Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH:19]([OH:22])[CH:20]=[CH2:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:30](OC(=O)C)(=[O:32])[CH3:31].O>ClCCl>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH:19]([O:22][C:30](=[O:32])[CH3:31])[CH:20]=[CH2:21])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=CC(O)c1cc2ccccc2n1S(=O)(=O)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(OC(C)=O)c1cc2ccccc2n1S(=O)(=O)c1ccccc1
Temperature: 3 °C
Reaction time: 2 h

Procedure:
To a solution of 19.1 g of 1-(1-benzenesulfonyl-1H-indol-2-yl)-allyl alcohol (74 mmol) in 244 ml dichloromethane were added 34 ml triethylamine and 0.7 g 4-dimethyl-aminopyridine. The solution was cooled to 3° C. To the magnetically stirred solution 23.5 ml of acetic anhydride qas added with a dropping funnel at a temperature below 5° C. The reaction mixture was stirred 2 h at 22° C. After cooling in an ice bath 250 ml of water was added at a temperature of 20 to 24° C. The mixture was vigorously stirred for 10 min. The phases were separated, and the water solution extracted with 250 ml of dichloromethane. The combined organic phases were extracted with 250 ml of water three times, and once with 250 ml of brine. The dichloromethane solution was dried on sodium sulfat and finally rotary evaporated (35° C., 50 mbar), yield 22.8 g. In the next step (the cyclocarbonylation) the resulting oil was used without purification (crude quality).
Reaction SMILES: [O-]S([O-])=O.[Na+:5].[Na+].C([O-])(O)=O.[Na+].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][C:15]=1[N+:24]([O-:26])=[O:25]>O.CC(C)=O>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O-:22])=[O:21])=[CH:16][C:15]=1[N+:24]([O-:26])=[O:25].[Na+:5]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(S(=O)[O-])cc1[N+](=O)[O-]
Temperature: 50 °C

Procedure:
A solution of Na2SO3 (400 mg, 3.2 mmol) and NaHCO3 (270 mg, 3.2 mmol) in H2O (10 mL) was treated slowly with a solution of 4-methoxy-3-nitrobenzenesulfonyl chloride (400 mg, 1.6 mmol) in acetone (3 mL), heated to 50° C. for 2 hours, cooled to room temperature, and washed with dichloromethane. The aqueous wash was filtered through cotton, lyophilized, suspended in methanol, filtered, concentrated, and dried under vacuum to provide the desired product.
Reaction SMILES: CC(=O)CC.[OH:6][C:7]1[C:16]([CH2:17][CH2:18][CH3:19])=[C:15]2[C:10]([C:11]([C:21]([F:24])([F:23])[F:22])=[CH:12][C:13](=[O:20])[O:14]2)=[CH:9][CH:8]=1.Br[CH2:26][CH2:27][CH2:28][CH2:29][N:30]1[C:34](=[O:35])[C:33]([CH3:37])([CH3:36])[N:32]([CH3:38])[C:31]1=[O:39].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:38][N:32]1[C:33]([CH3:37])([CH3:36])[C:34](=[O:35])[N:30]([CH2:29][CH2:28][CH2:27][CH2:26][O:6][C:7]2[C:16]([CH2:17][CH2:18][CH3:19])=[C:15]3[C:10]([C:11]([C:21]([F:24])([F:22])[F:23])=[CH:12][C:13](=[O:20])[O:14]3)=[CH:9][CH:8]=2)[C:31]1=[O:39]
Reactant: CN1C(=O)N(CCCCBr)C(=O)C1(C)C
Reactant: CCCc1c(O)ccc2c(C(F)(F)F)cc(=O)oc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CCCc1c(OCCCCN2C(=O)N(C)C(C)(C)C2=O)ccc2c(C(F)(F)F)cc(=O)oc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 103.8 %

