Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].N1C=CC=CC=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>ClCCl>[C:15]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8])(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccncc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1cnccc1C

Procedure:
To solution of 3-amino-4-methylpyridine (540.2 Mg, 5.0 Mmol, 1 equiv) in dichloromethane (20 mL) was added pyridine (0.8 mL, 10.0 Mmol, 2 equiv) and acetic anhydride (0.57 mL, 6.0 Mmol, 1.2 equiv). The resultant solution was stirred at room temperature for 16 h and concentrated in vacuo to provide a crude residue. The residue was diluted with dichloromethane (200 mL), and washed with saturated sodium bicarbonate aqueous solution (50 mL) and brine (50 mL). The organic layer was separated, dried over sodium sulfate, and concentrated in vacuo to yield 3-acetylamino-4-methylpyridine (400.2 Mg) as yellow solid which was used without further purification.
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:8][CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+].C([O-])(=O)C([O-])=O>CCO>[C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:8][CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:28][C:27]3[CH:30]=[CH:31][C:24]([I:23])=[CH:25][CH:26]=3)[CH2:13][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrCc1ccc(I)cc1
Reactant: c1ccc(C(OCCC2CCNCC2)c2ccccc2)cc1
Agent: O=C([O-])C(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Ic1ccc(CN2CCC(CCOC(c3ccccc3)c3ccccc3)CC2)cc1

Procedure:
4-[2-(diphenylmethoxy)ethyl]piperidine (0.23 g, 0.77 mmol) was reacted with 4-iodo benzyl bromide (0.76 g, 2.5 mmol) and K2CO3 (1.00 g, 7 mmol) in EtOH (10 mL) to give a thick oil, 0.17 g (%). 1H NMR (300 MHz, CDCl3): 1.21-1.63 (7H, m), 1.87-1.93 (t, J=11 Hz, 2H, N(CH2)—), 2.79-2.83 (bd, J=12 Hz, 2H, N(CH2)—), 3.41-3.49 (4H, m), 5.31 (s, 1H, Ph2CHO—), 7.05-7.63 (14H, m, ArH). Free base was converted into its oxalate sale, m.p.=160-161 ° C. Anal. C27H30INO. (COOH)2.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C@H:9]2[N:19]3[C:20]4[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=4[N:16]=[CH:17][C:18]3=[O:21])[CH2:10]2)[CH2:4][CH2:3]1.S1C2C=C(C=O)N=CC=2OC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.CO>[NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C@@H:9]2[N:19]3[C:20]4[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=4[N:16]=[CH:17][C:18]3=[O:21])[CH2:10]2)[CH2:4][CH2:3]1
Reactant: NC1CCN(C[C@@H]2Cn3c(=O)ccc4ncc(=O)n2c43)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=Cc1cc2c(cn1)OCS2
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: NC1CCN(C[C@H]2Cn3c(=O)ccc4ncc(=O)n2c43)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
(2R)-2-[(4-Amino-1-piperidinyl)methyl]-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione (100 mg, 0.332 mmol) was stirred with [1,3]oxathiolo[5,4-c]pyridine-6-carbaldehyde (for a synthesis see WO2004058144 Example 61) (45 mg, 0.811 eq.) in chloroform:methanol (9:1, v:v, 5 ml) at room temperature for 2 hours; the mixture was then treated with sodium triacetoxyborohydride (211 mg, 3.0 eq.) with vigorous stirring at room temperature for 30 mins. The mixture was quenched by addition of saturated aqueous sodium hydrogen carbonate (1 ml). DCM (10 ml) was added and vigorous stirring was continued for 10 mins, followed by separation of the phases (hydrophobic frit). The organic phase was evaporated under reduced pressure and the crude product was purified by column chromatography on silica (eluting with 0-12% (2M NH3 in MeOH) in DCM). Appropriate fractions were combined and evaporated under reduced pressure and dried on the vacuum line over the weekend to give the free base of the title compound as a pale yellow foam (70 mg, 44.3%)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23]([OH:25])=O)[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH:28][CH2:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32][CH:31]=1)[CH3:27]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:22][C:23]([N:28]([CH2:26][CH3:27])[CH2:29][C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:32][CH:31]=2)=[O:25])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: CCNCc1c[nH]c2ccccc12
