Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]/[C:2](=[CH:6]\[C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:11]=1)/[C:3](O)=[O:4].C(N(CC)CC)C.C1(P([N:39]=[N+:40]=[N-:41])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[CH3:1][C:2](=[CH:6][C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:11]=1)[C:3]([N:39]=[N+:40]=[N-:41])=[O:4]
Reactant: C/C(=C\c1cc(-c2ccccc2)cs1)C(=O)O
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=Cc1cc(-c2ccccc2)cs1)C(=O)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (E)-2-methyl-3-(4-phenyl-thiophen-2-yl)-acrylic acid (924 mg, 3.78 mmol) and triethylamine (617 μl, 4.43 mmol) in THF (10 ml) was added diphenylphosphoryl azide (897 μl, 6.27 mmol) at 0° C. The reaction was next stirred for 4 h at room temperature. At which point the contents of the reaction flask were partitioned between ethyl acetate (25 ml) and sodium hydrogencarbonate (25 ml). The organic phase was separated and the solvent removed in vacuo. The crude residue was suspended between methanol (25 ml) and distilled water (25 ml), the precipitate collected and dried (MgSO4) to afford the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.[CH2:11]([CH:13]([CH2:17][CH3:18])[C:14](Cl)=[O:15])[CH3:12].[N+](C)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-]>O>[CH2:11]([CH:13]([CH2:17][CH3:18])[C:14]([C:3]1[S:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2]=1[CH3:1])=[O:15])[CH3:12]
Reactant: Cc1csc2ccccc12
Reactant: CCC(CC)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: O
Product: CCC(CC)C(=O)c1sc2ccccc2c1C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a mixture of 3-methyl-1-benzothiophene (1.00 g), 2-ethylbutyryl chloride (1.02 mL) and nitromethane (10 mL) was added aluminum chloride (1.35 g) at 0° C., and the mixture was stirred for 3 hr. Water was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-10% ethyl acetate/hexane) to give the title object compound (1.65 g, 99%) as a pale-yellow oil.
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH:11]1[CH:16]=[CH:15][C:14]([O:17][C:18](Cl)=[S:19])=[CH:13][CH:12]=1.C(OCC)C>O>[O:17]([C:14]1[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=1)[C:18]([S:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[S:19]
Reactant: SCc1ccccc1
Reactant: S=C(Cl)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: S=C(Oc1ccccc1)SCc1ccccc1
Reaction time: 0.25 h
Yield: 74.9 %

Procedure:
Benzyl mercaptan (1.24 g, 10 mmol) was added to an aqueous (20 mL) solution of NaOH (0.8 g, 20 mmol) at room temperature and stirred for 15 minutes. Phenyl thionochloroformate (2.07 g, 12 mmol) was next added dropwise to this solution at the same temperature and stirred for a further 2 hours. Diethyl ether (20 mL) and water (50 mL) was added and the organic layer separated. The aqueous layer was extracted with diethyl ether (3×20 mL). The combined organic fractions were dried with Na2SO4, filtered, the solvent removed and the crude product chromatographed (using silica gel, 2% ethyl acetate in petroleum spirits) to afford the title compound (1.95 g, 75%) as a yellow oil. 1H-nmr (CDCl3) δ 4.43 (2H), 7.10-7.50 (10H). 13C-nmr (CDCl3) δ 41.7, 122.1, 126.7, 127.8, 128.8, 129.3, 129.6, 135.1, 154.0, 213.0.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([OH:14])[C:3]=1[C:15](=[O:17])[CH3:16].C([O-])([O-])=O.[K+].[K+].[C:24](Cl)(=O)[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1.O>CC(C)=O>[OH:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]2[C:3]=1[C:15](=[O:17])[CH:16]=[C:24]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[O:14]2
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC(=O)c1c(O)cc(N2CCOCC2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(-c2cc(=O)c3c(O)cc(N4CCOCC4)cc3o2)cc1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 5.4 %

