Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:23]([OH:25])=[O:24])[CH:19]=2)[CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.O.C(OCC)C>[CH2:1]([O:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:23]([OH:25])=[O:24])[CH:19]=2)[CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Reactant: CCCCCCCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCCCCCCCOc1ccc2cc(C(=O)O)ccc2c1
Yield: 68.8 %

Procedure:
After a solution of decylmonobromide (7 g), 2-hydroxy-6-carboxynaphthalene (2 g) and anhydrous potassium carbonate (4 g) in dimethylformamide (100 ml) was stirred at 130° C. for two hours, it was poured in water. Dilute aqueous hydrochloric acid solution was added thereto until the solution was neutral. To the solution was added diethylether in order to effect extraction. The extracted layer was distilled to remove the solvent. The residue was added to a solution of sodium hydroxide (3.3 g) in water (10 ml) and ethanol (50 ml). The mixture was refluxed for about one day. Thereto was added dilute aqueous hydrochloric acid solution until the solution was neutral. The solution was distilled to remove the solvent and concentrated. Solid precipitate was collected and recrystallized from water-ethanol mixture to obtain the titled compound (2.4 g).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:13][C:12]2[CH:15]=[CH:16][C:9]([O:8][CH3:7])=[CH:10][CH:11]=2)[CH:6]=1
Reactant: Ic1cn[nH]c1
Reactant: COc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(I)cn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Iodo-1H-pyrazole (2.0 g, 10.3 mmol), 4-methoxy-benzyl bromide (3.0 mL, 20.6 mmol), and cesium carbonate (5.0 g, 15.5 mmol) were combined in DMF (20 mL) and stirred at room temperature for 30 minutes. The mixture was subjected to standard aqueous workup, and the crude residue was purified on silica gel (0-20% EtOAc in hexanes) to afford the title compound.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].CCN(C(C)C)C(C)C.C[Al](C)C.[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH:38]=[C:37]([O:39][CH3:40])[C:36](=[O:41])[C:35]([C:42](OC)=[O:43])=[N:34]2)=[C:29]([F:46])[CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH:38]=[C:37]([O:39][CH3:40])[C:36](=[O:41])[C:35]([C:42]([N:3]([O:4][CH3:5])[CH3:2])=[O:43])=[N:34]2)=[C:29]([F:46])[CH:28]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CNOC
Reactant: COC(=O)c1nn(-c2ccc(OCc3ccccc3)cc2F)cc(OC)c1=O
Agent: C[Al](C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cn(-c2ccc(OCc3ccccc3)cc2F)nc(C(=O)N(C)OC)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
To a solution of N,O-dimethylhydroxylamine hydrochloride (5.27 g, 54 mmol) and iPr2NEt (9.41 mL, 54 mmol) in CH2Cl2 (50 mL) was added AlMe3 (1.8 M solution in toluene, 30 mL, 54 mmol) slowly at 0° C. under Ar atmosphere. After stirring for 1 h, a solution of methyl 1-[4-(benzyloxy)-2-fluorophenyl]-5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate (8.07 g, 21 mmol) in CH2Cl2 (50 mL) was added slowly, and the mixture was stirred for 1 h at 0° C. The reaction mixture was poured into ice-water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with AcOEt to give the title compound (7.79 g, 90% yield) as a pale yellow amorphous solid: 1H NMR (300 MHz, CDCl3): δ ppm 3.38 (3H, s), 3.70 (3H, s), 3.89 (3H, s), 5.11 (2H, s), 6.82-6.91 (2H, m), 7.33-7.45 (5H, m), 7.48-7.55 (1H, m), 7.73 (1H, d, J=1.9 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@H:9]1[C@@H:14]([NH:15]C(=O)OC(C)(C)C)[CH2:13][C@@H:12]([N:23]2[CH2:30][C:29]3[CH:28]=[N:27][NH:26][C:25]=3[CH2:24]2)[C:11](=O)[N:10]1[CH3:32].C(N(CC)CC)C.[F:40][C:41]([F:47])([F:46])[S:42](Cl)(=[O:44])=[O:43].[C:48]([OH:54])([C:50]([F:53])([F:52])[F:51])=[O:49].C(Cl)Cl>ClCCl>[F:51][C:50]([F:53])([F:52])[C:48]([OH:54])=[O:49].[F:51][C:50]([F:53])([F:52])[C:48]([OH:54])=[O:49].[F:51][C:50]([F:53])([F:52])[C:48]([OH:54])=[O:49].[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@H:9]1[C@@H:14]([NH2:15])[CH2:13][C@@H:12]([N:23]2[CH2:30][C:29]3[C:25](=[N:26][N:27]([S:42]([C:41]([F:47])([F:46])[F:40])(=[O:44])=[O:43])[CH:28]=3)[CH2:24]2)[CH2:11][N:10]1[CH3:32]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: CN1C(=O)[C@H](N2Cc3cn[nH]c3C2)C[C@H](NC(=O)OC(C)(C)C)[C@H]1c1cc(F)ccc1F
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C[C@H](N2Cc3cn(S(=O)(=O)C(F)(F)F)nc3C2)C[C@H](N)[C@H]1c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl [(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)-1-methyl-6-oxopiperidin-3-yl]carbamate (60 mg, 0.138 mmol) in dichloromethane (4 mL) at room temperature, triethylamine (0.048 mL, 0.346 mmol) and trifluoromethanesulfonyl chloride (0.029 mL, 0.277 mmol) were added. The mixture was stirred overnight at room temperature. The residue was purified by preparative TLC on silica gel, eluting with CH2Cl2/MeOH/aqueous NH3 (95/4/1) to give first eluting isomer as isomer A and second eluting isomer as isomer B. Isomer A was treated with 1:1 TFA/CH2Cl2 for 1 h to give the title compound. LC-MS: 465.84 (M+1).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[CH2:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][NH:7][O:6]1>C1(C)C=CC=CC=1>[CH2:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][N:7]([C:1]([Cl:4])=[O:2])[O:6]1
Reactant: c1ccc2c(c1)CCNOC2
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)N1CCc2ccccc2CO1
Yield: 81.5 %

