Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:12][CH2:13][OH:14])=[CH:5][CH:4]=1.[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:12][CH2:13][O:14][S:16]([CH3:15])(=[O:18])=[O:17])=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc2c(c1)C(CCO)CC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2c(c1)C(CCOS(C)(=O)=O)CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5.0 g (26.0 mmol) of crude 2-(6-methoxyindan-1-yl)ethanol are dissolved in 50 ml of dichloromethane and, while cooling with ice, 3.6 g (31 mmol) of methanesulphonic acid chloride and 3.1 g (31 mmol) of triethylamine are added dropwise. The mixture is stirred at room temperature for 3 hours, the triethyl-ammonium chloride which has precipitated is filtered off and the filtrate is extracted by shaking with ice-water. The organic phases are washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation at 40° under reduced pressure. Methanesulphonic acid 2-(6-methoxyindan-1-yl)ethyl ester is obtained which can be used without further purification.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:7]([CH:9]1[O:11][CH2:10]1)Cl>>[C:1]([O:6][CH2:7][CH:9]1[O:11][CH2:10]1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)O
Reactant: ClCC1CO1
Product: C=C(C)C(=O)OCC1CO1
Temperature: 25 °C
Reaction time: 36 h
Yield: 73 %

Procedure:
Methacrylic acid (34.4 g, 0.4 mole) was dissolved in 50 g (0.63 mole) of pyridine anhydride. The exothermic reaction was cooled by placing the reaction vessel in a liquid nitrogen-isopropyl alcohol bath. Thereafter, 50.8 g (0.55 mole) of epichlorohydrin was added dropwise. The cooling bath was removed, and the reaction mixture was stirred at room temperature for over 36 hours. The reaction was monitored using TLC. The reaction mixture was transferred to a separatory funnel, neutralized using 1 N aqueous sulfuric acid solution, and extracted with dichloromethane. The organic layer was washed with deionized water, concentrated under reduced pressure, and purified by distillation under reduced pressure to provide the product (yield 73%).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].CS(O)(=O)=O.[C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[S:21][C:22]([C:26]([NH:28][C@H:29]([CH3:46])[C@:30]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:39]=3[F:45])([OH:37])[CH2:31][N:32]3[CH:36]=[N:35][CH:34]=[N:33]3)=[O:27])=[C:23]([CH3:25])[N:24]=2)=[CH:16][CH:15]=1)#[N:13].Cl.[NH2:48][OH:49]>O.C1COCC1>[F:45][C:39]1[CH:40]=[C:41]([F:44])[CH:42]=[CH:43][C:38]=1[C@@:30]([OH:37])([CH2:31][N:32]1[CH:36]=[N:35][CH:34]=[N:33]1)[C@H:29]([NH:28][C:26]([C:22]1[S:21][C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:12]([NH:48][OH:49])=[NH:13])=[CH:15][CH:16]=2)=[N:24][C:23]=1[CH3:25])=[O:27])[CH3:46]
Reactant: Cc1nc(-c2ccc(C#N)cc2)sc1C(=O)N[C@H](C)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: NO
Agent: CS(=O)(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(=N)NO)cc2)sc1C(=O)N[C@H](C)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Na2CO3 (0.72 g, 6.77 mmol) in a mixture of H2O (5 mL) and THF (5 mL) was added (1R,2R)-2-(4-cyanophenyl)-N-[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1 -yl)propyl]-4-methyl-thiazole-5-carboxamide methanesulfonate (0.5 g, 0.84 mmol, obtained in example 31) and hydroxylamine hydrochloride (0.29 g, 4.23 mmol). The reaction mixture was stirred at room temperature overnight, and was then concentrated and the aqueous residue extracted with CHCl3. The organic phase was separated, dried over Na2SO4, filtered and the filtrate was concentrated to a solid. Purification by flash chromatography afforded the title compound as a pale yellow solid: mp 135°-148° C.; 1H NMR (300 MHz, MeOH--d4) δ (MeOH--d4) 8.24 (s, 1H, triazole), 8.03 (dt, Jt =1.6, Jd =8.5, 2H, arom), 7.78 (dt, Jt =1.6, Jd =8.5, 2H, arom), 7.71 (s, 1H, triazole), 7.38 (dt, Jd =6.5, Jt =8.8, 1H, arom), 6.97 (ddd, J=2.4, J=8.7, J=11.5, 1H, arom), 6.84 (dt, Jd =2.1, Jt =8.0, 1H, arom), 5.00 (q, J=7, 1H, CHMe), 4.99 (d, J=14.3, 1H, TrCH(H)), 4.58 (d, J=14.3, 1H, TrCH(H)), 2.74 (s, 3H, thiazole-Me), 1.05 (d, J=7, 3H, MeCH); MS 496 (M+ -NH2); [α]D =-77.2° (c 1, MeOH). Analysis calculated for C24H23F2N7O3S.H2O: C 52.84; H 4.62; N 17.97; S 5.88 Found: C 53.48; H 4.61; N 17.19; S 5.34.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[Br:16].C[Si]([N:21]=[N+:22]=[N-:23])(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CCOC(C)=O>[Br:16][C:3]1[CH:4]=[C:5]([C:8]2([C:14]3[N:21]=[N:22][NH:23][N:15]=3)[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: N#CC1(c2ccc(N)c(Br)c2)CCOCC1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Product: Nc1ccc(C2(c3nn[nH]n3)CCOCC2)cc1Br
Temperature: 120 °C
Reaction time: 18 h
Yield: 91 %

