Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:37]/[O:38][CH3:39])/[C:8]([NH:10][C@@H:11]2[C:35](=[O:36])[N:13]3[C:14]([C:23]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)=[O:24])=[C:15]([C@@H:18]4[CH2:22][CH2:21][CH2:20][O:19]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.ClC1C=CC=C(C(OO)=[O:48])C=1>C(OCC)(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:37]/[O:38][CH3:39])/[C:8]([NH:10][C@@H:11]2[C:35](=[O:36])[N:13]3[C:14]([C:23]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)=[O:24])=[C:15]([C@@H:18]4[CH2:22][CH2:21][CH2:20][O:19]4)[CH2:16][S@:17](=[O:48])[C@H:12]23)=[O:9])[N:6]=1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C([C@@H]3CCCO3)CS[C@H]12)c1csc(N)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C([C@@H]3CCCO3)C[S@](=O)[C@H]12)c1csc(N)n1
Yield: 69 %

Procedure:
4-Methoxybenzyl (6R,7R)-7-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]-3-[(S)-tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate (see example 7) (250mg, 0.44mmol) in ethyl acetate (25ml) was stirred in an ice bath and a solution of m-chloroperbenzoic acid (75mg, 0.44mmol) in ethyl acetate (5ml) was added. After 10 min the reaction mixture was washed with dilute aqueous sodium hydrogen carbonate then water followed by drying (magnesium sulphate) and evaporation under reduced pressure. The residue was chromatographed on silica gel eluting with acetone/ethyl acetate mixtures to give the title compound as a white solid (179mg, 69%); vmax (CHCl3) 1800, 1730, 1680 and 1610 cm-1 ; δH (CDCl3) 1.48-1.64 (1H,m), 1.89-2.00 (2H,m), 2.33-2.47 (1H,m), 3.29 and 3.75 (2H, ABq, J 19Hz), 3.82 (3H,s), 3.84-3.96 (2H,m), 4.09 (3H,s), 5.06 (1H,dd, J 7, 9Hz), 5.22 (2H,s), 5.55-5.8 (1H, br s, exch), 6.16 (1H,dd, J 4.5, 10Hz), 6.91 (2H,d, J 7,9Hz), 6.98 (1H,s), 7.35 (2H,d, J 9Hz) and 7.55-7.65 (1H,br, exch). [Mass spectrum: +ve ion (thioglycerol) MH+ (590)].
Reaction SMILES: [ClH:1].[OH:2][CH:3]1[O:22][C@H:21]([CH2:23][OH:24])[C@@H:8]([O:9][C@@H:10]2[O:18][C@H:17]([CH2:19][OH:20])[C@H:15]([OH:16])[C@H:13]([OH:14])[C@H:11]2[OH:12])[C@H:6]([OH:7])[C@H:4]1[NH2:5].CC(C)=O.O.CC(C)=O>O>[OH2:2].[ClH:1].[OH:2][C@H:3]1[O:22][C@H:21]([CH2:23][OH:24])[C@@H:8]([O:9][C@@H:10]2[O:18][C@H:17]([CH2:19][OH:20])[C@H:15]([OH:16])[C@H:13]([OH:14])[C@H:11]2[OH:12])[C@H:6]([OH:7])[C@H:4]1[NH2:5]
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@@H]1O
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: N[C@@H]1[C@@H](O)[C@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@@H](CO)O[C@@H]1O

Procedure:
Suitably, the method may further comprise the preliminary steps of: dissolving the anomeric mixture of lactosamine hydrochloride in water; and adding the solution to a much larger volume of acetone, such as a tenfold volume of acetone compared with the volume of the aqueous solution, to cause precipitation of a white powder, which powder is then used as the anomeric mixture in preparing the solution comprising the anomeric mixture, water and at least one water miscible organic solvent. This preliminary step forms an acetone adduct of the anomeric mixture that is insoluble in this water/acetone mixture, and so precipitates as a white powder leaving other impurities in solution.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)=[CH:7][CH:6]=1)[CH3:2]>[C].[Pd].O1CCCC1>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(/C=C/c2ccco2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(CCc2ccco2)cc1
