Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[K])(C)(C)C.F[C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].[CH3:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][OH:30].Cl>C1COCC1.CCOC(C)=O>[CH3:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: COCCOCCOCCOCCO
Reactant: O=C(O)c1cccnc1F
Agent: CC(C)(C)O[K]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCOCCOCCOCCOc1ncccc1C(=O)O
Temperature: 100 °C
Yield: 89.9 %

Procedure:
A solution of tBuOK in THF (20% wt, 561.0 uL, 1.0 mmol) was added to a mixture of 2-fluoronicotinic acid (70.6 mg, 0.50 mmol) and tetraethyleneglycol monomethyl ether (105.5 μL, 0.50 mmol) in THF (2.0 mL) at ambient temperature under N2. The mixture was heated at 100° C. for 3 h. The reaction mixture was diluted with EtOAc. The organic phase was acidified with 1 N HCl solution, washed with saturated NaCl solution, then dried over Na2SO4. Filtration and concentration in vacuo provided compound D as light yellow liquid (148.1 mg, 90%) for next step without further purification. ESMS: 330.0 [M+H]+, 352.0 [M+Na]+, 368.0 [M+K]+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4](OC)=[O:5].[NH2:13][NH2:14]>CO>[CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([NH:13][NH2:14])=[O:5]
Reactant: NN
Reactant: COC(=O)c1ccc(C)cc1C
Solvent: CO
Product: Cc1ccc(C(=O)NN)c(C)c1

Procedure:
To a solution of methyl 2,4-dimethylbenzoate (2 g, 12.2 mmol) in MeOH (10 mL) was added anhydrous hydrazine (1.95 mL, 61 mmol) and the mixture was heated under reflux for 40 hours. Then the mixture was evaporated and dried under vacuum to give 2,4-dimethylbenzohydrazide as a white solid (2 g, 100%; MS (M+H, 165).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:39](O)=[O:40])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([N:23]4[CH2:28][CH2:27][CH:26]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH2:25][CH2:24]4)=[O:22])=[CH:18][C:17]4[CH:35]=[CH:36][CH:37]=[CH:38][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.Cl.Cl.[NH2:45][CH2:46][C:47]1[NH:48][C:49]2[CH:55]=[CH:54][CH:53]=[CH:52][C:50]=2[N:51]=1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[NH:48]1[C:49]2[CH:55]=[CH:54][CH:53]=[CH:52][C:50]=2[N:51]=[C:47]1[CH2:46][NH:45][C:39]([C:11]1[CH:10]=[CH:9][C:8]2[C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[C:15]3[C:16]4[CH:38]=[CH:37][CH:36]=[CH:35][C:17]=4[CH:18]=[C:19]([C:21]([N:23]4[CH2:28][CH2:27][CH:26]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH2:25][CH2:24]4)=[O:22])[CH2:20][N:14]3[C:13]=2[CH:12]=1)=[O:40]
Reactant: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)N1CCC(N2CCOCC2)CC1)=Cc1ccccc1-3
Reactant: NCc1nc2ccccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1nc2ccccc2[nH]1)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)N1CCC(N2CCOCC2)CC1)=Cc1ccccc1-3
Temperature: 25 °C
Reaction time: 4 h
Yield: 14.6 %