Product: CCN(Cc1c[nH]c2ccccc12)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with ethyl-(1H-indol-3-ylmethyl)-amine
Reaction SMILES: [CH3:1][C:2]1([CH:23]=O)[CH2:6][O:5][C:4]([C:7]2[CH:8]=[N:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][N:17]3[CH2:21][CH2:20][CH2:19][CH:18]3[CH3:22])=[CH:11][CH:12]=2)=[N:3]1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClC(Cl)C>[CH3:1][C:2]1([CH2:23][N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][N:17]3[CH2:21][CH2:20][CH2:19][CH:18]3[CH3:22])=[N:9][CH:8]=2)=[N:3]1
Reactant: CC1CCCN1CCCOc1ccc(C2=NC(C)(C=O)CO2)cn1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: O
Product: CC1CCCN1CCCOc1ccc(C2=NC(C)(CN3CCCC3)CO2)cn1
Temperature: 22 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
A solution of 4-methyl-2-{6-[3-(2-methylpyrrolidin-1-yl)propoxy]pyridin-3-yl}-4,5-dihydro-1,3-oxazole-4-carbaldehyde ax57 (273 mg, ca. 80% pure, ca. 0.66 mmol) in dichloroethane (4 ml) is treated with pyrrolidine (0.27 ml, 3.28 mmol) and sodium triacetoxyborohydride (0.35 g, 1.64 mmol), and the turbid solution is stirred at 22° C. overnight. Fresh pyrrolidine (0.145 ml, 1.64 mmol) and sodium triacetoxyborohydride (0.35 g, 1.64 mmol) are added and the solution is stirred for an additional 2 hours at room temperature. Water is then added and the mixture stirred vigorously for 5 minutes. Extraction is performed with dichloromethane until the organic extract does not contain significant UV-active spots. The combined organic layers are dried over sodium sulfate and concentrated to yield a brown oil. The product is purified by chromatography over silicagel (eluent: gradient 10 to 20% triethylamine in 90 to 80% hexanes) to afford 66 mg of 5-[4-methyl-4-(pyrrolidin-1-ylmethyl)-4,5-dihydro-1,3-oxazol-2-yl]-2-[3-(2-methylpyrrolidin-1-yl)propoxy]pyridine 33.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]([C:16]#[N:17])[C:13]3[N:18]=[CH:19][NH:20][C:12]=3[CH:11]=2)=[CH:6][C:5]=1[C:21]([F:24])([F:23])[F:22])[CH3:2].[Br:25][CH2:26][CH2:27]O.C[N+](CC(O)=O)(C)C>C1COCC1>[Br:25][CH2:26][CH2:27][N:20]1[C:12]2[CH:11]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[C:5]([C:21]([F:23])([F:24])[F:22])[CH:6]=3)[N:15]=[C:14]([C:16]#[N:17])[C:13]=2[N:18]=[CH:19]1
Reactant: OCCBr
Reactant: CCOc1ccc(-c2cc3[nH]cnc3c(C#N)n2)cc1C(F)(F)F
Agent: C[N+](C)(C)CC(=O)O
Solvent: C1CCOC1
Product: CCOc1ccc(-c2cc3c(ncn3CCBr)c(C#N)n2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6-(4-Ethoxy-3-trifluoromethyl-phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (300 mg, 0.90 mmol) was dissolved in THF (10 ml), 2-bromoethanol was added (225 mg, 1.80 mmol) followed by betaine (738 mg, 1.80 mmol), and the mixture was stirred at room temperature for 3 hours. A further 0.5 equivalents of betaine (0.45 mmol, 162 mg) was added and the mixture was stirred at room temperature for a further hour. Mixture was partitioned between ethyl acetate (20 ml) and water (20 ml). Organics were dried and evaporated then flash chromatographed over silica (10 g Combiflash cartridge, DCM to 1% methanol in DCM) to afford a white solid which was mixture of N-1 and N-3 alkylated products. Mixture was flash chromatographed over silica (10 g Flashmaster cartridge, toluene to 20% ethyl acetate in toluene) to afford 130 mg of 1-(2-bromo-ethyl)-6-(4-ethoxy-3-trifluoromethyl-phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile as a white solid. 1H NMR (DMSO) δ 8.80 (s, 1H), 8.74 (s, 1H), 8.48-8.39 (m, 2H), 7.44 (d, 1H), 4.88 (t, 2H), 4.29 (q, 2H), 4.05 (t, 2H), 1.40 (t, 3H).