Procedure:
To a solution of 15.9 g. of phosgene in anhydrous toluene a solution of 19.8 g. (0.135 mole) of 1,3,4,5-tetrahydro-2,3-benzoxazepine in the same solvent was added at 0° - 15°C with stirring. After 6 hours it was washed with H2O, dried over Na2SO4 and the solvent evaporated. Recrystallization from EtOH yielded 22.85 g. (81.5%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]#[N:14])=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].OO.C(=O)([O-])[O-:18].[K+].[K+]>CS(C)=O>[NH2:1][C:2]1[C:3]([C:13]([NH2:14])=[O:18])=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(N)c(C#N)cc1C
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1cc(N)c(C(N)=O)cc1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 208 %

Procedure:
Methyl 5-amino-4-cyano-2-methylbenzoate (151 mg, 0.79 mmol) (synthesized according to reagent preparation 41) was dissolved in DMSO (1.5 mL). 30% Aqueous hydrogen peroxide (0.3 mL) and potassium carbonate (35 mg, 0.25 mmol) were added, and the mixture was stirred at ambient temperature for 1.5 h. The reaction mixture was partitioned between ethyl acetate and water. The aqueous portion was extracted (2×) with ethyl acetate. The combined organic portion was dried over sodium sulfate, filtered and concentrated to a yellow oil which was purified by preparative reverse phase HPLC to afford methyl 5-amino-4-(aminocarbonyl)-2-methylbenzoate (108 mg, 0.52 mmol, 66% yield). NMR (400 MHz, CDCl3): δ 7.85 (s, 1H), 7.45 (br s, 1H), 7.26 (s, 1H), 7.19 (br s, 1H), 6.48 (s, 2H), 3.80 (s, 3H), 2.32 (s, 3H); MS (EI) for C10H12N2O3: 209 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][CH2:11][O:12][CH:13]=2)=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.[Pt]=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][CH2:11][O:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(C2=COCCC2)cc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: Clc1ccc(C2CCCOC2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 96 %

Procedure:
To a solution of 5-(4-chlorophenyl)-3,4-dihydro-2H-pyran (350 mg, 1.80 mmol) in ethyl acetate (8 mL) was added platinum oxide (41 mg, 0.18 mmol) and the reaction was charged with a hydrogen ballon and stirred at room temperature for 6 hours. The reaction was filtered, and the filtrate was evaporated to give crude title compound (340 mg, 96.3%) as white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:12])=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9].CS[C:15]1C2C(=CC(Br)=CC=2Br)N[C:16]=1SC>Cl.CCO>[CH2:15]([O:9][C:8](=[O:10])[C:7]1[CH:11]=[C:3]([CH2:2][NH2:1])[CH:4]=[CH:5][C:6]=1[Cl:12])[CH3:16]
Reactant: NCc1ccc(Cl)c(C(=O)O)c1
Reactant: CSc1[nH]c2cc(Br)cc(Br)c2c1SC
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc(CN)ccc1Cl