Yield: 65.7 %

Procedure:
To an anhydrous tetrahydrofuran (25 mL) solution of 4-((E)-2-furan-2-yl-vinyl)benzoic acid ethyl ester (1.07 g, 4.4 mmol) described in Manufacturing Example 80-1-1 was added 10% palladium-carbon (50% hydrate, 500 mg), which was added for 2 hours under a hydrogen atmosphere at room temperature. The reaction product was filtered, and the filtrate was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (t-butylmethyl ether:heptane=5:95) to obtain the title compound (706 mg, 65.4%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([NH2:25])[C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:16]3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.CCN(C(C)C)C(C)C.[CH2:35]([O:42][C:43]([N:45]1[CH2:50][CH2:49][CH:48]([C:51](Cl)=[O:52])[CH2:47][CH2:46]1)=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl>[CH2:35]([O:42][C:43]([N:45]1[CH2:50][CH2:49][CH:48]([C:51](=[O:52])[NH:25][CH:8]([C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[CH:5][N:4]=2)[C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:16]3)=[CH:11][CH:10]=2)[CH2:47][CH2:46]1)=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Reactant: O=C(Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A CH2Cl2 solution (111.0 mL) of C-(3-chloro-pyrazin-2-yl)-C-(2-phenyl-quinolin-7-yl)-methylamine (1.9 g, 5.5 mmol) and PS-DIPEA (2.8 g, 11.1 mmol) in a round bottom flask under N2 atmosphere was charged with 4-chlorocarbonyl-piperidine-1-carboxylic acid benzyl ester (1.4 g, 5.0 mmol) and stirred at rt for 1.5 h. The reaction mixture was filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (Jones Flashmaster, 20 g/70 mL cartridge, eluting with 100% CH2Cl2 to 10% CH3CN/CH2Cl2) to afford 4-{[(3-chloro-pyrazin-2-yl)-(2-phenyl-quinolin-7-yl)-methyl]-carbamoyl}-piperidine-1-carboxylic acid benzyl ester as a pale yellow solid; MS (ES+): m/z 592/594 (100/50) [MH+]; HPLC: tR=3.7 min (OpenLynx, polar—5 min).
Reaction SMILES: F[C:2]1[N:7]=[C:6]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[C:21]([CH:23]5[CH2:26][O:25][CH2:24]5)[CH:22]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)[CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH2:33][CH:32]([OH:34])[CH2:31][NH:30][CH2:29][CH2:28]1>>[O:25]1[CH2:26][CH:23]([C:21]2[CH:22]=[C:17]([C:14]3[N:13]=[CH:12][C:11]4[CH:10]=[N:9][N:8]([C:6]5[N:7]=[C:2]([N:27]6[CH2:33][CH:32]([OH:34])[CH2:31][NH:30][CH2:29][CH2:28]6)[CH:3]=[CH:4][CH:5]=5)[C:16]=4[CH:15]=3)[CH:18]=[N:19][CH:20]=2)[CH2:24]1
Reactant: OC1CNCCNC1
Reactant: Fc1cccc(-n2ncc3cnc(-c4cncc(C5COC5)c4)cc32)n1
Product: OC1CNCCN(c2cccc(-n3ncc4cnc(-c5cncc(C6COC6)c5)cc43)n2)C1
Yield: 6 %

Procedure:
