O:23]C(=O)C)[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][C:11](Br)=[CH:12][CH:13]=1)(=O)C.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][C:30]=1B(O)O>>[O:7]([C:8]1[CH:9]=[N:10][C:11]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][C:29]=2[O:28][CH3:27])=[CH:12][CH:13]=1)[C@@H:6]1[S:15][CH2:16][C@@H:17]([OH:23])[C@H:18]([OH:19])[C@H:5]1[OH:4]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(Br)nc1
Reactant: COc1ccncc1B(O)O
Product: COc1ccncc1-c1ccc(O[C@@H]2SC[C@@H](O)[C@H](O)[C@H]2O)cn1

Procedure:
By carrying out the operation analogously to example 239, starting from 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, and 4-methoxy-3-pyridineboronic acid, the desired product is obtained in the form of a white solid (yield=37%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18]2[S:19][C:20]([S:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([C:30]([O:32]C)=[O:31])[C:25]=3[F:34])=[CH:21][N:22]=2)=[N:15][CH:16]=1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O.Cl>C1COCC1>[C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18]2[S:19][C:20]([S:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([C:30]([OH:32])=[O:31])[C:25]=3[F:34])=[CH:21][N:22]=2)=[N:15][CH:16]=1)[CH3:9])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1nccc(Sc2cnc(Nc3ccc(CN(C)C(=O)OC(C)(C)C)cn3)s2)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1ccc(Nc2ncc(Sc3ccnc(C(=O)O)c3F)s2)nc1)C(=O)OC(C)(C)C
Temperature: 23 °C
Reaction time: 0.17 h
Yield: 104.1 %

Procedure:
A solution of methyl 4-(2-(5-((tert-butoxycarbonyl(methyl)amino)methyl)pyridine-2-ylamino)thiazol-5-ylthio)-3-fluoropicolinate (2.56 g, 5.06 mmol) in THF (100 mL) was treated with NaOH 5N (6 eq, 30.4 mmol, 6 mL) and stirred at 23° C. for 10 min. Water (10 mL) was added to the mixture which was them stirred at 23° C. for 2 hours. The mixture was then acidified with HCl conc. to pH 4. Water was added and the aqueous phase was extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over MgSO4, filtered and evaporated to give the crude title material (2.59 g) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm: 1.41 (9H, s), 2.75 (3H, s), 4.33 (2H, s), 7.04-7.18 (2H, m) 7.66 (1H, d, J=7.33 Hz) 7.84 (1H, s) 8.20 (1H, d, J=1.52 Hz) 8.30 (1H, d, J=4.80 Hz) 11.92 (1H, s). LC/MS (M+H)+: 492. Ret. time: 1.308 min. (Condition B).
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[N:10]1([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:14][CH2:13][CH2:12][CH2:11]1>ClCCl.C(O)C>[I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:18]2[CH2:19][CH2:20][CH:15]([N:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)[CH2:16][CH2:17]2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(I)cc1
Reactant: C1CCN(C2CCNCC2)C1
Solvent: CCO
Solvent: ClCCl
Product: Ic1ccc(CN2CCC(N3CCCC3)CC2)cc1

Procedure:
Prepared analogously to Example 1.1.c. from 4-iodobenzyl bromide and 4-pyrrolidin-1-ylpiperidine. Yield: 0.57 g (51% of theory); C16H23IN2 (M=370.28); calc.: molecular ion peak (M+H)+: 371; found: molecular ion peak (M+H)+: 371; Rf value: 0.3 (silica gel, dichloromethane/ethanol (20:1)).
Reaction SMILES: [NH2:1][C:2]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3]1.O[CH2:11][C:12]1(N)[CH2:16][CH2:15][CH2:14][CH2:13]1.OCCN.C1(=O)CCCCC1>>[CH2:3]1[C:2]2([CH2:7][O:9][C:11]3([CH2:12][CH2:16][CH2:15][CH2:14][CH2:13]3)[NH:1]2)[CH2:6][CH2:5][CH2:4]1
Reactant: NC1(CO)CCCC1
Reactant: NC1(C(=O)O)CCCC1
Solvent: NCCO
Solvent: O=C1CCCCC1
Product: C1CCC2(CC1)NC1(CCCC1)CO2