Procedure:
To a suspension of 1-(2,6-dihydroxy-4-morpholin-4-yl-phenyl)-ethanone (112 mg, 0.472 mmol) and K2CO3 (326 mg, 2.36 mmol) in acetone (3 mL) was added p-anisoyl chloride (0.066 mL, 0.472 mmol). The reaction vessel was sealed and heated to 80° C. for 4 days. After cooling to room temperature, water (about 2 mL) was added, and the mixture was allowed to stir for about 15 min. The contents were transferred to a separatory funnel containing water (5 mL) and extracted with EtOAc (3×15 mL). The organic layer was dried (MgSO4) and concentrated. The concentrate was purified via Biotage chromatography with gradient elution from 100% hexanes to 30% EtOAc/hexanes to yield 9 mg (5%) of 5-hydroxy-2-(4-methoxy-phenyl)-7-morpholin-4-yl-chromen-4-one. Me is CH3—.
Reaction SMILES: [I-:1].[K+].S(F)(O[C:7]([F:14])([F:13])[C:8]([F:12])=[C:9]([F:11])[F:10])(=O)=O>COCCOCCOCCOCCOC>[F:13][C:7]([I:1])([F:14])[C:8]([F:12])=[C:9]([F:11])[F:10]
Reactant: O=S(=O)(F)OC(F)(F)C(F)=C(F)F
Reactant: [I-]
Agent: COCCOCCOCCOCCOC
Agent: [K+]
Product: FC(F)=C(F)C(F)(F)I
Temperature: 20 °C
Reaction time: 12 h

