Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7](O)=[O:8].S(Cl)([Cl:13])=O>>[CH3:1][C:2]1([CH3:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7]([Cl:13])=[O:8]
Reactant: CC1(C)C(C(=O)O)C1(C)C
Reactant: O=S(Cl)Cl
Product: CC1(C)C(C(=O)Cl)C1(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a flask containing 2,2,3,3-tetramethylcyclopropane carboxylic acid (Aldrich, 13.5 g, 95 mmol) was added 30 mL of thionyl chloride (410 mmol, excess). This solution was warmed to reflux and stirred for 2 h. The mixture was then cooled to ambient temperature and concentrated under reduced pressure. The residue was azeotroped three times with 10 mL of benzene to remove any remaining thionyl chloride, and used without further purification.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH2:20][OH:21])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:22])[CH2:3]1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH3:13][C@:12]12[CH2:14][CH2:15][C@H:16]3[C@@H:7]([CH2:6][CH:5]=[C:4]4[C@:17]3([CH:20]=[O:21])[CH2:18][CH2:19][C:2](=[O:1])[CH2:3]4)[C@@H:8]1[CH2:9][CH2:10][C:11]2=[O:22]
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](O)CC[C@@]43CO)[C@@H]1CCC2=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: C[C@]12CC[C@H]3[C@@H](CC=C4CC(=O)CC[C@@]43C=O)[C@@H]1CCC2=O

Procedure:
To a solution of 3β,19-dihydroxy-5-androsten-17-one in acetone at 10° C. is added two equivalents of Jones Reagent with stirring. After an additional 15 minutes the upper acetone layer is decanted and poured onto ice water. The precipitate which forms is filtered, washed with water and dissolved in ether. The ether solution is dried over magnesium sulfate and concentrated under reduced pressure. Crystallization of the residue from an acetone-hexane solution yields 5-androstene-3,17,19-trione.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:9][C:8]1=[O:19])([O-])=O.[Cl-].[NH4+].O>C(O)C.[Fe]>[NH2:1][C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:9][C:8]1=[O:19]
Reactant: O=C1OC(c2ccccc2)CCN1Cc1ccccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccccc1CN1CCC(c2ccccc2)OC1=O
Temperature: 25 °C
Yield: 99.3 %

Procedure:
3-(2-Nitrobenzyl)-6-phenyl-[1,3]-oxazinan-2-one (1.59 g, 5.10 mmol), iron powder (1.42 g, 25.4 mmol), ammonium chloride (0.14 g, 2.62 mmol) were suspended in ethanol (30 ml) and water (15 ml) and heated to reflux for 1.5 hours. After cooling to room temperature, the reaction mixture was filtered with suction and extracted with ethyl acetate. The organic layer was washed with a saturated brine and then dried over anhydrous sodium sulfate, and 3-(2-aminobenzyl)-6-phenyl-[1,3]-oxazinan-2-one (1.43 g) was obtained by evaporating the solvent under reduced pressure.
Reaction SMILES: Cl.Cl.Cl[CH:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[C:5]1=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=1.S(Cl)(Cl)=O.[C].[C]>[Ni].[Pd]>[NH2:19][C:15]1[CH:14]=[C:13]([CH2:12][CH:5]2[CH2:4][CH:9]3[CH2:10][CH2:11][N:6]2[CH2:7][CH2:8]3)[CH:18]=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1cccc(C=C2C(Cl)C3CCN2CC3)c1
Agent: [Ni]
Agent: [Pd]
Agent: Cl
Solvent: O=S(Cl)Cl
Product: Nc1cccc(CC2CC3CCN2CC3)c1