Procedure:
A 2-butanone (2 mL) solution of 7-hydroxy-8-propyl-4-(trifluoromethyl)-2H-chromen-2-one (30 mg, 0.11 mmol), 3-(4-bromobutyl)-1,5,5-trimethylimidazolidine-2,4-dione (30.5 mg, 0.11 mmol), and potassium carbonate (22.8 mg, 0.165 mmol) was heated and stirred overnight at 80° C. The reaction solution was added with water and extracted with ethyl acetate. Subsequently, the organic layer was washed with saturated saline, dried using anhydrous sodium sulfate, and concentrated under vacuum. The obtained residue was purified using thin-layer silica-gel chromatography (hexane:ethyl acetate=1:1), and 53.5 mg of the title compound (yield 100%) was obtained as colorless oil.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([OH:25])=O)[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:26][CH2:27][CH2:28][C:29]#[N:30]>>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([NH:30][CH2:29][CH2:28][C:27]#[N:26])=[O:25])[N:21]=2)[CH:7]=[N:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: N#CCCN
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)NCCC#N)cs2)c1-c1ccc(F)cc1

Procedure:
Using 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid and 3-aminopropionitrile and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][N:7]2[S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13].C([O-])(O)=O.[Na+].C([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)(OC(C)(C)C)=O.C(Cl)(Cl)[Cl:40].CCO>C(O)C>[ClH:40].[C:15]1([S:12]([N:7]2[C:8]3[C:4](=[C:3]([CH2:2][N:33]4[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]4)[CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(CBr)cccc21
Reactant: ClC(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cl
Product: O=S(=O)(c1ccccc1)n1ccc2c(CN3CCNCC3)cccc21
Yield: 24 %

Procedure:
4-(Bromomethyl)-1-(phenylsulfonyl)-1H-indole Intermediate 2 (1.025 g), NaHCO3 (1.5 eq) and N—BOC-piperazine (1.5 eq) were refluxed in ethanol for 40 min. The reaction was monitored by TLC (eluent-system CHCl3-EtOH 20:1). The work up of the crude-extraction and further purification by column chromatography (eluent —CHCl3)—yielded the final product as an oil. This material was treated with HCl 5M in i-PrOH to yield the salt of the final product (300 mg, 24%). The synthetic route followed for preparing Example 1 is depicted in the following scheme:
Reaction SMILES: CI.[C:3]([O-:6])([O-])=O.[K+].[K+].[Br:9][C:10]1[CH:15]=[C:14]([F:16])[C:13](O)=[C:12]([F:18])[CH:11]=1.C(OCC)(=O)C>CN(C=O)C>[Br:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:6][CH3:3])=[C:12]([F:18])[CH:11]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1c(F)cc(Br)cc1F
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: COc1c(F)cc(Br)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.6 %