Following the procedures as described in EXAMPLE 8 and starting with 1-(6-fluoropyridin-2-yl)-6-(5-(oxetan-3-yl)pyridin-3-yl)-1H-pyrazolo[4,3-c]pyridine and 1,4-diazepan-6-ol, 116 was obtained as an off-white solid (7.2 mg, 6%). 1H NMR (400 MHz, DMSO) δ 9.35-9.29 (s, 1H), 9.23-9.16 (dd, J=8.9, 2.0 Hz, 1H), 9.11-9.04 (d, J=8.6 Hz, 1H), 8.77-8.62 (m, 2H), 8.55-8.46 (dd, J=15.4, 8.6 Hz, 1H), 7.74-7.67 (t, J=8.1 Hz, 1H), 7.21-7.16 (d, J=7.7 Hz, 1H), 6.77-6.68 (dd, J=8.5, 2.9 Hz, 1H), 5.69-5.45 (d, J=72.4 Hz, 1H), 5.06-5.00 (dd, J=8.1, 6.2 Hz, 1H), 4.81-4.70 (dd, J=13.5, 6.7 Hz, 2H), 4.48-4.40 (m, 1H), 4.06-3.85 (dd, J=32.4, 13.9 Hz, 3H), 3.74-3.53 (m, 2H), 3.00-2.93 (d, J=2.3 Hz, 2H), 2.83-2.77 (dd, J=13.8, 3.8 Hz, 1H), 2.70-2.62 (dd, J=13.2, 6.0 Hz, 1H); MS (ESI) m/z: 444.2 [M+H]+
Reaction SMILES: [CH3:1][N:2]([CH:4]([CH3:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:3].[CH2:11](O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]CC.C[O-].[Na+].C(O)C>C1(C)C=CC=CC=1>[CH3:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:9][CH2:8][O:7][C:5]([CH:4]([N:2]([CH3:3])[CH3:1])[CH3:10])=[O:6]
Reactant: CCOC(=O)C(C)N(C)C
Reactant: CCCCCCCCCCCCO
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCOC(=O)C(C)N(C)C

Procedure:
DDAIP was prepared by transesterification of ethyl 2-(N,N-dimethylamino)-propionate obtained from Varsal Instruments Inc. (Warminster, Pa.). Specifically, a mixture ethyl 2-(N,N-dimethylamino)-propionate, 1-dodecanol, and sodium methoxide predissolved in toluene was refluxed for about 2 hours. As ethanol formed, it was removed by azeotropic distillation. After about 2 hours of refluxing, the remaining reaction product was filtered to remove solids.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[N:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]=[C:16]([Cl:17])[C:11]=2[CH:10]=[C:9]1[CH2:24]Br)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC[OH:28]>CS(C)=O.O>[C:1]([O:5][C:6]([N:8]1[C:12]2[N:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]=[C:16]([Cl:17])[C:11]=2[CH:10]=[C:9]1[CH:24]=[O:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1c(CBr)cc2c(Cl)nc(-c3ccccc3)nc21
Reactant: CCO
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)n1c(C=O)cc2c(Cl)nc(-c3ccccc3)nc21
Temperature: 48 °C
Reaction time: 1 h

Procedure:
A suspension of the bromide 7 (2.00 g, 4.73 mmol), Na2HPO4 (806 mg, 5.68 mmol) and NaH2PO4 (227 mg, 1.89 mmol) in DMSO (50 mL) is heated under nitrogen to 48° C. After 1 h, all solids are dissolved, and the reaction is continued for 2 h. The solution is then poured in H2O (600 mL), and the mixture is extracted with EtOAc (2×150 mL). The combined EtOAc layers are washed with H2O (3×400 mL) and brine and dried over MgSO4. Filtration and concentration yields a yellow solid, which is triturated with EtOH giving 1.06 g (2.97 mmol, 63%) of the title compound as a yellow solid. MS (ES): m/z 304.7/306.7 (33/10) [MH+-Boc-H2O+2 MeOH], 272.7/274.7 (100/32) [MH+-Boc-H2O+MeOH]. 1H NMR (200 MHz, CDCl3): δ=1.79 (s, 9H), 7.44 (s, 1H), 7.48-7.55 (m, 3H), 8.51-8.60 (m, 2H), 10.39 (s, 1H). tR (method A)=10.4 min.