Procedure:
The manner in which 2-[(3-aminophenyl)methyl]-1-azabicyclo[2.2.2]octane is synthesized can vary. For example, in one method, 3-nitrobenzaldehyde can be condensed with 3-quinuclidinone in an aldol reaction using potassium hydroxide and ethanol to yield 2-[(3-nitrophenyl)methylene]-1-azabicyclo[2.2.2]octan-3-one. The latter compound can be converted to the corresponding dithioketal by treatment with 1,2-ethanedithiol and boron triflouride etherate. Reduction and desulfurization can be effected by hydrogenation using Raney nickel to yield 2-[(3-aminophenyl)methyl]-1-azabicyclo[2.2.2]octane. Alternatively, in another method, the aldol product, 2-[(3-nitrophenyl)methylene]-1-azabicyclo[2.2.2]octan-3-one can be reduced by treatment with sodium borohydride in methanol to give the alcohol, 2-[(3-nitrophenyl)methylene]-1-azabicyclo[2.2.2]octan-3-ol. The latter compound can be converted to the chloro intermediate, 3-chloro-2-[(3-nitrophenyl)methylene]-1-azabicyclo[2.2.2]octane dihydrochloride upon treatment with thionyl chloride. Dechlorination by hydrogenation with Raney nickel and carbon-carbon double bond reduction by hydrogenation over 10% palladium on carbon can then be effected to yield 2-[(3-aminophenyl)methyl]-1-azabicyclo[2.2.2]octane. Replacement of 3-nitrobenzaldehyde with 2-nitrobenzaldehyde or 4-nitrobenzaldehyde in the above synthetic approach affords the isomeric compounds, 2-[(2-aminophenyl)methyl]-1-azabicyclo[2.2.2]octane and 2-[(4-aminophenyl)methyl]-1-azabicyclo[2.2.2]octane, respectively.
Reaction SMILES: Cl.C1(CN2CCCC(=O)C2)C=CC=CC=1.Br.Br.FC1C=CC(C[N:26]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[N:28]=[C:27]2[NH:35]C2CCNCC2)=CC=1.S1C=CC=C1.C([O-])(=O)C.[K+].[H][H]>C(O)C.[Pd].COCCO>[NH:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=[C:27]1[NH2:35]
Reactant: [H][H]
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)cc1
Agent: [Pd]
Agent: Br
Agent: CC(=O)[O-]
Solvent: COCCO
Solvent: CCO
Solvent: c1ccsc1
Product: Nc1nc2ccccc2[nH]1

Procedure:
A mixture of 25 parts of 1(phenylmethyl)-3-piperidinone hydrochloride, 55 parts of 1-[(4-fluorophenyl)methyl]-N-(4-piperidinyl)-1H-benzimidazol-2-amine dihydrobromide, 1 part of a solution of thiophene in ethanol 4%, 50 parts of potassium acetate and 500 parts of 2-methoxyethanol was hydrogenated at normal pressure and at 50° C. with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filrate was evaporated. The residue was taken up in water and the whole was alkalized with sodium hydroxide. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized twice from acetonitrile. The product was filtered off and dried, yielding 9.75 parts of 1-[(4-fluorophenyl)methyl]-N-[1'-(phenylmethyl)-[1,3'-fluorophenyl)methyl]-N-[1'-(phenylmethyl)-[1,3'-bipiperidin]-4yl[-1H-benzimidazol-2-amine; mp. 174.6° C. (intermediate 70).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].OS(O)(=O)=O.N([O-])=O.[Na+].[Na+].[I-:25]>O>[I:25][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12]
Reactant: Nc1ccc([N+](=O)[O-])cc1C(F)(F)F
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc(I)c(C(F)(F)F)c1
Yield: 94.6 %

Procedure:
To a mixture of 3.1 g (15.0 mmol) of 2-amino-5-nitrobenzotrifluoride in 60 mL of 40% (v/v) H2SO4 stirred in an ice-bath was added dropwise a solution of 2.1 g (30.4 mmol) of NaNO2 in 10 mL of H2O. The resulting yellow solution was stirred in an ice-bath for 1 h and it was added dropwise into a well stirred solution of 10 g of NaI in 250 mL of H2O cooled in an ice bath. Gas releasing and precipitate was observed. The mixture was stirred overnight at 25° C., filtered and washed by water, and dried to leave pale yellow solid (4.5 g, 94%), mp 81°-82° C. 1H NMR (CDCl3), 8.047 (dd, 1), 8.272 (d, 1), 8.483 (d, 1).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH:9]1[CH2:13][NH:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])[CH3:3].C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:21]1[CH:22]=[C:23]([Cl:27])[CH:24]=[CH:25][CH:26]=1.C1(P(C2C=CC=CC=2)C2(P(C3C=CC=CC=3)C3C=CC=CC=3)CC=C3C(C=CC=C3)=C2C2C3C(=CC=CC=3)C=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:27][C:23]1[CH:22]=[C:21]([N:12]2[CH2:11][CH2:10][CH:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[CH2:13]2)[CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: Clc1cccc(Br)c1
Agent: C1=c2ccccc2=C(c2cccc3ccccc23)C(P(c2ccccc2)c2ccccc2)(P(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1CCN(c2cccc(Cl)c2)C1
Temperature: 110 °C
Reaction time: 15 h
Yield: 62.7 %