Procedure:
Perfluoroallyl iodide (CF2CFCF2I) was prepared by transferring 8.5 g of dry potassium iodide, 20 ml of tetraglyme and 42.5 millimoles of perfluoroallyl fluorosulfate by vacuum line to a 100-ml flask. The mixture was warmed to 20° C. and stirred for 12 hours in a dark room. The mixture was then fractionated through -100° C. and -196° C. traps, with the product being collected in the -100° C. trap.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]([NH:14][CH2:15][CH2:16][NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:7]=2[CH:24]=1)#[N:2].C(N(CC)CC)C.Cl[C:33](OC1C=CC([N+]([O-])=O)=CC=1)=[O:34]>C(Cl)Cl>[CH3:12][C:10]1([CH3:13])[CH2:9][CH:8]([N:14]2[CH2:15][CH2:16][N:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:33]2=[O:34])[C:7]2[CH:24]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=2[O:11]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC1(C)CC(NCCNc2ccccc2)c2cc(C#N)ccc2O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)CC(N2CCN(c3ccccc3)C2=O)c2cc(C#N)ccc2O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of N-(6-cyano-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-4yl)-N'-phenylethylene-diamine (0.36 g, 1.12 mmole, from Example 21, part A) and triethylamine (0.12 g, 1.18 mmole) in methylene chloride (4 ml) cooled to 0° C. was added a solution of 4-nitrophenyl chloroformate (0.24 g, 1.18 mmole) dissolved in methylene chloride (3 ml). The reaction mixture was stirred at room temperature for four hours. The solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate and 5% aqueous HCl solution. The organic phase was washed with 2N NaOH solution, saturated NaCl solution, dried over MgSO4 and solvent evaporated to obtain 420 mg of an orange gum. The crude product was chromatographed on silica eluting with hexane/ethyl acetate (4:1) to obtain 0.30 g of the title compound as a pure white solid. m.p.=166°-168° C. 1H NMR (DMSO-d6) δ7.61 (m, 4H), 7.35 (m,2H), 7.03 (m, 1H), 6.95 (d, J=8.21 Hz, 1H), 5.21 (dd, J=6.45 and 11.73 Hz, 1H), 3.88 (m, 2H), 3.36 (m 1H), 3.14 (m, 1H), 2.03 (m, 2H), 1.47 (s, 3H), 1.33 (s, 3H); 13C NMR (DMSO-d6) δ158.08, 157.13, 140.58, 132.86, 131.56, 128.63, 121.86, 121.63, 119.15, 118.52, 117.05, 102.54, 77.31, 44.68, 42.06, 36.56, 34.06, 29.36, 24.01; MS: (M+H)+ @348.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(OCC)(=[O:20])C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[O:20])=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: O=C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Product: O=C(C(=O)c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
The dione product was obtained using the same synthetic methods as shown in Example 25, step 6, using 1,2-bis(4-chlorophenyl)ethanone (2.12 g, 8.00 mmol, 1.00 equiv) and SeO2 (5.11 g, 46.0 mmol, 5.75 equiv) as reactants. The solution was allowed to react, with stifling, for 2 hr at 120° C., then diluted with ethyl acetate, washed with saturated aqueous NaCl, and concentrated under vacuum. This afforded 2.19 g (crude) of 1,2-bis(4-chlorophenyl)ethane-1,2-dione as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[H-].[Na+].Br[CH:12]([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH:12]([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:7]=1
Reactant: O=c1ccc(Br)c[nH]1
Reactant: CCOC(=O)C(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)n1cc(Br)ccc1=O
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 5-bromo-2(1H)-pyridone (7.8 g, 45 mmol) in 80 mL of DMF at 0° C. was added sodium hydride (60% dispersion in mineral oil, 2.1 g, 90 mmol). The mixture was stirred at 0° C. for 45 minutes. Ethyl 2-bromopropionate (9.7 g, 54 mmol) was then added via a syringe. The reaction was warmed up to rt and let stir for 16 hours. The reaction mixture was then poured into an ice-HCl (2N) solution until pH˜2. The aqueous mixture was extracted with 2×100 mL of EtOAc. The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on a silica gel column (30% EtOAc/hexane to EtOAC) to give yellow oil (9.0 g, 73% yield) as desired product. MS (ESI pos. ion) m/z (MH+): 273.9. Calc'd Exact Mass for C10H12BrNO3: 273.00.
Reaction SMILES: Br[C:2]1[C:19]2=[C:20]3[C:9]([C:10]4[C:21]5[C:14](=[CH:15][CH:16]=[CH:17][C:18]2=5)[CH:13]=[CH:12][CH:11]=4)=[CH:8][CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.C(C1C=C(C=C(C#C)C=1)[CH:27]=[O:28])#C>>[C:2]1([CH:27]=[O:28])[C:19]2=[C:20]3[C:9]([C:10]4[C:21]5[C:14](=[CH:15][CH:16]=[CH:17][C:18]2=5)[CH:13]=[CH:12][CH:11]=4)=[CH:8][CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1
Reactant: Brc1ccc2cccc3c4cccc5cccc(c1c23)c54
Reactant: C#Cc1cc(C#C)cc(C=O)c1
Product: O=Cc1ccc2cccc3c4cccc5cccc(c1c23)c54
Yield: 8.9 %

Procedure:
The first route employs bromoperylene PMI-12 and 3,5-diethynylbenzaldehyde (16) as the starting materials. The reaction under copper-free conditions, similar to those employed for the Sonogashira coupling of two porphyrins (Wagner, R. W. et al., Chem. Mater. 1999, 11, 2974-2983) afforded only a small amount (8.9%) of perylene-aldehyde 18 (entry 1, Table 1). The same reaction in the presence of CuI failed to produce perylene-aldehyde 18 (entry 2). We next examined the reaction with the reverse ethyne/bromo substitution pattern on the perylene and benzaldehyde. The reaction of ethynylperylene PMI-12′ and 3,5-dibromobenzaldehyde (14) (2:1 ratio) with CuI cocatalysis afforded 18 in 31% yield (entry 3). A further increase in the amount of perylene PMI-12′ (2.4:1 ratio) gave 18 in 66% yield (entry 4). Repetition of this reaction furnished 18 in 83% yield. While of limited scope, the survey of the Sonogashira reaction of perylene PMI-12 or PMI-12′ with aldehyde 14 or 16 revealed important reactivity differences between a bromoperylene and an ethynylperylene. Unlike perylene-aldehyde 15, compound 18 proved to be very soluble, thereby enabling subsequent porphyrin-forming reactions.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]([OH:14])=[O:13])[CH2:8][CH2:7]1.[C:15](=O)(O)[O-].[Na+]>CO>[NH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8][CH2:7]1
Reactant: NC1CCC(C(=O)O)CC1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)C1CCC(N)CC1
Reaction time: 14 h