Procedure:
Methyl iodide (580 TL, 10.06 mmol) and K2CO3 (2.80 g, 20.12 mmol) were added to a solution of 4-bromo-2,6-difluorophenol (1.05 g, 5.03 mmol) in DMF (10 mL) and stirred at rt under Ar for 24 h. Upon completion, ethyl acetate was added and the reaction was washed with 1% HCl (2×20 mL), brine (1×), dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (hexane) to afford 4-bromo-2,6-difluoroanisole (747 mg, 67%) as a white solid. See, for example, Chambers, R. D.; et al. J. Fluorine Chem. 2000, 102, 169-174, which is incorporated by reference in its entirety. 1H NMR (CDCl3, 400 MHz) δ 7.06 (m, 2H), 3.97 (q, 3H, J=1.1 Hz). 13C NMR (CDCl3, 100 MHz) δ 155.8, 136.3, 116.2, 113.8, 61.9. LREIMS found for C7H5F2OBr (M+) 223.0.
Reaction SMILES: [CH3:1][C:2]1[O:12][C:5]2[CH2:6][N:7]([CH3:11])[CH2:8][CH:9]([OH:10])[C:4]=2[CH:3]=1.[Cl:13][C:14]1[CH:15]=[C:16](F)[CH:17]=[CH:18][C:19]=1[Cl:20]>>[ClH:13].[Cl:13][C:14]1[CH:15]=[C:16]([O:10][CH:9]2[CH2:8][N:7]([CH3:11])[CH2:6][C:5]3[O:12][C:2]([CH3:1])=[CH:3][C:4]2=3)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: Cc1cc2c(o1)CN(C)CC2O
Reactant: Fc1ccc(Cl)c(Cl)c1
Product: Cc1cc2c(o1)CN(C)CC2Oc1ccc(Cl)c(Cl)c1
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 2,6-dimethyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-4-ol (Reference Example 2) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3,4-dichloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: [C:1]([OH:4])(=[O:3])C.[CH:5]([C:8]1[S:9][CH:10]=[C:11]([C:13]([N:15]2[CH2:20][C:19]3([CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([CH3:37])([CH3:36])[CH2:33][CH:34]=O)[CH2:22][CH2:21]3)[O:18][CH2:17][CH2:16]2)=[O:14])[N:12]=1)([CH3:7])[CH3:6].C(O)(=O)C.[NH2:42][CH2:43][C@@H:44]([C:46]1[C:54]2[S:53][C:52](=[O:55])[NH:51][C:50]=2[C:49]([OH:56])=[CH:48][CH:47]=1)[OH:45].C([BH3-])#N.[Na+]>CO>[CH:1]([OH:4])=[O:3].[OH:56][C:49]1[C:50]2[NH:51][C:52](=[O:55])[S:53][C:54]=2[C:46]([C@@H:44]([OH:45])[CH2:43][NH:42][CH2:34][CH2:33][C:32]([CH3:37])([CH3:36])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][N:23]2[CH2:22][CH2:21][C:19]3([O:18][CH2:17][CH2:16][N:15]([C:13]([C:11]4[N:12]=[C:8]([CH:5]([CH3:7])[CH3:6])[S:9][CH:10]=4)=[O:14])[CH2:20]3)[CH2:25][CH2:24]2)=[CH:47][CH:48]=1
Reactant: NC[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Reactant: CC(=O)O
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCCCCCC(C)(C)CC=O)CC3)C2)cs1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCCCCCC(C)(C)CCNC[C@H](O)c4ccc(O)c5[nH]c(=O)sc45)CC3)C2)cs1
Product: O=CO
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Acetic acid (0.035 mL) was added to a stirred solution of 9-(4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-3,3-dimethylnonanal (example 279, step f) (195 mg) and (R)-7-(2-amino-1-hydroxyethyl)-4-hydroxybenzo[d]thiazol-2(3H)-one hydrochloride (WO2007027134, example 1, step d) (161 mg) in methanol (10 mL) and after a minute sodium cyanoborohydride (51 mg) was added and the reaction mixture stirred at room temperature for 1.5 h. The mixture was concentrated and then partitioned between THF (12 mL) and a mixture of brine and saturated sodium bicarbonate solution (10:1, 12 mL). The layers were separated and the organic phase dried over sodium sulfate, filtered and evaporated. The resulting material was purified by preparative HPLC (Phenomenex Gemini®, Gradient: 5-40% acetonitrile in 0.1% aqueous formic acid). The fractions containing product were combined and freeze-dried to afford the titled compound as a white solid. Yield 0.038 g.
Reaction SMILES: [CH2:1]([CH:3]([CH2:14][CH3:15])[CH2:4][C:5]1([C:11](O)=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH3:2].C(N(CCCC)CCCC)CCC.S(Cl)([Cl:31])=O.C(C(CC)CC1(C(OC(C2(CC(CC)CC)CCCCC2)=O)=O)CCCCC1)C>CCCCCCC>[CH2:1]([CH:3]([CH2:14][CH3:15])[CH2:4][C:5]1([C:11]([Cl:31])=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCC(CC)CC1(C(=O)O)CCCCC1
Agent: CCC(CC)CC1(C(=O)OC(=O)C2(CC(CC)CC)CCCCC2)CCCCC1
Solvent: CCCCN(CCCC)CCCC
Solvent: CCCCCCC
Product: CCC(CC)CC1(C(=O)Cl)CCCCC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
A mixture of 6.0 kg (28.3 mol) 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid and 20.6 mL tributylamine (0.085 mmol) in 10 L heptane was warmed to 50° C. 2.5 L (34.5 mol) of thionyl chloride was added during 40 minutes at a temperature of 40-50° C. (reaction is endothermic, vigorous gas evolution) and the reaction mixture was kept at 53-55° C. An IPC-control after 60 minutes indicated complete conversion (0.04% 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid and no 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid anhydride). After removing volatile components under reduced pressure (70° C. bath, 13-8 mbar) 6.86 kg of the residue was obtained (assay 92.5% 1-(2-ethyl-butyl)-cyclohexanecarbonyl chloride, yield 97.2%)
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13](S(C)=O)[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[C:7]2=[O:24])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:39]=[N:40][C:41]([NH2:44])=[CH:42][CH:43]=2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>C1(C)C=CC=CC=1>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:39]=[N:40][C:41]([NH:44][C:13]3[N:14]=[CH:15][C:10]4[CH:9]=[C:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[C:7](=[O:24])[N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:11]=4[N:12]=3)=[CH:42][CH:43]=2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(=O)OCc1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Solvent: Cc1ccccc1
Product: CC(=O)OCc1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 96 °C
Yield: 16.5 %

