Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](O)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23][CH3:24])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23][CH3:24])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSc1ccccc1C1(O)CCN(C(=O)OCc2ccccc2)CC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSc1ccccc1C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 16 h
Yield: 73.2 %

Procedure:
A solution of 1-benzyloxycarbonyl-4-hydroxy-4-(2-methylthiophenyl)piperidine (2.89 g) in dichloromethane (80 mL) was treated with 6.2 mL of trifluoroacetic acid followed by 25.7 mL of triethylsilane and stirred for 16 hours. At the end of this period, the volatile material was distilled under reduced pressure and the resulting residue was chromatographed. Elution with 3:1 hexane:ethyl acetate afforded the named material (2.02 g); MS: 342(M+1); NMR: 1.5-1.6 (br, 2), 1.8-1.9 (m, 2), 2.45 (s, 3), 2.8-2.9 (m, 2), 3.1-3.2 (m, 1), 4.3 (br, 2), 5.1 (s, 2), 7.1-7.2 (m, 2), 7.2-7.3 (m, 2), 7.3-7.4 (m, 5).
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[Br:7][C:8]1[CH:9]=[C:10]([NH2:19])[CH:11]=[N:12][C:13]=1[O:14][CH2:15][CH:16]1[CH2:18][CH2:17]1.N1C=CC=CC=1.Cl>C(Cl)Cl>[Br:7][C:8]1[CH:9]=[C:10]([NH:19][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:11]=[N:12][C:13]=1[O:14][CH2:15][CH:16]1[CH2:18][CH2:17]1
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1cnc(OCC2CC2)c(Br)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1cnc(OCC2CC2)c(Br)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 30 %

Procedure:
Ethylsulfonyl chloride (170 uL, 1.8 mmol) was added to a stirred solution of 5-bromo-6-(cyclopropylmethoxy)pyridin-3-amine (440 mg, 1.8 mmol) and pyridine (725 uL) in DCM (4.5 mL) at 0° C. under nitrogen. After the mixture was allowed to warm to rt and stir for 12 h, it was treated with 1N HCl (15 mL) and extracted with DCM (3×15 mL); the combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography using a gradient of EtOAc (0 to 100%) in DCM to afford the title compound (181 mg, 88%) as a tan solid. LCMS (M+H)+=336.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=1.C([Li])CCC.CN([CH:26]=[O:27])C>>[C:14]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[CH:26]=[O:27])([CH3:17])([CH3:16])[CH3:15]
Reactant: CN(C)C=O
Reactant: CC(C)(C)c1cc(Br)ccc1N1CCCCC1
Agent: [Li]CCCC
Product: CC(C)(C)c1cc(C=O)ccc1N1CCCCC1
Yield: 105.5 %

Procedure:
In a manner analogous to example 1 d, the process is carried out by a reaction of 9.9 g (34 mmol) of 1-(4-bromo-2-tert-butylphenyl)piperidine with 20 ml (50 mmol) of a 2.5M solution of n-butyllithium and 3.9 ml (50 mmol) of DMF. 8.8 g of 3-tert-butyl-4-piperidin-1-ylbenzaldehyde are obtained in the form of a yellow oil (yield=100%).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:17]=[CH:16][C:13]([CH2:14]Br)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([O:22][P:23]([O:29][Si](C)(C)C)[O:24][Si](C)(C)C)(C)C>>[C:1]1([S:7]([C:10]2[CH:17]=[CH:16][C:13]([CH2:14][P:23](=[O:22])([OH:29])[OH:24])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc(CBr)cc1
Reactant: C[Si](C)(C)OP(O[Si](C)(C)C)O[Si](C)(C)C
Product: O=P(O)(O)Cc1ccc(S(=O)(=O)c2ccccc2)cc1
Reaction time: 18 h
Yield: 32 %

