Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[O:11][CH3:12].[CH:13](OC(=O)C)=[O:14]>C1(C)C=CC=CC=1>[CH:13]([O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[O:11][CH3:12])=[O:14]
Reactant: COc1cc2cc[nH]c2cc1O
Reactant: CC(=O)OC=O
Solvent: Cc1ccccc1
Product: COc1cc2cc[nH]c2cc1OC=O
Yield: 30 %

Procedure:
A solution of 12 g (0.0735 mole) of 6-hydroxy-5-methoxyindole and 12.95 g (0.147 mole) of acetic formic anhydride in 100 ml of toluene is brought to reflux for 16 hours under nitrogen. After the mixture is cooled, 30 g of silica 60 are added to the reaction medium, the mixture is filtered and the filtrate concentrated two-fold. The white precipitate obtained is filtered off and then recrystallized again in 30 ml of toluene. After being dried under vacuum, 4.2 g of the derivative 8 (white powder, 30% yield) are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:20])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:27][C:28](=[O:33])[C:29]([F:32])([F:31])[F:30]>C(O)(C)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=3)[CH2:27][C:28]([OH:33])([C:29]([F:32])([F:31])[F:30])[N:20]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccc(F)cc2)cc1
Reactant: O=C(CBr)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2ccc(F)cc2)cc1

Procedure:
To a mixture of 4-fluoro-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (10 mmol) and sodium bicarbonate (20 mmol) in isopropanol (100 mL), 3-bromo-1,1,1-trifluoroacetone (20 mmol) is added. After heating the reaction mixture at 70°-75° C. for 20 hours, the solvent is removed. The residue is redissolved in methylene chloride and washed with water. The organic fractions are combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture is chromatographed (silica gel, toluene/ethyl acetate, 7/3) to give 2-(4-fluorophenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-4,5-dihydro-1H-imidazole.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]([CH3:41])[C:17]3[N:18]([C:20]([N:25]([C:27]4[S:28][C:29]([C:39]#[N:40])=[C:30]([C:32]5[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=5)[N:31]=4)[CH3:26])=[C:21]([CH2:23][CH3:24])[N:22]=3)[CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CCOCC>CO>[CH2:23]([C:21]1[N:22]=[C:17]2[C:16]([CH3:41])=[CH:15][C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:19][N:18]2[C:20]=1[N:25]([CH3:26])[C:27]1[S:28][C:29]([C:39]#[N:40])=[C:30]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[N:31]=1)[CH3:24]
Reactant: CCc1nc2c(C)cc(N3CCN(C(=O)OC(C)(C)C)CC3)cn2c1N(C)c1nc(-c2ccc(F)cc2)c(C#N)s1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CCc1nc2c(C)cc(N3CCNCC3)cn2c1N(C)c1nc(-c2ccc(F)cc2)c(C#N)s1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of 4-(3-{[5-Cyano-4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-2-ethyl-8-methyl-imidazo[1,2-a]pyridin-6-yl)-piperazine-1-carboxylic acid tert-butyl ester (24.4 g, 42 mmol, 1 eq.) in MeOH (100 mL) was added a 2 M HCl solution in Et2O (127 mL, 254 mmol, 6 eq.). The reaction mixture was stirred at r.t. for 3.5 h then concentrated in vacuo. The residue was partitioned between EtOAc and water. The aqueous layer was extracted twice with EtOAc. A 2 M NaOH solution was added to the aqueous layer until pH reached 8-9 and further extraction with EtOAc was performed. The combined organic layers were then washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The solid was triturated with heptane (100 mL) at r.t. overnight, filtered off, washed with heptane and Et2O, and dried to afford the expected compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[S:11].[CH2:12]([NH:14][CH2:15][C:16](O)=[O:17])[CH3:13].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:16](=[O:17])[CH2:15][N:14]([CH2:12][CH3:13])[C:10]1=[S:11]
Reactant: CCNCC(=O)O
Reactant: Cc1cccc(N=C=S)c1C
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCN1CC(=O)N(c2cccc(C)c2C)C1=S
Yield: 41.5 %