Procedure:
1-Aminocyclopentanecarboxylic acid was converted to the methyl ester according to Method B1c, Step 1. The ester reduced to 1-hydroxymethylcyclopentanamine according to Method B1c, Step 2. The hydroxyethylamine was reacted with cyclohexanone according to Method B4a, Step 1 to give 6-aza-13-oxadispiro[4.1.5.2]tetradecane. The oxazolidine was reduced according to Method B4a, Step 2 to give 1-(cyclohexylamino)-1-(hydroxymethyl)cyclopentane. The substituted 2-hydroxyethylamine was reacted with SOCl2 according to Method B7b to 1-(cyclohexylamino)-1-(chloromethyl)cyclopentane. The 2-chloroethylamine was reacted with 2-methyl-4-nitrophenyl isocyanate according to Method C4a to afford 1-cyclohexyl-2-(2-methyl-4-nitrophenylimino)-3-oxa-1-azaspiro[4.4]nonane.
Reaction SMILES: C[O:2][C:3](=[O:39])[CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([CH:35]2[CH2:37][CH2:36]2)[C:19]2[S:23][C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[N:21][C:20]=2[CH3:34])=[CH:13][C:12]=1[CH3:38])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[Li+].[OH-]>>[CH:35]1([CH:18]([C:19]2[S:23][C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[N:21][C:20]=2[CH3:34])[O:17][C:14]2[CH:15]=[CH:16][C:11]([CH2:10][CH:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([OH:39])=[O:2])=[C:12]([CH3:38])[CH:13]=2)[CH2:37][CH2:36]1
Reactant: CCCCCC(Cc1ccc(OC(c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)C2CC2)cc1C)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCCCCC(Cc1ccc(OC(c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)C2CC2)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], 2-(4-{cyclopropyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methoxy}-2-methyl-benzyl)-heptanoic acid methyl ester (mixture of two diastereomeric racemates) was treated with LiOH to obtain 2-(4-{cyclopropyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methoxy}-2-methyl-benzyl)-heptanoic acid as a mixture of two diastereomeric racemates as colorless oil.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]2[N:9]=[C:10]([N:15]([CH3:36])[C:16]3[CH:17]=[C:18]([NH:22][C:23](=[O:35])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([C:33]#[N:34])([CH3:32])[CH3:31])[CH:25]=4)[CH:19]=[CH:20][CH:21]=3)[N:11]=[CH:12][C:13]=2[N:14]=1)=[O:4].C(N(CC)CC)C.Cl.[F:45][CH:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1.C(=O)([O-])O.[Na+]>O1CCCC1>[C:33]([C:30]([C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[C:23]([NH:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([N:15]([C:10]2[N:11]=[CH:12][C:13]3[N:14]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:49]4[CH2:50][CH2:51][CH:46]([F:45])[CH2:47][CH2:48]4)[S:7][C:8]=3[N:9]=2)[CH3:36])[CH:17]=1)=[O:35])([CH3:32])[CH3:31])#[N:34]
Reactant: FC1CCNCC1
Reactant: CN(c1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1)c1ncc2nc(NC(=O)CCl)sc2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(c1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1)c1ncc2nc(NC(=O)CN3CCC(F)CC3)sc2n1
Temperature: 60 °C
Reaction time: 20 h
Yield: 50.1 %