Procedure:
To a stirred solution of 13-cyclohexyl-6-[[4-(4-morpholinyl)-1-piperidinyl]carbonyl]-7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid (134 mg, 0.24 mmol) in DMF (500 μL) were added 2-aminomethyl benzimidazole dihydrochloride hydrate (75 mg, 0.32 mmol), N,N-diisopropylethylamine (165 μL, 0.95 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (60 mg, 0.31 mmol), and 1-hydroxybenzotriazole (44 mg, 0.33 mmol). The suspension was allowed to stir at r.t. for 4 hr, at which point the solvent was removed under reduced pressure. CH2Cl2 (5 mL) was added, and the suspension filtered through Celite, and chromatographed on silica gel (gradient elution: 0%→10% MeOH in CH2Cl2) to afford the title compound as a pale yellow solid (24 mg, 14% yield). LC/MS (ESI) retention time: 1.57 min, m/z 683 (MH+); 1H NMR (400 MHz, CDCl3) δ 1.07-1.53 (m, 4 H) 1.63-1.78 (m, 3 H) 1.99 (s, 4 H) 2.25 (t, J=11.08 Hz, 1 H) 2.39 (s, 4 H) 2.59-2.87 (m, 3 H) 3.63 (s, 4 H) 4.14 (s, 1 H) 4.73-5.00 (m, 3 H) 6.78 (s, 1 H) 7.17 (ddd, J=9.63, 3.90, 3.59 Hz, 2 H) 7.34 (dd, J=7.05, 1.76 Hz, 1 H) 7.40-7.47 (m, 2 H) 7.50-7.58 (m, 4 H) 7.73 (d, J=8.31 Hz, 1 H) 8.16 (s, 1 H) 8.68 (s, 1 H).
Reaction SMILES: C(OC(N1CCN(C2N=CC([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=CN=2)CC1)=O)(C)(C)C.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([O:40][C:41]2[CH:46]=[CH:45][C:44](Br)=[CH:43][N:42]=2)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].FC1C=CC(B(O)O)=CC=1>>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([O:40][C:41]2[CH:46]=[CH:45][C:44]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[CH:43][N:42]=2)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)cn2)CC1
Agent: OB(O)c1ccc(F)cc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(-c3ccc(F)cc3)cn2)CC1
Yield: 34 %

Procedure:
Prepared according to the method for the preparation of 4-[5-(4-fluorophenyl)-pyrimidin-2-yl]piperazine-1-carboxylic acid tert-butyl ester, from 4-(5-bromo-pyridin-2-yloxy)piperidine-1-carboxylic acid tert-butyl ester (0.39 g) and 4-fluorophenylboronic acid (0.16 g), to yield the title compound as a white solid (0.13 g, 34%)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]([CH:20]([CH3:22])[CH3:21])[C:7]=1[NH:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)#[N:2].C([OH:25])C.OO.Cl>[OH-].[Na+]>[CH:20]([N:6]1[C:7]2=[N:8][C:9]([C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=3)=[N:2][C:1]([OH:25])=[C:3]2[CH:4]=[N:5]1)([CH3:22])[CH3:21]
Reactant: CC(C)n1ncc(C#N)c1NC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CCO
Agent: Cl
Agent: OO
Agent: [Na+]
Product: CC(C)n1ncc2c(O)nc(-c3ccc([N+](=O)[O-])cc3)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
A suspension of N-(4-cyano-1-isopropyl-1H-pyrazol-5-yl)-4-nitrobenzamide (1.3 g, 4.3 mmol) in 1 M aqueous sodium hydroxide solution (9 mL) was made into a homogeneous mixture by the addition of approximately 40 mL of ethanol. Aqueous hydrogen peroxide solution (30%, 5 mL) was added and the mixture was slowly heated to reflux, at which state it remained overnight. After the mixture was allowed to cool to room temperature, it was treated with concentrated hydrochloric acid (5 mL), precipitating a light yellow solid. The solid was collected via Buchner filtration, washed with water, and dried under house vacuum to provide 1-isopropyl-6-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol as a pale yellow solid (0.76 g, 58%). MS (ES+): 299.8 (M+H)+
Reaction SMILES: [CH3:1][CH2:2][N:3]([C:5]([O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([C@@H:14]([N:16]([CH3:18])[CH3:17])[CH3:15])[CH:13]=1)=[O:6])[CH3:4].[C:19]([OH:28])(=[O:27])[C@@H:20]([C@H:22]([C:24]([OH:26])=[O:25])[OH:23])[OH:21]>CC(C)=O>[CH3:1][CH2:2][N:3]([C:5]([O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([C@@H:14]([N:16]([CH3:18])[CH3:17])[CH3:15])[CH:13]=1)=[O:6])[CH3:4].[CH:20]([OH:21])([C:19]([OH:28])=[O:27])[CH:22]([OH:23])[C:24]([OH:26])=[O:25]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: CCN(C)C(=O)Oc1cccc([C@H](C)N(C)C)c1
Solvent: CC(C)=O
Product: O=C(O)C(O)C(O)C(=O)O
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
3 kg of rivastigmine freebase of Formula II in 105 lit of acetone, 1.8 kg of L-(+)-Tartaric acid was charged and heated to about 60° C. followed by stirring for about 30 minutes for complete dissolution. The resulting reaction solutions was passed through celite and wash the bed with 13.5 lit acetone to made particle free. The obtained clear solution was distilled off up to 50% of the initial volume and cooled to 30° C. 12 g of rivastigmine hydrogen tartrate was added and stirred for about 60 minutes. The reaction mixture was heated to reflux and stirred for about 60 minutes and cooled to about 30° C. and stirred for about 60 minutes for solid separation. The separated solid was filtered and washed the solid with 3 lit of acetone. Solid obtained was dried at about 60° C. for about 9 hours to afford 4.10 kg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[N:4][C:5]([F:21])=[C:6]([Cl:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH:17]([CH3:19])[CH3:18])[CH:10]=1.[C:23]([O:27][CH3:28])(=[O:26])[CH2:24][OH:25].[H-].[Na+].Cl>C1COCC1.[Cl-].[Na+].O>[Cl:20][C:6]1[C:5]([F:21])=[N:4][C:3]([O:25][CH2:24][C:23]([O:27][CH3:28])=[O:26])=[C:2]([Cl:1])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH:17]([CH3:19])[CH3:18])[CH:10]=1
Reactant: COc1ccc(Oc2c(Cl)c(F)nc(F)c2Cl)cc1C(C)C
Reactant: COC(=O)CO
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)COc1nc(F)c(Cl)c(Oc2ccc(OC)c(C(C)C)c2)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3,5-dichloro-2,6-difluoro-4-(3-isopropyl-4-methoxyphenoxy)pyridine (100 mg) and methyl glycolate (neat, 25 μl) in THF (2.0 mL) was added a 60% oil dispersion of sodium hydride (10 mg) in one portion. The resulting mixture was stirred at ambient temperature for 30 min. The reaction mixture was diluted with brine, neutralized with 1 N HCl, extracted with CH2Cl2 (50 mL×2), dried (Na2SO4) and concentrated in vacuo to afford the title compound as a colorless oil (120 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][S:10]1(=[O:19])=[O:18].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30]Cl>CN(C)C=O.C(OCC)C>[Cl:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][N:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:9]([C:3]2[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[F:1])[S:10]1(=[O:19])=[O:18]
Reactant: Cc1ccc(N2c3ccccc3NS2(=O)=O)c(F)c1
Reactant: ClC/C=C\CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1ccc(N2c3ccccc3N(C/C=C\CCl)S2(=O)=O)c(F)c1
Temperature: 22 °C
Reaction time: 14 h
Yield: 75.7 %

