Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:4]1[C:13]2[C:8](=[C:9]([O:17][CH3:18])[C:10]3[O:16][CH2:15][O:14][C:11]=3[CH:12]=2)[CH2:7][N:6]([CH3:19])[CH2:5]1)C.S(=O)(=O)(O)O>C(O)(=O)C.[C].[Pd]>[CH3:18][O:17][C:9]1[C:10]2[O:16][CH2:15][O:14][C:11]=2[CH:12]=[C:13]2[C:8]=1[CH2:7][N:6]([CH3:19])[CH2:5][CH2:4]2
Reactant: CCOC1CN(C)Cc2c1cc1c(c2OC)OCO1
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COc1c2c(cc3c1OCO3)CCN(C)C2
Yield: 88.6 %

Procedure:
0.27 g (1.02 mmol) of 4-ethoxy-8-methoxy-2-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline (8) was dissolved in 15 ml of acetic acid, and the solution was added with 200 mg of 5% palladium carbon and 0.1 ml of 97% sulfuric acid and hydrogenated at 75° C. for 1 hour and 40 minutes. After cooling, the catalyst was filtered off and the filtrate was added with a small quantity of an aqueous solution of sodium hydroxide and concentrated under reduced pressure. The residue was added with 10 ml of water and made basic with an aqueous solution of sodium hydroxide. The resulted solution was extracted twice with 5 ml of methylene chloride and the extract was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 0.20 g of 8-methoxy-2-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline (13) as a crystal. Yield: 89%.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:15]1([CH2:18][CH:19]([C:22]2[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=2)[CH2:20][NH2:21])[CH2:17][CH2:16]1>>[Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:22]1[CH:23]=[N:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=1)[CH2:18][CH:15]1[CH2:16][CH2:17]1)=[O:6]
Reactant: NCC(CC1CC1)c1ccc(C(F)(F)F)nc1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Product: O=C(NCC(CC1CC1)c1ccc(C(F)(F)F)nc1)c1cccc(C(F)(F)F)c1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2-chloro-3-trifluoromethylbenzoic acid and 3-cycl opropyl-2-(6-trifluoromethyl-pyridin-3-yl)-propylamine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=451.1, tR (minutes, Method G)=3.11. [α]D20=+26.0 (c=2.0 mg/mL,CHCl3)
Reaction SMILES: C[O:2][C:3](=[O:40])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:39])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:38])[C@H:16]([CH2:34][CH2:35][S:36][CH3:37])[NH:17][P:18]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19].[OH-].[Na+].O>CC(C)=O>[CH2:20]([P:18]([NH:17][C@H:16]([C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([N:5]1[CH2:6][CH2:7][CH2:8][C@H:4]1[C:3]([OH:40])=[O:2])=[O:39])=[O:38])[CH2:34][CH2:35][S:36][CH3:37])([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:19])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)[C@H](CCSC)NP(=O)(Cc1ccccc1)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CSCC[C@H](NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 4 h
Yield: 99.2 %