Procedure:
A solution of 4.3 g (14 mmol) of 4-(phenylsulfonyl)benzyl bromide and 30 g (0.1 mole) of tris-trimethylsilylphosphite was heated at 120° C. for 18 hours. The excess tris-trimethylsilylphosphite was distilled off under reduced pressure. The residue was dissolved in 200 ml of 9:1 tetrahydrofuran/water and was allowed to stand at room temperature for 18 hours. The tetrahydrofuran was evaporated and the resulting solids were filtered and washed with water to give 1.4 g of product; m.p. 217-219° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[C:6]([CH3:8])[O:5][N:4]=1.[N-:9]=[N+:10]=[N-:11].[Na+].O>CC(C)=O>[N:9]([CH2:2][C:3]1[CH:7]=[C:6]([CH3:8])[O:5][N:4]=1)=[N+:10]=[N-:11]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(CBr)no1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(CN=[N+]=[N-])no1
Reaction time: 48 h

Procedure:
To a solution of the 3-bromomethyl-5-methyl-isoxazole in acetone is added NaN3 at rt. The reaction mixture is then stirred for about 48 h. Then, the reaction mixture is poured into water and extracted with EtOAc, dried and evaporated.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[CH:16]1[O:20][CH2:19][CH2:18][O:17]1)([O-:3])=[O:2].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[C:26](Cl)=[O:27].N1C=CC=CC=1>ClCCl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:23]([O:22][CH3:21])[CH:24]=3)[CH2:12][CH2:11]2)=[CH:6][C:5]=1[CH:16]1[O:20][CH2:19][CH2:18][O:17]1)([O-:3])=[O:2]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1C1OCCO1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C(=O)N2CCN(c3ccc([N+](=O)[O-])c(C4OCCO4)c3)CC2)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(2-Nitro-5-piperazinylphenyl)-1,3-dioxolane (6.63 g, 24 mmol) was added portionwise over 1 hour to a stirred solution of 3,4-dimethoxybenzoyl chloride (4.76 g, 24 mmol) and pyridine (4.04 g, 48 mmol) in dry dichloromethane (200 mL). The mixture was stirred overnight at room temperature, washed twice with water and concentrated in vacuo to provide 2-[2-nitro-5-[4-(3,4-dimethoxybenzoyl)piperazinyl]phenyl]-1,3-dioxolane used without further purification below.
Reaction SMILES: O1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:14]=[CH:13][C:9]2[N:10]=[CH:11][NH:12][C:8]=2[CH:7]=1.[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:21]2[CH:5]=[N:4][N:3]=[C:2]2[C:6]2[CH:14]=[CH:13][C:9]3[NH:10][CH:11]=[N:12][C:8]=3[CH:7]=2)=[CH:18][CH:17]=1
Reactant: c1nc2ccc(-c3nnco3)cc2[nH]1
Reactant: NCc1ccc(Cl)cc1
Product: Clc1ccc(Cn2cnnc2-c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from 5-(1,3,4-oxadiazol-2-yl)benzimidazole (186 mg, 1 mmol) and 4-chlorobenzylamine (0.5 ml) as described above; yield: 0.063 g (20.4%);
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:46]1([CH2:52][CH2:53][CH2:54][NH:55][C:56](=[O:78])[C@H:57]([CH2:67][CH2:68][CH2:69][NH:70][C:71]([O:73][C:74]([CH3:77])([CH3:76])[CH3:75])=[O:72])[NH:58][CH2:59][CH2:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.C([O-])(=O)C>O1CCCC1>[C:46]1([CH2:52][CH2:53][CH2:54][NH:55][C:56](=[O:78])[C@H:57]([CH2:67][CH2:68][CH2:69][NH:70][C:71]([O:73][C:74]([CH3:76])([CH3:75])[CH3:77])=[O:72])[N:58]([C:10](=[O:12])[CH2:9][NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:59][CH2:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NCCc1ccccc1)C(=O)NCCCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(=O)[O-]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCC[C@@H](C(=O)NCCCc1ccccc1)N(CCc1ccccc1)C(=O)CNC(=O)OC(C)(C)C
Yield: 70.2 %