Procedure:
To a solution of N-{3-[{2-[(chloroacetyl)amino][1,3]thiazolo[5,4-d]pyrimidin-5-yl}(methyl)amino]phenyl}-3-(1-cyano-1-methylethyl)benzamide (140 mg, 269 μmol) produced in Example D10 in tetrahydrofuran (4 mL) were added triethylamine (112 μL, 807 μmol) and 4-fluoropiperidine hydrochloride (113 mg, 807 μmol), and the mixture was stirred at 60° C. for 20 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (10 mL), and the mixture was extracted with ethyl acetate (15 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=40/60→20/80), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate and hexane to give the title compound (79 mg, 50%) as colorless crystals.
Reaction SMILES: C(OO)(C)(C)C.[OH-].[NH4+:8].[Br:9][C:10]1[CH:23]=[C:22]2[C:13]([O:14][C:15]3[C:16]([F:35])=[CH:17][C:18]([O:33][CH3:34])=[CH:19][C:20]=3[C:21]32[C:27]2=[N:28][CH2:29][CH2:30][CH2:31][N:26]2[C:25](=S)[NH:24]3)=[CH:12][CH:11]=1>CO>[Br:9][C:10]1[CH:23]=[C:22]2[C:13]([O:14][C:15]3[C:16]([F:35])=[CH:17][C:18]([O:33][CH3:34])=[CH:19][C:20]=3[C:21]32[C:27]2=[N:28][CH2:29][CH2:30][CH2:31][N:26]2[C:25]([NH2:8])=[N:24]3)=[CH:12][CH:11]=1
Reactant: [NH4+]
Reactant: COc1cc(F)c2c(c1)C1(NC(=S)N3CCCN=C31)c1cc(Br)ccc1O2
Agent: CC(C)(C)OO
Agent: [OH-]
Solvent: CO
Product: COc1cc(F)c2c(c1)C1(N=C(N)N3CCCN=C31)c1cc(Br)ccc1O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
Tert-butyl hydroperoxide (70% in water) (1.945 mL, 20.08 mmol), ammonium hydroxide (13.03 mL, 335 mmol), and 7′-bromo-4′-fluoro-2′-methoxy-3,4-dihydro-2H-spiro[imidazo[1,5-a]pyrimidine-8,9′-xanthene]-6(7H)-thione (300 mg, 0.669 mmol) were combined in MeOH (50 mL) and stirred at RT overnight. The solution was concentrated. The product was purified from the crude concentrate via silica gel column chromatography (RediSep 40 g column) using 0-100% 90/10/1 (DCM/MeOH/ammonia) in DCM to afford 7′-bromo-4′-fluoro-2′-methoxy-3,4-dihydro-2H-spiro[imidazo[1,5-a]pyrimidine-8,9′-xanthen]-6-amine (150 mg, 0.348 mmol). MS m/z=431.0 [M+H].
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:22]([NH:24][C@H:25]([C:35]([NH:37][C@H:38]([C:47]([NH:49][C@H:50]([C:55]([NH:57][C@H:58]([C:63]([NH:65][CH:66]([CH2:72][C:73]([F:76])([F:75])[F:74])[CH:67]([OH:71])[C:68]([NH2:70])=[O:69])=[O:64])[CH2:59][CH:60]([CH3:62])[CH3:61])=[O:56])[C:51]([CH3:54])([CH3:53])[CH3:52])=[O:48])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH3:46])=[O:36])[CH2:26][CH2:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:23])[CH2:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>ClCCl>[C:1]([O:5][C:6]([CH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:22]([NH:24][C@H:25]([C:35]([NH:37][C@H:38]([C:47]([NH:49][C@H:50]([C:55]([NH:57][C@H:58]([C:63]([NH:65][CH:66]([CH2:72][C:73]([F:74])([F:75])[F:76])[C:67](=[O:71])[C:68]([NH2:70])=[O:69])=[O:64])[CH2:59][CH:60]([CH3:62])[CH3:61])=[O:56])[C:51]([CH3:52])([CH3:53])[CH3:54])=[O:48])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH3:46])=[O:36])[CH2:26][CH2:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:23])[CH2:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:11])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1ccccc1C[C@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CCC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)NC(CC(F)(F)F)C(O)C(N)=O)C(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cc1ccccc1C[C@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CCC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)NC(CC(F)(F)F)C(=O)C(N)=O)C(C)(C)C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
A solution of 0.7 g (0.645 mmol) of 3(RS)-[[N-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)-propionyl]-O-tert-butyl-L-α-aspartyl]-O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-5,5,5-trifluoro-2(RS)-hydroxyvaleramide and 328 mg (0.773 mmol) of 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one in 20 ml of dichloromethane was stirred under a nitrogen atmosphere at room temperature for 30 minutes. A further 328 mg. (0.773 mmol) of 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one were added and the mixture was stirred for 1 hour. The solution was extracted with a solution of 10 g of sodium thiosulphate in 40 ml of saturated sodium bicarbonate solution then dried over anhydrous magnesium sulphate, filtered and evaporated to dryness. The residue was triturated with diethyl ether/petroleum ether (1:1) and the solid was removed by filtration to give 660 mg of 3(RS)-[[N-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-α-aspartyl]-O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-5,5,5-trifluoro-2-oxovaleramide as a white solid. MS: m/e 1084.5 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[O:13][CH:12]([CH2:14][C:15]([OH:17])=[O:16])[C:11](=[C:18]=[CH2:19])[CH2:10]2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[C:26]1(I)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>CN(C)C=O.C(OCC)(=O)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>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[O:13][CH:12]3[C:11]([C:18]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH2:19])([O:16][C:15](=[O:17])[CH2:14]3)[CH2:10]2)=[CH:5][CH:4]=1
Reactant: Ic1ccccc1
Reactant: C=C=C1CC(c2ccc(OC)cc2)OC1CC(=O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=C(c1ccccc1)C12CC(c3ccc(OC)cc3)OC1CC(=O)O2
Temperature: 85 °C
Reaction time: 4 h