Procedure:
A solution of -(2-fluoro-4-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (0.5 g, 1.8 mmol) in dimethylformamide (15 mL) was treated with cesium carbonate (1.2 g, 3 mmol) and cis-1,4-dichloro-2-butene (3.2 mL, 20 mmol) and stirred at 22° C. for 14 h. The reaction mixture was diluted with ethyl ether (100 mL), washed with 2 M hydrochloric acid (100 mL) and concentrated. Flash chromatography (SiO2, 10→50% ethyl acetate/hexanes) provided 1-[(2Z)-4-chlorobut-2-en-1-yl]-3-(2-fluoro-4-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (0.5 g) as a yellow oil:
Reaction SMILES: [OH-].[Na+:2].[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:10][CH2:11][C:12]([P:18]([OH:21])([OH:20])=[O:19])([P:14]([OH:17])([OH:16])=[O:15])[OH:13])[CH3:9]>O.CO>[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:10][CH2:11][C:12]([P:18]([O-:21])([OH:20])=[O:19])([P:14]([OH:17])([OH:16])=[O:15])[OH:13])[CH3:9].[Na+:2]
Reactant: CCCCCN(C)CCC(O)(P(=O)(O)O)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCN(C)CCC(O)(P(=O)([O-])O)P(=O)(O)O
Temperature: 25 °C
Yield: 95.4 %