Procedure:
Thionyl chloride (4.15 g, 34.92) was added to a cold (0° C.) stirred solution of 4-aminocyclohexane carboxylic acid (1 g, 6.98 mmol) in MeOH (10 mL). The reaction mixture was stirred under reflux conditions for 12-16 h. The reaction mixture was then concentrated under reduced pressure. The residue obtained was diluted with ice cold water, basified with aqueous sodium bicarbonate solution and extracted with DCM. The DCM layer was washed with water followed by brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 650 mg of the title compound as a brown liquid. MS (ESI): m/z 158 (M+H)
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][C:14]1[N:15]=[C:16]([S:19][C:20]([CH3:29])([CH3:28])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[S:17][CH:18]=1)=[O:4].[OH-].[Na+]>CO.O1CCCC1>[F:36][C:33]1[CH:34]=[CH:35][C:30]([C:7]2[CH:8]=[CH:9][C:10]([O:11][CH2:12][CH2:13][C:14]3[N:15]=[C:16]([S:19][C:20]([CH3:29])([CH3:28])[C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[S:17][CH:18]=3)=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=2)=[CH:31][CH:32]=1
Reactant: COC(=O)c1cc(-c2ccc(F)cc2)ccc1OCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(-c3ccc(F)cc3)cc2C(=O)O)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.5 %

Procedure:
4-(2-{2-[(2-tert-Butoxy-1,1-dimethyl-2-oxoethyl)thio]-1,3-thiazol-4-yl}ethoxy)-4′-fluoro-biphenyl-3-carboxylic acid methyl ester (1.6 g) synthesized in Example 92-2 was dissolved in methanol (15 mL) and tetrahydrofuran (20 mL), aqueous sodium hydroxide solution (1 mol/L, 15 ml) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, aqueous 10% citric acid solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (1.3 g) as an oil.
Reaction SMILES: CN(C=O)C.[C:6]([O:10][C:11](=[O:28])[NH:12][CH2:13][CH2:14][CH2:15][C:16](=[O:27])[NH:17][C:18]1[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[CH:20][C:19]=1[NH2:26])([CH3:9])([CH3:8])[CH3:7].[H-].[Na+].I[CH2:32][CH2:33][CH3:34]>C(Cl)(Cl)Cl>[C:6]([O:10][C:11](=[O:28])[NH:12][CH2:13][CH2:14][CH2:15][C:16](=[O:27])[N:17]([C:18]1[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[CH:20][C:19]=1[NH2:26])[CH2:32][CH2:33][CH3:34])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)NCCCC(=O)Nc1cc(C#N)ccc1N
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCCN(C(=O)CCCNC(=O)OC(C)(C)C)c1cc(C#N)ccc1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A DMF solution (4.0 ml) containing the compound (0.501 g) obtained in Example 46-2 was added with 60% sodium hydride (76.0 mg) and the whole was stirred at room temperature for 30 minutes. The solution was cooled with ice and then 1-iodopropane (0.184 ml) was dropped thereto. The whole was stirred at room temperature for 23 hours. The solvent in the reaction solution was distillated off. The resultant was dissolved in chloroform, washed with a saturated aqueous sodium hydrogen carbonate solution, and dried with anhydrous magnesium sulfate. The residue obtained by distilling the solvent off was purified through silica gel column chromatography (ethyl acetate/chloroform), thereby obtaining the subject compound (0.378 g) as a colorless crystal.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[CH:3]=1.[OH-].[K+].[CH2:12](I)[CH3:13]>C(O)C>[CH2:12]([N:5]1[C:6]([CH3:8])=[CH:7][C:2]([CH3:1])=[CH:3][C:4]1=[O:9])[CH3:13]
Reactant: CCI
Reactant: Cc1cc(C)[nH]c(=O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCn1c(C)cc(C)cc1=O

