Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.C1CCC(N=C=NC2CCCCC2)CC1.C1C2C(COC([NH:62][C@H:63]([C:68](O)=[O:69])[C@H:64]([CH2:66][CH3:67])[CH3:65])=O)C3C(=CC=CC=3)C=2C=CC=1>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[NH2:62][C@H:63]([C:68]([O:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:69])[C@H:64]([CH2:66][CH3:67])[CH3:65]
Reactant: O=C(O)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2O)cc1
Reactant: CC[C@H](C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CC[C@H](C)[C@H](N)C(=O)O[C@@H]1c2ccccc2C[C@@]1(Cc1ccc(C(=O)O)cc1)C1=Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 34.1 %

Procedure:
To a solution of 4-(((1S,2S)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoic acid (250 mg, 0.65 mmol), DCC (160 mg, 0.78 mmol) and DMAP (8 mg, 0.06 mmol) in ethyl acetate (10 mL), was added N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-isoleucine (228 mg, 0.65 mmol) and then stirred at room temperature for 12 h. The solids were filtered, washed with ethyl acetate (25 ml) and the combined filtrate was washed with 1.5 N HCl (25 mL), water (25 mL), brine (10 mL), dried over anhydrous Na2SO4. The organic layer was evaporated under reduced pressure and the residue 1 (275 mg) was dissolved in dry THF (8 mL) and cooled to 0° C. Dimethylamine (8 mL, 20% in THF) was added drop wise at N2 atmosphere and the reaction mixture was slowly allowed to stir at room temperature for 1 h. The reaction mixture was evaporated under reduced pressure and the residue was purified by CombiFlash using 10% methanol in chloroform as an eluent to yield 110 mg (31%) of the title compound as an off white solid.
Reaction SMILES: [Cl:1][CH:2]([F:32])[C:3]([F:31])([F:30])[C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:27]=[CH:28][CH:29]=1)[O:10][CH:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:12](O)=[O:13])=[O:5].S(Cl)([Cl:35])=O>>[Cl:1][CH:2]([F:32])[C:3]([F:31])([F:30])[C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:27]=[CH:28][CH:29]=1)[O:10][CH:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:12]([Cl:35])=[O:13])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCCCC(Oc1cccc(NC(=O)C(F)(F)C(F)Cl)c1)C(=O)O
Product: CCCCCCCCCCCCC(Oc1cccc(NC(=O)C(F)(F)C(F)Cl)c1)C(=O)Cl

Procedure:
An amount of 31.5 g of 2-[m-(3-chloro-2,2,3-trifluoro-propionamido)-phenoxy]-myristic acid is refluxed for 30 min with thionyl chloride. The excess thionyl chloride is removed by evaporation. The oil obtained slowly solidifies.
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][OH:6].C[O:8][C:9](=O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:27])/[CH:17]=[CH:18]/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO>[OH:6][NH:5][C:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:27])/[CH:17]=[CH:18]/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:8]
Reactant: NO
Reactant: COC(=O)CCCCCNC(=O)/C=C/C=C/c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(/C=C/C=C/c1ccccc1)NCCCCCC(=O)NO
Reaction time: 0.17 h
Yield: 76.1 %

