Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19](=[O:28])[N:20]([CH3:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:16][CH:17]=1.C(N(CC)CC)C>ClCCl>[C:1]1([S:7]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][C:19](=[O:28])[N:20]([CH3:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:16][CH:17]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(C(=O)Oc1ccc(N)cn1)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)Oc1ccc(NS(=O)(=O)c2ccccc2)cn1)c1ccccc1
Reaction time: 4 h
Yield: 28.2 %

Procedure:
Benzenesulphonyl chloride (0.18 g, 1.00 mmol), dissolved in a small amount of dichloromethane, was added dropwise to a stirred solution of methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl ester (0.24 g, 1.00 mmol) and triethylamine (0.10 g, 1.00 mmol) in dichloromethane (10 mL). After stirring for 4 hours the solution was extracted with water and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane 40:60 followed by 50:50) yielding the title compound (108 mg, 23% yield) as a white solid.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].N([O-])=O.[Na+].[I-:14].[Na+]>Cl.O>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([OH:9])=[C:2]([I:14])[CH:7]=1
Reactant: Nc1cc(Cl)ccc1O
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Oc1ccc(Cl)cc1I
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.7 %

Procedure:
2-Amino-4-chlorophenol (50 g, 0.35 mol) was dissolved in 500 ml of 2.5 N hydrochloric acid, to which an aqueous solution of 25.25 g (0.37 mol) of sodium nitrite in 50 ml of water was gradually added dropwise with cooling at 0° C. After stirring for 30 minutes, the reaction mixture was confirmed to show "positive" in an iodostarch reaction and an aqueous solution of 70 g (0.42 mol) of sodium iodide in 100 ml of water was added slowly. The temperature of the reaction mixture was allowed to rise to room temperature, at which the reaction mixture was stirred overnight and then extracted with ethyl acetate. The ethyl acetate layer was concentrated, whereby 89.7 g of 4-chloro-2-iodophenol were obtained as a purple solid (yield: 99%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][C:9]#[N:10])=[CH:6][CH:5]=1.CS(O[CH2:18][CH2:19][C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)(=O)=O.Cl>CCCCCC.CN(C=O)C>[Cl:3][C:4]1[CH:12]=[CH:11][C:7]([CH:8]([CH2:18][CH2:19][C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[C:9]#[N:10])=[CH:6][CH:5]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: CS(=O)(=O)OCCc1cccs1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: N#CC(CCc1cccs1)c1ccc(Cl)cc1
Temperature: 10 °C
Reaction time: 1.5 h

Procedure:
To a flask under a nitrogen atmosphere was added, with stirring, 3.3 g. (0.0825 mole) of 60% sodium hydride, washed twice with hexane to remove the original mineral oil, in 75 ml. of a dry 2 to 1 mixture of DMF and toluene. To this slurry at room temperature was added 11.30 g. (0.075 mole) of 4-chlorobenzyl cyanide in 40 ml. of DMF. After 1.5 hours, the mixture was cooled to 10° C. and 13.7 g. (0.0782 mole) of 2-(2-thienyl)ethyl methanesulfonate in 25 ml. of DMF was added dropwise. The reaction was stirred at room temperature for 13 hours. Then aqueous 10% hydrochloric acid, 20 ml., was added followed by 150 ml. of diethyl ether which was washed three times with 50 ml. portions of water. After drying the ether and concentrating, the product was distilled at 130°-150° C. at 1-2 mm of Hg yielding 2-(4-chlorophenyl)-4-(2-thienyl)butyronitrile as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:9])[CH:7]=1.C([Sn](CCCC)(CCCC)[C:22]([O:24]CC)=[CH2:23])CCC>[Cl-].C([N+](CC)(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C>[F:16][C:5]1[CH:4]=[CH:3][C:2]([C:22](=[O:24])[CH3:23])=[CH:7][C:6]=1[CH:8]([OH:9])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: OC(c1ccccc1)c1cc(Br)ccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CC#N
Product: CC(=O)c1ccc(F)c(C(O)c2ccccc2)c1
Temperature: 150 °C