Procedure:
cold solution (0° C.) of Boc-glycine (543 mg, 3.1 mmol), diisopropylethylamine (1 ml, 6.2 mmol), and tetrahydrofuran (10 ml) was treated with PyBrop (1.45 g, 3.1 mmol), followed by the addition of Nα-phenethyl-Nδ-Boc-ornithine 3-phenylpropylamide (1.28 g, 2.8 mmol) in tetrahydrofuran (5 ml). The resulting solution was acetate. The filtrate was concentrated in vacuo and the product purified by chromatography (silica gel—hexane/ethyl acetate) to give N-Boc-glycyl-Nα-phenethyl-Nδ-Boc-ornithine 3-phenylpropylamide (1.2 g).
Reaction SMILES: [BH4-].[Li+].O1CCCC1.[CH2:8]([S:24][CH2:25][CH2:26][C:27](OCC)=[O:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>O>[CH2:8]([S:24][CH2:25][CH2:26][CH2:27][OH:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCCCCCCSCCC(=O)OCC
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCCCCCSCCCO
Yield: 99.1 %

Procedure:
To a slurry of 147.4 mg of lithium borohydride in ml of tetrahydrofuran is added 2.4 g of 3-(hexadecylthio)propanoic acid, ethyl ester. This mixture is refluxed overnight, poured into water and extracted with ethyl acetate, to give 2.1 g of the desired compound.
Reaction SMILES: I[C:2]1[C:11]([NH:12][C:13](=[O:15])[CH3:14])=[C:10]([Cl:16])[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=1[OH:17].[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20]>CCN(CC)CC.O1CCOCC1.[Cu]I>[CH3:18][Si:19]([C:22]#[C:23][C:2]1[C:11]([NH:12][C:13](=[O:15])[CH3:14])=[C:10]([Cl:16])[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=1[OH:17])([CH3:21])[CH3:20]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1cc(Cl)c(NC(C)=O)c(I)c1O
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)c1cc(Cl)c(NC(C)=O)c(C#C[Si](C)(C)C)c1O
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
To a solution of methyl 3-iodo-4-acetamido-5-chlorosalicylate (2 g) in distilled Et3N (60 ml) and dioxane (40 ml), trimethylsilylacetylene (1 ml), CuI (23 mg), and PdCl2 (PPh3)2 (152 mg) were added. The reaction mixture was stirred at 40° C. for 1.5 hours, after which time the solvents were removed in vacuo. A sample of the residue was purified by column chromatography for analytical purposes eluting with diethyl ether/hexane mixtures to yield the intermediate methyl 3-trimethylsilylethynyl-4-acetamido-5-chloro-salic ylate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([OH:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:23]I>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([O:20][CH3:23])([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccccc2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
1-t-Butoxycarbonyl-4-hydroxy-4-phenylpiperidine (300 mg, 1.1 mmol) was dissolved in tetrahydrofuran (9 ml). Thereto was added sodium hydride (43 mg, 1.1 mmol), and the resulting solution was stirred at a room temperature for 1 hour. The reaction solution was mixed with methyl iodide (0.1 ml, 1.6 mmol) and again stirred for 17 hours. The solvent was evaporated under a reduced pressure, and the thus obtained residue was mixed with ethyl acetate and water. The reaction product was extracted with ethyl acetate, washed with water and saturated brine and dried with anhydrous sodium sulfate. Then the compound obtained by the evaporation of the solvent under a reduced pressure was separated and purified by a silica gel column chromatography to obtain 240 mg of the title compound (0.82 mmol, 76% in yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][C@@H:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][CH2:26]2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[C:35](Cl)(=[O:37])[CH3:36]>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:14]=2[CH2:23][N:24]([C:35](=[O:37])[CH3:36])[C@@H:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][CH2:26]2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN[C@H]2CCc3ccccc32)c1
Reactant: CC(=O)Cl
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(C(C)=O)[C@H]2CCc3ccccc32)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: [2′-((S)-Indan-1-ylaminomethyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid methyl ester and acetyl chloride.
Reaction SMILES: [OH:1][C@:2]1([C:16]2[S:17][CH:18]=[CH:19][N:20]=2)[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][CH2:3]1.C1C(=O)N([Br:28])C(=O)C1.[O-]S([O-])=O.[Na+].[Na+]>CN(C=O)C.O>[Br:28][C:18]1[S:17][C:16]([C@@:2]2([OH:1])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:4][CH2:3]2)=[N:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@](O)(c2nccs2)CC1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@](O)(c2ncc(Br)s2)CC1
Temperature: 40 °C
Yield: 94.7 %