Procedure:
(Method J1B) A solution of sodium methylate (6 mmol) in methanol (5 ml) was added to a solution of hydroxylamine hydrochloride (0.28 g, 4 mmol) in methanol (8 ml). A mixture was stirred for 10 min. and the precipitate was filtered off. (2E)(4E)-6-(5-Phenylpenta-2,4-dienoylamino)hexanoic acid methyl ester (3/1) (0.30 g, 1 mmol) was added to the filtrate and the mixture was heated to the complete dissolving. The resultant mixture was stirred for 4 hours at ambient temperature and the solvent was removed under reduced pressure. The product was dissolved in water (10 ml) and acidified with 3% HCl. Precipitate was filtered off and crystallized from methanol. The title compound (0.23 g, 66%) was obtained as a white solid. M.p 160-161° C. 1H NMR (DMSO-d6, HMDSO), δ: 1.05-1.69 (6H, m, CH2); 1.81-2.07 (2H, m, CH2); 3.12 (2H, q, J=5.8 Hz, CH2H); 6.14 (1H, d, J=14.8 Hz, CH); 6.89-7.14 (2H, m, CH—CH); 7.23-7.65 (6H, m, C6H5, CH); 8.05 (1H, t, J=6.0 Hz, NH); 8.63 (1H, s, NH), 10.34 (1H, s, OH). HPLC analysis on Symmetry C18: impurities 1.0% (column size 3.9×150 mm; mobile phase acetonitrile −0.1 M phosphate buffer (pH 2.5), 30:70; detector UV 230 nm; sample concentration 0.1 mg/ml). Anal. Calcd for C17H22N2O3: C, 65.68; H, 6.61; N, 10.21. Found: C, 65.63; H, 6.60; N, 10.17.
Reaction SMILES: Br[C:2]1[C:3]2[C:29]([CH3:36])([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:28](=[O:37])[NH:27][C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=3)[N:10]([CH2:18][CH2:19][C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[N:9]=2)[N:7]=1.[CH3:38][NH2:39]>C1COCC1>[Cl:17][C:13]1[CH:12]=[C:11]2[C:16]([C:8]([C:6]3[N:7]=[C:2]([NH:39][CH3:38])[C:3]4[C:29]([CH3:36])([C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=5)[C:28](=[O:37])[NH:27][C:4]=4[N:5]=3)=[N:9][N:10]2[CH2:18][CH2:19][C:20]([F:26])([F:25])[C:21]([F:24])([F:22])[F:23])=[CH:15][CH:14]=1
Reactant: CC1(c2ccccc2)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4cc(Cl)ccc34)nc(Br)c21
Reactant: CN
Solvent: C1CCOC1
Product: CNc1nc(-c2nn(CCC(F)(F)C(F)(F)F)c3cc(Cl)ccc23)nc2c1C(C)(c1ccccc1)C(=O)N2

Procedure:
The intermediate from Step A above (35 mg, 0.058 mmol), methylamine (0.058 mL, 0.117 mmol, 2M in THF) and THF (0.5 mL) were stirred in a sealed tube at 50° C. for 1.5 h, then at 65° C. overnight. The reaction mixture was subjected to microwave irradiation at 150° C. for 2 h, The reaction mixture was partitioned between brine and EtOAc. The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by reverse phase HPLC to afford the indicated product, as a solid. 1H NMR (500 MHz, CD3OD): δ 8.64 (d, J=8.7 Hz, 1H); 7.77 (d, J=1.6 Hz, 1H); 7.38-7.31 (m, 4H); 7.32-7.28 (m, 2H); 4.82 (d, 7.1 Hz, 2H); 3.07 (s, 3H); 3.00-2.88 (m, 2H); 1.88 (s, 3H). m/z=551.0 (WE).
Reaction SMILES: C(O)(C(F)(F)F)=O.C([Cl:11])(=O)C.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[CH:24][CH:23]=2)=O)=[CH:15][CH:14]=1>>[Br:12][C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[C:20](\[Cl:11])/[C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[CH:24][CH:23]=2)=[CH:15][CH:14]=1
Reactant: CC(=O)Cl
Reactant: CCc1ccc(C(=O)Cc2ccc(Br)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(/C(Cl)=C/c2ccc(Br)cc2)cc1
Yield: 92 %

