Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](NC(C)C)([CH3:3])[CH3:2].C([Li])CCC.[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[CH2:19][CH:18]([C:23]([O:25][CH3:26])=[O:24])[CH2:17]2.C(Br)C=C.Cl>O1CCCC1.CCOCC.CCCCCC>[CH2:3]([C:18]1([C:23]([O:25][CH3:26])=[O:24])[CH2:17][C:16]2[C:20](=[CH:21][CH:22]=[C:14]([Cl:13])[CH:15]=2)[CH2:19]1)[CH:1]=[CH2:2]
Reactant: CC(C)NC(C)C
Reactant: COC(=O)C1Cc2ccc(Cl)cc2C1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCC1(C(=O)OC)Cc2ccc(Cl)cc2C1
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
To 50 ml of anhydrous tetrahydrofuran (THF), was added 4.37 g of diisopropylamine. To the mixture was added 29 ml of a hexane solution of n-butyllithium at -60° to -50° C. under a nitrogen stream. To the resulting solution, was added a solution of 7.0 g of methyl 5-chloroindane-2-carboxylate in 10 ml of anhydrous THF at -70° to -60° C. over a period of 10 minutes. After stirring for 30 minutes at the same temperature, a solution of 5.23 g of allyl bromide in 10 ml of anhydrous THF was added dropwise at -70° to -50° C. over a period of 10 minutes. The mixture was further stirred for 24 hours at room temperature to complete the reaction. The reaction mixture was poured into a mixture of 5% aqueous hydrochloric acid solution and ice, and mixed with ether. After the ether layer was separated, the aqueous layer was extracted twice with ether. The ether layers were combined, washed with saturated aqueous sodium hydrogencarbonate solution, then with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain 8.32 g of the intended product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16]C2C=CC(C(N3CCC3)=O)=CC=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4].[CH2:29]([O:36][C:37](=[O:46])[C:38]1[CH:43]=[CH:42][C:41](Br)=[CH:40][C:39]=1[F:45])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.COC(C1C=C(O)C2CC(C)(C)OC=2C=1)=O>>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:41]2[CH:42]=[CH:43][C:38]([C:37]([O:36][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:46])=[C:39]([F:45])[CH:40]=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: O=C(OCc1ccccc1)c1ccc(Br)cc1F
Reactant: COC(=O)c1cc(Oc2ccc(C(=O)N3CCC3)cc2)c2c(c1)OC(C)(C)C2
Agent: COC(=O)c1cc(O)c2c(c1)OC(C)(C)C2
Product: COC(=O)c1cc(Oc2ccc(C(=O)OCc3ccccc3)c(F)c2)c2c(c1)OC(C)(C)C2

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 35b, from 4-bromo-2-fluoro-benzoic acid benzyl ester (65a) and 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e). 1H NMR (400 MHz, CDCl3) δ 7.96 (t, J=8.46 Hz, 1 H) 7.44-7.49 (m, 2 H) 7.32-7.43 (m, 3 H) 7.28 (s, 1 H) 7.25 (s, 1 H) 6.76 (dd, J=8.72, 2.40 Hz, 1 H) 6.68 (dd, J=111.75, 2.40 Hz, 1 H) 5.38 (s, 2 H) 3.88 (s, 3 H) 2.87 (s, 2 H) 1.48 (s, 6 H); LCMS for C26H23FO6 m/z 450.00 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([OH:18])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:20]1[C:24]2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN.C(O)C>ClCCl.CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([NH:20][CH3:24])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)Cc1ccccc1OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CNC(=O)Cc1ccccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 64.7 %

Procedure:
2-(2-Benzyloxyphenyl)acetic acid (15.0 g, 62 mmol) was dissolved in dichloromethane (270 ml) and N,N-dimethylformamide (70 ml). 1-Hydroxybenzotriazole (8.37 g, 62 mmol) was added. The solution was cooled to 0° C. N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (11.89 g, 62 mmol) was added. The reaction mixture was stirred for 20 min. A 8.0 M solution of methylamine in ethanol (38.8 ml, 310 mmol) was added. The solution was stirred for 16 h, while it was warming up to room temperature. It was diluted with ethyl acetate (500 ml) and washed with a 10% aqueous solution of sodium hydrogen sulfate solution (500 ml). The aqueous phase was extracted with ethyl acetate (2×300 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogen carbonate (400 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The remaining crystalls were washed with a mixture of ethyl acetate/heptane 1:4 (100 ml). They were dried in vacuo. They were dissolved in ethyl acetate. The solution was washed with a saturated aqueous solution of sodium hydrogen carbonate (2×500 ml) and dried over magnesium sulfate. The solvent was removed in vacuo to give 10.24 g of 2-(2-benzyloxyphenyl)-N-methylacetamide.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16]([O:18][CH2:19]C)=[O:17])=[C:5]2[C@@H:4]2[CH2:21][CH2:22][CH2:23][N:3]12.[C-]#N.[K+]>CO>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:5]2[C@@H:4]2[CH2:21][CH2:22][CH2:23][N:3]12
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1ccccc1-2
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Product: COC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1ccccc1-2