Procedure:
Prepared analogously to example 42d with 5-aminomethyl-2-chlorobenzoic acid (2 g; 9.01 mmol) in 20 mL HCl in EtOH. Yield: 2.38 g (90%); MS: [M+H]+=214 (Cl isotope pattern); HPLC: Rt=1.20 min (Method MC-6)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:23])[C:7]=1[NH:8][C:9]1[C:18]2[C:13](=[C:14]([OH:21])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[NH:12][C:11](=[O:22])[CH:10]=1.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]Br.[CH3:31][NH:32][CH3:33]>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:23])[C:7]=1[NH:8][C:9]1[C:18]2[C:13](=[C:14]([O:21][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:32]([CH3:33])[CH3:31])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[NH:12][C:11](=[O:22])[CH:10]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1O
Reactant: CNC
Reactant: BrCCCCCBr
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCN(C)C

Procedure:
The title compound was prepared from 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxyquinolin-2(1H)-one (Example 11, Step 1), 1,5-dibromopentane, and dimethylamine following the procedures outlined in Example 13. 1H NMR (400 MHz, DMSO-d6): δ 9.91 (s, 1H), 8.83 (s, 1H), 8.75 (s, 2H), 7.87 (d, 1H), 7.04 (d, 1H), 4.77 (s, 1H), 3.96 (t, 2H), 3.90 (s, 3H), 2.19 (t, 2H), 2.10 (s, 6H), 1.76 (m, 2H), 1.48-1.32 (m, 4H) MS (ESI): 465.0.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:13](=[S:15])[NH2:14])[CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.Br[CH2:18][CH:19]([O:22]C)[O:20]C.[C:24]1(C)C=CC(S(O)(=O)=O)=C[CH:25]=1>C(O)(=O)C>[C:19]([OH:22])(=[O:20])[CH3:18].[CH3:12][CH:10]([CH3:11])[CH2:9][C@@H:8]([C:13]1[S:15][CH:24]=[CH:25][N:14]=1)[NH2:7]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC(CBr)OC
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(N)=S
Solvent: CC(=O)O
Product: CC(C)C[C@H](N)c1nccs1
Temperature: 120 °C
Yield: 897.2 %

Procedure:
A mixture of ((S)-3-methyl-1-thiocarbamoyl-butyl)-carbamic acid tert-butyl ester (1.38 g, 6 mmol), 2-bromo-1,1-dimethoxyethane (CAN:7252-83-7, 1.14 g, 7 mmol) and p-toluene sulfonic acid (50 mg) in acetic acid (20 mL) was stirred at 120° C. for 4. After evaporation of solvents, the residue was diluted with ethyl acetate (20 mL) and water (20 mL). The aqueous phase was washed with ethyl acetate (3×20 mL) and lyophilized to give a brown solid (0.6 g, 63%); MS: m/e 171.1 [M+H+].
Reaction SMILES: FC(F)(F)C(O)=O.ClC1C(N[C@@H]2[C@@H]3C[C@@H](C=C3)[C@@H]2C(N)=O)=C2N=C(C3C=CC(CN4CCOCC4)=CC=3)NC2=NC=1.[NH2:42][C:43]1[C:48]([NH2:49])=[C:47]([NH:50][C@H:51]2[C@H:56]3[CH2:57][C@H:53]([CH:54]=[CH:55]3)[C@H:52]2[C:58]([NH2:60])=[O:59])[C:46]([Cl:61])=[CH:45][N:44]=1.[CH3:62][O:63][C:64]1[CH:71]=[C:70]([N:72]2[CH2:77][CH2:76][CH:75]([N:78]3[CH2:83][CH2:82][O:81][CH2:80][CH2:79]3)[CH2:74][CH2:73]2)[CH:69]=[CH:68][C:65]=1[CH:66]=O>>[Cl:61][C:46]1[C:47]([NH:50][C@H:51]2[C@H:56]3[CH2:57][C@H:53]([CH:54]=[CH:55]3)[C@H:52]2[C:58]([NH2:60])=[O:59])=[C:48]2[N:49]=[C:66]([C:65]3[CH:68]=[CH:69][C:70]([N:72]4[CH2:73][CH2:74][CH:75]([N:78]5[CH2:83][CH2:82][O:81][CH2:80][CH2:79]5)[CH2:76][CH2:77]4)=[CH:71][C:64]=3[O:63][CH3:62])[NH:42][C:43]2=[N:44][CH:45]=1
Reactant: COc1cc(N2CCC(N3CCOCC3)CC2)ccc1C=O
Reactant: NC(=O)[C@H]1[C@@H](Nc2c(Cl)cnc(N)c2N)[C@@H]2C=C[C@H]1C2
Agent: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)nc23)[C@H]2C=C[C@@H]1C2
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(N2CCC(N3CCOCC3)CC2)ccc1-c1nc2c(N[C@@H]3[C@H](C(N)=O)[C@H]4C=C[C@@H]3C4)c(Cl)cnc2[nH]1
Yield: 8 %