Procedure:
In a 100 mL flask, TFA (24.7 mL; 322.8 mmol) and acetyl chloride (18.34 mL; 258.23 rnmol) were added in one portion into 2-(4-bromophenyl)-1-(4-ethylphenyl) ethanone (Vc) (9.787 g; 32.28 mmol) at RT. Protocol and work-up was then similar with -those-described above. The title compoumd (m=9.60 g) was obtained in a 92% yield. Melting point: 75° C.
Reaction SMILES: B(Cl)(Cl)Cl.CSC.[CH3:8][N:9]([CH3:45])[C:10]1[S:11][C@H:12]2[CH2:18][C@H:17]([CH2:19][O:20]OCC3C=CC=CC=3)[C@@H:16]([O:29]CC3C=CC=CC=3)[C@H:15]([O:37]CC3C=CC=CC=3)[C@H:13]2[N:14]=1>>[CH3:8][N:9]([CH3:45])[C:10]1[S:11][C@H:12]2[CH2:18][C@H:17]([CH2:19][OH:20])[C@@H:16]([OH:29])[C@H:15]([OH:37])[C@H:13]2[N:14]=1
Reactant: CN(C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](COOCc3ccccc3)C[C@@H]2S1
Agent: ClB(Cl)Cl
Solvent: CSC
Product: CN(C)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)C[C@@H]2S1
Yield: 37.3 %

Procedure:
Prepared by boron trichloride-methyl sulfide de-benzylation via a procedure as described above in Intermediate Example 4 Step 3 from (3aR,4R,5R,6R,7aS)-2-(dimethylamino)-4,5-bisbenzyloxy-6-(benzyloxyoxymethyl)-3a,4,5,6,7,7a-hexahydrobenzo[d]thiazole (0.270 g, 0.523 mmol). Purification on silica gel by flash column chromatography (1.0 M NH3 in MeOH/CH2Cl2, 1:4), afforded the product as an off-white solid (0.048 g, 36%). 1H NMR (400 MHz, CD3OD) δ 4.36-4.33 (m, 1H), 3.81-3.76 (m, 2H), 3.63 (dd, J=6.3, 10.8 Hz, 1H), 3.41 (t, J=9.1 Hz, 1H), 3.31 (t, J=9.8 Hz, 1H), 3.02 (s, 6H), 2.24-2.19 (m, 1H), 1.97-1.93 (m, 1H), 1.79-1.71 (m, 1H); 13C NMR (100 MHz, CD3OD) δ 171.90, 77.01, 73.49, 70.83, 63.54, 52.60, 41.98, 40.84, 26.53; MS, m/z=269 (M+23).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7](I)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[B:19](OC)([O:22]C)[O:20]C>C1COCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([B:19]([OH:22])[OH:20])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COB(OC)OC
Reactant: COc1ccc(C(C)(C)C)cc1I
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C(C)(C)C)cc1B(O)O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-tert-butyl-2-iodo-1-methoxybenzene (0.164 g, 0.56 mmol) in dry THF (5 mL) at −78° C., n-butyl lithium (0.27 mL, 0.68 mmol, 2.5 M) was added. The solution was stirred at −78° C. for 30 min. Trimethyl borate (0.19 mL, 1.70 mmol) was added. The solution was stirred at −78° C. for 3 h. The reaction was quenched with saturated aqueous NH4Cl. The aqueous layer was extracted with EtOAc (3×15 mL). The combined EtOAc layers were dried over Na2SO4. The residue was used without further purification after evaporation of the solvent.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[N:2]1.S(Cl)(Cl)=O.[CH3:17]O>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH3:17])=[O:11])=[N:2]1
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1n[nH]c2ccccc12
Yield: 92 %

Procedure:
To a stirred solution of indazole-3-carboxylic acid (80.5 grams, 0.497 mmol, obtained in above step) in methanol (2 L) cooled at 0° C. was added thionyl chloride (120 mL, 1.59 mmol) over a period of 1 hour. The reaction temperature was gradually raised and the reaction mixture was refluxed for 5 hours. The volatiles were removed and the crude mass was diluted with dichloromethane, washed with aqueous sodium bicarbonate, dried over anhydrous sodium sulphate and the solvent was removed under reduced pressure to obtain the title compound (80.2 grams).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[C:7]([NH2:9])=[O:8].C(=O)([O-])O.[Na+].[CH:15](I)([CH3:17])[CH3:16]>C(#N)C.ClCCl>[CH3:16][CH:15]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[C:7]([NH2:9])=[O:8])[CH3:17]
Reactant: NC(=O)C1COCCN1
Reactant: CC(C)I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)N1CCOCC1C(N)=O
Temperature: 150 °C
Yield: 97 %

