Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[I:9][C:10]1[CH:11]=[C:12]2[C:17](=O)[O:16][C:14](=[O:15])[C:13]2=[CH:19][CH:20]=1.N1C=CC=CC=1.C(OC(=O)C)(=O)C>O.CC(N(C)C)=O>[I:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[C:17](=[O:16])[C:12]3=[CH:11][C:10]([I:9])=[CH:20][CH:19]=[C:13]3[C:14]2=[O:15])=[CH:4][CH:3]=1
Reactant: Nc1ccc(I)cc1
Reactant: O=C1OC(=O)c2cc(I)ccc21
Solvent: O
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: O=C1c2ccc(I)cc2C(=O)N1c1ccc(I)cc1
Temperature: 70 °C

Procedure:
##STR19## A 100 milliliter round-bottomed flask, equipped with stirrer, was charged with p-iodoaniline (10.95 grams, 0.05 mol) and dimethylacetamide (DMAc) (35 milliliters). 4-iodophthalic anhydride (13.6 grams, 0.05 mol) was added slowly over 10 minutes. The reaction mixture was heated with stirring to a temperature of about 70° C. Pyridine (19.45 grams, 0.25 mol) was added, the reaction mixture was stirred for 15 minutes, then acetic anhydride (11.12 grams, 0.11 mol) was added dropwise over 20 minutes. The reaction mixture was stirred at 70° C. overnight. The reaction mixture was poured into water, producing a white solid product, which was collected by filtration, triturated with methanol (300 milliliters) and dried under vacuum at 60° C. overnight. Melting point, as determined by DSC was 235° C. Combustion analysis was: calculated: C=35.40, H=1.49, N=2.95; measured: C=35.47, H=1.59, N=2.94. Proton NMR was consistent with the above general structure.
Reaction SMILES: [CH2:1]([S:5][C:6]1[N:11]=[C:10](Cl)[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].[N+:13]([C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][NH:20]2)([O-:15])=[O:14].[H-].[Na+].CN1C(=O)CCC1>O>[CH2:1]([S:5][C:6]1[N:11]=[C:10]([N:20]2[C:21]3[C:17](=[C:16]([N+:13]([O-:15])=[O:14])[CH:24]=[CH:23][CH:22]=3)[CH:18]=[N:19]2)[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCSc1nccc(Cl)n1
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCCSc1nccc(-n2ncc3c([N+](=O)[O-])cccc32)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.5 %

Procedure:
To a flask loaded with 2-butylsulfanyl-4-chloro-pyrimidine (202 mg) was added 4-nitro-1H-indazole (228 mg), followed by NaH (60% dispersion in mineral oil, 84 mg) and NMP (4 mL). The resulting mixture was stirred at RT overnight, water added, and the mixture extracted with EtOAc. The combined organic extracts were washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (hexane/EtOAc, 80:20) to give 1-(2-butylsulfanyl-pyrimidin-4-yl)-4-nitro-1H-indazole (156 mg).
Reaction SMILES: Cl.C[O:3][C:4]1[C:9]2[O:10][C:11]3[C:16]([C:17]4([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:8]=2[CH:7]=[CH:6][CH:5]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3.Br.[C:24](=O)(O)[O-].[Na+]>C(O)(=O)C.O>[CH3:24][N:20]1[CH2:19][CH2:18][C:17]2([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]([OH:3])[C:9]=3[O:10][C:11]3[C:16]2=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:22][CH2:21]1
Reactant: O=C([O-])O
Reactant: COc1cccc2c1Oc1ccccc1C21CCNCC1
Agent: Br
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CN1CCC2(CC1)c1ccccc1Oc1c(O)cccc12