Reaction SMILES: C(=O)(OC)[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6](Br)=[CH:5][C:4]=1[CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.[CH3:21][N:22](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[CH:13]1([C:4]2[C:3]([OH:2])=[CH:8][C:7]([N+:9]([O-:11])=[O:10])=[C:6]([CH:5]=2)[C:21]#[N:22])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CN(C)C=O
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(Br)cc1C1CCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cc(C2CCCC2)c(O)cc1[N+](=O)[O-]
Temperature: 130 °C
Yield: 58 %

Procedure:
To a microwave vial charged with 4-bromo-2-cyclopentyl-5-nitrophenyl methyl carbonate (102 mg, 0.29 mmol), zinc cyanide (35 mg, 0.30 mmol) and Pd(PPh3)4 (21 mg, 0.02 mmol) under an N2 atmosphere was added DMF (500 μL). The reaction was heated under microwave irradiation at 130° C. for 30 min. The reaction was quenched with saturated aqueous Na2CO3 and extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to yield a brown oil. Purification by silica gel chromatography (0-15% ethyl acetate/hexanes) afforded 5-cyclopentyl-4-hydroxy-2-nitrobenzonitrile as a light yellow solid (40 mg, 58% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 11.62 (s, 1H), 7.84 (s, 1H), 7.70 (s, 1H), 3.29-3.24 (m, 1H), 1.99-1.93 (m, 2H), 1.78-1.76 (m, 2H), 1.66-1.57 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.[CH:44]([C:48]1[CH:54]=[CH:53][C:51]([NH2:52])=[CH:50][CH:49]=1)([CH2:46][CH3:47])[CH3:45]>C1COCC1>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH:52][C:51]1[CH:53]=[CH:54][C:48]([CH:44]([CH2:46][CH3:47])[CH3:45])=[CH:49][CH:50]=1)=[O:6]
Reactant: CS(=O)(=O)c1ccc(N)c(C(=O)O)c1
Reactant: CCC(C)c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCC(C)c1ccc(NC(=O)c2cc(S(C)(=O)=O)ccc2N)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a suspension of 2-amino-5-methanesulfonyl-benzoic acid (0.750 g, 3.48 mmol) in THF (50 mL) were added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.730 g, 3.83 mmol), 1-hydroxybenzotriazole (0.510 g, 3.83 mmol), and 4-methylmorpholine (0.380 g, 3.83 mmol). The reaction mixture was stirred at room temperature for 5 minutes and then 4-sec-butyl-aniline (0.780 g, 5.22 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated in vacuo, water was added, and the product was extracted with ethyl acetate. The solvent was evaporated in vacuo and the residue was washed with ether to obtain 2-amino-N-(4-sec-butyl-phenyl)-5-methanesulfonyl-benzamide as white solid. Yield: 0.75 g (62%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN(C)C=O.[NH2:54][C:55]1[CH:64]=[CH:63][CH:62]=[C:61]2[C:56]=1[CH:57]=[CH:58][N:59]([C@@H:66]([CH3:70])[C:67]([NH2:69])=[O:68])[C:60]2=[O:65]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:54][C:55]2[CH:64]=[CH:63][CH:62]=[C:61]3[C:56]=2[CH:57]=[CH:58][N:59]([C@@H:66]([CH3:70])[C:67]([NH2:69])=[O:68])[C:60]3=[O:65])=[O:11])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1C(F)(F)F
Reactant: C[C@@H](C(N)=O)n1ccc2c(N)cccc2c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](C(N)=O)n1ccc2c(NC(=O)Cc3ccc(Cl)cc3C(F)(F)F)cccc2c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A round bottom flask was charged with 2-(4-chloro-2-(trifluoromethyl)phenyl)acetic acid (0.13 g, 0.00056 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.3 g, 0.0009 mol), N,N-diisopropylethylamine (0.2 mL, 0.0009 mol), N,N-dimethylformamide (5 mL, 0.06 mol) and (S)-2-(5-amino-1-oxoisoquinolin-2(1H)-yl)propanamide (0.1 g, 0.0004 mol), and the reaction was stirred for 16 h at room temperature. The reaction was quenched with water and extracted with dichloromethane, washed with 2N HCl, saturated sodium bicarbonate solution, brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by flash chromatography (12 g, 0-10% MeOH/DCM) to yield the product as a white solid. MS m/z=452.4 (M+H). 1H NMR (400 MHz; DMSO-d6) δ 10.11 (s, 1H), 8.07 (d, J=8.80 Hz, 1H), 7.79-7.76 (m, 3H) 7.64-7.60 (m, 2H), 7.49 (d, J=8.08 Hz, 1H), 7.45 (t, J=7.7 Hz, 1H), 7.23 (bs, 1H), 6.71 (d, J=7.77 Hz, 1H), 5.50-5.45 (q, J=7.24 Hz, 1H), 4.06 (s, 2H), 1.55 (d, J=7.54 Hz, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[CH:11]=[C:12]([C:18]2[CH:23]=[C:22]([CH3:24])[C:21]([OH:25])=[C:20]([CH3:26])[CH:19]=2)[N:13]=[N:14][C:15]=1[O:16]C.C[Si](Cl)(C)C.[I-].[K+]>C(#N)C.O>[OH:25][C:21]1[C:22]([CH3:24])=[CH:23][C:18]([C:12]2[CH:11]=[C:10]([C:2]3[NH:1][C:9]4[C:4]([CH:3]=3)=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:15](=[O:16])[NH:14][N:13]=2)=[CH:19][C:20]=1[CH3:26]