Procedure:
To a solution of 1.1 g (6.3 mmol) of morpholine-3-carboxamide (a synthesis of which is described in WO-2005/026 156, Hennequin L. F. A. et al.) in acetonitrile (16 ml) are successively added 1.86 g (22.2 mmol) of sodium hydrogen carbonate powder and 0.7 ml (7.0 mmol) of isopropyl iodide, and the mixture is then heated at 150° C. by microwave for 30 minutes. The reaction mixture is cooled to room temperature, diluted with dichloromethane (30 ml) and filtered through Celite. The filtrate is concentrated under reduced pressure and 1.1 g of compound are obtained in the form of a beige-coloured powder, which is used without further purification in the following step. Yield: 97%. MH+: 173.2 (tr: 0.72 min., condition 1).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][C:8]1[CH:9]=[C:10]([C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18]Cl)[CH:11]=[CH:12][CH:13]=1.[CH3:21][CH:22]([CH3:38])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=1)=[O:24]>>[Br:7][C:8]1[CH:9]=[C:10]([C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18][N:35]2[CH2:36][CH2:37][CH:32]([C:28]3[CH:27]=[C:26]([NH:25][C:23](=[O:24])[CH:22]([CH3:21])[CH3:38])[CH:31]=[CH:30][CH:29]=3)[CH2:33][CH2:34]2)[CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCCCl)c1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(Br)c3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 (K2CO3) using 1-(3-bromophenyl)-5-chloro-1-pentanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 485.1 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[F:8][C:9]1[CH:10]=[C:11]([N+:16]([O-:18])=[O:17])[CH:12]=[CH:13][C:14]=1F>>[F:8][C:9]1[CH:10]=[C:11]([N+:16]([O-:18])=[O:17])[CH:12]=[CH:13][C:14]=1[N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: CN1CCNCC1
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 100 °C
Yield: 49.8 %

Procedure:
N-Methylpiperazine (30 mL, 27.1 g, 0.268 mol) was cooled in ice/water while adding 3,4-difluoronitrobenzene (2.0 g, 0.0126 mol) with stirring. The mixture was then heated at 100° C. overnight, evaporated to remove all excess N-methylpiperazine and the residue dissolved in 1M—hydrochloric acid (30 mL). After washing twice with 20 mL portions of DCM the solution was basified with 5 M—sodium hydroxide (10 mL). The product was extracted into DCM (twice with 20 mL), dried over sodium sulphate and evaporated giving 1.50 g yellow oil which solidified on standing
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C@@:12]([CH2:21][OH:22])([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:11][C:10]2=[O:23])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:24](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O>CN(C)C=O.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C@@:12]([CH2:21][OH:22])([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:11]([CH3:24])[C:10]2=[O:23])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1N[C@](CO)(c2ccccc2)C(=O)N1c1ccc(Cl)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)N(c2ccc(Cl)c(Cl)c2)C(=O)[C@@]1(CO)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
150 mg of (S)-1-(3,4-Dichlorophenyl)-4-hydroxymethyl-4-phenylimidazolidine-2,5-dione are dissolved in 5 mL of dimethylformamide then 165 mg of potassium carbonate are added followed by 137 μL of dimethylsulfate. The mixture is stirred overnight at room temperature then it is taken in a mixture of water and ethyl acetate. The aqueous phase is extracted with ethyl acetate. The extracts are washed with brine, dried over magnesium sulfate and evaporated to dryness. The residue is purified over silica gel while eluting with a gradient mixture from heptane to pure ethyl acetate to provide the expected product.
Reaction SMILES: [CH2:1](C1(N2C3C(=CC=CC=3)C(C([O-])=O)C2=O)OCCO1)[CH2:2]CCC.C(C1(C2C=C3C(=CC=2)NC(=O)C3C(OCC)=O)OCCO1)(C)C.[CH2:47]([C:52]1([C:57]2[CH:58]=[C:59]3[C:63](=[CH:64][CH:65]=2)[NH:62][C:61](=[O:66])[CH:60]3[C:67]([O:69][CH2:70][CH3:71])=[O:68])[O:56][CH2:55][CH2:54][O:53]1)C(C)(C)C.C(C1(C2C=C3C(=CC=2)NC(=O)C3C(OCC)=O)OCCO1)C1C=CC=CC=1>>[CH2:1]([N:62]1[C:63]2[C:59](=[CH:58][C:57]([C:52]3([CH3:47])[O:53][CH2:54][CH2:55][O:56]3)=[CH:65][CH:64]=2)[CH:60]([C:67]([O:69][CH2:70][CH3:71])=[O:68])[C:61]1=[O:66])[CH3:2]
Reactant: CCOC(=O)C1C(=O)Nc2ccc(C3(CC(C)(C)C)OCCO3)cc21
Reactant: CCCCCC1(N2C(=O)C(C(=O)[O-])c3ccccc32)OCCO1
Agent: CCOC(=O)C1C(=O)Nc2ccc(C3(C(C)C)OCCO3)cc21
Agent: CCOC(=O)C1C(=O)Nc2ccc(C3(Cc4ccccc4)OCCO3)cc21
Product: CCOC(=O)C1C(=O)N(CC)c2ccc(C3(C)OCCO3)cc21