Procedure:
(5-(4-methoxyphenyl)-3-vinylidene-tetrahydro-furan-2-yl)acetic acid (34 mg, 0.12 mmol), Pd(PPh3)4 (14 mg, 0.012 mmol) and K2CO3 (84 mg, 0.61 mmol) were dissolved in 3 mL of dimethylformamide, followed by addition of PhI (68 μL, 0.61 mmol). The solution was stirred for 4 hours at 85° C. When the reaction was completed, H2O was added and the solution was stirred for 5 minutes. The mixture was diluted with ethyl acetate, washed with H2O and NaCl. Organic layer was separated and dried with anhydride MgSO4. Solvent was removed under reduced pressure, and the remnant was purified through silica gel tube chromatography (EtOAc:n-Hexane=1:15, v/v), thus providing products (27 mg, 61%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][CH:4]=[C:3]1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1.C(N(CC)CC)C.[C:29](OC(=O)C)(=[O:31])[CH3:30]>CN(C)C1C=CN=CC=1.O1CCCC1>[C:29]([NH:1][CH:2]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][CH:4]=[C:3]1[C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)(=[O:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(F)cc2)C(N)C1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NC1CN(C(=O)OC(C)(C)C)CC=C1c1ccc(F)cc1
Temperature: 0 °C
Yield: 104.1 %

Procedure:
To a tetrahydrofuran solution (2.0 ml) of tert-butyl 5-amino-4-(4-fluorophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (100 mg, 0.342 mmol) synthesized in Reference Synthesis Example 202, triethylamine (52.0 μL, 0.374 mmol) and 4-dimethylaminopyridine (2.08 mg, 0.0170 mmol) were added and then acetic anhydride (26.0 μL, 0.374 mmol) was added with stirring at 0° C., followed by stirring the resultant reaction solution at 0° C. for 2 hours. After completion of the reaction, the reaction solution was purified by silica gel column chromatography to obtain the title compound (119 mg, yield 87%).
Reaction SMILES: [C:1]([O:14][C@H:15]([CH2:45][O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH2:16][S:17][CH2:18][C@@H:19]([C:38]([O:40]C(C)(C)C)=[O:39])[NH:20][C:21](=[O:37])[O:22][CH2:23][CH:24]1[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>C(O)(C(F)(F)F)=O.C(Cl)Cl.CC(OC)(C)C>[CH:35]1[C:36]2[CH:24]([CH2:23][O:22][C:21]([NH:20][C@@H:19]([CH2:18][S:17][CH2:16][C@H:15]([O:14][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:45][O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[C:38]([OH:40])=[O:39])=[O:37])[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]=2[CH:32]=[CH:33][CH:34]=1
Reactant: CCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C)OC(=O)CCCCCCCCCCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: CCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OC(=O)CCCCCCCCCCC