Procedure:
A mixture of 311 mg (1 mmol) of ethyl (S)-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate, 66 mg of potassium cyanide and 10 ml of absolute methanol is heated to boiling under reflux for 6 hours. The mixture is concentrated, a small amount of water is added, the mixture is extracted three times with 10 ml of chloroform each time, dried over magnesium sulphate, evaporated and recrystallised from ethyl acetate/hexane. There is obtained methyl (S)-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 165°-167° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([O:7][CH2:8][C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH:18]3[CH2:27][CH2:26][C:21]4(OCC[O:22]4)[CH2:20][CH2:19]3)[C:13](=[O:28])[C@@H:12]2[CH2:29][O:30][CH3:31])=[O:10])=[CH:4][CH:3]=1>C(O)(=O)C.O>[Cl:1][C:2]1[S:6][C:5]([O:7][CH2:8][C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH:18]3[CH2:27][CH2:26][C:21](=[O:22])[CH2:20][CH2:19]3)[C:13](=[O:28])[C@@H:12]2[CH2:29][O:30][CH3:31])=[O:10])=[CH:4][CH:3]=1
Reactant: COC[C@H]1C(=O)N(CC2CCC3(CC2)OCCO3)CCN1C(=O)COc1ccc(Cl)s1
Solvent: CC(=O)O
Solvent: O
Product: COC[C@H]1C(=O)N(CC2CCC(=O)CC2)CCN1C(=O)COc1ccc(Cl)s1
Temperature: 65 °C
Yield: 94.8 %

Procedure:
4-[(5-Chloro-thiophen-2-yloxy)-acetyl]-1-(1,4-dioxa-spiro[4.5]dec-8-ylmethyl)-3-(S)-methoxymethyl-piperazin-2-one (2.8 g, 5.9 mmol) is placed in 80:20 acetic acid/water and heated at 65° C. for 0.2 h. The mixture is evaporated and is diluted with ethyl acetate (200 mL). The organic phase is washed with 1 N NaOH, is dried (MgSO4) and is evaporated to provide the intermediate title compound as a clear colorless oil (2.4 g, 95%). MS (ES), 429 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][O:8][CH2:9]2)=[CH:4][CH:3]=1.C([Li])(C)(C)C.[I:17]I>O1CCCC1>[I:17][C:4]1[CH:3]=[CH:2][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][O:8][CH2:9]2
Reactant: II
Reactant: Brc1ccc2c(c1)COCC2
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Ic1cccc2c1CCOC2
Reaction time: 0.02 h

Procedure:
A solution of 7-bromoisochroman (6.6 g; 30.98 mmmol) in THF (100 ml) was cooled to -78° C. and treated with 2.1 eq of tert-butyllithium (40 ml of a 1.7M solution). After stirring the dark red solution for one minute, iodine (8.64 g; 34.08 mmol) was added as a tetrahydrofuran (THF) solution (50 ml). The reaction mixture was stirred for 30 minutes at -78° C. and one hour at room temperature (about 24° C.). The reaction was quenched with saturated aqueous ammonium chloride, and the organic phase was washed with aqueous sodium thiosulfate and brine, dried, and freed of solvent. The crude product was recrystallized from hexane to provide the pure 5-iodoisochroman as a white crystalline solid, mp=54°-56° C. (4.1 g; 51%). 1H NMR (CDCl3): 2.79 (t, 2H); 3.94 (t,2H); 4.70 (s,2H); 6.85 (d, 1H); 7.32 (s, 1H); 7.46 (d, 1H). IR (nujol): 2931, 2852, 1550, 1252, 1190, 1105, 1005, 987 cm-1.
Reaction SMILES: [C:1]([O:5]C)(=[O:4])[CH2:2][SH:3].[CH3:7][C:8]([C:11]1[CH:16]=[C:15]([S:17][C@@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]2O)[CH:14]=[C:13]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:12]=1[OH:29])([CH3:10])[CH3:9].FC(F)(F)C(O)=O.[OH-].[K+].O.[OH-].[Li+]>C(Cl)Cl.O.CO>[CH3:10][C:8]([C:11]1[CH:16]=[C:15]([S:17][C@@H:18]2[CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]2[S:3][CH2:2][C:1]([OH:5])=[O:4])[CH:14]=[C:13]([C:25]([CH3:26])([CH3:27])[CH3:28])[C:12]=1[OH:29])([CH3:7])[CH3:9]
Reactant: CC(C)(C)c1cc(S[C@@H]2CCCC[C@H]2O)cc(C(C)(C)C)c1O
Reactant: COC(=O)CS
Agent: [K+]
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1cc(S[C@@H]2CCCC[C@H]2SCC(=O)O)cc(C(C)(C)C)c1O
Reaction time: 0.25 h