Procedure:
The title compound was prepared by the procedure described in Example 9 using 16.3 g of 2,3-dimethylphenyl-isothiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 250 mL of chloroform. Crystallization from ethanol afforded the title compound (10.3 g) as a light pink solid, m.p. 120°-121° C. Anal. Calcd. for. C13H16N2OS: C, 62.87; H, 6.49; N, 11.28. Found: C, 62.72; H, 6.44; N, 11.47. Mass spectrum (EI, M.+) m/z 248.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:15][O:16][CH3:17]>CN(C)C=O>[CH3:15][O:16][CH2:17][O:11][C:1]1[CH:2]=[CH:3][CH:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2
Reactant: COCCl
Reactant: Oc1cccc2c1CCCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1cccc2c1CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.0 g 5,6,7,8-tetrahydro-naphthalen-1-ol was dissolved in 20 ml of N,N-dimethylformamide. To this solution was added slowly 0.256 g of 95% NaH, followed by addition of 0.768 ml of chloromethoxymethane. The reaction was flushed with nitrogen and left stirring overnight at room temperature. The reaction mixture was then diluted with 50 ml of water and extracted with 50 ml of diethyl ether. The organic layer was washed with 50 ml of water, dried over magnesium sulphate and concentrated in vacuo to afford a crude oil. This was purified by flash chromatography (silica, heptanes/dichloro-methane) to afford 1.0 g of 5-methoxymethoxy-1,2,3,4-tetrahydro-naphthalene.
Reaction SMILES: [CH2:1]([OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[O:11]1[CH:17]2[CH:12]1[CH2:13][CH:14]([C:18](OC)=[O:19])[CH2:15][CH2:16]2.N12CCN(CC1)CC2.C1(C)C=CC=CC=1>CO>[CH2:1]([O:10][C:18]([CH:14]1[CH2:15][CH2:16][CH:17]2[O:11][CH:12]2[CH2:13]1)=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: COC(=O)C1CCC2OC2C1
Reactant: CCCCCCCCCO
Agent: C1CN2CCN1CC2
Solvent: Cc1ccccc1
Solvent: CO
Product: CCCCCCCCCOC(=O)C1CCC2OC2C1

Procedure:
To a 3-neck 250 mL flask equipped with an argon inlet, stir bar and distillation apparatus was added 1-nonanol (19.99 g, 0.14 mol, obtained from Sigma-Aldrich), methyl 3,4-epoxycyclohexanecarboxylate (ERL-4140, 23.80 g, 0.15 mol, obtained from Dow Chemical Company), 1,4-diazabicyclo[2.2.2]octane (DABCO™, 3.96 g, 35 mmol, obtained from Sigma-Aldrich) and toluene (60 mL). The reaction mixture was refluxed until methanol ceased collecting in the receiving flask and the completion of the reaction was confirmed by 1H NMR spectroscopy. The still pot from the distillation was diluted with toluene (60 mL) and washed with brine (3×60 mL). The organic layer was separated, dried over MgSO4 and filtered. The solvent was removed in vacuo. The excess methyl 3,4-epoxycyclohexane carboxylate was removed via Kugelrohr distillation under reduced vacuum to give 33.39 g (90%) of a clear, colorless oil of nonyl-3,4-epoxycylohexanecarboxylate 1H NMR (CDCl3, δ): 4.06 (td, J=6.7, 1.9 Hz, 2H), 3.25-3.10 (m, 2H), 2.55-2.42 (m, 1H), 2.31-1.27 (m, 20H), 0.88 (t, J=6.7 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH:11]1([NH2:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:17][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:9]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: NC1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCCCC1)c1cncc(Br)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of 5-bromonicotinic acid (XLII) (500 mg, 2.49 mmol) in DMF (8 mL) was added cyclohexanamine (XLIII) (247 mg, 2.49 mmol) and DIPEA (643 mg, 4.98 mmol). The reaction was cooled at 0° C. before adding HATU (947 mg, 2.49 mmol). The reaction was warmed to room temperature and stirred for 4 hrs. The reaction was diluted with EtOAc, washed with 2× water, brine, dried over MgSO4 and concentrated under vacuum to yield crude 5-bromo-N-cyclohexylnicotinamide (XLIV). The product was used without further purification. ESIMS found for C12H15BrN2O m/z 283 (M+H).
Reaction SMILES: [OH-].[Na+].[C:3]([C:7]1[CH:8]=[C:9]([C:18]2[CH:19]=[C:20]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([O:38]CC)=[O:37])=[CH:32][CH:31]=3)[CH:21]=[CH:22][C:23]=2[O:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29])[CH:10]=[CH:11][C:12]=1[N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])([CH3:6])([CH3:5])[CH3:4].Cl>O1CCCC1.O.CCCCCCC>[C:3]([C:7]1[CH:8]=[C:9]([C:18]2[CH:19]=[C:20]([C:30]3[CH:31]=[CH:32][C:33]([C:36]([OH:38])=[O:37])=[CH:34][CH:35]=3)[CH:21]=[CH:22][C:23]=2[O:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29])[CH:10]=[CH:11][C:12]=1[N:13]([CH2:14][CH3:15])[CH2:16][CH3:17])([CH3:5])([CH3:6])[CH3:4]
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCCO)c(-c3ccc(N(CC)CC)c(C(C)(C)C)c3)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)c1ccc(-c2cc(-c3ccc(C(=O)O)cc3)ccc2OCCCCO)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.8 %