Procedure:
3-N-Boc-amino pyrrolidine (120 mg, 0.644 mmol), cesium carbonate (252 mg, 0.773 mmol), and 3-bromochlorobenzene (75.7 μl, 0.644 mmol) were suspended in dry toluene. Argon was bubbled through the suspension for 2 minutes and then tris(dibenyzlideneacetone)dipalladium (35.4 mg, 0.0387 mmol) and rac-2,2-bis(diphenylphosphino)-1,1′-binaphthyl (60.4 mg, 0.0966 mmol) were added. The reaction vial was capped and heated to 110° C. with rapid stirring. After 15 hours, reaction was cooled to ambient temperature and applied directly to a silica gel column. Elution was a gradient of 5-70% ethyl acetate-hexanes provided the title compound (120 mg, 0.404 mmol, 62.8% yield) as an oil.
Reaction SMILES: Br[C:2]1[C:3]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:5][C:6]=1[N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[CH3:27][CH:28]([C:30]1[CH:35]=[C:34](C(C)C)[C:33](C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=[C:32](C(C)C)[CH:31]=1)C.C1(C#C)C=CC=CC=1.CN(C=O)C>CCOC(C)=O.O.CC#N.CC#N.Cl[Pd]Cl>[Cl:26][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[Cl:25])[CH2:18][C:3]1[C:2]([C:27]#[C:28][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:6]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[S:5][C:4]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Reactant: CCOC(=O)c1sc(N2CCOCC2)c(Br)c1Cc1ccc(Cl)c(Cl)c1
Agent: Cl[Pd]Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(N2CCOCC2)c(C#Cc2ccccc2)c1Cc1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Yield: 248.4 %

Procedure:
To a suspension of ethyl 4-bromo-3-(3,4-dichlorobenzyl)-5-(morpholin-4-yl)thiophene-2-carboxylate (0.125 g, 0.000222 mol), XPhos (0.0172 g, 0.0000362 mol), CsCO3 (0.199 g, 0.000612 mol) and phenylacetylene (0.146 mL, 0.00133 mol) in DMF (1.2 mL, 0.015 mol) was added bis(acetonitrile)palladium(II) chloride (0.00288 g, 0.0000111 mol) and the mixture was heated at 50° C. overnight. The reaction mixture was diluted with EtOAc (30 mL) and water (15 mL), and the layers were separated. The aqueous layer was extracted with EtOAc (2×15 mL). Combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude residue was purified using a dry load on a silica gel column (eluent: 0-30% EtOAc:hexane), affording ethyl 3-(3,4-dichlorobenzyl)-5-(morpholin-4-yl)-4-(phenylethynyl)thiophene-2-carboxylate (45 mg, 40% yield). LCMS: (FA) ES+ 500, 501, 502; 1H NMR (400 MHz, DMSO) δ 7.55-7.51 (m, 2H), 7.43-7.37 (m, 5H), 7.20 (dd, J=8.3, 2.0 Hz, 1H), 4.38 (s, 2H), 4.22 (q, J=7.1 Hz, 2H), 3.79-3.74 (m, 4H), 3.57-3.52 (m, 4H), 1.23 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:29]=[C:5]2[NH:6][C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.I[CH:31]([CH2:33][CH3:34])[CH3:32].C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>C(OCC)(=O)C>[CH3:1][C:2]1[N:29]=[C:5]2[N:6]([CH:31]([CH3:32])[CH2:33][CH3:34])[C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2nc(C)nn12
Reactant: CCC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C(C)CC)c2nc(C)nn12
Temperature: 100 °C
Reaction time: 16 h
Yield: 22 %