Procedure:
In the same fashion as for Compound III, (1R,2R,3S,4S)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 2-Methoxy-4-(4-morpholin-4-yl-piperidin-1-yl)-benzaldehyde were reacted to produce the title compound (8%). 1H NMR (d-6 DMSO): 12.26 (br s, 1H), 9.70 (br s, 1H), 8.02 (m, 1H), 7.79 (s, 1H), 7.42 (br s, 1H), 7.26 (s, 1H), 6.78 (d, J=9 Hz, 1H), 6.66 (s, 1H), 6.38 (s, 2H), 5.17 (m, 1H), 4.11 (m, 2H), 4.03 (m, 2H), 4.00 (s, 3H), 3.68 (m, 2H), 3.48 (m, 4H), 3.12 (m, 2H), 2.92-2.77 (m, 3H), 2.63 (d, J=8 Hz, 1H), 2.24 (m, 1H), 2.13 (m, 2H), 1.68 (m, 2H), 1.40 (d, J=9 Hz, 1H). MS: 578.20 (M+H). HPLC retention time: 1.92 minutes (G Method).
Reaction SMILES: [CH2:1]([CH:3]1[O:8][C:7]2[CH:9]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]([CH3:27])([CH3:26])[C:22]([O:24][CH3:25])=[O:23])=[N:17][CH:18]=3)[CH:11]=[CH:12][C:6]=2[NH:5][CH2:4]1)[CH3:2].N1C=CC=CC=1.[Cl:34][C:35](Cl)([O:37]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Cl:34][C:35]([N:5]1[CH2:4][CH:3]([CH2:1][CH3:2])[O:8][C:7]2[CH:9]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]([CH3:26])([CH3:27])[C:22]([O:24][CH3:25])=[O:23])=[N:17][CH:18]=3)[CH:11]=[CH:12][C:6]1=2)=[O:37]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCC1CNc2ccc(-c3ccc(OCC(C)(C)C(=O)OC)nc3)cc2O1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC1CN(C(=O)Cl)c2ccc(-c3ccc(OCC(C)(C)C(=O)OC)nc3)cc2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
A solution of methyl 3-(5-(2-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)pyridin-2-yloxy)-2,2-dimethylpropanoate B-10 (248.0 mg, 0.60 mmol) and dry pyridine (97.0 μL, 1.20 mmol) in anhydrous methylene chloride (3.0 mL) was added dropwise to a solution of triphosgene (71.2 mg, 0.24 mmol) in anhydrous methylene chloride (3.0 mL) at −20° C. under an atmosphere of argon. The reaction mixture was allowed to warm to room temperature over 30 mins and was stirred for 3 h at room temperature. It was then successively diluted with methylene chloride (25 mL), quenched with a 1 N aqueous solution of hydrogen chloride (1.0 mL), diluted with water (10 mL) and decanted. The aqueous layer was extracted with methylene chloride (3×30 mL); the combined extracts were washed with a 1 N aqueous solution of hydrogen chloride (20 mL), brine (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The light pink solid methyl 3-(5-(4-(chlorocarbonyl)-2-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)pyridin-2-yloxy)-2,2-dimethylpropanoate B-11 (265.0 mg, Yield=100%) was used for the next step without purification and stored at −20° C. under an atmosphere of nitrogen. MS (ESI) [M+1]+ 433.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[C:42](O)=[O:43])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:45][NH:46][CH3:47]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=2)[CH2:13][C@H:12]1[C:42](=[O:43])[N:46]([CH3:47])[CH3:45])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](C(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](C(=O)N(C)C)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
Similar to example 6a, 50.0 mg of (2S,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidin-1,2-dicarboxylic acid 1-benzyl ester (from example 3b) are allowed to react with dimethylamine to afford the title compound as a yellow oil. Rf=0.04 (dichlormethane-methanol 98:2); Rt=4.85.
Reaction SMILES: [CH3:1][C:2]1[C:3]([Cl:26])=[CH:4][C:5](C(C)(C)C)=[C:6]([C:9]2[C:10]([OH:21])=[C:11]([CH3:20])[C:12]([Cl:19])=[CH:13][C:14]=2C(C)(C)C)[C:7]=1[OH:8].C1(C)C=CC=CC=1.FC(F)(F)S(O)(=O)=O.O>C(Cl)(Cl)Cl>[CH3:20][C:11]1[C:12]([Cl:19])=[CH:13][CH:14]=[C:9]([C:6]2[C:7]([OH:8])=[C:2]([CH3:1])[C:3]([Cl:26])=[CH:4][CH:5]=2)[C:10]=1[OH:21]
Reactant: Cc1c(Cl)cc(C(C)(C)C)c(-c2c(C(C)(C)C)cc(Cl)c(C)c2O)c1O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1c(Cl)ccc(-c2ccc(Cl)c(C)c2O)c1O
Temperature: 5 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
The optically active 6,6′-dimethyl-5,5′-dichloro-3,3′-di(t-butyl)-2,2′-biphenol obtained in Example 6 (110 mg, optical purity: >99% ee, 0.28 mmol), toluene (5 ml) and trifluoromethanesulfonic acid (45 mg, 0.5 mmol) were mixed followed by stirring the entire volume for 1 hour at 5° C. Water (1 ml) and chloroform were then added to the reaction mixture followed by extraction and liquid separation. The organic phase was then washed with water and dried with anhydrous magnesium sulfate followed by distilling off the solvent under reduced pressure. N-hexane (10 ml) was added to the remaining slurry followed by stirring at room temperature, washing and filtering to obtain optically active 6,6′-dimethyl-5,5′-dichloro-2,2′-biphenol (70 mg, yield: 82%, optical purity: >99% ee).
Reaction SMILES: [CH2:1]([C:7]1[C:8](=[O:12])[CH2:9][CH2:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(O)C.C(O)(=O)C.[C-:20]#[N:21].[K+]>O>[CH2:1]([CH:7]1[CH:11]([C:20]#[N:21])[CH2:10][CH2:9][C:8]1=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCC1=CCCC1=O
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCC1C(=O)CCC1C#N
Temperature: 35 °C
Reaction time: 3 h