Procedure:
0.9 mL of aqueous 1N sodium hydroxide solution is added to a solution of 300 mg of ethyl 3″-tert-butyl-4″-diethylamino-4′-(4-hydroxybutoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate (Example 2b) in a mixture of 10 mL of tetrahydrofuran and 3 mL of water. The reaction medium is stirred at room temperature for 12 hours. 0.5 mL of aqueous 1N sodium hydroxide solution is then added. After 12 hours at room temperature, the reaction medium is heated to 50° C. and then left at room temperature for 3 days. The reaction is stopped by adding 5 mL of water. The reaction medium is acidified to pH 5 by adding aqueous 1N hydrochloric acid solution and is then extracted with ethyl acetate. The organic phase is dried over magnesium sulfate. The solid obtained is taken up in heptane and then filtered. 235 mg of 3″-tert-butyl-4″-diethylamino-4′-(4-hydroxybutoxy)-[1,1′;3′,1″]terphenyl-4-carboxylic acid are obtained in the form of a white solid (yield=83%, m.p.=165° C.).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[F:25])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:25][C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][C:15]=1[O:14][CH2:13][CH:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1ccc(OCC2CCCN2C(=O)OC(C)(C)C)c(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(OCC2CCCN2)c(F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.5 %

Procedure:
To a stirred solution of methyl 4-[1-(tert-butoxycarbonyl)-2-pyrrolidinyl]methoxy-3-fluorobenzoate (323.0 mg, 0.914 mmol) in CH2Cl2 (6.5 mL) was added TFA (1.3 mL) at 0° C., and the mixture was stirred 1.5 hr at room temp. The solvent was removed under a reduced pressure and the residue was made basic by the addition of 1N NaOH. The mixture was extracted with CHCl3. The extract was washed with brine, dried over Na2SO4, and concentrated under a reduced pressure to afford 174.8 mg (76%) methyl 3-fluoro-4-(2-pyrrolidinyl)methoxybenzoate as a brownish oil. 1H-NMR (400 MHz, CDCl3) δ1.54-1.63 (m, 1H), 1.76-2.02 (m, 3H), 2.93-3.07 (m, 2H), 3.57 (ddd, J=4.9, 6.9, 14.3 Hz, 1H), 3.89 (s, 3H), 3.97 (dd, J=6.8, 9.3 Hz, 1H), 4.04 (dd, J=5.0, 8.8 Hz, 1H), 6.98 (t, J=17.6 Hz, 1H), 7.73 (dd, J=2.0, 11.7 Hz, 1H), 7.78 (dt, J=2.0, 8.8 Hz, 1H); MS (FAB) m/z 253 (M++1).
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@H:11]1[C:19](=[O:20])[N:18]2[C@@H:12]1[CH2:13][C:14](=O)[CH2:15][CH:16]=[C:17]2[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:22])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.F[C:45](F)(F)[S:46](OS(C(F)(F)F)(=O)=O)(=O)=O>C(#N)C>[Si:1]([O:8][C@@H:9]([C@H:11]1[C:19](=[O:20])[N:18]2[C@@H:12]1[CH2:13][C:14]([S:46][CH3:45])=[CH:15][CH:16]=[C:17]2[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:22])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCC(=O)C[C@H]12
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CSC1=CC=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]2C1
Temperature: -40 °C
Reaction time: 0.08 h
Yield: 48.7 %