Procedure:
Methyl thioglycolate (4.8 g, 0.0448 mole) was added to a solution of the compound of Example 15 (15.0 g, 0.0448 moles) in methylene chloride (20 ml). After stirring for 15 minutes, trifluoroacetic acid (18 ml) was added to the reaction mixture. The reaction mixture was stirred for 64 hours and then poured into methyl alcohol (100 ml) containing potassium hydroxide (13g, 0.23 moles) and lithium hydroxide hydrate (9.7 g, 0.23 moles). Over the next 3 hours water was added to bring the final volume to 300 ml. The solution was washed twice with 150 ml of ethyl acetate. The aqueous layer was made acidic to pH 2 with concentrated hydrochloric acid. The reaction mixture was extracted twice with 200 ml of ethyl acetate. The combined ethyl acetate extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give the product as an oil. The product was purified by silica gel chromatography. The resulting oil was heated at 65° C. under vacuum to remove a trace amount of ethyl acetate. The structure assignment was supported-by NMR, infrared spectroscopy, and elemental analysis.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:41]#[N:42])=[C:12]([C:14]2[C:19]([O:20][CH3:21])=[CH:18][N:17]([CH:22]([CH2:38][CH3:39])[C:23]([NH:25][C:26]3[CH:35]=[C:34]([F:36])[C:29]([C:30]([O:32]C)=[O:31])=[C:28]([F:37])[CH:27]=3)=[O:24])[C:16](=[O:40])[CH:15]=2)[CH:13]=1>CO.O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:41]#[N:42])=[C:12]([C:14]2[C:19]([O:20][CH3:21])=[CH:18][N:17]([CH:22]([CH2:38][CH3:39])[C:23]([NH:25][C:26]3[CH:35]=[C:34]([F:36])[C:29]([C:30]([OH:32])=[O:31])=[C:28]([F:37])[CH:27]=3)=[O:24])[C:16](=[O:40])[CH:15]=2)[CH:13]=1
Reactant: CCC(C(=O)Nc1cc(F)c(C(=O)OC)c(F)c1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CO
Product: CCC(C(=O)Nc1cc(F)c(C(=O)O)c(F)c1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
67 mg (0.20 mmol, 2 eq.) of caesium carbonate were added to a solution of 53 mg (0.10 mmol) of methyl 4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)-2,6-difluorobenzoate (racemate) in 1.25 ml of a mixture of methanol/water (4/1), and the resulting suspension was stirred at 60° C. for 1 h. Methanol was removed at 30° C. under reduced pressure. The reaction mixture was cooled to RT and adjusted to pH 3 using aqueous hydrochloric acid (1N). The aqueous phase was extracted with ethyl acetate. The combined organic phases were dried (sodium sulphate), filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (water/acetonitrile/0.1% formic acid gradient). Yield: 11 mg (21% of theory)
Reaction SMILES: [F:1][C:2]1[C:10]2[S:9][C:8]([C:11](=O)[CH2:12][C:13](=O)[CH:14]([F:16])[F:15])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([NH:30][NH2:31])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>>[F:1][C:2]1[C:10]2[S:9][C:8]([C:11]3[N:30]([C:27]4[CH:26]=[CH:25][C:24]([S:21]([CH3:20])(=[O:23])=[O:22])=[CH:29][CH:28]=4)[N:31]=[C:13]([CH:14]([F:16])[F:15])[CH:12]=3)=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(NN)cc1
Reactant: O=C(CC(=O)C(F)F)c1nc2cccc(F)c2s1
Agent: Cl
Product: CS(=O)(=O)c1ccc(-n2nc(C(F)F)cc2-c2nc3cccc(F)c3s2)cc1
Yield: 63 %