Procedure:
Dibenzylphosphoryl-L-methionyl-L-prolyl-L-proline methylester (1.87 g, 3.0 m mole) was dissolved in acetone (18 ml), and 1N sodium hydroxide (4.5 ml) was added thereto under cooling and the mixture was stirred for 4 hours. To the solution, water (100 ml) was added, and the solution was washed with diethyl ether. Ethyl acetate (200 ml) was added thereto and the mixture was adjusted to pH 2 with 1N hydrochloric acid while stirring strongly. The ethyl acetate phase was separated and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain an oily dibenzylphosphoryl-L-methionyl-L-prolyl-L-proline (1.81 g, yield: 99.1%). All of the thus obtained product (3.0 m mole) was dissolved in ethanol (15 ml) and a L-arginine (0.58 g, 3.0 m mole) water (5 ml) solution was added thereto. The solvent was evaporated, water was added thereto, and the thus obtained solution was freeze-dried to obtain dibenzylphosphoryl-L-methionyl-L-prolyl-L-proline L-arginine salt (2.27 g, yield: 98.7% from dibenzylphosphoryl-L-methionyl-L-prolyl-L-proline methylester). This product gave a single spot respectively having a Rf =0.8 for peptides in the free form and an Rf =0.25 for arginine by thin layer chromatography (developing solvent, n-butanol:acetic acid:water=2:1:1, Colour forming method, spraying of 25% hydrobromic acid and 0.1 ninhydrin, and heating). After hydrolysis of the product with 6N hydrochloric acid, the amino acids were analyzed. Methionine:Proline:Arginine=1.00:2.03:0.95.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.[Cl:43][C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([F:50])C=1CCl>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[C:46]([F:50])=[CH:47][CH:48]=[CH:49][C:44]=3[Cl:43])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Fc1cccc(Cl)c1CCl
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3c(F)cccc3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-chloro-2-(chloromethyl)-3-fluorobenzene and isolated as white solid (5.4 mg, 31%). MS (m/e): 425.4 (MH+).
Reaction SMILES: [O:1]([C@H:13]1[C@H:19]([OH:20])[C@@H:18]([CH2:21][OH:22])[O:17][CH:15]([OH:16])[C@@H:14]1[NH:23][C:24]([CH3:26])=[O:25])[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[F-].[Na+].C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1.C1N([C@@H]2O[C@H](COP(OP(O[C@H:97]3[O:102][C@H:101]([CH2:103]O)[C@@H:100]([OH:105])[C@H:99]([OH:106])[C@@H:98]3[OH:107])(O)=O)(O)=O)[C@@H](O)[C@H]2O)C2NC(N)=NC(=O)C=2N=1.CC1OC(OP(OP(OCC2OC(N3C4NC(N)=NC(=O)C=4N=C3)C(O)C2O)(O)=O)(O)=O)C(O)C(O)C1O>CC(O)C>[O:1]([C@H:13]1[C@H:19]([O:20][C@@H:97]2[O:102][C@@H:101]([CH3:103])[C@@H:100]([OH:105])[C@@H:99]([OH:106])[C@@H:98]2[OH:107])[C@@H:18]([CH2:21][OH:22])[O:17][CH:15]([OH:16])[C@@H:14]1[NH:23][C:24]([CH3:26])=[O:25])[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: Nc1nc(=O)c2ncn([C@@H]3O[C@H](COP(=O)(O)OP(=O)(O)O[C@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]4O)[C@@H](O)[C@H]3O)c2[nH]1
Reactant: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Agent: CC1OC(OP(=O)(O)OP(=O)(O)OCC2OC(n3cnc4c(=O)nc(N)[nH]c43)C(O)C2O)C(O)C(O)C1O
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: [F-]
Solvent: CC(C)O
Product: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O[C@@H]2O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]2O)[C@@H]1O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of GTP Na salt (6.0 mg, 10 μmol), Man-1-P K salt (3.5 mg, 10 μmol), Galβ1,3GlcNAc (3.8 mg, 10 μmol), NaF (0.42 mg, 10 μmol), NADPH (9.4 mg, 10 μmol), PEP K salt (4.1 mg, 20 μmol), MgCl2—6H2O (2.6 mg, 10 μmol), MnCl2—4H2O (2 mg, 10 μmol), 2-propanol, (50 μL), ADH (12 U), PK (200 U), PPase (100 U), crude enzyme preparation of GDP-mannose pyrophosphorylase (1.0 mL), and crude enzyme preparation of GDP-Fuc producing enzyme (1.0 mL) in 100 mM tris buffer (pH 7.5) and diluted to 3 mL. α1,3/4-Fucosyltransferase (0.01 U) was added to the mixture and the resulting mixture was stirred under Ar for three days at room temperature. The mixture was filtered and the filtrate was applied to a column of Dowex 1-X8 [OH−) form followed with a column of Dowex 50W-X8 [H+] with water. The fractions were collected and lyophilized. The residual material was purified with a column of Sephadex G-25 (superfine) with water. The appropriate fractions were pooled and lyophilized to give Galβ1,3(Fucα1,4)GlcNAc. Its 1H-NMR spectrum was in good agreement with that reported. [Dumas et al., Biomed. Chem. Lett., 1:425 (1991).]
Reaction SMILES: [CH2:1]([C:12]([CH3:14])=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[OH:15][NH:16]Cl.[OH-].[Na+]>C(O)C.O>[CH3:14][C:12](=[N:16][OH:15])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCCC(C)=O
Reactant: ONCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCC(C)=NO
Yield: 93 %