Procedure:
A mixture of 4-(4-amino-3-bromo-phenyl)-tetrahydro-pyran-4-carbonitrile (as prepared in the previous step, 141 mg, 0.500 mmol), trimethylsilylazide (133 μL, 1.00 mmol) and tetrabutylammonium fluoride (65 mg, 0.25 mmol) was stirred at 120° C. for 18 h under Ar. After cooling to RT, the mixture was treated with 30 mL of EtOAc and washed with H2O (2×10 mL), 15% citric acid aqueous solution (3×10 mL) and brine (10 mL). After drying over Na2SO4, the organic layer was concentrated in vacuo to afford the title compound (147 mg, 91%) as a faint yellow solid. Mass spectrum (ESI, m/z): Calcd. for C12H14BrN5O, 324.0 (M+H). found 324.1.
Reaction SMILES: C[O:2][C:3]1[C:4]([C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:16])=[CH:5][CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br>ClCCl.[OH-].[Na+]>[Cl:15][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:16])[C:9]=1[C:4]1[C:3]([OH:2])=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1ccccc1-c1c(Cl)cccc1Cl
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Oc1ccccc1-c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 90.7 %

Procedure:
To a solution of 2′,6′-dichloro-1,1′-biphenyl-2-yl methyl ether (5.83 g, 0.023 mol) in anhydrous dichloromethane (100 mL) at 0° C. under nitrogen was added a solution of boron tribromide (1.0 M in dichloromethane, 27.6 mL, 0.0276 mol) dropwise over 40 minutes via a syringe pump. The reaction mixture was then stirred at room temperature for 17 hours, then quenched by the addition of absolute ethanol (50 mL). The mixture was stirred at room temperature for 1.5 hours then concentrated under reduced pressure to afford a dark oil. The oil was dissolved in 2.0 M aqueous sodium hydroxide solution (200 mL) and the resulting milky suspension extracted with diethyl ether (200 mL). The separated aqueous phase was then cooled to 0° C. and acidified to pH 1 by the addition of concentrated hydrochloric acid. The resulting milky suspension was extracted with ethyl acetate (300 mL), the separated organic phase washed with water (200 mL) and saturated brine (200 mL), dried over magnesium sulfate and concentrated under reduced pressure to afford a yellow oil. Purification by flash chromatography using a solvent gradient of 3 to 15% ethyl acetate in hexane gave 4.99 g (91%) of 2′,6′-dichloro-1,1′-biphenyl-2-ol as a white solid. MS (EI) m/z 238 (M+).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[Cl:43][C:44]1[CH:54]=[CH:53][C:47]([CH:48]=[CH:49][C:50](O)=[O:51])=[CH:46][CH:45]=1>>[C:9]([C:8]1[CH:7]=[C:6]([CH:13]=[CH:12][CH:11]=1)[O:5][CH2:4][CH2:3][NH:2][C:50](=[O:51])/[CH:49]=[CH:48]/[C:47]1[CH:53]=[CH:54][C:44]([Cl:43])=[CH:45][CH:46]=1)#[N:10]
Reactant: N#Cc1cccc(OCCN)c1
Reactant: O=C(O)C=Cc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: N#Cc1cccc(OCCNC(=O)/C=C/c2ccc(Cl)cc2)c1