Procedure:
Acetic acid 8-cyclopentyl-2-methanesulfinyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-ylmethyl ester (0.80 g, 2.29 mmol), prepared as in Example 27, and 4-(6-Amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (1.17 g, 4.20 mmol) were added to toluene (8 ml), heated to 96° C. for 6 hours. The reaction mixture was allowed to cool, then filtered and the residue washed with toluene. The resulting solid was dried in vacuo then recrystallized from chloroform/diethyl ether to provide 4-[6-(6-acetoxymethyl-8-cyclopentyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester as a solid (0.213 g, 16.5%). MS (APCI) M++1; Calc'd, 564.2, Found, 564.3.
Reaction SMILES: Br[C:2]1[C:3]([Cl:12])=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:7]=1.N1C=CC=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:12][C:3]1[C:2]([CH:14]=[CH2:15])=[CH:7][N:6]=[C:5]([NH:8][C:9](=[O:11])[CH3:10])[CH:4]=1
Reactant: CC(=O)Nc1cc(Cl)c(Br)cn1
Reactant: c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: C=Cc1cnc(NC(C)=O)cc1Cl
Temperature: 85 °C
Yield: 98.6 %

Procedure:
To a stirred solution of N-(5-bromo-4-chloropyridin-2-yl)acetamide (7 g, 28.1 mmol), 2,4,6-trivinyl-1,3,5,2,4,6-trioxatriborinane complex with pyridine (1:1) (8.78 g, 36.5 mmol), sodium carbonate (5.95 g, 56.1 mmol) solution in 7 mL of water and tetrakis(triphenylphosphine)palladium (0.973 g, 0.842 mmol) in a mixture of Toluene (50 mL) and Ethanol (8 mL), nitrogen gas was bubbled for 5 min. The reaction mixture was heated at 85° C. for 14 hours. After the completion, the reaction was diluted with EtOAc (50 mL), filtered through diatomaceous earth (Celite®). The filtrate was diluted with water and the organic layer was separated, washed with brine solution, dried over sodium sulfate. The organics were concentrated under reduced pressure and residue so obtained was purified by comb flash column 120 g using hexane/ethyl acetate. Product eluted at 30% EtOAc in hexane and required fractions were concentrated to yield N-(4-chloro-5-vinylpyridin-2-yl)acetamide (5.92 g, 27.7 mmol, 99% yield) as yellow solid. LC/MS (ESI) m/e 197.2 [(M+H)+, calcd for C9H10ClN2O 197.04] LC/MS retention time (method A): tR=1.50 min; 1H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 8.64 (s, 1H), 8.18 (d, J=6.40 Hz, 1H), 6.88 (dd, J=11.20, 17.60 Hz, 1H), 5.99 (dd, J=0.80, 17.60 Hz, 1H), 5.47 (dd, J=0.80, 11.40 Hz, 1H), 2.12 (s, 3H).
Reaction SMILES: COC(C[C:6]1([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[CH2:11][CH2:10][N:9]([CH3:12])[C:8](=[O:13])[C:7]1=[CH2:14])=O.[OH-].[K+].CO.O.C(Cl)(Cl)Cl>CO.O>[CH3:12][N:9]1[CH:10]=[CH:11][C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([CH3:14])[C:8]1=[O:13]
Reactant: C=C1C(=O)N(C)CCC1(CC(=O)OC)c1cccc(OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: COc1cccc(-c2ccn(C)c(=O)c2C)c1
Reaction time: 20 h
Yield: 19.6 %