Procedure:
A solution of sodium hydroxide (0.63 g) in water:methanol (40:60 v/v, 12 ml) was added dropwise to a solution of amorphous ibandronic acid (5 g) in water:methanol (40:60 v/v, 71 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for an additional 1.5 hours to obtain a pH of 4.04. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was filtered, washed with methanol (2×25 ml), and dried in a vacuum oven at 50° C. for 21 hours to give 5.1 g of ibandronate sodium crystal form R.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[S:9][C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[F:27])[NH2:23]>ClCCCl.CC(O)(C)C>[Cl:19][C:20]1[CH:21]=[C:22]([NH:23][C:2]2[C:3]3[CH:11]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)[S:9][C:4]=3[N:5]=[C:6]([CH3:8])[N:7]=2)[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: Cc1nc(Cl)c2cc(-c3ccc(F)cc3)sc2n1
Solvent: ClCCCl
Solvent: CC(C)(C)O
Product: Cc1nc(Nc2ccc(F)c(Cl)c2)c2cc(-c3ccc(F)cc3)sc2n1
Temperature: 90 °C
Yield: 56.7 %

Procedure:
To a solution of 4-chloro-6-(4-fluorophenyl)-2-methylthieno[2,3-d]pyrimidine (15 mg, 0.05 mmol) in 1,2-dichloroethane/t-BuOH (1:1, 2 ml) was added 3-chloro-4-fluoroaniline (16 mg, 0.11 mmol). The mixture was heated at 90° C. for 2 days. After cooling down to room temperature, the solvents were removed under reduced pressure. The crude residue was purified by silica gel chromatography (CH2Cl2/MeOH 100:1) to yield the title compound as a white solid (11 mg, 53%).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[C@@H:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:17]([CH3:26])([CH3:25])[O:16][C:15]3=[O:27])=[CH:10][CH:9]=2)=[CH:6][C:5](C2N=CC=CN=2)=[CH:4][N:3]=1.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36](B(O)O)[CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[F:1][C:2]1[N:3]=[CH:4][C:5]([C:36]2[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=2)=[CH:6][C:7]=1[C:8]1[CH:9]=[CH:10][C:11]([N:14]2[C@@H:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:17]([CH3:25])([CH3:26])[O:16][C:15]2=[O:27])=[CH:12][CH:13]=1
Reactant: OB(O)c1cccnc1
Reactant: CC1(C)OC(=O)N(c2ccc(-c3cc(-c4ncccn4)cnc3F)cc2)[C@H]1c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)OC(=O)N(c2ccc(-c3cc(-c4cccnc4)cnc3F)cc2)[C@H]1c1ccccc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
A microwave vial was charged with (S)-3-(4-(5-bromo-2-fluoropyridin-3-yl)phenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one (Example 3)(0.040 g, 0.091 mmol), 3-pyridylboronic acid (commercially available from Sigma-Aldrich, Milwaukee, Wis., 0.022 g, 0.181 mmol), sodium carbonate (0.029 g, 0.272 mmol), dioxane (2.0 mL), and water (0.40 mL). Tetrakis(triphenylphosphine)-palladium(0) (10.47 mg, 9.06 mol) was added, the system was purged with argon, and the tube was sealed. The mixture was then stirred at 100° C. in the microwave for 1 hour. The reaction mixture was next filtered through Celite® brand filter aid and the filtrate was concentrated to afford a yellow oil. The oil thus obtained was purified using column chromatography on silica gel (RediSep 40 g column, gradient elution with 50-100% EtOAc-hexane) to afford (S)-3-(4-(6-fluoro-[3,3′-bipyridin]-5-yl)phenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one (0.033 g, 0.075 mmol, 83% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.93 (s, 3H), 1.65 (s, 3H), 5.53 (s, 1H), 7.24-7.45 (m, 5H), 7.51 (ddd, J=8.00, 4.82, 0.88 Hz, 1H), 7.60-7.75 (m, 4H), 8.23 (ddd, J=8.00, 2.42, 1.61 Hz, 1H), 8.41 (dd, J=9.63, 2.49 Hz, 1H), 8.56 (dd, J=2.40, 1.32 Hz, 1H), 8.62 (dd, J=4.74, 1.61 Hz, 1H), 9.02 (dd, J=2.45, 0.78 Hz, 1H). m/z (ESI) 440 (M+H)+.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:20]([O:21]C(=O)C)[C@H:19]([O:25]C(=O)C)[CH2:18][S:17][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[O:16])[CH3:15])(=O)C.C[O-].[Na+]>CO>[O:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[O:16])[CH3:15])[C@@H:6]1[S:17][CH2:18][C@@H:19]([OH:25])[C@H:20]([OH:21])[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]1Oc1ccccc1C(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)c1ccccc1O[C@@H]1SC[C@@H](O)[C@H](O)[C@H]1O
Yield: 83.7 %