Reactant: COc1nnc(-c2cc(C)c(O)c(C)c2)cc1-c1cc2ccccc2[nH]1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(-c2cc(-c3cc4ccccc4[nH]3)c(=O)[nH]n2)cc(C)c1O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
100 mg of 4-[5-(1H-indol-2-yl)-6-methoxy-pyridazin-3-yl]-2,6-dimethyl-phenol is suspended in 2 ml acetonitrile and 40 μl of trimethylsilyl chloride and 53 mg of potassium iodide are added. The solution is heated to 80° C. for 3 h, then a further 120 μl of trimethylsilyl chloride and 159 mg of potassium iodide are added. The solution is heated to 80° C. for 3 h then stirred at RT for 16 h. The reaction solution is diluted with water and the product is purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid). Yield 15 mg. LC-MS (ES+) 332 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:25][C:26]([F:37])([F:36])[C:27]1[N:31]2[CH2:32][CH2:33][NH:34][CH2:35][C:30]2=[N:29][N:28]=1>>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:10][C:11]([N:34]1[CH2:33][CH2:32][N:31]2[C:27]([C:26]([F:37])([F:25])[F:36])=[N:28][N:29]=[C:30]2[CH2:35]1)=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: FC(F)(F)c1nnc2n1CCNC2
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Agent: Cl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F

Procedure:
(3R)-3-[N-(tert-Butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (07) was coupled with 3-trifluoromethyl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (11) to obtain Boc-protected sitagliptin free base, 7-[(3R)-3-[N-(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoyl]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine (12). The coupling was preferably carried out by using coupling agents such as EDC-HCl, 1-hydroxybenzotriazole and a suitable base such as N,N-diisopropylethylamine. The coupling was preferably carried out in an aprotic solvent such as N,N-dimethylformamide or N,N-dimethylacetamide at 0-30° C. for 1-12 hours, preferably at 25-30° C. for 8-10 hours. The Boc-protected sitagliptin free base (12) was preferably isolated by an aqueous work up procedure, preferably involving removal of N,N-dimethylformamide at 50-55° C. under reduced pressure followed by basification preferably using sodium carbonate, and extraction of the product into an organic solvent such as ethyl acetate. The Boc-protected sitagliptin free base (12) was preferably isolated by removal of the organic solvent under reduced pressure to obtain a white solid, which was preferably triturated with a non-polar solvent such as hexane.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].C(=O)([O-])[O-].[K+].[K+].[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[N:18]=[C:17](S(C)(=O)=O)[N:16]=1.O>CN(C)C=O>[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[N:18]=[C:17]([S:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])[N:16]=1
Reactant: COC(=O)CS
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CSc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
25 g (230 mmol) Methyl thioglycolate was dissolved in 250 ml dimethylformamide and treated with 16.3 g (115 mmol) potassium carbonate. After 20 minutes stirring at room temperature, 50 g (2.3 mmol) 4,6-dimethoxy-2-methylsulphonylpyrimidine was added and the mixture heated for 3 hours at 90° C. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic phase was washed with water and dried over magnesium sulphate. The solvent was distilled and the resulting crude product was recrystallised from diisopropyl ether.