Procedure:
A 5 mL microwave tube was charged with (5-bromo-2-fluorophenyl)-(phenyl)methanol (1 eq), tributyl-(1-ethoxyvinyl)tin (1 eq), tetraethylammonium chloride (3 eq), bis(triphenylphosphine)palladium(II) chloride (10 mol %) and acetonitrile (3.5 mL). The reaction was heated to 150° C. for one hour using microwave irradiation. The reaction was concentrated to dryness and the residue was taken up in water and extracted with ethyl acetate. The organics were dried over magnesium sulfate, filtered and then concentrated to an oil. Purification by silica gel chromatography provided 1-{4-fluoro-3-[hydroxy(phenyl)methyl]phenyl}ethanone as an oil. H1 NMR (d6-dmso): 8.16 (dd, 1H), 7.89 (m, 1H), 7.18-7.34 (m, 6H), 6.14 (d, 1H), 5.93 (d, 1H), 2.53 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([OH:13])(=[O:12])=O)[CH:7]=[N:8][CH:9]=1)([O-:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)Cl.P(Cl)(Cl)(Cl)=O.[CH2:25]([NH2:27])[CH3:26]>O>[CH2:25]([NH:27][S:10]([C:6]1[CH:7]=[N:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:12])=[O:13])[CH3:26]
Reactant: CCN
Reactant: O=[N+]([O-])c1cncc(S(=O)(=O)O)c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCNS(=O)(=O)c1cncc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A mixture of 0.5g. of 5-nitro-3-pyridinesulfonic acid, 0.5g. of phosphorous pentachloride and 15 ml. of phosphorous oxychloride was heated under reflux for 6 hours. After removing the solvent by evaporation, dry chloroform was added to give a powdery crystal. After adding the crystal to 2.5 ml. of 20% ethyl amine under cooling, the mixture was stirred for 1 at room temperature. Then, the mixture was diluted with water and extracted with ethyl acetate. The extact was washed with water and dried. After removing the solvent by evaporation and purification by chromatography, 0.2g. of the desired compound was obtained. m.p. 117°-118° C. Similarly, the following compounds were synthesized.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=1[SH:33].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:5]2[N:6]([C:8]3[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:15])=[O:16])=[CH:10][CH:9]=3)[CH:7]=[C:3]([CH2:2][S:33][C:27]3[C:26]([Cl:25])=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:32])[N:4]=2)=[CH:19][CH:20]=1
Reactant: Sc1c(Cl)cccc1Cl
Reactant: CS(=O)(=O)c1ccc(-n2cc(CCl)nc2-c2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-n2cc(CSc3c(Cl)cccc3Cl)nc2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4-chloromethyl-2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole (Example 159, Step 1) (250 mg, 0.656 mmole) and 2,6-dichlorothiophenol in 5 ml of dimethylformamide (235 mg, 1.31 mmol) was added 226 mg (1.64 mmol) of potassium carbonate. The resulting mixture was stirred rapidly at room temperature for two days. The mixture was partitioned between ethyl acetate and water and the aqueous layer was further extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and evaporated. Chromatography of the residue over silica gel using 50% ethyl acetate in hexane gave the title compound, 282 mg, as a pure white solid: mp (DSC) 202° C. Anal. Calc'd. for C23H17Cl3N2O2S2 (MW 523.89): C, 52.73; H, 3.27; N, 5.35. Found: C, 52.55; H, 2.98; N, 5.19.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH2:11][CH:12]=C)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].CSC.C[OH:18]>>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH2:11][CH:12]=[O:18])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: CO
Reactant: C=CCc1ccc(C#N)c(OC)c1
Solvent: CSC
Product: COc1cc(CC=O)ccc1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 25 mL flask containing a stir bar was added compound 2-(methyloxy)-4-prop-2-en-1-ylbenzonitrile (0.150 g, 0.866 mmol) and MeOH (8 mL). The flask was placed in a cold bath of −78° C. Ozone was bubbled through the flask for about 10 min. followed by addition of dimethyl sulfide (1.5 mL, 0.024 mmol). The flask was taken out of the cold bath and stirred at room temperature for 1 h; LC indicated completion of the reaction. The reaction mixture was concentrated to dryness to give 2-(methyloxy)-4-(2-oxoethyl)benzonitrile.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]3[O:18][C:19]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:20]=4[C:21]=3[C:22](=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26])[CH:13]=2)[C:8]=1[Br:33])C.[OH-].[K+]>C1COCC1.O>[Br:33][C:8]1[C:9]2[C:14](=[CH:13][C:12]([C:17]3[O:18][C:19]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:20]=4[C:21]=3[C:22](=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26])=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:7]=1[O:6][CH2:5][C:4]([OH:34])=[O:3]
Reactant: CCCCC(=O)c1c(-c2ccc3c(Br)c(OCC(=O)OCC)ccc3c2)oc2ccc(Cl)cc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCC(=O)c1c(-c2ccc3c(Br)c(OCC(=O)O)ccc3c2)oc2ccc(Cl)cc12
Yield: 88.5 %