Procedure:
A solution of 40 g of methyl undecyl ketone and 18 g of hydroxylamino hydrochloride in 200 ml of ethanol, 60 ml of water and 10 g of NaOH is refluxed for 5 hours and thereafter cooled. The ethanol is distilled off in vacuo and the reaction mixture is then diluted with water, extracted with ether and the ethereal extract is dried over Na2SO4. The ether is distilled off and the solid residue is then distilled in vacuo, affording 40 g of 2-tridecanone oxime. Melting point (after recrystallisation from ether); 51°-53° C.
Reaction SMILES: [Si](O[C@@H]1[C@@]2(C)C(=CC=C3[C@@H]2CC[C@@]2(C)[C@H]3CC=C2[C@H](O)C)C[C@@H](O[Si](C(C)(C)C)(C)C)C1)(C(C)(C)C)(C)C.CC(C)([O-])C.[K+].C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1.O1[C@@H](C(CC)C)C1.[Si]([O:85][C@@H:86]1[C@@:111]2([CH3:112])[C:90](=[CH:91][CH:92]=[C:93]3[C@@H:110]2[CH2:109][CH2:108][C@@:107]2([CH3:113])[C@H:94]3[CH2:95][CH:96]=[C:97]2[C@H:98]([O:100][CH2:101][C@@H:102]([OH:106])[CH:103]([CH3:105])[CH3:104])[CH3:99])[CH2:89][C@@H:88]([O:114][Si](C(C)(C)C)(C)C)[CH2:87]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C1(C)C=CC=CC=1>[OH:85][C@@H:86]1[C@@:111]2([CH3:112])[C:90](=[CH:91][CH:92]=[C:93]3[C@@H:110]2[CH2:109][CH2:108][C@@:107]2([CH3:113])[C@H:94]3[CH2:95][CH:96]=[C:97]2[C@H:98]([O:100][CH2:101][C@@H:102]([OH:106])[CH:103]([CH3:105])[CH3:104])[CH3:99])[CH2:89][C@@H:88]([OH:114])[CH2:87]1
Reactant: CC(C)[C@H](O)CO[C@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)(C)[O-]
Agent: CCC(C)[C@H]1CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)[C@H](O)CO[C@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 61.3 %

Procedure:
Using 1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-hydroxypregna-5,7,16-triene (79.0 mg, 0.141 mmol), potassium t-butoxide (190 mg, 1.69 mmol), dibenzo-18-crown-6(25.0 mg, 0.0694 mmol), toluene (4.5 ml) and (S)-(+)-1,2-epoxy-3-ethylbutane (0.15 ml, 1.43 mmol), alkylation reaction (108° C., 1 hour) and work up were performed by the same procedure as in Example 119, and then the residue was separated by preparative thin layer chromatography (0.5 mm×3, hexane:dichloromethane:ethyl acetate=45:5:2, developed three times) to give a fraction containing 1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-{2(S)-hydroxy-3-methylbutyloxy}pregna-5,7,16-triene (27.8 mg). This was deprotected with tetrahydrofuran (1 ml) and 1M tetra-n-butylammonium fluoride solution in tetrahydrofuran (0.25 ml) (reaction temperature 76° C., reaction period 13 hours) and worked up by the same procedure as in Example 119, and then the residue was purified by preparative thin layer chromatography (0.25 mm×1, dichloromethane:ethanol=15:1, developed twice) to give the title compound as a colorless oil (11.0 mg, 19%).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[CH3:29][N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[CH2:36][NH2:37]>>[CH3:28][N:4]1[C:3]([CH2:2][NH:37][CH2:36][CH:31]2[CH2:32][CH2:33][CH2:34][CH2:35][N:30]2[CH3:29])=[N:11][C:10]2[C:5]1=[N:6][C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])=[N:8][C:9]=2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Reactant: CN1CCCCC1CN
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CNCC3CCCCN3C)n(C)c2n1

Procedure:
4-(8-(bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with (1-methylpiperidin-2-yl)methanamine via General Procedure E to give 4.1 mg of 282 following reverse phase purification. MS (Q1) 490.2 (M)+
Reaction SMILES: [C:1]12([CH2:11][C:12](=[N:14]O)[CH3:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2>O=[Pt]=O.C(O)(=O)C>[C:1]12([CH2:11][CH:12]([NH2:14])[CH3:13])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: CC(CC12CC3CC(CC(C3)C1)C2)=NO
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CC(N)CC12CC3CC(CC(C3)C1)C2
Reaction time: 0.5 h

Procedure:
1-Adamantyl-2-propanone oxime (59 gm.) was dissolved in 775 ml. acetic acid, 10 gm. PtO2 added and the mixture hydrogenated at about 40 lbs. pressure. The solution was filtered and concentrated. The residue was dissolved in 2 liters of ether, added, over 5-10 minutes, to 84 gm. NaHCO3 in 10 liters of water and stirred for 1/2 hour. The ether was separated and concentrated and the residue treated with 50 ml. acetic acid, and concentrated. The acetic acid residue was dissolved in 200 ml. ether, added to 8.4 gm. NaHCO3 in 1 liter of water and this solution added to the main solution. NaOH (53 ml. of 50% solution) was added to the combined aqueous solutions, stirred 5 minutes and extracted with 2 × 1.5 liters of ether. The ether extract was dried and concentrated and the residue distilled to give 42.2 gm. product, b25 161°.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=2[S:5][C:6]=1[CH:7]=O.[CH:13]([CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:14]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:3]2[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=2[S:5][C:6]=1/[CH:7]=[CH:15]/[CH:13]=[O:14]
Reactant: Cc1c(C=O)sc2ccccc12
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1c(/C=C/C=O)sc2ccccc12
Temperature: 80 °C
Yield: 52 %