Procedure:
To a solution of 4-nitrobenzyl (7R,8S)-8-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-5,9-dioxo-1-azabicyclo[5.2.0]non-2-ene-2-carboxylate (1.5 g, 3.07 mmol) in acetonitrile (15 ml) was added at 0° C. N,N-diisopropylethylamine (1.1 ml, 6.45 mmol). The reaction mixture was cooled at -40° C. and trifluoromethanesulfonic anhydride (0.57 ml; 3.38 mmol) was added. After 5 minutes, further N,N-diisopropylethylamine (1.1 ml, 6.45 mmol) was added to the reaction mixture. Methylmercaptan was then bubbled through the solution at -40° C. during a few seconds. The mixture was allowed to warm to ambient temperature over 1.5 hours. The solvent was evaporated and the residue purified by chromatography on silica gel eluting with ethyl acetate/dichloromethane 3:97 to give 4-nitrobenzyl (7R,8S)-8-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]5-methylthio-9-oxo-1-azabicyclo[5.2.0]non-2,4-diene-2-carboxylate (776 mg, 47%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15](=[O:20])[NH:16][CH:17]=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC([O-])(C)C.[K+].CS(O[CH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=1[F:43])(=O)=O.O>C1COCC1.CCOC(C)=O>[F:43][C:36]1[CH:37]=[C:38]([F:42])[C:39]([F:41])=[CH:40][C:35]=1[CH2:34][CH2:33][CH2:32][N:16]1[CH:17]=[CH:18][N:19]=[C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]2)[C:15]1=[O:20]
Reactant: CS(=O)(=O)OCCCc1cc(F)c(F)cc1F
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc[nH]c2=O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2nccn(CCCc3cc(F)c(F)cc3F)c2=O)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.8 %

Procedure:
To a solution of 3-(4-tert-butoxycarbonyl-1-piperazinyl)-2(1H)-pyrazinone (obtained in Example 48, Step 1; 0.53 g, 1.91 mmol) in THF (10 mL) was added t-BuOK (0.21 g, 1.91 mmol) and the mixture was stirred at room temperature for 10 min. The resultant mixture was added dropwise to a solution of 3-(2,4,5-trifluorophenyl)propyl methanesulfonate (0.66 g, ˜2.1 mmol; from Step 3) in THF (10 mL). The mixture was stirred at 35° C. for 3 days. Then, the solution was cooled to 0° C. and water (20 mL) and EtOAc (25 mL) were added. The aqueous phase was saturated with NaCl (2 g) and extraction performed. After separation and repeated extraction with EtOAc (15 mL) the combined organic layers were washed with brine and dried over Na2SO4. Concentration in vacuum gave 0.75 g of a yellowish oil which was purified by column chromatography on silica gel using EtOAc/n-hexane (4:1) as eluent. This gave 0.50 g (57%) of the title compound as a colorless oil. HPLC purity: 91%. 1H NMR and MS analyses support the stated structure.
Reaction SMILES: O=[C:2](Cl)[O:3][C:4](Cl)(Cl)Cl.[C:9]([S:12][CH2:13][C@@H:14]([C:16]([OH:18])=[O:17])[NH2:15])(=[O:11])[CH3:10].C>O1CCOCC1>[N-:15]=[C:4]=[O:3].[CH3:2][O:17][C:16](=[O:18])[C@H:14]([CH2:13][S:12][C:9](=[O:11])[CH3:10])[NH2:15]
Reactant: CC(=O)SC[C@H](N)C(=O)O
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H](N)CSC(C)=O
Product: [N-]=C=O