Procedure:
Following the procedure described in Step 4 of Example 6, [1-bromo-6-(5-chloro-3-pentanoyl-benzofuran -2-yl)-naphthalen-2-yloxy]-acetic acid ethyl ester (0.25 g, 0.46 mmol) was hydrolyzed with potassium hydroxide (0.300 g, 5.36 mmol) in THF (10 mL) and water (10 mL). Crystallization from ethyl acetate afforded the title compound as an off-white solid (0.21 g), mp 130-132° C. Mass spectrum (−APCl, [M−H]−) m/z 513, 515, 517. 1HNMR (400 MHz, DMSO-d6): δ13.25 (br s,1H), 8.48 (d,1H, J=1.5 Hz), 8.25 (d, 1H, J=9.0 Hz), 8.14 (d, 1H, J=9.0 Hz), 8.04 (d, 1H, J=2.2 Hz), 7.99 (dd, 1H, J=9.0, 1.8 Hz), 7.79 (d, 1H, J=8.8 Hz), 7.52-7.48 (m, 2H), 5.03 (s, 2H), 2.72 (t, 2H, J=7.3 Hz), 1.56-1.48 (m, 2H), 13H, 1.17-1.07 (m, 2H), and 0.70 ppm (t, 3H, J=7.4 Hz). Elemental Analysis for C25H20BrClO5: Calculated: C, 58.22; H, 3.91; N, 0.00. Found: C, 58.24; H, 3.73; N, 0.03.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:34])[C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]5([C:32]#[N:33])[CH2:31][CH2:30]5)[CH:24]=4)[CH:18]=[CH:19][CH:20]=3)=[N:10][N:9]2[CH:35]=1)=[O:4].[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>C(#N)C>[C:32]([C:29]1([C:25]2[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=2)[C:22]([NH:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([O:14][C:11]3[CH:12]=[CH:13][C:8]4[N:9]([CH:35]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:36]5[CH2:41][CH2:40][O:39][CH2:38][CH2:37]5)[N:7]=4)[N:10]=3)[CH:16]=2)=[O:34])[CH2:31][CH2:30]1)#[N:33]
Reactant: C1COCCN1
Reactant: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(NC(=O)CCl)cn5n4)c3)c2)CC1
Solvent: CC#N
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(NC(=O)CN6CCOCC6)cn5n4)c3)c2)CC1
Yield: 79 %

Procedure:
Using N-[3-({2-[(chloroacetyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-(1-cyanocyclopropyl)benzamide (140 mg, 0.287 mmol), morpholine (1 mL) and acetonitrile (2 mL) as starting materials and in the same manner as in Example 408, the title compound (123 mg, 79%) was obtained as a white powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][C@H:10]([NH:19][C:20]([C:22]2([CH2:27]CC(C(OCC)=O)CC(O)=O)[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])[C:9]1=[O:39])([CH3:4])([CH3:3])[CH3:2].C[C@@H]1[O:47][C@@H:46]([O:48][C@@H:49]2[C:54]3=C(O)C4C(=O)C5C(=CC=CC=5OC)C(=O)C=4C(O)=C3C[C@@](O)(C(CO)=O)C2)[CH2:45][C@H:44](N)[C@@H:43]1[OH:79].Cl>CO>[C:1]([O:5][C:6](=[O:40])[CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][C@H:10]([NH:19][C:20]([C:22]2([CH2:27][CH:45]([CH2:44][C:43]([NH:8][CH:14]([CH3:15])[CH3:13])=[O:79])[C:46]([O:48][CH2:49][CH3:54])=[O:47])[CH2:23][CH2:24][CH2:25][CH2:26]2)=[O:21])[C:9]1=[O:39])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(CCC1(C(=O)N[C@H]2CCc3ccccc3N(CC(=O)OC(C)(C)C)C2=O)CCCC1)CC(=O)O
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)CO)C[C@@H]3O[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1
Agent: Cl
Solvent: CO
Product: CCOC(=O)C(CC(=O)NC(C)C)CC1(C(=O)N[C@H]2CCc3ccccc3N(CC(=O)OC(C)(C)C)C2=O)CCCC1