Procedure:
In a 3-L three necked flask fitted with a mechanical stirrer, a reflux condenser, a dropping funnel and a thermometer, are placed 83 g of 2-n-hexyl-cyclopentenone, 1.75 L 95% ethyl alcohol and 30 g of glacial acetic acid. The mixture is warmed up with sirring to 35°C and a solution of 65 g of potassium cyanide in 190 ml of water is added over a period of 15 minutes. Stirring is continued for 3 hours, the temperature being maintained at 35°C. The methanol is then distilled off at a reduced pressure the organic layer is separated, and the water phase is extracted with ether. The combined organic layer and other extract are washed with sodium carbonate solution and water and dried over anhydrous sodium sulphate. The solvent is removed at atmospheric pressure and the residue is distilled through a short Vigreux column. 2-n-Hexyl-3-cyanocyclopentanone is collected at 106°-110°C/0,2 mm, yield 85 g (88%), nD20 1.4658.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH:9]1([C:12](Cl)=[O:13])[CH2:11][CH2:10]1>>[F:1][C:2]1[CH:3]=[C:4]([O:8][C:12]([CH:9]2[CH2:11][CH2:10]2)=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(F)c1
Reactant: O=C(Cl)C1CC1
Product: O=C(Oc1cccc(F)c1)C1CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To 31.4 parts of 3-fluorophenol were added dropwise 29.3 parts of cyclopropanecarbonyl chloride at 80° C. Upon completion, the whole was stirred for 1 hour 80° C. The reaction mixture was distilled, yielding 49.7 parts (98%) of (3-fluorophenyl)cyclopropanecarboxylate; bp. 75°-85° C. at 0.5 mm. pressure (intermediate 86).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)=[C:2]=S.C1(C([O-])=O)C=C(C)C=C(C)C=1.[NH2:25][N+:26]1[CH:31]=[CH:30][N:29]=[CH:28][C:27]=1[NH2:32].C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.[Cl:53]CCl>>[Cl:53][C:28]1[C:27]2[N:26]([N:25]=[C:2]([NH:1][C:4]3[CH:5]=[C:6]4[C:10](=[CH:11][CH:12]=3)[NH:9][C:8](=[O:13])[CH2:7]4)[N:32]=2)[CH:31]=[CH:30][N:29]=1
Reactant: O=C1Cc2cc(N=C=S)ccc2N1
Reactant: Nc1cncc[n+]1N
Reactant: ClCCl
Agent: CCN=C=NCCCN(C)C
Agent: Cc1cc(C)cc(C(=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1Cc2cc(Nc3nc4c(Cl)nccn4n3)ccc2N1
Reaction time: 6 h
Yield: 55 %