Procedure:
0.35 mol diphosgene is added dropwise over 1 hour to a mixture of 0.28 mol of the methyl ester of S-acetylcysteine and 0.4 g activated charcoal in 400 mL dioxane under N2. The reaction mixture is then heated and stirred at reflux for 21/2 hours. The reaction mixture is then cooled, filtered, and concentrated to dryness by rotary evaporator, keeping exposure to moisture to a minimum. The crude product is re-dissolved in 100 mL THF, and the pH of the solution is adjusted to 5.5-6.0 by addition of pyridine. The product mixture is again filtered, and the filtrate is fractionally distilled to give S-acetylcysteine methyl ester isocyanate.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:7]=[C:8]([C:14]([NH2:16])=O)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:19]N.[F:21][C:22]([F:27])([F:26])[CH2:23][NH:24][NH2:25]>C1(C)C=CC=CC=1.C(O)(=O)C>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:24]([CH2:23][C:22]([F:27])([F:26])[F:21])[N:25]=[CH:19][N:16]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1
Reactant: NNCC(F)(F)F
Reactant: NC(=O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CN
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Temperature: 95 °C

Procedure:
To a solution of 8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide 25 (10.76 g, 0.03308 mol) in toluene (200 mL) was added methanamine, 1,1-Dimethoxy-N,N-dimethyl-(19.683 g, 0.1640 moles). The reaction was heated to 95° C. for 3 hours. The toluene was removed in vacuo to give a beige powder. The crude (12.58 g, 0.03308 mol) was redissolved in acetic acid (120 mL) and trifluoroethyl hydrazine (6.269 mL, 0.04962 mol) was added. The reaction was heated to 95° C. for 4 h. The AcOH was removed in vacuo. The product was loaded as a solid onto silica and purified by flash chromatography (5-70% EtOAc in hexanes). The appropriate fractions were combined and concentrated to give 8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (6.176 g) as an off-white solid. MS(ESI+) 431.0/433.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[N:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)=[CH:4][CH:3]=1.[CH2:19]=[C:20]([CH3:22])[CH3:21].B(F)(F)F.CCOCC.C(#N)C>[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[NH:8][CH:9]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)[CH2:19][C:20]2([CH3:22])[CH3:21]
Reactant: O=[N+]([O-])c1cccc(/C=N/c2ccc(Cl)cc2)c1
Reactant: C=C(C)C
Agent: FB(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CC#N
Product: CC1(C)CC(c2cccc([N+](=O)[O-])c2)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 75.2 %

Procedure:
To a mixture of 4-chloro-phenylamine (12.8 g 100 mmol) and 3-nitro-benzaldehyde (15.1 g, 100 mmol) was added 100 mL of toluene. The resulting solution was heated to reflux with a dean-stark trap for 3 h. The toluene was removed and the residue was collect to afford (4-chloro-phenyl)-[1-(3-nitro-phenyl)-meth-(E)-ylidene]-amine as yellow solid (26.5 g, yield: 95%). (4-Chloro-phenyl)-[1-(3-nitro-phenyl)-meth-(E)-ylidene]-amine (10.0 g, 36.5 mmol), isobutene (31 ml, 365.4 mmol, 10 g), boron trifluoride etherate (1.98 ml, 7.31 mmol) and acetonitrile (40 ml) were added into a autoclave and was stirred at room temperature for 72 h. Brine was added and the organic layer was separated, dried and concentrated to afford 6-chloro-4,4-dimethyl-2-(3-nitro-phenyl)-1,2,3,4-tetrahydro-quinoline as yellow solid (8.7 g, yield: 73%).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][CH2:15][CH2:16][N:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.[Cl:33]CCl>C(O)C>[ClH:33].[C:24]1([N:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCOCCN(c2ccccc2)c2ccccc2)C1
Reactant: ClCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(CCOCCN(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The ester prepared in Example 1 (3.5 g, 8.8 mmol) was dissolved in ethanol (10 ml) and a 12 N sodium hydroxide solution (1.5 ml) was added. The reaction mixture was stirred at room temperature for 5 h. A concentrated hydrochloric acid solution (2.2 ml) was added with cooling of the reaction vessel in an ice-bath and dichloromethane (300 ml) was added. The resulting emulsion was dried (Na2SO4) and the solvent evaporated in vacuo to give a residue which was crystallised from acetone. This afforded 1.5 g (43%) of the title compound.
Reaction SMILES: BrCCBr.C[Si](C)(C)Cl.[C:10]([O:18][CH2:19]I)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl:21][C:22]1[CH:27]=[C:26](Cl)[N:25]=[CH:24][N:23]=1>C1COCC1.[Zn].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>[C:10]([O:18][CH2:19][C:26]1[CH:27]=[C:22]([Cl:21])[N:23]=[CH:24][N:25]=1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: O=C(OCI)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: O=C(OCc1cc(Cl)ncn1)c1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 22 %