Procedure:
Similarly, were prepared ethyl 5-(2-n-pentyl-4,5-dihydro-1,3-dioxol-2-yl-oxindole-3-carboxylate, ethyl 5-(2-isopropyl-4,5-dihydro-1,3-dioxol-2-yl)oxindole-3-carboxylate, ethyl 5-(2-neopentyl-4,5-dihydro-1,3-dioxol-2-yl)oxindole-3-carboxylate and ethyl 5-(2-benzyl-4,5-dihydro-1,3-dioxol-2-yl)oxindole-3-carboxylate.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[C:9]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:8]1.C[O:23][C:24](=[O:37])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=1[O:33][CH2:34][CH2:35]Cl>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[C:9]([CH:16]2[CH2:21][CH2:20][N:19]([CH2:35][CH2:34][O:33][C:26]3[CH:27]=[C:28]([O:31][CH3:32])[CH:29]=[CH:30][C:25]=3[C:24]([OH:37])=[O:23])[CH2:18][CH2:17]2)=[CH:8]1
Reactant: COC(=O)c1ccc(OC)cc1OCCCl
Reactant: c1coc(Cn2cc(C3CCNCC3)c3cccnc32)c1
Product: COc1ccc(C(=O)O)c(OCCN2CCC(c3cn(Cc4ccco4)c4ncccc34)CC2)c1
Yield: 36 %

Procedure:
This compound was prepared following the procedure described in example 4, part E and F starting with 3.6 g (11 mmol) of 1-furan-2-ylmethyl-3-piperidin-4-yl-1H-pyrrolo[2,3-b]pyridine and 4.0 g (16.5 mmol) of 2-(2-chloroethoxy)-4-methoxy-benzoic acid methyl ester. After standard purification the overall yield was 36% (1.93 g).
Reaction SMILES: [CH3:1]OC([C@]1(C)C[C@@H](O)CN1C(OC(C)(C)C)=O)=O.[CH3:19][O:20][C:21]([C@@H:23]1[CH2:27][C@H:26]([NH2:28])[CH2:25][N:24]1[CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:22]>>[CH3:19][O:20][C:21]([C@:23]1([CH3:1])[CH2:27][C@H:26]([NH2:28])[CH2:25][N:24]1[CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:22]
Reactant: COC(=O)[C@]1(C)C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: COC(=O)[C@@H]1C[C@H](N)CN1CC1CCCCC1
Product: COC(=O)[C@]1(C)C[C@H](N)CN1CC1CCCCC1