Procedure:
4-Carboxymethyl-4-(3'-methoxyphenyl-1-methyl-3-methylene-2-piperidone (29). To methyl ester 28 of Example 10 (1.20 g, 3.97 mmol) dissolved in CH3OH (5 mL, 0° C.) was rapidly added KOH (775 mg, 11.9 mmol) in 5 mL of 1/1 CH3OH/H2O. After 20 h at 25° C., CHCl3 (20 mL) and H2O (20 mL) were added, the separated aqueous layer was extracted with CHCl3 (20 mL) and the combined organic phases were dried and evaporated to give 178 mg (20%) of 1,3-dimethyl-4-(3'-methoxyphenyl)-2-pyridone (this arises from unreacted allylic alcohol under the alkaline hydrolysis conditions): NMR δ7.20 (m, 2H), 6.86 (m, 3H), 6.07 (d,J=7 Hz, 1H), 3.81 (s, 3H), 3.57 (s, 3H), 2.10 (s, 3H): IR (neat) 1640 cm-1 (broad); mass spectrum m/e (rel intensity) 229 (63), 228 (100). Anal. Calcd for C14H15NO2 : C, 73.3; H, 6.6; N, 6.1. Found: C, 73.0; H, 6.6; N, 6.1.
Reaction SMILES: [C:1]1([C@H:11]([N:13]([CH2:21][C@@H:22]2[C@@H:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:25][NH:24][CH2:23]2)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C([N:35](CC)CC)C.CC#N.[N+](C1C=CC([O:50][C:51]([O:53][C:54]2[CH:63]=[CH:62][CH:61]=[CH:60][C:55]=2[C:56]([O:58][CH3:59])=[O:57])=O)=CC=1)([O-])=O>C(OCC)(=O)C>[C:16]([O:15][C:14]([N:13]([CH2:21][C@H:22]1[C@@H:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:25][N:24]([NH:35][C:51]([O:53][C:54]2[CH:63]=[CH:62][CH:61]=[CH:60][C:55]=2[C:56]([O:58][CH3:59])=[O:57])=[O:50])[CH2:23]1)[C@@H:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH3:12])=[O:20])([CH3:18])([CH3:19])[CH3:17]
Reactant: COC(=O)c1ccccc1OC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CNC[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Reactant: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1ccccc1OC(=O)NN1C[C@@H](CN(C(=O)OC(C)(C)C)[C@H](C)c2cccc3ccccc23)[C@@H](c2ccccc2)C1
Temperature: 25 °C
Yield: 58.5 %

Procedure:
A mixture of 223 mg of tert-butyl [(1R)-1-(1-naphthyl)ethyl]{[(3R,4S)-4-phenylpyrrolidin-3-yl]methyl}carbamate, 78.6 mg of triethylamine and 4.5 ml of MeCN was mixed, under ice-cooling, with 215 mg of methyl 2-{[(4-nitrophenoxy)carbonyl]oxy}benzoate and stirred at room temperature for 4Hours. The reaction solution was mixed with ethyl acetate, washed with saturated sodium bicarbonate aqueous solution and saturated brine in that order and dried with anhydrous magnesium sulfate. The solvent was evaporated under a reduced pressure, and the thus obtained residue was purified by a silica gel column chromatography (hexane-ethyl acetate) to obtain 189 mg of 2-(methoxycarbonyl)phenyl (3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidine-1-carbamate as a white amorphous substance.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](C=O)=[CH:3][CH:2]=1.[CH3:9][O:10][CH:11](OC)[O:12][CH3:13].S(=O)(=O)(O)O.C[O-].[Na+]>CO>[CH3:9][O:10][CH:11]([O:12][CH3:13])[C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: O=Cc1ccncc1
Reactant: COC(OC)OC
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(OC)c1ccncc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-pyridinecarboxaldehyde (100.00 g, 0.93 mol) and trimethylorthoformate (159.20 g, 1.50 mol) in methanol (180 mL) at 0° C., under N2, was added concentrated sulfuric acid (41 mL, 0.45 mol). The resulting white suspension was heated to reflux and stirred for 24 hours. The reaction solution became clear after 2 h. After cooling to room temperature, the reaction mixture was poured slowly into a solution of 25 wt. % sodium methoxide (360 mL) in methanol (300 mL). The mixture was then concentrated in vacuo to a light brown thick oil. To this crude oil was added t-butylmethyl ether (500 mL), followed by the slow addition of water (40 mL) (to convert the inorganics to filterable solids). After filtration through a pad of Celite, the filtrate was concentrated to yield a light brown oil. The crude oil was vacuum distilled to yield the desired product as a colorless oil
Reaction SMILES: [O:1]1C2C(=CC=CC=2)C(=O)C(C2C=CC=CC=2)=[CH:2]1.[CH:18]1[C:23]([C:24]2[C:33](=[O:34])[C:32]3[C:31](O)=[CH:30][C:29]([OH:36])=[CH:28][C:27]=3[O:26][CH:25]=2)=[CH:22][CH:21]=[C:20]([OH:37])[CH:19]=1.C1C(C2C(=O)C3C=CC(O)=CC=3OC=2)=CC=C(O)C=1>>[CH3:2][O:1][C:30]1[CH:31]=[C:32]2[C:33](=[O:34])[C:24]([C:23]3[CH:18]=[CH:19][C:20]([OH:37])=[CH:21][CH:22]=3)=[CH:25][O:26][C:27]2=[CH:28][C:29]=1[OH:36]
Reactant: O=c1c(-c2ccc(O)cc2)coc2cc(O)cc(O)c12
Reactant: O=c1c(-c2ccccc2)coc2ccccc12
Agent: O=c1c(-c2ccc(O)cc2)coc2cc(O)ccc12
Product: COc1cc2c(=O)c(-c3ccc(O)cc3)coc2cc1O
Yield: 4 %