Procedure:
A mixture of 4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (1.5 g), 2-iodobutane (1.4 mL), potassium carbonate (1 g) and N,N-dimethylacetamide (15 mL) was stirred at 100° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.36 g, 22%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Br:10][C:11]1[CH:16]=[C:15]([C:17]([O-:19])=O)[CH:14]=[CH:13][C:12]=1[C:20]([O:22][CH3:23])=[O:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[OH:49][C:50]1[CH:51]=[C:52]([CH2:56][NH2:57])[CH:53]=[CH:54][CH:55]=1.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[Br:10][C:11]1[CH:16]=[C:15]([C:17]([NH:57][CH2:56][C:52]2[CH:53]=[CH:54][CH:55]=[C:50]([OH:49])[CH:51]=2)=[O:19])[CH:14]=[CH:13][C:12]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: NCc1cccc(O)c1
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1Br
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
Diisopropylethylamine (8.4 mL, 48.2 mmol) was added dropwise to a cooled (˜0° C.) solution of 2-bromo-1,4-benzenedicarboxylic acid, 1-methyl ester (Example 2; 5.00 g, 19.3 mmol), HBTU (7.31 g, 19.3 mmol), 3-hydroxybenzylamine HCl salt (Example 7; 3.37 g, 21.2 mmol), and HOBT (2.6 g, 19.2 mmol) in N,N-dimethylformamide (50 mL). The solution was allowed to stir at ˜0° C. for 1 h, then at room temperature for 4 h, and it was then concentrated to remove most of the N,N-dimethylformamide. The residue was partitioned between ethyl acetate and 1 M HCl (200 mL each). The ethyl acetate layer was washed with 1 M HCl (2×100 mL) and the combined aqueous layers were extracted with ethyl acetate (50 mL). The combined ethyl acetate layers were washed with saturated sodium hydrogen carbonate solution (2×100 mL), and brine, then dried (MgSO4), filtered, evaporated and recrystallized from hot ethyl acetate (˜60 mL) and hexanes (15 mL) to give 2-bromo-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoic acid, methyl ester (5.15 g, 73%) as white crystals.
Reaction SMILES: C1([Mg]Br)C=CC=CC=1.[C:9]1([C:15]2([NH2:25])[CH2:24][CH2:23][C@H:22]3[C@H:17]([CH2:18][CH2:19][CH2:20][CH2:21]3)[CH2:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:9]1([C:15]2([NH2:25])[CH2:24][CH2:23][CH:22]3[CH:17]([CH2:18][CH2:19][CH2:20][CH2:21]3)[CH2:16]2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: NC1(c2ccccc2)CC[C@@H]2CCCC[C@@H]2C1
Agent: Br[Mg]c1ccccc1
Product: NC1(c2ccccc2)CCC2CCCCC2C1

Procedure:
This material was prepared from cis/trans-2-tetralone and phenylmagnesium bromide utilizing a procedure analogous to those described in Preparation 89. The crude HCl salt of the amine was purified by preparative C18-RP-HPLC using a 15%→100% CH3CN pH 4.5, 50 mm NH4OAc gradient, followed by concentration in vacuo and extraction of the free-base into Et2OAc from 1N NaOH to obtain a 2:1 mixture of pure trans/cis-2-phenyl-decahydronaphthalen-2-ylamine.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[O:18][C:19]2[C:25]([O:26][CH2:27][CH2:28][O:29][Si](C(C)(C)C)(C)C)=[CH:24][CH:23]=[CH:22][C:20]=2[CH:21]=1)=[O:16])(C)(C)C.NC1C=CC=CC=1NC(C1SC2C=CC(OCCO)=CC=2C=1)=O>>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[O:18][C:19]2[C:25]([O:26][CH2:27][CH2:28][OH:29])=[CH:24][CH:23]=[CH:22][C:20]=2[CH:21]=1)=[O:16]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1cc2cccc(OCCO[Si](C)(C)C(C)(C)C)c2o1
Agent: Nc1ccccc1NC(=O)c1cc2cc(OCCO)ccc2s1
Product: Nc1ccccc1NC(=O)c1cc2cccc(OCCO)c2o1

Procedure:
was prepared from [2-({7-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-benzofuran-2-carbonyl}-amino)-phenyl]-carbamic acid tert-butyl ester (38) in an analogous manner to that described for the preparation of (39) example 16, step 2; mp. 182–183° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([Cl:14])[C:12]=1[NH2:13])C(OCC)=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:10]=[C:11]([Cl:14])[C:12]=1[NH2:13]
Reactant: CCOC(=O)c1cc(Cl)c(N)c(Cl)c1
Solvent: O
Product: Nc1c(Cl)cccc1Cl
Temperature: 250 °C
Reaction time: 2.5 h
Yield: 90.8 %