Procedure:
1'-Methyl)-4-methoxyxanthene-9-spiro-4'-piperidine hydrochloride (1.0 g.) in a solution of 45% w/v hydrobromic acid in glacial acetic acid (10 ml.) is heated under reflux for 2 hours. The solution is basified with sodium bicarbonate, diluted with water and extracted with chloroform. The chloroform extract is washed with water, dried over MgSO4, and evaporated to dryness. The residue is recrystallised from toluene-petroleum ether (b.p. 60°-80° C.) to give 1'-methyl-4-hydroxyxanthene-9-spiro-4'-piperidine, m.p. 171°-173° C.
Reaction SMILES: [OH-].[Na+].[SH:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9].[Cl:17][C:18](Cl)=[CH:19][N+:20]([O-:22])=[O:21].Cl.[Cl-].[Na+]>CO>[Cl:17][C:18]([S:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9])=[CH:19][N+:20]([O-:22])=[O:21]
Reactant: O=S(=O)(NCCCS)c1ccccc1
Reactant: O=[N+]([O-])C=C(Cl)Cl
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])C=C(Cl)SCCCNS(=O)(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of 0.08 g of sodium hydroxide in 3 ml of methanol was added drop-by-drop over 5 minutes to a solution of 0.23 g of 3 in 5 ml of methanol. The resulting mixture was added drop-by-drop over 20 minutes to a solution of 0.28 g of 13A in 6 ml of methanol at 0° C. The mixture was held at 0° C. for 30 minutes, then poured into 2% hydrochloric acid saturated with sodium chloride. The resulting mixture was extracted with methylene chloride, the solvent was evaporated from the extract and the residue was chromatographed over silica gel to give 14, as a solid, m.p.: 105°-106° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]#[N:12].[K].[C:14]1([SH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(S)C=CC=CC=1.[OH-].[K+]>CO.CN(C)C=O>[C:14]1([S:20][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[C:11]#[N:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: Sc1ccccc1
Agent: [K+]
Agent: [K]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: N#Cc1cc([N+](=O)[O-])ccc1Sc1ccccc1
Temperature: 105 °C
Reaction time: 2.5 h

Procedure:
4-Chloro-3-cyanonitrobenzene (12.5 g, 6.84 mmol) was added portionwise to a stirred N,N-dimethylformamide (50 mL) solution of thiophenol potassium salt [prepared by adding thiophenol (7.1 mL, 6.9 mmol) to a solution of potassium hydroxide (3.84 g, 6.84 mmol) in methanol followed by removal of the methanol in vacuo]. After stirring at 105° C. for 2.5 hours the mixture was poured into ice-water, filtered, the collected solid washed with water, dissolved in 300 mL of refluxing ethanol (charcoal), filtered, treated with 35 mL of water and refrigerated. The resulting pale yellow solid weighed 13.3 g (76%), mp 82°-84° C. 1H--NMR (250 MHz, CDCl3): 6.93 (d, 1H, J=9.0 Hz, aromatic), 7.51-7.62 (m, 5H, aromatic), 8.12(dd, 1H, J=9.2, 2.5 Hz, aromatic), 8.46 (d, 1H, J=2.5 Hz, aromatic). MS (CI, CH4): 257(M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.[C:19](OCC)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1.C(O)(=O)C>[C:20]1([C:19]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[O:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1ccccn1
Reactant: CCOC(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(Cc1ccccn1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.1 %

Procedure:
To a solution of 2-methylpyridine (9.31 g) in tetrahydrofuran (200 ml) was added a 1.5 M hexane solution of n-butyllithium (73.3 ml) at -20° C. The resulting solution was stirred for 30 minutes at room temperature and added to a solution of ethyl benzoate (15.02 g) in tetrahydrofuran (100 ml) at -60° C. After stirring for 2 hours at -60° C, acetic acid (15 ml) was added and the resulting mixture was allowed to warm to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water. The aqueous layer was reextracted with ethyl acetate and the combined extracts were washed with water, 10% aqueous solution of sodium hydrogen carbonate, and saturated aqueous sodium chloride. After drying over magnesium sulfate, the ethyl acetate extracts were filtered and evaporated. The residue (20.5 g) was chromatographed on silica gel (Merck 70-230 mesh, 308 g) eluting with chloroform to give 2-pyridylmethyl phenyl ketone (10.86 g) as an oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[C:9]([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][NH2:23])[CH2:18][CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:23][CH2:22][CH:19]2[CH2:20][CH2:21][N:16]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:17][CH2:18]2)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(CNc2cc(Cl)ncn2)CC1
Temperature: 120 °C
Yield: 105.6 %