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][C:10]1[C:15]([Cl:16])=[C:14]([Cl:17])[CH:13]=[CH:12][C:11]=1[CH2:18][CH2:19][NH2:20].Cl>CO.CCOCC>[OH:7][CH2:8][CH2:9][C:10]1[C:15]([Cl:16])=[C:14]([Cl:17])[CH:13]=[CH:12][C:11]=1[CH2:18][CH2:19][NH2:20]
Reactant: NCCc1ccc(Cl)c(Cl)c1CCOC1CCCCO1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: NCCc1ccc(Cl)c(Cl)c1CCO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
81 g of the product obtained above according to (b) are dissolved in 38 ml of methanol. 80 ml of a saturated solution of hydrogen chloride in ether are added, the temperature being kept between 20° and 25° C. The mixture is stirred for 30 minutes at room temperature and then concentrated to dryness. The residue is dissolved in 250 ml of water, washed twice with ethyl ether, rendered alkaline with a solution of NaOH and extracted with CH2Cl2. After drying over MgSO4, the extract is concentrated to dryness, the residue is taken up in 800 ml of isopropyl ether, an insoluble material is filtered off on Celite, the filtrate is concentrated under vacuum to about 300 ml and seeded with crystals of amino alcohol and the mixture is stirred overnight. The crystals are filtered off and rinsed with isopropyl ether and then with n-pentane to give 30.2 g of the expected product. M.p.=90°-91° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[CH3:12][O:13][C:14](=[O:40])[CH2:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([C:22]2[CH:27]=[CH:26][C:25]([NH:28][CH2:29][C@H:30]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH3:31])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1>C1COCC1>[CH3:12][O:13][C:14](=[O:40])[CH2:15][C@H:16]1[CH2:17][CH2:18][C@H:19]([C:22]2[CH:23]=[CH:24][C:25]([N:28]([CH2:29][C@H:30]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:34])[CH3:35])[CH3:31])[C:8]([C:7]3[C:6]([Cl:11])=[N:5][CH:4]=[N:3][C:2]=3[Cl:1])=[O:9])=[CH:26][CH:27]=2)[CH2:20][CH2:21]1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC[C@@H](C)O[Si](C)(C)C(C)(C)C)cc2)CC1
Reactant: O=C(Cl)c1c(Cl)ncnc1Cl
Solvent: C1CCOC1
Product: COC(=O)C[C@H]1CC[C@H](c2ccc(N(C[C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)c3c(Cl)ncnc3Cl)cc2)CC1

Procedure:
A mixture of 4,6-dichloropyrimidine-5-carbonyl chloride (2.27 g, 10.7 mmol), methyl[trans-4-(4-{[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}propyl]-amino}phenyl)cyclohexyl]acetate (4.50 g, 10.7 mmol), from Step 1, and TEA (2.24 mL, 16.1 mmol) in THF (150 mL) was stirred at room temperature under nitrogen for 14 hours. The reaction mixture was concentrated to remove THF. The residue was diluted with EtOAc (300 mL), washed with water (2×200 mL), dried over MgSO4 and concentrated. The crude material was purified by a 120 g silica gel column eluted with 3-15% EtOAc in heptane to give methyl[trans-4-(4-{[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}propyl][(4,6-dichloropyrimidin-5-yl)carbonyl]amino}phenyl)cyclohexyl]acetate as a colorless oil 4.01 g (63%). m/z=594.2 (M+1). 