Procedure:
With a retention time of 6.5 min., there was obtained 33 g of the second stereoisomer, which was assigned the designation “rel2” in relation to the chiral center “*Ca” bearing the group “—COOR1”, as (2“rel2”)-3-{[1-({[(3S)-1-(2-tert. butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]ethyl}4-ethoxy-4-oxobutyric acid, 1H-NMR (CDCl3): 7.31-7.17, m, [3]; 7.11, d, [2]; 6.81, d, [1]; 4.60, 4.56, 4.35, 4.31, AB-Q. [2]; 4.48, m, [1]; 4.10, m, [1]; [α]D=−136° (1% in methanol).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](O)=[O:9])=[O:4]>C1COCC1.CCOC(C)=O>[OH:9][CH2:8][C:7]1[CH:6]=[C:5]([CH:13]=[CH:12][CH:11]=1)[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)c1cccc(C(=O)O)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cccc(CO)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.7 %

Procedure:
To a solution of 3-(methoxycarbonyl)benzoic acid (0.200 g, 1.11 mmol) in THF (6.0 mL) at 0° C. was added borane tetrahydrofuran complex (5.55 mL, 5.55 mmol) slowly. The reaction mixture was slowly warmed to room temperature and stirred at for 3 h. After this time, the reaction mixture was diluted with EtOAc and quenched very slowly with water. The organic layer was separated, washed with water and brine, dried over anhydrous MgSO4, filtered, and concentrated to afford the title compound (0.16 g, 84% yield) as a colorless oil. LCMS, [M+H]+=167.0.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[C:4](F)[CH:3]=1.O.[NH2:13][NH2:14]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([C:8]([CH3:9])=[N:13][NH:14]2)=[CH:6][CH:7]=1
Reactant: NN
Reactant: CC(=O)c1ccc(Br)cc1F
Solvent: O
Product: Cc1n[nH]c2cc(Br)ccc12
Temperature: 120 °C
Reaction time: 24 h
Yield: 93.6 %

Procedure:
A suspension of 1-(4-bromo-2-fluorophenyl)ethanone (8.33 g, 38.4 mmol) in 15 mL of hydrazine monohydrate (309 mmol, 8 equiv) was heated to 120° C. under a reflux condenser for 23 hours. The resulting suspension (after cooling to room temperature) was filtered. The white solids were washed with water (2×15 mL), sucked under house vacuum at room temperature for 24 hours, and then dried under vacuum at room temperature over P2O5 for 24 hours to afford the title compound (7.59 g) as a yellow solid. LC-MS (ES) m/z=211, 213 [M+H]+.
Reaction SMILES: [N:1]1([C:7](=[O:14])[CH2:8][C:9](=[CH2:13])[C:10]([OH:12])=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:15]([O-:18])(=[S:17])[CH3:16].[K+]>CN(C=O)C>[C:15]([S:17][CH2:13][CH:9]([CH2:8][C:7]([N:1]1[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1)=[O:14])[C:10]([OH:12])=[O:11])(=[O:18])[CH3:16]
Reactant: C=C(CC(=O)N1CCOCC1)C(=O)O
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SCC(CC(=O)N1CCOCC1)C(=O)O
Temperature: 25 °C

Procedure:
2-(2-morpholin-4-yl-2-oxo-ethyl)-acrylic acid (55.19 g, 277.0 mmol) was dissolved in 120 mL DMF and set to stir at room temperature. Potassium thioacetate (25 g, 219.0 mmol) was added in one portion, and the reaction mixture was allowed to stir at ambient temperature for 20 hours. Upon completion (LCMS), DMF was removed by vacuum under reduced pressure. Crude Yield: 75 g. Percent Purity (LCMS): 40%. The crude product was used without further purification.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([F:11])[C:3]=1[CH3:12].[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:13]([O:20][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([F:11])[C:3]=1[CH3:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCc1ccccc1
Reactant: Cc1c(F)ccc([N+](=O)[O-])c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(OCc2ccccc2)ccc([N+](=O)[O-])c1F
Temperature: 100 °C
Yield: 33.3 %