Procedure:
109 mg (0.55 mmol) of 3-(2-aminoethoxy)benzonitrile hydrochloride, 85 mg (0.55 mmol) of 1-hydroxybenzotriazole (hydrate), 105 mg (0.55 mmol) of 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride, 61 mg (0.6 mmol) of triethylamine, and 100 mg (0.55 mmol) of p-chloro-cinnamic acid were used, and the title compound was obtained in the same manner as in step 1 in Example 211.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+](N[C:20]1[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)=[CH:22][N:21]=1)([O-])=O>N1C=CC=CC=1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:20]2[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)=[CH:22][N:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1[nH]c(N[N+](=O)[O-])ncc1Cc1cccnc1
Reactant: OCCCCCCCCc1ccccc1
Solvent: c1ccncc1
Product: O=c1[nH]c(OCCCCCCCCc2ccccc2)ncc1Cc1cccnc1

Procedure:
A mixture of 8-phenyl-1-octanol (1.5 g), 2-nitroamino-5-(pyrid-3-ylmethyl)pyrimidin-4-one (1.0 g) and pyridine (5 ml) was stirred at reflux for 24 hours, then the pyridine was removed by evaporation. Water was added, and the product extracted into dichloromethane, which was dried and evaporated. The residue was purified by chromatography (silica, 0-5% methanol in dichloromethane) and recrystallisation from ether to give 2-(8-phenyloct-1-yl)oxy-5-(pyrid-3-ylmethyl)pyrimidin-4-one as a pale buff solid (0.1 g). MPt 53-55° C.; 1H-NMR (CDCl3) δ 1.32 (8H, m), 1.60 (2H, m), 1.74 (2H, m), 2.58 (2H, t), 3.72 (2H, t), 4.31 (2H, t), 7.1-7.3 (6H, m), 7.54 (1H, m), 7.63 (1H, m), 8.45 (1H, m) and 8.55 (1H, d); MS (EI) Found M=391; C24H29N3O2 requires 391.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:32]([O:36][CH3:37])(=[O:35])[CH:33]=[CH2:34].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:37][O:36][C:32](=[O:35])/[CH:33]=[CH:34]/[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Br)cc1)C1CC1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1ccc(C(=O)C2CC2)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 47.1 %

Procedure:
A mixture of (4-bromophenyl)-(cyclopropyl)methanone (0.450 g, 2.00 mmol), palladium acetate 49 mg, 0.220 mmol), triphenylphosphine (55 mg, 0.21 mmol), methyl acrylate (0.43 g, 2.50 mmol) and triethylamine (10 ml, 72 mmol) was heated to 100° C. for 48 in a closed reaction vial. The reaction mixture was cooled to room temperature. The solid was removed by filtration. A mixture of ice and 1 N hydrochloric acid was added to the liquid. The mixture was stirred for 1 h at room temperature. It was extracted with ethyl acetate (2×150 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate (100 ml) and dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (40 g) using a mixture of dichloromethane/ethyl acetate/heptane (1:1:1) as eluent, to give 217 mg of (E)-3-(4-(cyclopropanecarbonyl)phenyl)acrylic acid methyl ester.
Reaction SMILES: [CH3:1][N:2]([C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:20][CH:21]=[CH:22][N:23]=1)=[CH:15]2)[C:3]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)=O.B.O1CCCC1.CO>O1CCCC1>[CH3:1][N:2]([CH2:3][C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:20][CH:21]=[CH:22][N:23]=1)=[CH:15]2
Reactant: CN(C(=O)c1cccs1)c1cccc2cc(-c3nccs3)[nH]c12
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: CN(Cc1cccs1)c1cccc2cc(-c3nccs3)[nH]c12
Temperature: 25 °C
Yield: 38.2 %