Procedure:
3-Methylbenzo[b]thiophene-2-carboxaldehyde (4.2 g, 23.8 mmol) was dissolved in dry toluene (100 ml) and treated with (formylmethylene)triphenylphosphorane (7.35 g, 24.2 mmol). The reaction mixture was heated to 80° C. for 10 hours, allowed to cool and the residue was washed with 200 ml of hexane/Et2O 1/1 and then triturated with isopropyl ether to give pure title compound (2.5 g, 12.38 mmol, yield 52.0%), m.p.=90-92+ C.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26](=[O:35])[C:27]3[CH:32]=[CH:31][C:30]([CH2:33]Cl)=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][C@H:9]1[OH:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[CH2:1]([C@H:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26](=[O:35])[C:27]3[CH:32]=[CH:31][C:30]([CH2:33][N:41]4[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]4)=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][C@H:9]1[OH:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: O=C(Oc1ccc(S(=O)(=O)CCN2CC[C@H](Cc3ccccc3)[C@H](O)C2)cc1)c1ccc(CCl)cc1
Product: CN1CCN(Cc2ccc(C(=O)Oc3ccc(S(=O)(=O)CCN4CC[C@H](Cc5ccccc5)[C@H](O)C4)cc3)cc2)CC1
Yield: 27 %

Procedure:
The title compound was prepared from 4-chloromethyl-benzoic acid (3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenyl ester and 4-methylpiperazin in 27% yield as a colorless oil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11]Br)=[C:9]([F:15])[CH:8]=1>C(#N)C>[Br:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:9]([F:15])[CH:8]=1
Reactant: C1CCNC1
Reactant: Fc1cc(Br)ccc1CBr
Solvent: CC#N
Product: Fc1cc(Br)ccc1CN1CCCC1
Temperature: 10 °C
Reaction time: 4 h
Yield: 89.8 %

Procedure:
A 4-L RB flask, equipped a magnetic stirring bar was charged with pyrrolidine (363 g, 426 mL, 5.1 mol) and acetonitrile (2750 mL). The mixture was cooled with an ice bath to 10° C., then solid 4-bromo-2-fluorobenzylbromide (MATRIX, Cat. #: 1707, 375 g, 1.4 mol) was added in 6 portions, keeping temperature below 20° C. The mixture was stirred at RT for 4 h. The solvent was removed under vacuum. Then 2 L of sat. Na2CO3 aq. and 500 mL of water was added, and the mixture was extracted with DCM (3×700 mL). The extract was dried over Na2SO4 and evaporated. The resulting light yellow oil was distilled under vacuum (˜1 mm, bp. 125° C.) to give 324.5 g (90%) of the product as a colorless oil. LCMS (M+H): 258.5.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:21]([OH:23])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]=[CH2:20])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH3:49][O:50][C:51](=[O:57])[C@H:52]([CH:54]([CH3:56])[CH3:55])[NH2:53].CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH3:49][O:50][C:51](=[O:57])[C@@H:52]([NH:53][C:21](=[O:23])[C@@H:9]([NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH:19]=[CH2:20])=[CH:15][CH:16]=1)[CH:54]([CH3:56])[CH3:55]
Reactant: C=CCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)OC)C(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-BOC-O-allyl-tyrosine (5.0 g, 16.3 mmol), HATU (17.9 mmol) and valine methyl ester hydrochloride (32.6 mmol) were dissolved in anhydrous DMF (25 mL). DIPEA (22.7 mL, 65 mmol) was added and the reaction mixture was stirred at rt for 18 h before being partitioned between EtOAc and 1M hydrochloric acid. The organic phase was then washed sequentially with 1M hydrochloric acid and brine before being dried (MgSO4), filtered and concentrated in vacuo. Purification was achieved using flash chromatography, eluting with a gradient of (50/70) petroleum ether to EtOAc to yield a white solid, 6.08 g, 69%. Rf=0.29 (1/2 EtOAc/(50/70) petroleum ether). m.p. 74-76° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>CCOC(C)=O.O.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]>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Brc1ccccn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCN(c2ccccn2)CC1
Temperature: 100 °C
Yield: 312.9 %