1H NMR (400 MHz, chloroform-d) δ −0.06 (s, 6H) 0.71 (s, 9H) 0.99-1.14 (m, 2H) 1.25-1.30 (m, 3H) 1.30-1.42 (m, 2H) 1.78 (dd, J=28.30, 11.90 Hz, 5H) 2.20 (d, J=7.03 Hz, 2H) 2.28-2.39 (m, 1H) 3.64 (s, 3H) 3.83-3.97 (m, 2H) 4.04-4.14 (m, 1H) 7.00 (d, J=8.20 Hz, 2H) 7.19 (d, J=8.59 Hz, 2H) 8.53 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([Cl:30])[N:18]=[C:17](Cl)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:32]1([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([Cl:30])[N:18]=[C:17]([N:41]3[CH2:42][CH2:43][N:38]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:39][CH2:40]3)[N:16]=2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccccc1Oc1c(Cl)nc(Cl)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: c1ccc(N2CCNCC2)cc1
Product: COc1ccccc1Oc1c(Cl)nc(N2CCN(c3ccccc3)CC2)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
The procedure described in Synthesis Example 2 was repeated by use of 4-t-butyl-N-[2,6-dichloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide (5) and 1-phenylpiperazine, to thereby obtain the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[K+].C(OCC)(=O)C>CS(C)=O>[CH2:13]([N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[CH:8]=[CH:9]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: ClCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc2ccn(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
6-Nitroindole (1.0 g) and benzyl chloride (2.2 g) are dissolved in dimethylsulfoxide (10 ml), and thereto is added potassium hydroxide (1.0 g), and the mixture is stirred at room temperature for 12 hours. To the mixture is added ethyl acetate, and the organic layer is washed with water, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate) to give N-benzyl-6-nitroindole (1.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[C:30]3[N:31]=[CH:32][N:33]=[C:34]([NH2:35])[C:29]=3[C:28]([C:36](=[O:44])[C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([NH2:43])[CH:38]=3)=[CH:27]2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>N1C=CC=CC=1>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[C:30]3[N:31]=[CH:32][N:33]=[C:34]([NH2:35])[C:29]=3[C:28]([C:36](=[O:44])[C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([NH:43][S:9]([C:4]4[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=4)(=[O:11])=[O:10])[CH:38]=3)=[CH:27]2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(C(=O)c3cccc(N)c3)c3c(N)ncnc32)CC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(C(=O)c3cccc(NS(=O)(=O)c4cc(Cl)cc(Cl)c4)c3)c3c(N)ncnc32)CC1
Reaction time: 12 h
Yield: 40.8 %

Procedure:
3,5-Dichlorophenyl sulfonylchloride (2.8 g, 11.5 mmol) was added to a solution of 4-[4-amino-5-(3-amino-benzoyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-piperidine-1-carboxylic acid tert-butyl ester (2.5 g, 5.7 mmol) in pyridine (55 mL). The reaction mixture was stirred at 40 C for 12 h in a sealed tube, quenched with H2O (45 mL), and extracted with EtOAc (3×50 mL). The combined organic extracts were washed with CuSO4 (3×150 mL), H2O (200 mL), and brine (200 mL) and dried (MgSO4), filtered, and concentrated in vacuo. The crude reaction mixture was filtered to obtain the titled compound as an off-white solid (1.5 g, 41%). MS: 646.5 (MH+); HPLC Rf: 6.95 min. (HPLC method 4); HPLC purity: 100%.