Procedure:
1,3-difluoro-2-methyl-4-nitrobenzene (16 g, 0.092 mol), benzyl alcohol (10 g, 0.092 mol) and K2CO3 (25.3 g, 0.18 mol) were combined in DMF (250 mL) and heated to 100° C. overnight. The mixture was poured into water and extracted with EtOAc (3×200 mL). The combined organics were washed with brine, dried (Na2SO4), concentrated in vacuo and purified by column chromatography on silica gel to give 1-benzyloxy-3-fluoro-2-methyl-4-nitrobenzene (8 g, 33% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.04 (t, J=8.8 Hz, 1H), 7.30-7.46 (m, 5H), 7.08 (d, J=9.2 Hz, 1H), 5.28 (s, 2H), 2.13 (s, 3H).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:6])[CH:4]=[CH2:5].[CH:7]([NH2:11])([CH2:9][CH3:10])[CH3:8]>C(O)C>[CH3:8][CH:7]([NH:11][CH2:5][CH2:4][C:3]([NH:2][CH3:1])=[O:6])[CH2:9][CH3:10]
Reactant: CCC(C)N
Reactant: C=CC(=O)NC
Solvent: CCO
Product: CCC(C)NCCC(=O)NC
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
A mixture of N-methylacrylamide (ABCR; 500 mg, 5.87 mmol), sec-butylamine (Aldrich; 530 mL, 5.22 mmol) and ethanol (4 mL) was heated in a microwave to 140° C. for 45 minutes and then at 150° C. for 30 minutes. The reaction mixture was cooled and poured onto an SCX-2 cartridge (5 g) and cartridge washed through with methanol (˜50 mL). Products were then eluted with 2M ammonia in methanol (˜50 mL) and evaporated to afford the title compound as a straw coloured oil (563 mg; 61%)
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10](=[O:50])[C@H:11]([CH:47]([CH3:49])[CH3:48])[CH2:12][C@H:13]([OH:46])[C@@H:14]([NH:38]C(OC(C)(C)C)=O)[CH2:15][C@H:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][OH:31])=[C:23]([O:32][CH2:33][CH2:34][CH2:35][O:36][CH3:37])[CH:22]=2)[CH:17]([CH3:19])[CH3:18])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[ClH:51]>O1CCOCC1>[ClH:51].[N:1]1([CH2:7][CH2:8][NH:9][C:10](=[O:50])[C@H:11]([CH:47]([CH3:49])[CH3:48])[CH2:12][C@H:13]([OH:46])[C@@H:14]([NH2:38])[CH2:15][C@H:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][OH:31])=[C:23]([O:32][CH2:33][CH2:34][CH2:35][O:36][CH3:37])[CH:22]=2)[CH:17]([CH3:19])[CH3:18])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@H](C(=O)NCCN2CCOCC2)C(C)C)C(C)C)ccc1OCCCO
Agent: Cl
Solvent: C1COCCO1
Product: COCCCOc1cc(C[C@@H](C[C@H](N)[C@@H](O)C[C@H](C(=O)NCCN2CCOCC2)C(C)C)C(C)C)ccc1OCCCO
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
30 mg of 5(S)-(tert-butoxycarbonyl) amino-4(S)-hydroxy-2(S)-isopropyl-7(S)-[4-(3-hydroxypropoxy)-3-(3-methoxypropoxy)-benzyl]-8-methyl-nonanoic acid N-(2-morpholin-4-yl-ethyl)amide are dissolved in 1.5 ml of a 4N solution, cooled to 0° C., of hydrochloric acid in dioxane and the solution is stirred further for 10 minutes at 0° C. The reaction mixture is concentrated to dryness by evaporation under reduced pressure at room temperature. The residue is purified by means of FC (5 g of silica gel, dichloromethane/methanol 98:2) to yield the title compound: Rf (dichloromethane/methanol 8:2)=0.20; Rt =10.43 minutes; FAB-MS (M+H)+ =610.
Reaction SMILES: [C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12]C(=O)OC(C)(C)C)[C:8](=[O:20])[N:7]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][C:23]=2[CH3:32])[C:6]2[CH:33]=[CH:34][C:35]([C:37]#[N:38])=[CH:36][C:5]1=2)(=[O:3])[CH3:2].[ClH:39]>O1CCOCC1.CCOCC>[ClH:39].[C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH2:12])[C:8](=[O:20])[N:7]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][C:23]=2[CH3:32])[C:6]2[CH:33]=[CH:34][C:35]([C:37]#[N:38])=[CH:36][C:5]1=2)(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2cc(C#N)ccc2N(Cc2c(C)ccc3ccccc23)C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H]1C
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(=O)N1c2cc(C#N)ccc2N(Cc2c(C)ccc3ccccc23)C(=O)[C@@H](N)[C@@H]1C
Yield: 79 %