Reaction SMILES: [OH:1][CH:2]([CH3:10])/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6].N1C=CC=CC=1.[CH3:17][O:18][C:19](Cl)=[O:20]>CN(C1C=CN=CC=1)C.C1COCC1>[CH3:17][O:18][C:19]([O:1][CH:2]([CH3:10])/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:20]
Reactant: CCOC(=O)/C=C/C(C)O
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/C(C)OC(=O)OC
Temperature: 1 °C

Procedure:
rac-Ethyl (2E)-4-hydroxypent-2-enoate (21) (10.09 g, 70 mmol), DMAP (1.71 g, 14 mmol) and pyridine (17 mL, 210 mmol) are dissolved in THF (400 mL). The solution is cooled to 1° C. Methylchloroformate (16.1 mL, 210 mmol) in THF (50 ml) is then added dropwise over 3 hours under stirring at 1° C. After 2 hours methylchloroformate (199 ml, 2.50 mol) in THF (150 ml) is added dropwise in four portions. After every portion, the reaction mixture is stirred for 5 hours at 1° C. The reaction mixture is quenched with 10% HCl (0.5 l) and extracted with tBuOMe (1.5 and 0.5 l). The organic phases are washed with 10% HCl (0.6 l), saturated NaHCO3 (0.3 l) and brine (2×0.2 l) successively. The combined organic phases are dried with N2SO4 and evaporated under reduced pressure. The residue is purified by flash chromatography (tBuOMe:heptane fraction 15:85 to 25:75) and yields 1 (rac-Ethyl (2E)-4-(methoxycarbonyloxy)pent-2-enoate) (8.64 g, 61%) as a yellowish oil.
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[CH:8][NH:9][C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])=[C:6]2[C:5](=[O:19])[N:4]([CH3:20])[C:3]1=[O:21].Br[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[C:14]([C:13]1[CH:12]=[C:11]([C:10]2[N:9]([CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH:8]=[C:7]3[C:6]=2[C:5](=[O:19])[N:4]([CH3:20])[C:3](=[O:21])[N:2]3[CH3:1])[CH:18]=[CH:17][CH:16]=1)#[N:15]
Reactant: COC(=O)CCCBr
Reactant: Cn1c(=O)c2c(-c3cccc(C#N)c3)[nH]cc2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CCCn1cc2c(c1-c1cccc(C#N)c1)c(=O)n(C)c(=O)n2C
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 3-(1,3-dimethyl-2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-yl)benzonitrile (step 4) (300 mg, 1.07 mmol), methyl 4-bromobutanoate (291 mg, 1.61 mmol) and cesium carbonate (697 mg, 2.14 mmol) in DMF (4 mL) was stirred at 80° C. for 2 hours. The reaction mixture was diluted with ethyl acetate (20 mL) and was washed with 1M HCl (3×10 mL). After the third wash, the mixture was concentrated in vacuo. The residue was triturated with diethyl ether and dried under vacuum at 50° C.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[NH:8][C:7]([C:11]2[CH:12]=[C:13]([CH:22]=[CH:23][C:24]=2[Cl:25])[CH2:14][NH:15]C(=O)C(F)(F)F)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].O>C1COCC1>[C:1]([N:5]1[C:9](=[O:10])[NH:8][C:7]([C:11]2[CH:12]=[C:13]([CH2:14][NH2:15])[CH:22]=[CH:23][C:24]=2[Cl:25])=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1nc(-c2cc(CNC(=O)C(F)(F)F)ccc2Cl)[nH]c1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)n1nc(-c2cc(CN)ccc2Cl)[nH]c1=O
Yield: 100.6 %

Procedure:
The title compound was prepared according to the procedure described in Intermediate-66 by using N-(3-(1-tert-butyl-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-4-chlorobenzyl)-2,2,2-trifluoroacetamide (Example-120, 0.400 g, 1.062 mmol), KOH (0.119 g, 2.12 mmol), water (5 mL) and THF (5.0 mL) to afford 0.300 g of the desired product.