Procedure:
The procedure of Example 9 was repeated using 1-(7-fluorobenzothiazol-2-yl)-4,4-difluorobutane-1,3-dione and 4-methylsulfonylphenylhydrazine hydrochloride as the starting materials to obtain 7-fluoro-2-[1-(4-methylsulfonylphenyl)-3-difluoromethyl-1H-pyrazol-5-yl]benzothiazole (yield, 63%). NMR(CDCl3) δ: 3.11 (3H, s), 6.81 (1H, t, J=54.8 Hz), 7.09 (1H, app t, J=8.6 Hz), 7.24 (1H, s), 7.48 (1H, dt, J=5.4 Hz, 8.0 Hz), 7.72-7.75 (3H, m), 8.03-8.07 (2H, m); mp 193-195° C. (methanol)
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:10]=[CH:11][CH:12]=1.[N-:20]=[N+:21]=[N-:22].[Na+].[Cl-].[NH4+]>C(O)C>[N:20]([CH2:3][CH:2]([OH:1])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:8]=1)=[N+:21]=[N-:22]
Reactant: c1cc(CN2CCCCC2)cc(OCCC2CO2)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Product: [N-]=[N+]=NCC(O)CCOc1cccc(CN2CCCCC2)c1
Yield: 101 %

Procedure:
A solution of 1-[[3-(2-oxiranylethoxy]phenyl]methyl]piperidine (17 g), sodium azide (5.1 g) and ammonium chloride 2.73 g) in 25% aqueous ethanol (200 ml) was refluxed for 6 h and concentrated to ca. 130 ml. The concentrate was diluted with water (50 ml), saturated with potassium carbonate and extracted with isopropanol. The extract was dried and evaporated to give an oil (20 g) which was chromatographed on silica using dichloromethane:ethanol:ammonia (200:8:1) to give the title compound (10.5 g) as a colourless oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]([NH:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=O)C.[CH:27]1([NH2:30])[CH2:29][CH2:28]1>>[CH:27]1([NH:30][C:4]([C:6]2[N:7]=[N:8][C:9]([NH:12][CH2:13][C:14]3[C:15]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)=[N:16][O:17][C:18]=3[CH3:19])=[CH:10][CH:11]=2)=[O:3])[CH2:29][CH2:28]1
Reactant: NC1CC1
Reactant: CCOC(=O)c1ccc(NCc2c(-c3ccc(F)cc3)noc2C)nn1
Product: Cc1onc(-c2ccc(F)cc2)c1CNc1ccc(C(=O)NC2CC2)nn1
Yield: 66 %

Procedure:
As described for example 81, 6-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-pyridazine-3-carboxylic acid ethyl ester (89 mg, 0.25 mmol) was converted, using cyclopropylamine instead of aminomethylcyclopropane, to the title compound (61 mg, 66%) which was obtained as a white foam. MS: m/e=368.1 [M+H]+.
Reaction SMILES: [OH-].[K+].[CH3:3]C1C=CC(S(N(N=O)C)(=O)=O)=CC=1.C(O)CO.CCOCC.[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([C:40]4[CH:45]=[C:44]([F:46])[CH:43]=[C:42]([F:47])[C:41]=4[F:48])[C:38]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)=[C:37]([OH:55])[C:36]3=[O:56])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1>CO.O>[NH:28]1[C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH:39]([C:40]4[CH:45]=[C:44]([F:46])[CH:43]=[C:42]([F:47])[C:41]=4[F:48])[C:38]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)=[C:37]([O:55][CH3:3])[C:36]3=[O:56])=[CH:31][C:30]=2[N:26]=[CH:27]1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Reactant: O=C1C(O)=C(c2ccccc2)C(c2cc(F)cc(F)c2F)N1c1ccc2nc[nH]c2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Solvent: CO
Product: COC1=C(c2ccccc2)C(c2cc(F)cc(F)c2F)N(c2ccc3[nH]cnc3c2)C1=O