Procedure:
Zinc (4.81 g, 73.6 mmol) was suspended in THF (6 mL), treated with 1,2-dibromoethane (0.313 mL, 3.63 mmol) and the resulting mixture was heated at 60° C. under argon for 30 minutes. The reaction mixture was allowed to cool to room temperature, treated with trimethylchlorosilane (0.120 mL, 0.938 mmol) and the resulting mixture was stirred at room temperature for 30 minutes. A solution of iodomethyl benzoate (Intermediate 23, 3.15 g, 12.02 mmol) in THF (6 mL) was added and the resulting mixture was stirred at room temperature for 1 hour. This reaction mixture was added to a solution of 4,6-dichloropyrimidine (1.075 g, 7.21 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.695 g, 0.601 mmol) in THF (11 mL) and the resulting mixture was stirred at room temperature under argon for 18 hours. The reaction mixture was filtered through celite, diluted with saturated ammonium chloride solution and extracted with ethyl acetate (×2). The ethyl acetate layers were combined, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Biotage SP4) eluting with a gradient of 0-20% ethyl acetate and isohexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound as a yellow solid (394 mg);
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:14][C:15]([O:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][C:21]=2[CH3:29])=[O:16])[CH:6]=[CH:7][C:8]=1[S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])#[N:2].[NH2:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[C:37]([N:41]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[N:36][CH:35]=[CH:34]2.O.[C:57]([OH:61])(=[O:60])[CH:58]=O>>[C:52]([O:51][C:49]([N:41]([C:42]([O:44][C:45]([CH3:46])([CH3:47])[CH3:48])=[O:43])[C:37]1[C:38]2[C:33](=[CH:32][C:31]([NH:30][CH:58]([C:23]3[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][O:17][C:15](=[O:16])[NH:14][C:5]4[CH:6]=[CH:7][C:8]([S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])=[C:3]([C:1]#[N:2])[CH:4]=4)=[C:21]([CH3:29])[CH:22]=3)[C:57]([OH:61])=[O:60])=[CH:40][CH:39]=2)[CH:34]=[CH:35][N:36]=1)=[O:50])([CH3:55])([CH3:54])[CH3:53]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(N)ccc12
Reactant: CCS(=O)(=O)c1ccc(NC(=O)OCCc2ccc(B(O)O)cc2C)cc1C#N
Reactant: O=CC(=O)O
Solvent: O
Product: CCS(=O)(=O)c1ccc(NC(=O)OCCc2ccc(C(Nc3ccc4c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc4c3)C(=O)O)cc2C)cc1C#N
Yield: 44 %

Procedure:
Using a procedure analogous to that used to prepare 2D, 31B (468 mg, 1.1 mmol) was reacted with Intermediate 1 and glyoxylic acid monohydrate to afford 31C (419 mg, 44%) as a pale yellow solid. MS (ESI) m/z 788.07 (M+H)+.