Procedure:
To a solution of N-methyl-N-[2-(1,3-thiazol-2-yl)-1H-indol-7-yl]thiophene-2-carboxamide (150 mg) in tetrahydrofuran (10 mL) was added borane-tetrahydrofuran complex (1.0 M tetrahydrofuran solution, 10 mL). The reaction mixture was stirred with heating under reflux for 1 hr. The reaction mixture was cooled to room temperature, and methanol (5 mL) was added. The reaction mixture was stirred with heating under reflux for 1 hr, and the reaction mixture was concentrated. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:3) to give the title compound (55 mg, yield 38%) as a yellow oil. M+1=326.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([C:5]1[S:6][C:7]2[CH:14]=[CH:13][C:12]3[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:11]=3[C:10](=[O:20])[C:8]=2[N:9]=1)[CH3:4]>ClCCl.C(O)C>[CH2:3]([C:5]1[S:6][C:7]2[CH:14]=[CH:13][C:12]3[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:11]=3[CH:10]([OH:20])[C:8]=2[N:9]=1)[CH3:4]
Reactant: CCc1nc2c(=O)c3ccc(C)cc3ccc2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CCc1nc2c(s1)C=Cc1cc(C)ccc1C2O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Sodium borohydride (78 mg) was added to a stirred solution of the product from step (ii) (0.87 g) in dichloromethane (4 ml) and ethanol (16 ml) at 5° C. The reaction mixture was stirred for 2.5 h, warmed to room temperature and left for 2 h before a further 200 mg of sodium borohydride was added. The reaction mixture was quenched with 1M sodium hydroxide solution then partitioned between dichloromethane and water. The organic phase was washed with water, dried (MgSO4) and evaporated under reduced pressure.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[NH:6][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[C:13](=[O:15])[CH:14]=1)[CH3:4].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([B:24]([OH:26])[OH:25])=[CH:20][CH:19]=1.O>CN(C=O)C>[CH2:3]([C:5]1[CH:14]=[C:13]([O:15][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([B:24]([OH:26])[OH:25])=[CH:20][CH:19]=2)[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[N:6]=1)[CH3:4]
Reactant: OB(O)c1ccc(CBr)cc1
Reactant: CCc1cc(=O)c2c([nH]1)CCCC2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cc(OCc2ccc(B(O)O)cc2)c2c(n1)CCCC2
Reaction time: 40 h
Yield: 99.3 %

Procedure:
Sodium hydride (60% dispersion in oil; 180 mg) was added to a mixture of 2-ethyl-5,6,7,8-tetrahydro-4(1H)-quinolone (660 mg) and 4-bromomethylphenylboronic acid (800 mg) (obtained as described in J. Amer. Chem. Soc. 1958, 80, 835) in DMF (12 ml) under an atmosphere of argon. The mixture was stirred for 40 hours and then water (0.2 ml) was added. Volatile material was removed by evaporation and the residue was dissolved in warm 0.5M sodium hydroxide solution (10 ml). Insoluble material was removed by filtration and the filtrate was acidified to pH 4 with 20% citric acid solution. The precipitate solid was collected by filtration, washed with water (20 ml) and dried under high vacuum to give 4-[(2-ethyl-5,6,7,8-tetrahydroquinolin-4-yl)oxymethyl]phenylboronic acid (C) (1.15 g), m.p. 229°-231° C.; NMR (d6 -DMSO): 1.3(t,3H), 1.6-1.9(m,4H), 2.5-2.7(m,2H), 2.75-2.95(m,4H), 5.4(s,2H), 7.3(d,2H), 7.4(s,1H, 7.5(d,2H).
Reaction SMILES: Br[C:2]1[C:3]([O:18][CH2:19][CH:20]2[CH2:22][CH2:21]2)=[N:4][CH:5]=[C:6]([CH:17]=1)[C:7]([NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[OH:16])=[O:8].[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[F:30]>>[CH:20]1([CH2:19][O:18][C:3]2[C:2]([C:27]3[CH:26]=[CH:25][C:24]([F:23])=[C:29]([F:30])[CH:28]=3)=[CH:17][C:6]([C:7]([NH:9][C@@H:10]3[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]3[OH:16])=[O:8])=[CH:5][N:4]=2)[CH2:22][CH2:21]1
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(OCC2CC2)c(Br)c1
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(OCC2CC2)c(-c2ccc(F)c(F)c2)c1