Procedure:
If the procedure described in Preparation LXXXIV is followed starting from 0.88 g (2.1.10-3 mol) of 2-acetylphenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 0.1 ml of a solution of sodium methylate in methanol (8% w/v of Na), reacted in 50 ml of methanol for 30 min, 0.51 g (yield: 84%) of the expected product is obtained after purification by chromatography on silica gel using a chloroform/methanol mixture (12/1 v/v) as the eluent, and lyophilization.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:10]=1I)=[O:5])[CH3:2].[Cu](C#N)[C:18]#[N:19]>[C-]#N.C([N+](CC)(CC)CC)C.CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:10]=1[C:18]#[N:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]nc(-c2cccs2)c1I
Reactant: N#C[Cu]C#N
Agent: [Fe+2]
Agent: [Pd]
Agent: CC[N+](CC)(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1[nH]nc(-c2cccs2)c1C#N
Temperature: 120 °C
Reaction time: 5 h

Procedure:
1.57 g (4.5 mmol) of 4-Iodo-5-thiophen-2-yl-2H-pyrazole-3-carboxylic acid ethyl ester, 0.81 g (9.0 mmol) of copper cyanide and 352 mg (2.3 mmol) of tetraethylammonium cyanide were dissolved in 10 ml of DMF and 20 ml of tetrahydrofuran and the solution was degassed with argon. 223 mg (0.2 mmol) of Tris(dibenzylideneacetone)dipalladium (0) and 374 mg (0.7 mmol) of 1,1′-bis-(diphenylphosphino) ferrocene were added at RT. The reaction was stirred at 120° C. for 5 h. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and this solution was washed with saturated aqueous sodium bicarbonate. The organic phase was dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The product was purified by silica gel chromatography eluting with n-heptane:ethyl acetate/1:1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH:17]1([C:20]([NH2:28])([C:22]2[N:26]=[C:25]([CH3:27])[O:24][N:23]=2)[CH3:21])[CH2:19][CH2:18]1>>[CH:17]1([C:20]([NH:28][C:8]([C:5]2[CH:4]=[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[C:2]([Cl:1])=[CH:7][N:6]=2)=[O:10])([C:22]2[N:26]=[C:25]([CH3:27])[O:24][N:23]=2)[CH3:21])[CH2:19][CH2:18]1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(Cl)cn1
Reactant: Cc1nc(C(C)(N)C2CC2)no1
Product: Cc1nc(C(C)(NC(=O)c2cc(OCC(F)(F)F)c(Cl)cn2)C2CC2)no1

Procedure:
The title compound was synthesized in analogy to Example 24d, using 5-Chloro-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 24c) and 1-Cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (CAN 1155536-64-3) as starting materials and isolated (27.7 mg, 35%) as colorless oil; MS (ESI, m/z): 405.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([O:25]C(C)C)=[CH:18][C:11]=3[C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1.B(Cl)(Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([OH:25])=[CH:18][C:11]=3[C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(-c2ccc(Cl)cc2)oc2cc([N+](=O)[O-])c(OC(C)C)cc12
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1c(-c2ccc(Cl)cc2)oc2cc([N+](=O)[O-])c(O)cc12
Yield: 103.7 %