Procedure:
The product of Step 2 (14.5 g, 48.6 mmol) was dissolved in DMF (58 mL) and then treated with NBS (11.24 g, 63.2 mmol) and warmed to 40° C. for 3 hours. The reaction was quenched with Na2SO3 (3.0 g, 24.30 mmol) in H2O (50 mL) and the solution was then extracted with EtOAc (100 mL), washed with brine (50 mL) and then chromatographed on silica gel to afford tert-butyl (4R)-4-(5-bromo-1,3-thiazol-2-yl)-4-hydroxyazepane-1-carboxylate (18.3 g, 46 mmol). MS ESI: [M+H-tBu]+ m/z 320.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)[CH2:3]1.C[O:20][C:21]([CH:23]1[CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][C:29]=2[S:32](Cl)(=[O:34])=[O:33])[CH2:24]1)=[O:22]>>[CH3:1][C@H:2]1[CH2:3][N:4]([C:8]2[CH:9]=[CH:10][C:11]([O:14][C:15]([F:18])([F:16])[F:17])=[CH:12][CH:13]=2)[CH2:5][CH2:6][N:7]1[S:32]([C:29]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:30]=1[CH2:31][CH:23]([C:21]([OH:22])=[O:20])[CH2:24]2)(=[O:34])=[O:33]
Reactant: C[C@H]1CN(c2ccc(OC(F)(F)F)cc2)CCN1
Reactant: COC(=O)C1Cc2cccc(S(=O)(=O)Cl)c2C1
Product: C[C@H]1CN(c2ccc(OC(F)(F)F)cc2)CCN1S(=O)(=O)c1cccc2c1CC(C(=O)O)C2

Procedure:
The compound 4-[2-(S)-Methyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indan-2-carboxylic acid was prepared from 3-(S)-methyl-1-(4-trifluoromethoxy-phenyl)-piperazine and 4-chlorosulfonyl-indan-2-carboxylic acid methyl ester following the procedure outlined in Example 79. 1H NMR (400 MHz, DMSO-d6): δ 7.65 (d, 1H), 7.53 (d, 1H), 7.38 (t, 1H), 7.18 (d, 2H), 6.98-6.92 (m, 2H), 4.15-4.00 (m, 1H), 3.60-3.12 (m, 9H), 2.83-2.75 (m, 1H), 2.64-2.50 (m, 1H), 1.18 (d, 3H); MS (ESI): 485.3 (M+H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:17]2([C:20]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[CH:34]=[CH:33][C:32]([S:35]([N:38]5[CH2:42][CH2:41][CH2:40][C@@H:39]5[CH2:43][OH:44])(=[O:37])=[O:36])=[CH:31][CH:30]=4)[N:24]=3)=[O:21])[CH2:19][CH2:18]2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([C:17]2([C:20]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[CH:34]=[CH:33][C:32]([S:35]([N:38]5[CH2:42][CH2:41][CH2:40][C@@H:39]5[CH2:43][OH:44])(=[O:37])=[O:36])=[CH:31][CH:30]=4)[N:24]=3)=[O:21])[CH2:18][CH2:19]2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: COc1ccc(C2(C(=O)Nc3cccc(-c4ccc(S(=O)(=O)N5CCC[C@@H]5CO)cc4)n3)CC2)cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C2(C(=O)Nc3cccc(-c4ccc(S(=O)(=O)N5CCC[C@@H]5CO)cc4)n3)CC2)cc1O
Yield: 33.2 %