Procedure:
The title compound was synthesized in analogy to the Suzuki reaction procedure described for the preparation of Example 5a, from 5-Bromo-6-cyclopropylmethoxy-N-(trans-2-hydroxy-cyclohexyl)-nicotinamide and 3,4-difluorophenylboronic acid (commercially available). MS (ISP): 403.4 (M+H)+.
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].[CH:29]1[C:34](/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38])=[CH:33][CH:32]=[C:31]([OH:40])[CH:30]=1>C(OCC)(=O)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:37]([O-:39])(=[O:38])/[CH:36]=[CH:35]/[C:34]1[CH:33]=[CH:32][C:31]([OH:40])=[CH:30][CH:29]=1
Reactant: O=C(O)/C=C/c1ccc(O)cc1
Agent: N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Solvent: CCOC(C)=O
Product: O=C([O-])/C=C/c1ccc(O)cc1
Reaction time: 2 h

Procedure:
Sitagliptin free base (2.0 gms) and coumaric acid (0.80 gms) were dissolved in ethyl acetate (32 ml) at 60° C. to 65° C. and the resultant reaction solution left for slow solvent evaporation at room temperature for 2 hours. Precipitated solids were filtered and dried at 50° C. to 55° C. for 6 hours to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:37]=[C:38]([CH3:40])[CH:39]=1)[C:5]([N:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:18][CH2:17][C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:19]([O:21]CC)=[O:20])[CH2:15][CH2:14]2)[CH2:9][C@@H:8]1[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:6]>[OH-].[Na+].O1CCOCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:37]=[C:38]([CH3:40])[CH:39]=1)[C:5]([N:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:18][CH2:17][C:16]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)([C:19]([OH:21])=[O:20])[CH2:15][CH2:14]2)[CH2:9][C@@H:8]1[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:6]
Reactant: CCOC(=O)C1(c2ccccc2)CCN([C@H]2CCN(C(=O)c3cc(C)cc(C)c3)[C@@H](Cc3ccccc3)C2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc(C)cc(C(=O)N2CC[C@H](N3CCC(C(=O)O)(c4ccccc4)CC3)C[C@@H]2Cc2ccccc2)c1
Yield: 38.8 %

Procedure:
A solution of (±)-ethyl cis-1-[1-(3,5dimethylbenzoyl)-2-(phenylmethyl)-4-piperidinyl]-4-phenyl-4-piperidinecarboxylate (2.96 g) in NaOH (20 ml) and dioxane (50 ml) was stirred and refluxed for 30 hours. The mixture was evaporated and HCl, (1N; 20 ml) was added. The precipitate was filtered off, water (100 ml) and CH2Cl2 (10 ml) were added and filtered again. The precipitate was taken up in water, heated, cooled, filtered off and dried. The product was purified by HPLC (eluent: ammoniumacetate and CH3CN). The pure fractions were collected, evaporated and dried, yielding 1.09 g (39%) of (±)-cis-1-[1-(3,5-dimethylbenzoyl)-2-(phenylmethyl)-4-piperidinyl]-4-phenyl-4-piperidinecarboxylic acid (compound 38, mp. 259.1° C.).
Reaction SMILES: C[CH2:2][CH:3]([OH:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:20]CCC(O)CCCCCCCCCCCCCC.CCCCC(O)CCCCCCCCCCCCC>>[CH3:2][CH:3]([OH:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:20]
Reactant: CCCCCCCCCCCCCCC(O)CCC
Reactant: CCCCCCCCCCCCCCCC(O)CC
Agent: CCCCCCCCCCCCCC(O)CCCC
Product: CCCCCCCCCCCCCCCCC(C)O

Procedure:
3-octadecanol; 4-octadecanol; 5-octadecanol;
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:8](OC)([O:9]C)[CH2:7][CH2:6][N:5]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:4]1.O.[OH-].[Na+].CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>Cl.O1CCOCC1>[CH3:1][O:2][CH:3]1[C:8](=[O:9])[CH2:7][CH2:6][N:5]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:4]1
Reactant: COC1CN(C(=O)OC(C)(C)C)CCC1(OC)OC
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC1CN(C(=O)OC(C)(C)C)CCC1=O
Reaction time: 8 h