Procedure:
A solution of ((5R,9R)-5-(tert-butoxycarbonyl)-1-(9H-fluoren-9-yl)-3-oxo-2,11-dioxa-7-thia-4-azatricosan-9-yl dodecanoate in 40% TFA in DCM (0.3 M) was stirred at room temperature until complete deprotection of tert-butyl group (2 hours). The reaction mixture was diluted in MTBE, washed three times with 1M citric acid (adjusted to pH3), and once with 1:2 1N HCl/brine. The organic layer was dried over anhydrous Na2SO4 and concentrated en vaccuo. The resulting waxy solid was used without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]2[CH2:15][CH:14]([F:16])[CH2:13]2)[CH2:9]1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:16][CH:14]1[CH2:15][N:12]([CH:10]2[CH2:11][NH:8][CH2:9]2)[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CC(N2CC(F)C2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC1CN(C2CNC2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.8 %

Procedure:
A 25 mL round-bottomed flask was charged with a solution of 3-fluoro-[1,3′]biazetidinyl-1′-carboxylic acid tert-butyl ester (0.109 g, 0.47 mmol) in DCM/TFA (2 mL/2 mL). The reaction mixture was stirred for 90 min at room temperature. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH to give 3-Fluoro-[1,3′]biazetidinyl as a colourless oil (0.058 g, 94%). 1H NMR (CDCl3, 400 MHz) δ 5.14 (dp, J=57.2, 5.3 Hz, 1 H); 3.75-3.46 (m, 8 H); 3.34-3.24 (m, 1 H); 3.27-3.10 (m, 1 H).
Reaction SMILES: I[C:2]1[N:10]=[CH:9][C:8]2[NH:7][C:6]3[N:11]=[CH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][N:22]5[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]5)=[CH:17][CH:16]=4)=[CH:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:28][N:29]1[C:33]([Sn](C)(C)C)=[CH:32][N:31]=[N:30]1.C(N(CC)C(C)C)(C)C>O1CCOCC1.C(Cl)Cl.CO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:28][N:29]1[C:33]([C:2]2[N:10]=[CH:9][C:8]3[NH:7][C:6]4[N:11]=[CH:12][C:13]([C:15]5[CH:16]=[CH:17][C:18]([CH2:21][N:22]6[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]6)=[CH:19][CH:20]=5)=[CH:14][C:5]=4[C:4]=3[CH:3]=2)=[CH:32][N:31]=[N:30]1
Reactant: Cn1nncc1[Sn](C)(C)C
Reactant: Ic1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cn1nncc1-c1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Temperature: 100 °C
Yield: 22.5 %

Procedure:
A degassed mixture of 6-iodo-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (100 mg, 0.21 mmol), 1-methyl-5-(trimethylstannyl)-1H-1,2,3-triazole (158 mg, 0.64 mmol) and bis(triphenylphosphine)palladium(II) dichloride (15 mg, 0.021 mmol) in N,N-diisopropylethylamine (0.74 mL, 0.43 mmol) in 1,4-dioxane (1.7 mL) was heated at 100° C. for 1 h. The cooled reaction mixture was diluted with DCM (20 mL) and methanol (2 mL) and washed with water (15 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford a residue that was purified by preparative HPLC (20-60% MeCN in water (0.1% ammonium hydroxide) over 30 min, 35 mL/min) to afford the title compound as a pale yellow solid (20 mg, 20%). 1H NMR (DMSO-D6, 400 MHz): 12.47 (s, 1H), 9.05 (s, 1H), 9.04 (d, J=2.2 Hz, 1H), 8.96 (d, J=2.2 Hz, 1H), 8.78 (s, 1H), 8.18 (s, 1H), 7.77 (d, J=8.1 Hz, 2H), 7.45 (d, J=8.1 Hz, 2H), 4.37 (s, 3H), 3.50 (s, 2H), 2.35 (s, 4H), 1.52 (m, 4H), 1.41 (m, 2H). LCMS (method D): RT=8.04 min, M+H+=424.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17](Cl)[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[NH:24]1[CH2:28][CH2:27][CH2:26][C:25]1=[O:29]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([N:24]4[CH2:28][CH2:27][CH2:26][C:25]4=[O:29])[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(Nc2nccc(-c3ccnc(Cl)c3)n2)c1
Reactant: O=C1CCCN1
Agent: [H-]
Agent: [Na+]
Product: O=C1CCCN1c1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1