Procedure:
A mixture of 4,6-dimethyl2(1H)-pyridone (2.46 g., 0.02 moles), potassium hydroxide (1.58 g., 0.024 moles) and ethyl iodide (6.24 g., 0.04 moles) in 50 ml. ethanol is heated at reflux for 3 hours. The ethanol is removed under vacuum leaving a solid residue which is extracted with methylene chloride. The methylene chloride extracts are washed with 2.5 N sodium hydroxide, water, a saturated salt solution, and dried over sodium sulfate. Evaporation of the dried extracts affords 1-ethyl-4,6-dimethyl-2(1H)-pyridone as a pale yellow oil (1.5 g., 48%) which shows a single spot on thin layer chromatography.
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[CH:4]/[C@:5]1([CH3:29])[S:11][C@H:10]2[N:7]([C:8](=[O:12])[CH2:9]2)[C@H:6]1[C:13]([O:15][CH:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].[Cl:30][CH2:31][C:32]([N:34]=[C:35]=[O:36])=[O:33]>O1CCCC1>[Cl:30][CH2:31][C:32]([NH:34][C:35]([O:1][CH2:2]/[CH:3]=[CH:4]/[C@:5]1([CH3:29])[S:11][C@H:10]2[N:7]([C:8](=[O:12])[CH2:9]2)[C@H:6]1[C:13]([O:15][CH:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:14])=[O:36])=[O:33]
Reactant: C[C@@]1(/C=C/CO)S[C@@H]2CC(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Reactant: O=C=NC(=O)CCl
Solvent: C1CCOC1
Product: C[C@@]1(/C=C/COC(=O)NC(=O)CCl)S[C@@H]2CC(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Reaction time: 3 h

Procedure:
300 mg (0.73 mmol) of benzhydryl (E)-(2S,3S,5R)-3-(3-hydroxy- propenyl)-3-methyl-7-oxo-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylate were dissolved in 10 ml of tetrahydrofuran under argon and treated with 90 μl (1.05 mmol) of chloroacetyl isocyanate. The mixture was stirred for 3 hours, evaporated and chromatography was carried out over silica gel (particle size 0.040-0.063 mm) with ethyl acetate:n-hexane (9:16) as the eluent. Yield: 300 mg (77%) of colorless foam IR (KBr): 3300(br), 1779, 1753, 1730, 1495, 1203 cm-1MS: (M+NH4)+ 546.4
Reaction SMILES: [CH3:1][CH:2]([O:4][CH2:5][CH:6]1[CH2:11][NH:10][CH2:9][CH2:8][NH:7]1)[CH3:3].[CH2:12]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([F:25])=[C:21](F)[CH:22]=2)[C:17](=[O:26])[C:16]([C:27]([OH:29])=[O:28])=[CH:15]1)[CH3:13].N1C=CC=CC=1>CCOCC>[CH2:12]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([F:25])=[C:21]([N:10]3[CH2:9][CH2:8][NH:7][CH:6]([CH2:5][O:4][CH:2]([CH3:1])[CH3:3])[CH2:11]3)[CH:22]=2)[C:17](=[O:26])[C:16]([C:27]([OH:29])=[O:28])=[CH:15]1)[CH3:13]
Reactant: CC(C)OCC1CNCCN1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(COC(C)C)C3)cc21
Temperature: 80 °C
Yield: 107 %

Procedure:
A mixture of 2 g of 2-[(1-methylethoxy)methyl]piperazine, 1.27 g of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 5 ml of pyridine was heated at 80° C. for 3 hours, then evaporated in vacuo. The residue was reevaporated three times from toluene, giving a gum. Ether was added to the gum which solidified. The solid was triturated with ether containing methanol and then dried giving 2.1 g of solid. A 1 g portion was purified by chromatography, giving 650 mg of the desired product, mp 144°-146° C.
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12]2)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:20]([O:19][C:17](=[O:18])[CH:16]=[C:11]1[CH2:10][CH:9]2[NH:8][CH:13]([CH2:14][CH2:15]2)[CH2:12]1)[CH3:21]
Reactant: CCOC(=O)C=C1CC2CCC(C1)N2C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C=C1CC2CCC(C1)N2
Reaction time: 8 h