Procedure:
To a solution of 1,1-dimethylethyl 3,4,4-tris(methyloxy)-1-piperidinecarboxylate D17 (4.85 g) in HCl/1,4-Dioxane (50 mL) was heated at 50° C. and stirred overnight. Water (50 ml) was added to the reaction mixture and the pH adjusted to 10.0 using sodium hydroxide. After that BOC anhydride (4.22 g, 19.4 mmol) was added to the reaction mixture and stirred for 4 hours. The resulting mixture was extracted with EtOAc (3×100 ml). The organic layer was dried over anhydrous MgSO4, concentrated in vacuo to afford the desired product D18 in 3.1 g. LCMS [M-55]=174@1.29 min (5 min run)
Reaction SMILES: [C:1]([O:4]C(C)(C)C)(=[O:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].[Br:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1.FC(F)(F)C(O)=O>O1CCCC1>[Br:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][CH2:2][C:1]([OH:4])=[O:3])=[CH:20][CH:19]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CC(=O)OC(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc(Br)cc1
Reaction time: 4 h

Procedure:
t-Butyl acetate (159 mL, 1180 mmol) was added to lithium diisopropylamide (941 mmol) in tetrahydrofuran at -78° C. followed by 4-bromobenzylbromide (200 g, 784 mmol). The bath temperature was kept at -15° C. for 4 hours whereupon the reaction was quenched with ammonium chloride. The mixture was extracted with diethyl ether and the organic layer was washed with dilute hydrochloric acid, water, and brine, drying with sodium sulfate to yield a pale oil. This was refluxed with trifluoroacetic acid (150 mL, 1960 mmol) for 1 hour. The trifluoroacetic acid was removed under vacuum and the residue was partitioned between diethyl ether and aqueous sodium hydroxide. The aqueous layer was acidified with concentrated hydrochloric acid at 0° C. and extracted with diethyl ether. This organic layer was washed with water and brine and was dried over sodium sulfate to obtain a white solid after removing solvent under vacuum, (167 g, 93%), 132-134° C. m.p.
Reaction SMILES: C([O:4][CH:5]1[C:14]2[N:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:8][CH:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:6]1)(=O)C.C(O)C.[Na].[Cl-].[NH4+]>C(OC(=O)C)(=O)C.O1CCCC1>[OH:4][CH:5]1[C:14]2[N:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:8][CH:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:6]1
Reactant: CCOC(=O)C1Cc2cccnc2C(OC(C)=O)C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C1Cc2cccnc2C(O)C1
Temperature: 130 °C
Reaction time: 1 h

Procedure:
At 0° C. 1.04 kg of metachloroperbenzoic acid was added to chloroform (6 L) solution of 689 g of the compound obtained in the above, and stirred at room temperature for 3 hours. 1:1 mixed solution of aqueous saturated sodium hydrogencarbonate solution and aqueous saturated sodium sulfite solution was added to the reaction liquid, and extracted with chloroform. The organic layer was washed with aqueous saturated sodium hydrogencarbonate solution and aqueous saturated sodium chloride solution, and dried with anhydrous sodium sulfate, and the solvent was evaporated off under reduced pressure to obtain ethyl 5,6,7,8-tetrahydroquinoline-6-carboxylate 1-oxide. The obtained compound was dissolved in 2 L of acetic anhydride, and stirred at 130° C. for 1 hour. The reaction liquid was distilled under reduced pressure, and diluted with aqueous saturated sodium hydrogencarbonate solution, and extracted with chloroform. The solvent was evaporated off under reduced pressure to obtain a mixture of ethyl (6RS,8SR)-8-acetoxy-5,6,7,8-tetrahydroquinoline-6-carboxylate and ethyl (6RS,8RS)-8-acetoxy-5,6,7,8-tetrahydroquinoline-6-carboxylate. At 0° C., ethanol (3.36 L) solution of 77.2 g of sodium was added to tetrahydrofuran (3 L) solution of the resulting mixture, and stirred at 0° C. for 1 hour. Aqueous saturated ammonium chloride solution was added to the reaction liquid, then extracted with chloroform, and the organic layer was dried with anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was separated and purified through silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain 336 g of ethyl (6RS,8SR)-8-hydroxy-5,6,7,8-tetrahydroquinoline-6-carboxylate as a brown oily substance. This compound contained impurities.