Reaction SMILES: [NH2:1][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.[CH3:13][S:14](Cl)(=[O:16])=[O:15].O1CCCC1.Cl>[OH-].[Na+]>[CH3:13][S:14]([NH:1][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)(=[O:16])=[O:15]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CS(=O)(=O)N[C@H](Cc1ccccc1)C(=O)O
Reaction time: 0.08 h
Yield: 41.1 %

Procedure:
To a solution of L-phenylalanine 1.65 g (10 mmol) in 2N sodium hydroxide aqueous solution, cooled in an ice-water bath and under vigorous stirring, a mixture of methanesulfonyl chloride 1.26 g (11 mmol) and tetrahydrofuran 3 ml, and 2N sodium hydroxide aqueous solution 6 ml were added dropwise and alternately each in three portions. After completion of addition stirring was continued under ice-water cooling for 5 minutes, further, at room temperature for 1 hour. 6N hydrochloric acid 2 ml was added, and extraction was made with 30 ml of chloroform. Organic layer was washed with water and dried, and the solvent distilled off to obtain crude N-Ms-L-Phe as an oil. The crude product was purified by silica gel column chromatography- (eluent: chloroform, ethyl acetate) to give pure N-Ms-L-Phe 1.00 g as an oil. The yield based on the used L-phenylalanine was 41.0%.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[C:35]1([CH3:44])[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][OH:43])=[CH:37][CH:36]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:27]=[CH:28][C:29]([O:43][CH2:42][CH2:41][C:38]3[CH:39]=[CH:40][C:35]([CH3:44])=[CH:36][CH:37]=3)=[CH:30][CH:31]=2)[C:17]=1[N:18]1[CH2:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][CH2:23]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(CCO)cc1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(O)cc2)c1N1CCC(C)(C)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(CCOc2ccc(-c3c(C)nc(C)c([C@H](OC(C)(C)C)C(=O)O)c3N3CCC(C)(C)CC3)cc2)cc1
Reaction time: 18 h
Yield: 30.2 %

Procedure:
To a stirred solution of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-hydroxyphenyl)-2,6-dimethylpyridin-3-yl)acetate (20 mg, 0.043 mmol), 2-(p-tolyl)ethanol (29.1 mg, 0.213 mmol) and Ph3P-resin (55.8 mg, 0.213 mmol) in THF (2 mL) was added DEAD (0.014 mL, 0.085 mmol) at rt. After 18 h, mixture was filtered to remove polymer, concentrated and treated with 1N NaOH (0.854 mL, 0.854 mmol) in MeOH (1 mL) at 75° C. for 16 h. Mixture was then cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(4-(4-methylphenethoxy)phenyl)pyridin-3-yl)acetic acid (7.3 mg, 0.013 mmol, 30.6% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.17 (d, J=7.7 Hz, 3H), 7.09 (d, J=8.1 Hz, 2H), 7.02-6.93 (m, 3H), 5.80 (br. s., 1H), 4.25-4.13 (m, 2H), 2.96 (t, J=6.2 Hz, 2H), 2.41 (s, 3H), 2.24 (s, 3H), 2.03 (s, 3H), 1.21 (br. s., 2H), 1.09 (s, 9H), 0.77 (s., 3H), 0.62 (s., 3H). 6H of piperidine were not resolved. LCMS (M+H)=559.15.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:7]=1[N:13]([CH2:22][CH:23](O)[CH3:24])[C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1C=CC=CC=1>[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:7]=1[N:13]([CH2:22][CH:23]([Cl:3])[CH3:24])[C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cccc(C)c1N(CC(C)O)C(=O)c1ccccc1
Solvent: c1ccccc1
Product: Cc1cccc(C)c1N(CC(C)Cl)C(=O)c1ccccc1
Reaction time: 0.75 h
Yield: 94.8 %

Procedure:
4.65 ml (7.7 g, 65 mmoles) of thionyl chloride are added dropwise, at room temperature, to a solution of 14.2 g (50 mmoles) of 1-[N-(2,6-dimethylphenyl)-benzamido]-2-propanol in 100 ml of dry benzene, and the mixture is boiled then for 45 minutes. The solvent is evaporated under reduced pressure, and 30 ml of benzene is distilled off from the residue in order to remove the traces of thionyl chloride. This latter operation is repeated. The solid residue is triturated with n-hexane, the crystalline product is filtered off, washed with n-hexane and dried. 14.3 g (95%) of 1-[N-(2,6-dimethylphenyl)-benzamido]-2-chloro-propane are obtained as a white, crystalline substance; m.p.: 106°-109° C.