Procedure:
(2S,4S)-4-Amino-1-cyclohexylmethyl-2-methyl-pyrrolidine-2-carboxylic acid methyl ester was prepared from (2S,4R)-4-hydroxy-2-methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester in a similar reaction sequence used in the preparation of (2S,4S)-4-amino-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methyl ester.
Reaction SMILES: C([Si](C)(C)[O:6][CH:7]1[CH:12]([O:13][Si](C(C)(C)C)(C)C)[CH2:11][CH2:10][N:9]([CH2:21][CH2:22][CH2:23][CH2:24][N:25]2[C:31](=[O:32])[CH2:30][CH2:29][N:28]([C:33](=[O:44])/[CH:34]=[CH:35]/[C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=3)[CH2:27][CH2:26]2)[CH2:8]1)(C)(C)C.Cl>CO.O1CCOCC1>[ClH:42].[Cl:43][C:38]1[CH:37]=[C:36](/[CH:35]=[CH:34]/[C:33]([N:28]2[CH2:29][CH2:30][C:31](=[O:32])[N:25]([CH2:24][CH2:23][CH2:22][CH2:21][N:9]3[CH2:10][CH2:11][CH:12]([OH:13])[CH:7]([OH:6])[CH2:8]3)[CH2:26][CH2:27]2)=[O:44])[CH:41]=[CH:40][C:39]=1[Cl:42]
Reactant: CC(C)(C)[Si](C)(C)OC1CCN(CCCCN2CCN(C(=O)/C=C/c3ccc(Cl)c(Cl)c3)CCC2=O)CC1O[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CCCCN2CCC(O)C(O)C2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 145.4 %

Procedure:
A solution of 0.100 g (0.14 mmol) of 4-{4-[(3RS,4SR)-3,4-bis-(tert-butyl-dimethyl-silanyloxy)-piperidin-1-yl]-butyl}-1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one in 2 mL of MeOH was cooled (0° C.), treated with 0.35 ml (1.40 mmol) of 4M HCl in dioxane and stirred at RT for 2 h. The solution was evaporated, dissolved in toluene and evaporated (2×) to yield 0.053 g (73%) of the title compound as light brown foam. MS: 484.2 (MH+, 2Cl).
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8](Cl)[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].[K].[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([SH:20])=[CH:16][CH:15]=1.[OH-].[K+]>C(O)C>[Cl:1][C:2]1[N:9]=[C:8]([S:20][C:17]2[CH:18]=[CH:19][C:14]([CH3:13])=[CH:15][CH:16]=2)[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Reactant: Cc1ccc(S)cc1
Agent: [K+]
Agent: [K]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(Sc2nc(Cl)c(C#N)cc2F)cc1

Procedure:
2,6-Dichloro-5-fluoronicotinonitrile (32.5 g) in ethanol (400 ml) was treated at room temperature with potassium salt of p-thiocresol, prepared from p-thiocresol (23.2 g) and potassium hydroxide (12.2 g), to give 2-chloro-6-(p-tolylthio)-5-fluoronicotinonitrile (42.4 g), m.p. 124°-125° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([N+:11]([O-:13])=[O:12])=[C:8](Br)[CH:9]=1)=[O:4].[CH3:14][C:15]1[O:16][CH:17]=[CH:18][C:19]=1[SH:20]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([N+:11]([O-:13])=[O:12])=[C:8]([S:20][C:19]2[CH:18]=[CH:17][O:16][C:15]=2[CH3:14])[CH:9]=1)=[O:4]
Reactant: Cc1occc1S
Reactant: COC(=O)c1cc(Br)c([N+](=O)[O-])s1
Solvent: C1CCOC1
Product: COC(=O)c1cc(Sc2ccoc2C)c([N+](=O)[O-])s1

Procedure:
4-Bromo-5-nitro-thiophene-2-carboxylic acid methyl ester ((Example 114, step c) 532 mg, 2 mmol), 2-methyl-furan-3-thiol (600 mg, 5.26 mmol), and DMAP-polystyrene resin (2 g, 2.86 mmol) were stirred in THF (10 mL) for 12 h at rt. The resin was filtered and washed with several portions of DCM (100 mL total volume). The filtrate was concentrated in vacuo and the yellow residue (480 mg, 80%) was used without further purification. 1H-NMR (CDCl3): δ 7.46 (d, 1H, J=1.9 Hz), 7.05 (s, 1H), 6.43 (d, 1H, J=1.9 Hz), 3.90 (s, 3H), 2.38 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[CH:9][CH:8]=1>O1CCCC1.Cl>[F:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][C:3]([OH:22])=[O:2])=[CH:12][CH:11]=1
Reactant: COC(=O)CCOc1ccc(OCc2cccc(F)c2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(O)CCOc1ccc(OCc2cccc(F)c2)cc1
Temperature: 70 °C
Yield: 23.9 %