Procedure:
Ethyl 2-(4-chlorophenyl)-5-isopropoxy-6-nitrobenzofuran-3-carboxylate (11 g, 27.2 mmol) was dissolved in anhydrous DCM (150 mL) and cooled in an ice bath under an atmosphere of nitrogen. Boron trichloride (41 mL, 41.0 mmol) was added over ˜20 minutes. After the reaction was complete, the reaction mixture was quenched by pouring into an ice/water mixture. The mixture was extracted with DCM, and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give ethyl 2-(4-chlorophenyl)-5-hydroxy-6-nitrobenzofuran-3-carboxylate (10.2 g, 84%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5](C=O)=[CH:4][CH:3]=1.CO.CO[CH:14]([O:17][CH3:18])[O:15][CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>>[CH3:18][O:17][CH:14]([O:15][CH3:16])[C:5]1[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: COC(OC)OC
Reactant: O=Cc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(OC)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 4.88 g (40 mmol) of 4-hydroxybenzaldehyde, 6.6 g (206 mmol) of methanol and 5.1 g (48 mmol) of trimethylorthoformate and 28 mg of p-toluene sulfonic acid was stirred at room temperature for 12 h. An excess of NaHCO3 was then added and the mixture stirred for a further 60 h. The mixture was then filtered, the solvent removed in-vacuo and the residue purified by flash chromatography (silica; 20% ethyl acetate in hexanes) to give the title compound as a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5](Cl)=[O:6].[CH3:12][C:13]1[CH:14]=[C:15]([CH:38]=[C:39]([CH3:41])[CH:40]=1)[C:16]([N:18]1[CH2:23][CH2:22][C@@H:21]([N:24]2[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26][CH2:25]2)[CH2:20][C@@H:19]1[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:17].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([O:30][CH:27]1[CH2:28][CH2:29][N:24]([C@@H:21]2[CH2:22][CH2:23][N:18]([C:16](=[O:17])[C:15]3[CH:14]=[C:13]([CH3:12])[CH:40]=[C:39]([CH3:41])[CH:38]=3)[C@@H:19]([CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:20]2)[CH2:25][CH2:26]1)=[O:6]
Reactant: Cc1cc(C)cc(C(=O)N2CC[C@@H](N3CCC(O)CC3)C[C@@H]2Cc2ccccc2)c1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)cc(C(=O)N2CC[C@@H](N3CCC(OC(=O)c4cc(Cl)cc(Cl)c4)CC3)C[C@@H]2Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.3 %

Procedure:
3,5-Dichlorobenzoyl chloride (1 g) was added to a mixture of compound 31 (2 g) and triethylamine (0.5 g) in CH2Cl2 (25 ml) and the mixture was stirred at RT for 1 hour. The mixture was washed with water. The organic layer was dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 97/3). The pure fractions were collected and their solvent evaporated. The residue was dried, yielding 0.34 g (11.7%) of (±)-trans-1-[1-(3,5-dimethylbenzoyl)-2-(phenylmethyl)-4-piperidinyl]-4-piperidinyl 3,5-dichloro-benzoate (compound 33, mp. 83.3° C.).
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1/[CH:11]=[CH:12]/[C:13]([OH:15])=O.[CH3:23][C:24]([O:27][C:28]([NH:30][CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:29])([CH3:26])[CH3:25].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1/[CH:11]=[CH:12]/[C:13]([N:34]1[CH2:33][CH2:32][CH:31]([NH:30][C:28](=[O:29])[O:27][C:24]([CH3:25])([CH3:23])[CH3:26])[CH2:36][CH2:35]1)=[O:15]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=C(O)/C=C/c1cnccc1Oc1ccc([N+](=O)[O-])cc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)/C=C/c2cnccc2Oc2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.8 %

Procedure:
A solution of (E)-3-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)acrylic acid (143 mg, 0.42 mmol), 4-N-Boc-aminopiperidine (Aldrich, 84 mg, 0.42 mmol) in DMF (1.5 mL) was treated with DIPEA (160 μL, 0.92 mmol), and TBTU (160 mg, 0.50 mmol) and the mixture stirred at rt for 2 h. The mixture was diluted with EtOAc, washed with saturated aq. NaHCO3 solution and brine, dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting first with 30-100% EtOAc/hexanes then 5% MeOH/CH2Cl2 to give the title compound (110 mg, 54%) as a light brown solid. 1H NMR (DMSO-d6) δ 9.15 (s, 1H), 8.48 (d, 1H, J=5.6 Hz), 8.44 (dd, 1H, J=2.5, 10.5 Hz), 8.18 (d, 1H, J=9.2 Hz), 7.69 (d, 1H, J=15.3 Hz), 7.58 (dd, 1H, J=8.6, 8.6 Hz), 7.50 (d, 1H, J=15.7 Hz), 6.97 (d, 1H, J=5.6 Hz), 6.89 (d, 1H, J=7.6 Hz), 4.31-4.16 (m, 2H), 3.55-3.46 (m, 1H), 3.20-3.14 (m, 1H), 2.83-2.81 (m, 1H), 1.82-1.71 (m, 2H), 1.34-1.18 (m, 2H), 1.37 (s, 9H); MS (ESI+): m/z 431.04 (100) [(M−C4H9)+H]+; m/z 487.10 (90) (M+H)+.