Procedure:
A rt solution of tert-butyl(3S,4S)-5-acetyl-7-cyano-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (235 mg, 458 μmol) in 4 M HCl in dioxane (2.29 ml) was stirred for 2 h. The reaction was diluted with Et2O and the solids were collected by vacuum filtration to provide (3S,4S)-5-acetyl-3-amino-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile hydrochloride (162 mg, 79%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20](OC1C=CC=CC=1)=[O:21].Cl.[OH:30][CH:31]1[CH2:34][NH:33][CH2:32]1>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20]([N:33]1[CH2:34][CH:31]([OH:30])[CH2:32]1)=[O:21]
Reactant: OC1CNC1
Reactant: Cn1c(Nc2ccc(I)cc2F)c(C(=O)Oc2ccccc2)c(=O)n(C)c1=O
Agent: Cl
Product: Cn1c(Nc2ccc(I)cc2F)c(C(=O)N2CC(O)C2)c(=O)n(C)c1=O
Yield: 52 %

Procedure:
The title compound was synthesized from compound 2A and 3-hydroxyazetidine hydrochloride in 52% yield following a similar procedure described in the synthesis of Example 5. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.83 (s, 1H) 7.65 (d, J=9.85 Hz, 1H) 7.52 (d, J=9.60 Hz, 1H) 6.90-6.99 (m, 1H) 5.64 (d, J=5.31 Hz, 1H) 4.25-4.34 (m, 1H) 3.96-4.04 (m, 1H) 3.69-3.75 (m, 1H) 3.39-3.47 (m, 1H) 3.35 (s, 3H) 3.17-3.23 (m, 1H) 3.16 (s, 3H). [M+H] calc'd for C16H16FIN4O4, 475. found, 475.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.O1CCCC1.[Br:24]N1C(=O)CCC1=O>O>[Br:24][C:5]1[N:1]=[C:2]([CH:6]2[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]2)[NH:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncc[nH]2)CC1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2nc(Br)c[nH]2)CC1
Temperature: -78 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
A 100-mL round-bottom flask was charged with tert-butyl 4-(1H-imidazol-2-yl)piperidine-1-carboxylate (0.300 g, 1.19 mmol) and tetrahydrofuran (10 mL), and the solution was cooled to −78. N-Bromosuccinimide (0.185 g, 1.04 mmol) was added, and the resulting solution stirred at −78° C. for 2 h. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 2:1, ethyl acetate/petroleum ether) to afford tert-butyl 4-(4-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate (0.26 g, 66%) as a white solid. MS (ESI, pos. ion) m/z 330, 332 [M+H]+.
Reaction SMILES: COC1C=CC(C[S:10][CH2:11][CH:12]([S:27][CH3:28])[C:13]([N:15]2[C@H:23]([C:24]([OH:26])=[O:25])[CH2:22][C:17]3([S:21][CH2:20][CH2:19][S:18]3)[CH2:16]2)=[O:14])=CC=1.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[SH:10][CH2:11][CH:12]([S:27][CH3:28])[C:13]([N:15]1[C@H:23]([C:24]([OH:26])=[O:25])[CH2:22][C:17]2([S:21][CH2:20][CH2:19][S:18]2)[CH2:16]1)=[O:14]
Reactant: COc1ccc(CSCC(SC)C(=O)N2CC3(C[C@H]2C(=O)O)SCCS3)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CSC(CS)C(=O)N1CC2(C[C@H]1C(=O)O)SCCS2

Procedure:
The product from part (b) is mixed with trifluoroacetic acid and anisole under nitrogen. The solvents are removed under vacuum to yield as a residue [8S]-7-(3-mercapto-2-methylthio-1-oxo-propyl)-7-aza-1,4-dithiaspiro[4.4]nonane-8-carboxylic acid.