Procedure:
The compound was synthesized starting from KOH (10 eq in water), diazald (5 eq), ethylene glycol/Et2O (3/1 v/v), 1-(1H-benzo[d]imidazol-6-yl)-5-(2,3,5-trifluorophenyl)-3-hydroxy-4-phenyl-1H-pyrrol-2(5H)-one (0.230 g, 0.5 mmol, 1 eq) and MeOH/H2O (90/10 v/v); yield: 0.015 g (6.9%); MS m/z: 436.4 [M+H]+; 1H-NMR: (400 MHz, DMSO-D6) δ: 4.11 (s, 1H), 6.94 (s, 1H), 7.22-7.42 (m, 6H), 7.58-7.68 (m, 3H), 7.73-7.76 (m, 1H), 7.95 (s, 1H), 9.07 (s, 1H); HPLC (METHOD [A]): rt 15.38 min (82%)
Reaction SMILES: Cl.Cl.Cl.[C:4]([C:7]1[CH:31]=[CH:30][C:10]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH:20]([O:22][C:23]3[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=3)[CH3:21])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)([OH:6])=[O:5].[C:32](OC(=O)C)(=[O:34])[CH3:33]>>[C:4]([C:7]1[CH:8]=[CH:9][C:10]([CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH:20]([O:22][C:23]3[CH:24]=[CH:25][C:26]([NH:29][C:32]([CH3:33])=[O:34])=[CH:27][CH:28]=3)[CH3:21])[CH2:17][CH2:18]2)=[CH:30][CH:31]=1)([OH:6])=[O:5]
Reactant: CC(=O)OC(C)=O
Reactant: CC(CN1CCN(CCc2ccc(C(=O)O)cc2)CC1)Oc1ccc(N)cc1
Agent: Cl
Product: CC(=O)Nc1ccc(OC(C)CN2CCN(CCc3ccc(C(=O)O)cc3)CC2)cc1

Procedure:
A mixture of 9.3 g. (18.9 mmole) 1-(4-carboxyphenethyl)-4-[2-(4-aminophenoxy)-propyl]-piperazine trihydrochloride and 50 ml. acetic anhydride is kept for 2 hours at 100° C. and then cooled. The precipitate obtained is filtered off with suction and recrystallised from acetic acid. There are obtained 8.2 g. (87% of theory) of the desired compound in the form of a dihydrochloride; m.p. 234°-235° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][C@H:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[O:6].[CH3:16][Mg]Br>C(OCC)C>[OH:6][CH:5]([C@@H:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH:2]([CH3:15])[CH3:1])[CH3:16]
Reactant: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Reactant: C[Mg]Br
Solvent: CCOCC
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(C)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.5 %

Procedure:
A solution of (S)-tert-butyl (4-methyl-1-oxopentan-2-yl)carbamate (1.3 g, 6.04 mmol) in diethyl ether (50 mL) was cooled to −78° C. and treated with methyl magnesium bromide (1.4 M in diethyl ether) (8.63 mL, 12.08 mmol). The slurry was stirred at 0° C. for 1 h and then stirred for an additional hour at RT. The reaction mixture was quenched with NH4Cl. The reaction mixture was extracted with diethyl ether (3×100 mL). The combined organic layers were washed with brine, dried over MgSO4, and concentrated to afford the product, tert-butyl ((3S)-2-hydroxy-5-methylhexan-3-yl)carbamate (1 g, 4.32 mmol, 72% crude yield) as colorless oil. The material was carried on without further purification. 1H NMR (300 MHz, DMSO-d6): δ 0.78-0.93 (m, 6H), 0.98 (d, 3H), 1.11-1.41 (m, 2H), 1.42 (s, 9H), 1.45-1.64 (m, 1H), 3.30-3.63 (m, 2H), 4.37 (d, 1H), 6.19 (d, 1H).
Reaction SMILES: [CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].[C:29]([OH:39])(=[O:38])[CH:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[OH:31]>C(O)(C)C>[CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].[C:29]([O-:39])(=[O:38])[CH:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[OH:31]
Reactant: O=C(O)C(O)c1ccccc1
Agent: N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Solvent: CC(C)O
Product: O=C([O-])C(O)c1ccccc1
Temperature: 80 °C
Reaction time: 21.5 h

Procedure:
Sitagliptin (4 g) and isopropanol (60 mL) are charged into a round-bottom flask and the mixture is heated to about 80° C. for about 30 minutes to obtain a clear dissolution. Mandelic acid (1.49 g) is added and the reaction mixture is refluxed for about 1.5 hours. The reaction mixture is cooled to about 30° C. and stirred for about 21.5 hours. The separated solid is filtered, washed with isopropanol (4 mL), and dried under reduced pressure at about 45° C. for about 2 hours to afford the title compound. (Yield: 4.4 g; MC: 0.51% w/w; HPLC purity: 99.56%)
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].S(Cl)(Cl)=O.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][C:27]3[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=3[N:29]=2)=[C:21]([O:34][CH3:35])[CH:20]=1.CCN(C(C)C)C(C)C>C1COCC1>[S:26]1[C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=[C:25]1[C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)=[CH:20][C:21]=1[O:34][CH3:35]
Reactant: COc1cc(N)ccc1-c1nc2ccccc2s1
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: COc1cc(NC(=O)c2ccc(F)c([N+](=O)[O-])c2)ccc1-c1nc2ccccc2s1
Temperature: 25 °C
Yield: 73.8 %