Procedure:
A dried aglucone isoflavone material weighing 7.3 g and containing 49% genistein, 19% daidzein, and 4% glycitein is obtained.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=1.C(NC(C(C)C)C)(C)C.O>CN1CCCC1=O>[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH:15][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=2)=[CH:12][CH:11]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: Fc1cccc(F)n1
Agent: CC(C)NC(C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: Fc1cccc(NCc2ccc(Cl)cc2)n1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To 2,6-difluoropyridine (58, 9.85 g, 0.0856 mol) in N-methylpyrrolidinone (50.0 mL) were added p-chlorobenzylamine (61, 10.5 mL, 8.63 mmol) and N,1-diisopropylethylamine (30.0 mL, 0.172 mol). The reaction was stirred at 90° C. overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 25% ethyl acetate in hexane, then washed with ethyl acetate/hexane to give a white solid (536, 10 g, 50%).
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]([C@@H:17]([NH:23][C:24]([C@@H:26]2[CH2:31][CH2:30][CH2:29][N:28]([C:32](=[O:48])[CH2:33][CH2:34][CH:35]3[CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37][CH2:36]3)[CH2:27]2)=[O:25])[CH2:18][C:19]([O:21]C)=[O:20])[CH:14]=[CH:15][CH:16]=1.CO.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>C(O)(C)(C)C>[F:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]([C@@H:17]([NH:23][C:24]([C@@H:26]2[CH2:31][CH2:30][CH2:29][N:28]([C:32](=[O:48])[CH2:33][CH2:34][CH:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[CH2:27]2)=[O:25])[CH2:18][C:19]([OH:21])=[O:20])[CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cccc(OCCOCCOCCF)c1
Agent: [Ba+2]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCNCC2)C1)c1cccc(OCCOCCOCCF)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
Tert-butyl 4-{3-[(3R)-3-{[(1S)-1-(3-{2-[2-(2-fluoroethoxy)ethoxy]ethoxy}phenyl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (20.3 mg, 27 μmol) was solved in tert.-butanol (0.77 mL) and methanol (0.76 mL) and barium hydroxide octahydrate (42 mg, 0.13 mmol) was added. After stirring for 60 minutes room temperature the solvent was distilled off at 0° C. by high vacuum. The residue was solved in water (1 mL) and acidified by formic acid (2 mL). After 18 hours at 5° C. additional formic acid (2 mL) was added. After 3 hours at room temperature the solvent was distilled off at 0° C. by high vacuum and the residue was purified by preparative HPLC to yield 8.4 mg of (3S)-3-(3-{2-[2-(2-fluoroethoxy)ethoxy]ethoxy}phenyl)-3-[({(3R)-1-[3-(piperidin-4-yl)propanoyl]piperidin-3-yl}carbonyl)amino]propanoic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9]([CH3:14])=[CH:10][C:11](Cl)=[O:12]>>[C:2]1([NH:1][C:11](=[O:12])[CH:10]=[C:9]([CH3:14])[CH3:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)=CC(=O)Cl
Reactant: Nc1ccccc1
Product: CC(C)=CC(=O)Nc1ccccc1
Yield: 86 %

Procedure:
This is prepared analogously to a) from aniline and 3,3-dimethylacryloyl chloride. Yield 86% of theory; m.p. 124°-126° C.