Procedure:
The reaction mixture of tert-butyl piperidin-4-ylcarbamate (200 mg, 0.10 mmol), 2-bromopyridine (205 mg, 1.30 mmol), Pd2(dba)3 (18.0 mg, 0.02 mmol), Xantphos (35.0 mg, 0.06 mmol) and Cs2CO3 (490 mg, 1.50 mmol) was heated at 100° C. for 1 day. Additional 2-bromopyridine (205 mg, 1.30 mmol), Pd2(dba)3 (18.0 mg, 0.02 mmol), Xantphos (35.0 mg, 0.06 mmol), Cs2CO3 (490 mg, 1.50 mmol) were added to the reaction mixture, and heated at 100° C. for 1 day. The reaction mixture was cooled to room temperature, diluted with EtOAc and water. The separated aqueous layer was extracted with EtOAc, the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (EtOAc) to give tert-butyl 1-(pyridin-2-yl)piperidin-4-ylcarbamate (86.8 mg, 31%) as a pale yellow solid. m/z=278.06 [M+1]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1)[CH3:2].Cl.[Br:13]Br>C(OCC)C.C(Cl)(Cl)Cl>[Br:13][CH2:10][C:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1)=[O:11]
Reactant: CCc1ccc(C(C)=O)cc1
Reactant: BrBr
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CCc1ccc(C(=O)CBr)cc1
Reaction time: 4 h

Procedure:
20 mmol of 1-(4-ethylphenyl)ethan-1-one, 1 ml conc. HCl were mixed in 20 ml diethyl ether at 0° C. under nitrogen. To this solution a solution of 20 mmol Br2 in 20 ml chloroform was added drop wise and left for four hours and then concentrated in vacuo to obtain 2-bromo-1-(4-ethylphenyl)ethan-1-one.
Reaction SMILES: FC(F)(F)S(O[C@H:7]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)[C:8]([F:11])([F:10])[F:9])(=O)=O.C([O-])([O-])=O.[K+].[K+].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH2:38][NH2:39])[CH:33]=[CH:34][C:35]=1[O:36][CH3:37].O>C1CCCCC1>[Cl:19][C:14]1[CH:13]=[C:12]([CH:7]([NH:39][CH2:38][C:32]2[CH:33]=[CH:34][C:35]([O:36][CH3:37])=[C:30]([O:29][CH3:28])[CH:31]=2)[C:8]([F:11])([F:10])[F:9])[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: COc1ccc(CN)cc1OC
Reactant: O=S(=O)(O[C@H](c1ccc(Cl)c(Cl)c1)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCCCC1
Solvent: O
Product: COc1ccc(CNC(c2ccc(Cl)c(Cl)c2)C(F)(F)F)cc1OC
Yield: 36.1 %

Procedure:
A solution of 144 (10.9 g, 28.9 mmol), K2CO3 (5.99 g, 43.4 mmol) and (3,4-dimethoxyphenyl)methanamine (6.77 g, 40.5 mmol) in cyclohexane (200 mL) and heated to 65° C. for 24 h. Water was added and the organic layer was concentrated and the crude product was purified by SiO2 chromatography eluting with EtOAc/hexane (5 to 20% EtOAc) to afford 4.11 g (36.1%) of 1-(3,4-dichlorophenyl)-N-(3,4-dimethoxybenzyl)-2,2,2-trifluoroethanamine (146).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Br[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)CC(O)=O.Cl>O1CCOCC1.O.[Cu]I>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:20]2[CH:21]=[CH:22][C:17]([C:14]3[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=3)=[CH:18][CH:19]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(O)cc1
Reactant: Brc1ccc(-c2ccccc2)cc1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Oc2ccc(-c3ccccc3)cc2)cc1
Temperature: 90 °C
Reaction time: 18 h
Yield: 132.3 %

Procedure:
To a solution of 4-methoxyphenol (3.99 g, 32.17 mmol) and 4-bromobiphenyl (5 g, 21.45 mmol) in anhydrous dioxane (40 mL) were added cesium carbonate (13.98 g, 42.9 mmol) and N,N-dimethylglycine.HCl (0.898 g, 6.4 mmol). The reaction mixture was flushed with nitrogen. Copper (I) iodide (0.408 g, 2.145 mmol) was added and the reaction mixture was stirred at 90° C. for 18 h under an atmosphere of nitrogen. The mixture was diluted with water (100 mL) and extracted with EtOAc (250 mL). Aqueous layer was re-extracted with EtOAc (150 mls). The organic layers were combined, dried over anhydrous Na2SO4, and concentrated to obtain the title product 7.84 g.