Procedure:
To 3-ethoxycarbonylmethylene-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (12.3 g, 41.8 mmol) in CH2Cl2 was added TFA (10 ml) and the reaction was stirred for 8 h. The solution was concentrated under reduced pressure, diluted with CH2Cl2, and washed first with 2 M NaOH and followed by brine. The water phases were thereafter back-extracted with EtOAc and the combined organic phase was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude title product was used without further purification (7.04 g, 37.9 mmol, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([NH:13][CH2:12][CH2:11][C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=4)[NH:7][CH:6]=3)=[O:22])[CH:16]=2)=[CH:26][CH:25]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(-c2ccc(Cl)cc2)c1
Yield: 45.8 %

Procedure:
4′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), 4-chlorophenylboronic acid (0.029 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.033 g (45%) of 4′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-3-carboxamide as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][N:5]([CH3:27])[C:6]2[C:7]=1[CH:8]=[CH:9][C:10]1[N:19]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:18][CH:17]=[C:12]3[NH:13][C:14](=[O:16])[C:15]=2[C:11]=13.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:61][N:62]1[CH:66]=[C:65]([CH2:67][C:68](O)=[O:69])[CH:64]=[N:63]1>CN(C)C(=O)C>[F:26][C:23]1[CH:22]=[CH:21][C:20]([N:19]2[C:10]3=[C:11]4[C:15](=[C:6]5[N:5]([CH3:27])[CH:4]=[CH:3][C:2]([NH:1][C:68](=[O:69])[CH2:67][C:65]6[CH:64]=[N:63][N:62]([CH3:61])[CH:66]=6)=[C:7]5[CH:8]=[CH:9]3)[C:14](=[O:16])[NH:13][C:12]4=[CH:17][CH2:18]2)=[CH:25][CH:24]=1
Reactant: CN1C=CC(N)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
Reactant: Cn1cc(CC(=O)O)cn1
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: CC(=O)N(C)C
Product: CN1C=CC(NC(=O)Cc2cnn(C)c2)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
Yield: 68 %

Procedure:
A stock solution of Example 23e and N,N-diisopropylethylamine (0.165 M and 0.47 M in N,N-dimethylacetamide, respectively, 275 μL, 0.042 mmol Example 23e and 0.13 mmol N,N-diisopropylethylamine), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.25 M in N,N-dimethylacetamide, 253 μL, 0.063 mmol), and 2-(1-methyl-1H-pyrazol-4-yl)acetic acid (0.40 M in N,N-dimethylacetamide, 125 μL, 0.05 mmol) were aspirated from their respective source vials, mixed through a perfluoroalkoxy mixing tube (0.2 mm inner diameter), and loaded into an injection loop. The reaction segment was injected into the flow reactor (Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume) set at 100° C., and passed through the reactor at 180 μL per minute (10 minute residence time). Upon exiting the reactor, the reaction mixture was loaded directly into an injection loop and purified using reverse phase HPLC(C8, acetonitrile/water (0.1% TFA), 5-100%) to give 0.0168 g (68%) of the title compound as the TFA salt. 1H NMR (400 MHz, DMSO-d6/D2O) δ 8.03 (d, J=2.14 Hz, 1H), 7.57 (s, 2H), 7.42 (dd, J=8.54, 2.44 Hz, 1H), 7.38 (s, 1H), 7.16 (d, J=8.54 Hz, 1H), 6.97 (s, 1H), 6.78 (m, 2H), 6.50 (m, 2H), 4.59 (m, 2H), 4.06 (s, 3H), 3.81 (s, 3H), 3.52 (s, 2H). MS (APCI+) m/z 483.1 (M+H)+.