Procedure:
(R)-1-(3-(Benzyloxy)-4-methoxyphenyl)-N-(6-(4-(2-(hydroxymethyl)pyrrolidin-1-ylsulfonyl)phenyl)pyridin-2-yl)cyclopropanecarboxamide (28 mg, 0.046 mmol) was dissolved in ethanol (3 mL). Palladium on charcoal (10%, 20 mg) was added and the reaction was stirred overnight under 1 atm of hydrogen. The catalyst was filtered off and the product was isolated by silica gel chromatography (50-80% EtOAc in hexane) to provide (R)-1-(3-hydroxy-4-methoxyphenyl)-N-(6-(4-(2-(hydroxymethyl)pyrrolidin-1-ylsulfonyl)phenyl)pyridin-2-yl)cyclopropanecarboxamide (8 mg, 34%). ESI-MS m/z calc. 523.4, found 524.3 (M+1)+. Retention time of 3.17 minutes.
Reaction SMILES: N[C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.N([O-])=[O:14].[Na+]>OS(O)(=O)=O.O>[OH:14][C@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:10]([OH:12])=[O:11]
Reactant: O=N[O-]
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)[C@H](O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 54.2 %

Procedure:
Following the procedure of Johnson, 1980, D-phenylalanine (16.5 g, 100 mmol) was dissolved in 1N H2SO4 (150 ml) and cooled to 0° C. A solution of NaNO2 (10.5 g, 150 mmol) in water (50 ml) was added dropwise. The mixture was stirred for 2 h at 0° C. and for 3 h at 25° C. The product was extracted into ether (5×100 ml) and the combined ether extracts were dried over Na2SO4 and concentrated in vacuo to about 100 ml. Hexane (300 ml) was added and the product which crystallized out was collected by vacuum filtration to afford the title compound as a colorless solid (9 g, 54%); mp=124°-125° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:15]([Mg]Br)=[CH2:16].C1COCC1>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH:15]=[CH2:16])([OH:14])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=C[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
4-Oxo-piperidine-1-carboxylic acid tert-butyl ester (2.5 g, 12.5 mmol) was dissolved in 25 ml of diethylether and cooled to 0° C. A 1M solution of vinylmagnesiumbromide in THF (16.3 ml, 16.31 mmol) was added dropwise at 0° C. After 90 min stirring at 0° C., the reaction mixture was quenched with NH4Cl solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2 SO4 and evaporated. The crude product was further purified by flash chromatography (silicagel, cyclohexane/ethylacetate 4:1).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[C:4]([Cl:12])[CH:3]=1.[NH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.C(N(CC)CC)C>C(O)CCC>[C:24]([O:23][C:21]([N:18]1[CH2:19][CH2:20][CH:15]([CH2:14][NH:13][C:2]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[C:4]([Cl:12])[CH:3]=2)[CH2:16][CH2:17]1)=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: COC(=O)c1cnc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: COC(=O)c1cnc(Cl)cc1NCC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 84 %

Procedure:
A solution of methyl 4,6-dichloronicotinate (1.20 g, 5.8 mmol), tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (1.24 g, 5.8 mmol) and triethylamine (4.09 mL, 29.1 mmol) in n-butanol (13 mL) was heated at 120° C. for 90 minutes by microwave irradiation. The solvent was evaporated and the mixture was purified by flash chromatography on silica, eluting with ethyl acetate-hexane (1:4), to give methyl 4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methylamino)-6-chloronicotinate as a colourless solid (1.87 g, 84%).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[NH:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH:7]=[CH:6]1.[Cl:14][C:15]1[N:20]=[CH:19][C:18]([C:21](Cl)=[O:22])=[CH:17][CH:16]=1.CO>C(Cl)Cl>[Cl:14][C:15]1[N:20]=[CH:19][C:18]([C:21]([C:7]2[C:8]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:5][CH:6]=2)=[O:22])=[CH:17][CH:16]=1
Reactant: c1cnc2[nH]ccc2c1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CO
Product: O=C(c1ccc(Cl)nc1)c1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 89.1 %