Procedure:
To a solution of (3-chloro-phenyl)-[4-(2-chloro-pyridin-4-yl)-pyrimidin-2-yl]-amine (4.8 g, 0.015 mol) in pyrrolidon (20 ml) is added sodium hydride (1.93 g, 0.06 mmol of a 75% dispersion in oil) in several portions. The reaction temperature is slowly raised to +150° C. After 30 minutes the heating bath is removed and the mixture is poured onto crushed ice. The reaction mixture is partitioned between ethyl acetate and water. The organic phase is separated, dried over magnesium sulfate, filtered and evaporated under reduced presssure. The residue is purified by silicagel chromatography and recrystallized from ethyl acetate to give the title compound, m.p. 165–166° C.
Reaction SMILES: [CH2:1]([O:4][C:5]([O:7][C@@H:8]([C@H:10]1[C:23](=[O:24])[N:12]2[C@@H:13]([C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18])[C:14](=O)[CH2:15][C@H:11]12)[CH3:9])=[O:6])[CH:2]=[CH2:3].C(N(CC)C(C)C)(C)C.P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.[CH2:51]([O:54][C:55]([N:57]1[CH2:61][C@@H:60]([SH:62])[CH2:59][C@H:58]1[CH2:63][OH:64])=[O:56])[CH:52]=[CH2:53]>C(#N)C>[CH2:51]([O:54][C:55]([N:57]1[CH2:61][C@@H:60]([S:62][C:14]2[CH2:15][C@@H:11]3[C@@H:10]([C@H:8]([O:7][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[CH3:9])[C:23](=[O:24])[N:12]3[C:13]=2[C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18])[CH2:59][C@H:58]1[CH2:63][OH:64])=[O:56])[CH:52]=[CH2:53]
Reactant: C=CCOC(=O)N1C[C@@H](S)C[C@H]1CO
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2[C@@H](C(=O)OCC=C)C(=O)C[C@H]12
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(S[C@H]3C[C@@H](CO)N(C(=O)OCC=C)C3)C[C@H]12
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
To a solution of allyl (3R,5R,6S)-6-[(R)-1-allyloxycarbonyloxyethyl]-2-oxo-1-carbapenam-3-carboxylate (1.01 g, 3 mmol) and N,N-diisopropylethylamine (0.73 ml, 4.2 mmol) in acetonitrile (20 ml) was dropwise added diphenyl chlorophosphate (0.75-3.6 mmol) under ice-cooling, and then the mixture stirred for 30 minutes. The reaction mixture under ice-cooling was treated successively with N,N-diisopropylethylamine (0.73 μl, 4.2 mmol) and (2S,4S)-N-allyloxycarbonyl-2-hydroxymethyl-4-mercaptopyrrolidine (780 mg, 3.6 mmol) in acetonitrile (4 ml), stirred for 1 hour, and partitioned between ethyl acetate (60 ml) and water (40 ml). The organic layer was successively washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated, and the residue purified by flash column chromatography on silica gel (Wakogel® C-300, 40 ml, elution with ethyl acetate-hexane 1:1) to afford the title compound (1.20 g, 75% yield).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1>CCO.O.O=[Pt]=O>[CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@H:3]1[C:8]([OH:10])=[O:9]
Reactant: Cc1cccnc1C(=O)O
Agent: O=[Pt]=O
Solvent: CCO
Solvent: O
Product: C[C@H]1CCCN[C@H]1C(=O)O
Reaction time: 18 h

Procedure:
3-Methylpicolinic acid (10 g, 72.9 mmol) in EtOH (80 mL) and water (80 mL) was treated with PtO2 (4 g) and placed under a H2 atmosphere (60 psi). The mixture was shaken vigorously for 18 h, and then the PtO2 was degassed via vacuum for 30 min. The mixture was filtered through a Celite pad, which was washed with EtOH (3 50 mL) and H2O (3 80 mL). The solution was concentrated to afford (+/−) cis-3-methylpiperidine-2-carboxylic acid, which was used without further purification.