Procedure:
0.2 mole=49.3 g of ethyl 3,5-dichloro-4-amino-benzoate were initially introduced into an autoclave together with 250 ml of water. The mixture was heated to 250° C. and stirred at this temperature for 2.5 hours. Reaction gas formed was continuously removed to maintain a pressure of about 40 bar. The product was subsequently recovered by steam distillation. 31 g of 2,6-dichloroaniline were obtained, corresponding to a yield of 94%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2([C:22](N)=[O:23])[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH-:25].[K+].Cl.[OH-].[Na+]>O.C(O)CO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2([C:22]([OH:25])=[O:23])[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: Cc1ccc(NC2(C(N)=O)CCN(Cc3ccccc3)CC2)cc1
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: OCCO
Solvent: O
Product: Cc1ccc(NC2(C(=O)O)CCN(Cc3ccccc3)CC2)cc1

Procedure:
A mixture of 100 parts of 4-[(4-methylphenyl)amino]-1-(phenylmethyl)-4-piperidinecarboxamide, 52.2 parts of potassium hydroxide and 638 parts of 1,2-ethanediol is stirred and refluxed for 25 hours. After cooling, 1200 parts of water are added and the whole is acidified with a concentrated hydrochloric acid solution. The acid aqueous phase is alkalized with a sodium hydroxide solution 60%: exothermic reaction. After cooling, the precipitated crude product is filtered off and dissolved in water. This solution is acidified with acetic acid (pH about 6.5) and the product is filtered off. It is crystallized from N,N-dimethylformamide, filtered off again, washed with 2-propanone and dried, yielding 4-[(4-methylphenyl)amino]-1-(phenylmethyl)-4-piperidinecarboxylic acid; mp. 270° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl.[NH2:12][C@@H:13]([C:15]([NH2:17])=[O:16])[CH3:14].CC(N(C)C)=O.CCOC(C)=O>CS(C)=O.O>[Br:1][C:2]1[CH:9]=[C:8]([NH:12][C@H:13]([CH3:14])[C:15]([NH2:17])=[O:16])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C[C@@H](N)C(N)=O
Reactant: N#Cc1ccc(F)cc1Br
Agent: Cl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: C[C@@H](Nc1ccc(C#N)c(Br)c1)C(N)=O
Yield: 69 %

Procedure:
A solution of 2-bromo-4-fluorobenzonitrile (200 mg, 1.00 mmol), D-alanine amide hydrochloride (148 mg, 1.19 mmol) and DMA (0.620 mL, 3.56 mmol) in DMSO (3 mL) was stirred at 100 C for 18 h. EtOAc and water were added. The organic phase was separated, dried over Na2SO4, concentrated in vacuo. The residue was purified by a silica gel column, eluted first with 30% EtOAc in hexane, then with 100% EtOAc to give (R)-2-(3-bromo-4-cyanophenylamino)propanamide (185 mg).
Reaction SMILES: [ClH:1].[I:2][C:3]1[C:4]([CH3:10])=[CH:5][C:6](N)=[N:7][CH:8]=1.N([O-])=O.[Na+]>O>[Cl:1][C:6]1[CH:5]=[C:4]([CH3:10])[C:3]([I:2])=[CH:8][N:7]=1
Reactant: Cl
Reactant: Cc1cc(N)ncc1I
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(Cl)ncc1I
Temperature: 25 °C
Reaction time: 16 h
Yield: 30 %