Procedure:
Into a round bottom flask was added aluminum trichloride (16.0 g, 0.12 mol) and methylene chloride (100.0 mL) under an atmosphere of nitrogen. Into the reaction mixture, was added 1H-Pyrrolo[2,3-b]pyridine 1 (3.2 g, 0.027 mol) in methylene dichloride (20.0 mL). The reaction was stirred at room temperature for 70.0 minutes, and then 6-Chloropyridine-3-carbonyl chloride 8 (5.4 g, 0.031 mol) in methylene chloride (10.0 mL) was added. The reaction mixture was stirred at room temperature for 3 hours. Methanol (10 mL) was added to the reaction mixture and the solvent was evaporated in vacuo. The residue was poured into water, and the precipitated product was removed by filtration. The aqueous layer was extracted with ethyl acetate, and then the organic layer was dried and concentrated and combined with the solid isolated by filtration to give 7 (6.2 g, yield 88.6%) as a white solid (M+1=258).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[Cl:11])=[N+:2]=[N-:3].[Br:12]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C.O>C1C=CC=CC=1>[N:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][Br:12])=[CH:6][C:5]=1[Cl:11])=[N+:2]=[N-:3]
Reactant: Cc1ccc(N=[N+]=[N-])c(Cl)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: c1ccccc1
Product: [N-]=[N+]=Nc1ccc(CBr)cc1Cl
Yield: 57.6 %

Procedure:
4-Azido-3-chlorotoluene (17.14 g, 0.1 mol) was dissolved in dry benzene (80 ml) and thereto were added N-bromosuccinimide (19.6 g, 0.11 mol) and AIBN (1.64 g, 0.01 mol). The resulting mixture was refluxed in the shade in a nitrogen stream for 10 hr. Water (100 ml) was added and the mixture was filtrated. The aqueous layer of the filtrate was taken and extracted with ether. The organic layers were combined, washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained brown oil was purified by silica gel column chromatography (eluent; hexane) to give the title compound (14.2 g, yield 58%). m.p.: 75-77° C.
Reaction SMILES: [CH3:1][O:2][C:3]([F:18])([F:17])[C:4]([C:7]([C:9]([F:16])([F:15])[C:10]([F:14])([F:13])[O:11][CH3:12])=[O:8])([F:6])[F:5].Cl[CH2:20][CH2:21][OH:22].C([O-])([O-])=O.[K+].[K+]>CCOCC>[CH3:12][O:11][C:10]([F:13])([F:14])[C:9]([F:15])([F:16])[C:7]1([C:4]([F:6])([F:5])[C:3]([F:17])([F:18])[O:2][CH3:1])[O:22][CH2:21][CH2:20][O:8]1
Reactant: COC(F)(F)C(F)(F)C(=O)C(F)(F)C(F)(F)OC
Reactant: OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: COC(F)(F)C(F)(F)C1(C(F)(F)C(F)(F)OC)OCCO1
Reaction time: 8 h
Yield: 60.9 %

Procedure:
A mixture of 58 g (about 0.2 mol) of crude bis(2-methoxytetrafluoroethyl) ketone, 16.9 g (0.21 mol) of 2-chloroethanol, and 50 mL of ether was stirred while 29.0 g (0.21 mol) of anhydrous K2CO3 were added in portions with cooling. The resulting reaction mixture was stirred overnight, filtered and distilled to give 40.7 g of 2,2-bis(2-methoxytetra- fluoroethyl)-1,3-dioxolane, b.p. 81° at 40 Pa (0.3 mm), m.p. 39°-40° . Dissolution of the resulting filter cake in water, filtration of the resulting mixture and drying gave another 8.5 g of product, m.p. 38.5°-40° , for a total yield of 49.2 g (74%). IR (CCl4) and NMR (CCl4) of the product were consistent with the assigned structure. Anal.: Calcd. for C9H10F8O4 : C, 32.35; H, 3.02; F, 45.48. Found: C, 32.14; H, 3.19; F, 45.22.