Procedure:
4,6-Dichloropyrimidine (284 mg, 1.9 mmol), N-Boc-4-aminomethyl piperidine (409 mg, 1.9 mmol) and potassium carbonate (317 mg, 2.3 mmol) were dissolved in acetonitrile (5 mL) and the solution was heated for 30 minutes at 120° C. using microwave irradiation. The reaction mixture was partitioned between water and dichloromethane and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried (Na2SO4) and evaporated to give tert-butyl 4-((6-chloropyrimidin-4-ylamino)methyl)-piperidine-1-carboxylate (656 mg, 100%) as a yellow oil which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:29])[C:8]2[CH:13]=[N:12][C:11](S(C)(=O)=O)=[N:10][C:9]=2[N:18]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[CH2:25][CH2:24][CH2:23]3)[CH:19]=1)=[O:5])[CH3:2].OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.[NH2:51][C:52]1[CH:57]=[CH:56][C:55]([CH:58]2[CH2:63][CH2:62][N:61]([C:64](=[O:73])[CH2:65][N:66]3[CH2:71][CH2:70][N:69]([CH3:72])[CH2:68][CH2:67]3)[CH2:60][CH2:59]2)=[CH:54][CH:53]=1>CC(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:29])[C:8]2[CH:13]=[N:12][C:11]([NH:51][C:52]3[CH:57]=[CH:56][C:55]([CH:58]4[CH2:63][CH2:62][N:61]([C:64](=[O:73])[CH2:65][N:66]5[CH2:67][CH2:68][N:69]([CH3:72])[CH2:70][CH2:71]5)[CH2:60][CH2:59]4)=[CH:54][CH:53]=3)=[N:10][C:9]=2[N:18]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[CH2:25][CH2:24][CH2:23]3)[CH:19]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Reactant: CN1CCN(CC(=O)N2CCC(c3ccc(N)cc3)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(C4CCN(C(=O)CN5CCN(C)CC5)CC4)cc3)ncc2c1=O
Temperature: 90 °C
Reaction time: 3 h
Yield: 16.8 %

Procedure:
(4-Piperidin-4-yl-phenyl)-carbamic acid tert-butyl ester (0.20 g, 0.72 mmol), (4-methyl-piperazin-1-yl)-acetic acid (0.11 g, 0.72 mmol), HOBt (0.10 g, 0.72 mmol), DCI (0.14 g, 0.72 mmol), and DIEA (0.10 g, 0.72 mmol) were all combined in DMF (5 mL). After 16 h, water (10 mL) and CH2Cl2 (10 mL) were added. The organic layer was washed with water (3×10 mL), dried (MgSO4) and concentrated. Chromatography (0-15% EtOAc/hexanes gradient) provided 0.24 g (83%) of (4-{1-[2-(4-methyl-piperazin-1-yl)-acetyl]-piperidin-4-yl}-phenyl)-carbamic acid tert-butyl ester. (4-{1-[2-(4-Methyl-piperazin-1-yl)-acetyl]-piperidin-4-yl}-phenyl)-carbamic acid tert-butyl ester (0.72 mmol) was diluted in CH2Cl2 (3 mL) and TFA (3 mL) was added. After 1 h, the reaction mixture was concentrated. Water (2 mL) was added and the solution was frozen and lyophilized overnight to provide (0.16 g) (72%) of 1-[4-(4-Amino-phenyl)-piperidin-1-yl]-2-(4-methyl-piperazin-1-yl)-ethanone. 8-Indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (32.5 mg, 0.079 mmol) and 1-[4-(4-Amino-phenyl)-piperidin-1-yl]-2-(4-methyl-piperazin-1-yl)-ethanone tri-TFA salt (52 mg g, 0.079 mmol) were combined in i-PrOH (1 mL) and TEA (25 mg, 0.25 mmol) was added and the mixture was heated to 90° C. After 3 h, the reaction mixture was concentrated and purified by preparative HPLC (30 mL/min 5-100% MeCN/H2O gradient over 10 min) and lyophilized to provide 8.6 mg of 8-indan-5-yl-2-(4-{1-[2-(4-methyl-piperazin-1-yl)-acetyl]-piperidin-4-yl}-phenylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.23 (s, 1H), 8.39 (s, 1H), 7.40-7.42 (m, 2H), 7.17-7.26 (m, 3H), 7.06-7.09 (m, 2H), 4.30 (q, 2H, J=7.1 Hz), 3.07 (br s, 1H), 2.87-2.93 (m, 6H), 2.48-2.67 (m, 7H), 2.28 (br s, 3H), 2.05-2.12 (m, 2H), 1.72-1.82 (m, 2H), 1.49 (br s, 2H), 1.31 (t, 3H, J=7.1 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[C:20]([C:29](O)=[O:30])=[C:19]([CH3:32])[NH:18][C:17]=2[CH3:33])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:34]1([CH2:40][CH2:41][CH2:42][NH2:43])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CCN=C=NCCCN(C)C.Cl.Cl>CN(C)C1C=CN=CC=1.ClCCl.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]([C:16]2[C:17]([CH3:33])=[N:18][C:19]([CH3:32])=[C:20]([C:29](=[O:30])[NH:43][CH2:42][CH2:41][CH2:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:21]=2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCCCc1ccccc1
Reactant: CC1=C(C(=O)O)C(c2cccc(Cl)c2)C(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)=C(C)N1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: Cc1nc(C)c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c(-c2cccc(Cl)c2)c1C(=O)NCCCc1ccccc1