Reaction SMILES: [Br-].[CH3:2]OC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[NH2-].[Na+].[NH2:26][C:27]1[C:32]([CH:33]=O)=[C:31]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[C:30]([C:42]([O:44][CH3:45])=[O:43])=[C:29]([CH:46]([CH3:48])[CH3:47])[N:28]=1.[Br-].COC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[NH2-].[Na+].Cl.[OH-].[Na+]>O1CCCC1>[F:41][C:38]1[CH:39]=[CH:40][C:35]([C:31]2[C:30]([C:42]([O:44][CH3:45])=[O:43])=[C:29]([CH:46]([CH3:47])[CH3:48])[N:28]=[C:27]3[NH:26][CH:2]=[CH:33][C:32]=23)=[CH:36][CH:37]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1c(C(C)C)nc(N)c(C=O)c1-c1ccc(F)cc1
Agent: Cl
Agent: [Br-]
Agent: [NH2-]
Solvent: C1CCOC1
Product: COC(=O)c1c(C(C)C)nc2[nH]ccc2c1-c1ccc(F)cc1
Reaction time: 0.25 h

Procedure:
23.9 g (55 mmol) of a mixture of methoxymethyltriphenylphosphonium bromide and sodium amide are covered with a layer of 145 ml of anhydrous tetrahydrofuran and the mixture is stirred vigorously for 15 min. 17.4 g (55 mmol) of the compound from Example V are added to 145 ml of tetrahydrofuran and the mixture is stirred at room temperature for 1 h. A further 23.9 g (55 mmol) of methoxymethyltriphenylphosphonium bromide/sodium amide are added and the mixture is stirred at room temperature for 60 min. 185 ml (1.11 mol) of 6 M hydrochloric acid are added, and the mixture is heated to reflux for 1 h and cooled. It is neutralized using 5 M sodium hydroxide solution and the phases are separated. The aqueous phase is extracted twice with ethyl acetate, and the combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated to dryness. The residue which remains is dissolved in dichloromethane and added to a glass frit (porosity 3) which contains 450 g of silica gel 230-400 mesh. The mixture is eluted without sucking dry using a gradient of petroleum ether/ethyl acetate of 4:1 to 2:1. The eluate is concentrated to dryness in vacuo and the residue is thoroughly stirred in a mixture of ether/petroleum ether. Yield: 13.8 g (80% of theory) of colorless crystals M.p.: 187° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[Br:10]Br>C(O)(=O)C>[Br:10][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:9])[C:3]=1[O:2][CH3:1]
Reactant: COc1ccccc1N
Reactant: BrBr
Solvent: CC(=O)O
Product: COc1c(N)cccc1Br
Reaction time: 0.17 h
Yield: 71.8 %

Procedure:
To a cooled solution of 2-anisidine (2.7 mL, 23.7 mmol) in cetic acid (20 mL) at 10° C. was slowly added a solution of bromine (1.22 mL, 23.7 mmol) in acetic acid (10 mL) over a 10 min period. After stirring for 10 min, the solvents were removed by rotoevaporation and the residue dissolved in ethyl acetate. This solution was successively washed with saturated sodium bicarbonate solution and dried over anhydrous magnesium sulfate. After filtering, the solvents were removed by rotoevaporation and the product purified by flash column chromatography on silica gel eluted with 45% methylene chloride in hexanes to yield 3.44 g (72% yield) of the title compound.