Procedure:
A mixture of 4-fluoro-3-nitrobenzoic acid (0.062 g, 0.336 mmol) and thionyl chloride (5 ml) was heated under reflux for 2 h. The reaction mixture was cooled to room temperature and the excess reagent was removed under reduced pressure to give the crude acid chloride. The amide was prepared as described in the Amide Coupling section using the crude acid chloride, 2-(4-amino-2-methoxyphenyl)benzothiazole (0.086 g, 0.336 mmol) and Hunig's base (0.052 g, 0.403 mmol) in dry THF (5 ml) to give the title compound (0.105 g, 74%) as a pale yellow solid after work-up.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][N:20]1[C:26](=[O:27])[CH:25]([C:28](=[O:32])[CH2:29][O:30][CH3:31])[C:24]2[CH:33]=[CH:34][CH:35]=[CH:36][C:23]=2[C:22]2[CH:37]=[CH:38][CH:39]=[CH:40][C:21]1=2>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][N:20]2[C:26](=[O:27])[CH:25]([C:28](=[O:32])[CH2:29][O:30][CH3:31])[C:24]3[CH:33]=[CH:34][CH:35]=[CH:36][C:23]=3[C:22]3[CH:37]=[CH:38][CH:39]=[CH:40][C:21]2=3)=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COCC(=O)C1C(=O)N(N)c2ccccc2-c2ccccc21
Agent: Cl
Product: COCC(=O)C1C(=O)N(NC(=O)[C@H](C)NC(=O)Cc2cc(F)cc(F)c2)c2ccccc2-c2ccccc21

Procedure:
Following General Procedure D and using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 5-amino-7-(methoxyacetyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (Example 7-G), the title compound was prepared as a colorless solid. The product was purified by flash chromatography.
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([C:7]1([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20]C)[CH:15]=2)[CH2:13][CH2:12][CH2:11][CH2:10][NH:9][CH2:8]1)[CH3:6]>C(Cl)Cl>[CH2:5]([C:7]1([C:14]2[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=2)[CH2:13][CH2:12][CH2:11][CH2:10][NH:9][CH2:8]1)[CH3:6]
Reactant: CCC1(c2cccc(OC)c2)CCCCNC1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCC1(c2cccc(O)c2)CCCCNC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A 1M solution of BBr3(2.56 mL, 2.56 mmol) in CH2Cl2 was added to 3-ethyl-3-(3-methoxy-phenyl)-azepane (as described in Step I above) (0.300 g, 0.1.28 mmol) dissolved in anhydrous CH2Cl2 (10 mL) at −78° C. After 20 h of stirring at room temperature, the reaction was quenched with sat. NaHCO3 solution, extracted with CH2Cl2 (3×), dried (MgSO4) and concentrated to give the title compound.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17](O)=[O:18])=[CH:12][CH:11]=1.B(F)(F)F.CCOCC.C([O-])(=O)C.[Na+]>>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([C:6]2[CH:7]=[CH:8][C:1]([OH:2])=[CH:3][C:4]=2[OH:5])=[O:18])=[CH:12][CH:11]=1
Reactant: Oc1cccc(O)c1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: FB(F)F
Agent: [Na+]
Solvent: CCOCC
Product: O=C(Cc1ccc(Cl)cc1)c1ccc(O)cc1O
Temperature: 85 °C
Reaction time: 1.75 h

Procedure:
A mixture of resorcinol (100 g, 0.908 mol), 4-chlorophenylacetic acid (170 g, 0.999 mol) and boron trifluoride etherate is stirred mechanically at 85° C. for 1.75 h. The dark red-brown reaction mixture is allowed to cool to room temperature and then poured slowly into aqueous sodium acetate (1 l, 30% w/v). The suspension is stirred overnight at room temperature. The orange brown precipitate is removed by filtration, dried in vacuo and then triturated with isopropyl ether/hexane (1:9) to give a yellow solid. This solid is washed with hexane and dried in vacuo to provide the title compound. A further three crops of material are obtained from the sodium acetate work-up mixture.