Procedure:
To a solution of 5-isothiocyanato-1,3-dihydro-indol-2-one (2.3 g, 12.09 mmol) in dry dichloromethane (200 ml), 1,2-diamino-pyrazinium mesitylenate (5.21 g, 15.12 mmol), diisopropylethylamine (7.81 g, 60.45 mmol) and EDCI (4.63 g, 24.18 mmol) are added and stirred for 6 hours. The reaction mixture is concentrated and the residue is taken in water (100 ml), triturated and filtered, the crude solid is purified by silica column using (60-120) mesh to get the titled product as yellow solid (2.0 g, 55%);
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1.[CH2:9](O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH2:9]([O:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Br:1])[CH:7]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCc1ccccc1
Reactant: Oc1cncc(Br)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Brc1cncc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 31.9 %

Procedure:
To a vial is added 3-bromo-5-hydroxypyridine (200 mg, 1.15 mmol), benzyl alcohol (137 mg, 1.27 mmol) and triphenylphosphine (332 mg, 1.27 mmol) in THF (5 ml) at 0° C., followed by the addition of diisopropyl azodicarboxylate (256 mg, 1.27 mmol). The reaction mixture is stirred at room temperature for 18 hours. The reaction mixture is concentrated in vacuo. The residue is diluted with EtOAc, washed with sat NaHCO3, water, brine, dried under anhy. Na2SO4, filtered and concentrated. The residue is purified by flash chromatography (SiO2, 0-5% MeOH/CH2Cl2) to afford title compound (97 mg); m/z 264.0, 266.0 [M, M+2H]
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:65][S:66][C:67]1[CH:72]=[CH:71][CH:70]=[C:69]([NH2:73])[CH:68]=1>C(Cl)Cl>[CH3:65][S:66][C:67]1[CH:68]=[C:69]([NH:73][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]2)=[O:29])[CH:70]=[CH:71][CH:72]=1
Reactant: CSc1cccc(N)c1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CSc1cccc(NC(=O)C2NC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (250 mg, 0.44 mmol) in methylene chloride (10 mL), HATU (Aldrich, 332 mg, 0.88 mmol) was added followed by the addition of DIPEA (0.230 mL, 1.31 mmol) and 3-amino-phenyl methyl sulfide (Aldrich, 122 mg, 0.88 mmol). The mixture was stirred at rt for 2 hr. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (50 g column, eluent EtOAc/Hexanes, 5-10%) to give a white solid. 178 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](O)=[O:10])=[CH:4][C:3]=1[Br:12].C[Si]([CH:17]=[N+:18]=[N-])(C)C.C(OCC)C>CO.ClCCl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:18][CH3:17])=[O:10])=[CH:4][C:3]=1[Br:12]
Reactant: Nc1ccc(CC(=O)O)cc1Br
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Solvent: ClCCl
Product: CNC(=O)Cc1ccc(N)c(Br)c1
Temperature: 25 °C

Procedure:
To 2-(4-amino-3-bromo-phenyl)acetic acid (5 g, 21.73 mmol) in methanol (50 mL) and dichlormethane (100 mL) is added at −5° C. trimethylsilyldiazomethane in diethylether 2 mol/L (31.51 mL, 63.03 mmol) dropwise over a period of 30 min. The reaction mixture is allowed to warm up to r.t. and concentrated. The crude product is used without further purification.