Procedure:
To a stirred solution of concentrated hydrochloride acid (233 mL) at 0° C. was added 5-iodo-4-methyl-pyridin-2-ylamine (25 g, 107 mmol, 1 eq) followed by addition of pre-dissolved sodium nitrite (29.5 g, 427 mmol, 4 eq) in water (100 mL) in drop wise manner over period of 30 minutes. Resulting reaction mixture was stirred at room temperature for 16 hours. After complete consumption of starting material, reaction mixture was cooled to 0° C. and pH was adjusted to 12 by saturated aqueous sodium hydroxide solution, extracted with DCM (3×200 mL). Combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to get brown oil (23 g, crude). Crude was purified by column chromatography using silica gel (100-200 mesh). Desired compound was eluted at 4% ethyl acetate in hexane to get title compound as brown oil (8 g, 30%). 1H NMR (400 MHz, CDCl3) δ: 2.38 (s, 3H), 7.21 (s, 1H), 8.59 (s, 1H). LC-MS (m/z): 253.7 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][O:6][C:7]1[CH:20]=[CH:19][C:10]([CH2:11][N:12]2[C:16](=[O:17])[NH:15][C:14](=[O:18])[O:13]2)=[CH:9][CH:8]=1.[F:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([F:33])[C:26]=1B(O)O.[Cl-].[Li+].C(=O)([O-])[O-].[Na+:43].[Na+].Cl.[OH-].[Na+]>C1COCC1.C(O)C.COCCOC>[F:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([F:33])[C:26]=1[C:2]1[CH:23]=[CH:22][CH:21]=[C:4]([CH2:5][O:6][C:7]2[CH:20]=[CH:19][C:10]([CH2:11][N:12]3[C:16](=[O:17])[N-:15][C:14](=[O:18])[O:13]3)=[CH:9][CH:8]=2)[CH:3]=1.[Na+:43]
Reactant: O=c1[nH]c(=O)n(Cc2ccc(OCc3cccc(Br)c3)cc2)o1
Reactant: COc1cc(F)c(B(O)O)c(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COCCOC
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(F)c(-c2cccc(COc3ccc(Cn4oc(=O)[n-]c4=O)cc3)c2)c(F)c1
Temperature: 90 °C
Reaction time: 13 h
Yield: 59.7 %

Procedure:
A mixture of 2-{4-[(3-bromobenzyl)oxy]benzyl}-1,2,4-oxadiazolidine-3,5-dione (500 mg), 2,6-difluoro-4-methoxyphenyl boronic acid (325 mg), tetrakistriphenylphosphine palladium (80 mg), lithium chloride (6 mg), a sodium carbonate aqueous solution (562 mg/5 ml), ethanol (5 ml) and 1,2-dimethoxyethane (25 ml) was stirred at 90° C. for 5 hours in an atmosphere of nitrogen. 2,6-Difluoro-4-methoxyphenyl boronic acid (325 mg) was further added thereto, followed by stirring at 90° C. for 13 hours. Further, 2,6-difluoro-4-methoxyphenyl boronic acid (325 mg) was added thereto, followed by stirring at 90° C. for 2 hours. Further, 2,6-difluoro-4-methoxyphenyl boronic acid (325 mg) was added thereto, followed by stirring at 90° C. for 5 hours and spontaneous cooling to room temperature. A 1 M hydrochloric acid (50 ml) was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate and filtered. Silica gel (3 g) was added to the filtrated, followed by concentration under a reduced pressure. The carrying product thus obtained was purified by silica gel column chromatography (chloroform-methanol) to obtain a light yellow foamy substance (614 mg). The resulting foamy substance (614 mg) was dissolved in THF (5 ml)-ethanol (5 ml), a 1 M sodium hydroxide aqueous solution (1.32 ml) was added, followed by concentration under a reduced pressure. By recrystallizing the resulting residue from isopropanol-water, sodium 2-{4-[(2′,6′-difluoro-4′-methoxybiphenyl-3-yl)methoxy]benzyl}-3,5-dioxo-1,2,4-oxadiazolidin-4-ide (366 mg) was obtained as a colorless solid.
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:7]=[C:6]([Cl:14])[CH:5]=1.O.[OH-].[Li+]>O1CCCC1.O>[Cl:14][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:7]=1)[C:3]([OH:15])=[O:2]
Reactant: COC(=O)c1cc(Cl)cc(S(C)(=O)=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1cc(Cl)cc(C(=O)O)c1
Reaction time: 1 h
Yield: 82.9 %

Procedure:
To a solution of 3-chloro-5-methanesulfonyl-benzoic acid methyl ester (2.3 g, 9.25 mmol) in tetrahydrofuran (30 mL) and water (15 mL) was added lithium hydroxide monohydrate (1.164 g, 27.75 mmol) at 25° C. and the reaction mixture was stirred for 1 h. The solvent was evaporated, the residue dissolved in water (25 mL), acidified with 2M aqueous hydrochloric acid to pH 3 and extracted three times with ethyl acetate (40 mL each). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and evaporated to afford the desired compound as a colorless solid (1.8 g, 83%). MS (ESI−): m/z=233.2 ([M−H]−).