Procedure:
A solution of 500 mg of 3-[4-(3-fluoro-benzyloxy)-phenoxy]-propionic acid methyl ester in a mixture of 5 ml of tetrahydrofurane and 25 ml of hydrochloric acid (19%) was heated at 70° C. for 7 h. For the working-up, the tetrahydrofurane was evaporated under reduced pressure and the aqueous was extracted three times with 40 ml of ethyl acetate. The combined organic layers were dried over magnesium sulphate and evaporated under reduced pressure. The crude product was triturated in ether and the solid material collected on a filter funnel. After drying there were obtained 114 mg (30% of theory) of 3-[4-(3-fluoro-benzyloxy)-phenoxy]-propionic acid as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[N:13]3)=[O:9])[CH:7]=1.[CH2:21]([S:24](Cl)(=[O:26])=[O:25])[CH2:22][CH3:23]>C(Cl)Cl>[F:20][C:5]1[CH:4]=[CH:3][C:2]([N:1]([S:24]([CH2:21][CH2:22][CH3:23])(=[O:26])=[O:25])[S:24]([CH2:21][CH2:22][CH3:23])(=[O:26])=[O:25])=[CH:7][C:6]=1[C:8]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][CH:14]=[N:13]2)=[O:9]
Reactant: Nc1ccc(F)c(C(=O)c2ccc3nccnc3c2)c1
Reactant: CCCS(=O)(=O)Cl
Solvent: ClCCl
Product: CCCS(=O)(=O)N(c1ccc(F)c(C(=O)c2ccc3nccnc3c2)c1)S(=O)(=O)CCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.8 %

Procedure:
To a solution of (5-amino-2-fluorophenyl)(quinoxalin-6-yl)methanone (50 mg, 0.187 mmol, 1.0 eq.) in DCM (10 mL) were added TEA (0.26 mL, 1.87 mmol, 10.0 eq.) and propane-1-sulfonyl chloride (133 mg, 0.935 mmol, 5.0 eq.). The resulting mixture was stirred at rt for 1 h, then washed with water and extracted with DCM (20 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The resulting residue was purified by flash column chromatography (PE/EA=2/1, v/v) to afford N-(4-fluoro-3-(quinoxaline-6-carbonyl)phenyl)-N-(propylsulfonyl)propane-1-sulfonamide (50 mg, 56.8%).
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@@H:7]1[CH2:12][C:11](=[O:13])[CH2:10][CH2:9][C@H:8]1[C:14]([OH:16])=[O:15].[CH2:18](O)[CH2:19][OH:20].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1COCC1>[CH3:17][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@H:7]1[C@H:8]([C:14]([OH:16])=[O:15])[CH2:9][CH2:10][C:11]2([O:20][CH2:19][CH2:18][O:13]2)[CH2:12]1
Reactant: Cc1ccccc1[C@@H]1CC(=O)CC[C@H]1C(=O)O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1[C@@H]1CC2(CC[C@H]1C(=O)O)OCCO2

Procedure:
(1R,2R)-2-(o-tolyl)-4-oxo-cyclohexanecarboxylic acid (500 mg, 2.153 mmol) in THF (6.0 ml) was reacted with ethylene glycol (0.600 ml, 10.76 mmol) and p-toluenesulfonic acid (82 mg, 0.431 mmol), and then aged at rt until the reaction was complete. The mixture was poured into water and extracted with EtOAc. The combined organic portions were dried (Na2SO4), filtered and concentrated to afford the title compound. HPLC/MS: 231.0 (M-CO2H+1), Rt=1.04 min (LC-2).