Procedure:
1.13 g (2.37 mmol) of 4-[5-carboxy-4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3-carbonyl] piperazine-1-carboxylic acid-t-butyl ester, 0.51 ml (3.59 mmol) of 3-phenylpropylamine, 548 mg (2.86 mmol) of WSC hydrochloride and 21 mg (0.17 mmol) of 4-dimethylaminopyridine were stirred in 10 ml of dichloromethane at room temperature overnight. After adding 25 ml of water and 25 ml of 1 N hydrochloric acid, the reaction mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (chloroform/methanol=300/1) to obtain the title compound.
Reaction SMILES: CN(C(O[N:9]1N=N[C:11]2[CH:12]=CC=C[C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[Si:35]([O:42][CH2:43][C:44]1[C:45]([N+:53]([O-:55])=[O:54])=[C:46]([CH:50]=[CH:51][CH:52]=1)[C:47]([OH:49])=O)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].C(N(CC)C(C)C)(C)C.C(N)C#C>CN(C=O)C.CCOC(C)=O>[Si:35]([O:42][CH2:43][C:44]1[C:45]([N+:53]([O-:55])=[O:54])=[C:46]([CH:50]=[CH:51][CH:52]=1)[C:47]([NH:9][CH2:10][C:11]#[CH:12])=[O:49])([C:38]([CH3:39])([CH3:40])[CH3:41])([CH3:37])[CH3:36]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(C(=O)O)c1[N+](=O)[O-]
Agent: C#CCN
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C#CCNC(=O)c1cccc(CO[Si](C)(C)C(C)(C)C)c1[N+](=O)[O-]
Yield: 55 %

Procedure:
HBTU (183 mg, 0.482 mmol) and HOBt (65.1 mg, 0.482 mmol) were added to a stirring solution of Compound 10 (150 mg, 0.482 mmol) in anhydrous DMF (4.82 mL) followed by N,N-diisopropylethylamine (187 mg, 1.45 mmol) and propargyl amine (79.6 mg, 1.45 mmol). The resulting solution was stirred for 30 h at room temperature after which time 25 mL of EtOAc were added and the solution was washed with water (3×10 mL), aqueous saturated NH4Cl (1×10 mL), and brine (1×10 mL). The organic layer was dried over MgSO4, filtered, and concentrated on a rotary evaporator. The resulting oil was purified by silica gel chromatography (50% EtOAc:hexanes) to yield Compound 11 as a white solid (92.3 mg, 55%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]1[O:20][C:19]2[C:9](=[C:10]([CH:16]=[CH:17][CH:18]=2)[CH:11]=[CH:12][C:13](O)=[O:14])[O:8]1.CN(C)C=O.Cl.[NH2:27][C:28]([NH2:30])=[NH:29]>ClCCl.[OH-].[Na+].C(Cl)(Cl)Cl>[CH2:7]1[O:20][C:19]2[C:9](=[C:10]([CH:16]=[CH:17][CH:18]=2)[CH:11]=[CH:12][C:13]([NH:29][C:28]([NH2:30])=[NH:27])=[O:14])[O:8]1
Reactant: N=C(N)N
Reactant: O=C(O)C=Cc1cccc2c1OCO2
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N=C(N)NC(=O)C=Cc1cccc2c1OCO2
Reaction time: 25 h
Yield: 66 %

Procedure:
Oxalyl chloride (0.68 mL, 7.8 mmol) was added to a suspension of 2,3-methylenedioxycinnamic acid (500 mg, 2.6 mmol) in dichloromethane (5 nm) containing a drop of dimethylformamide. The mixture was stirred for 25 hours and the resulting solution was evaporated to dryness under reduced pressure. The residue was dissolved in dry tetrahydrofuran (5 mL) and added to a solution of guanidine hydrochloride (1.24 g, 13 mmol) in 2M aqueous sodium hydroxide (8 mL). The reaction was stirred at room temperature for 1 hour and chloroform was then added. The resulting precipitate of crude product (100 mg) was collected by filtration. The filtrate was extracted with chloroform (3×30 mL) and ethyl acetate (20 mL). The combined organic extracts were washed with 2M aqueous sodium hydroxide (20 mL), water (20 mL), dried (Na2SO4) and concentrated under reduced pressure to give a further quantity of crude product (400 mg). The two crops of crude product were combined, suspended in chloroform (10 mL) and stirred vigorously for 20 minutes. The resulting 2,3-methylenedioxycinnamoylguanidine (420 mg) was collected by filtration and dried under vacuum.
Reaction SMILES: [CH:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:19]=[C:18]([O:20][CH:21]3[CH2:38][CH:37]4[CH:23]([C:24](=[O:44])[N:25]([CH3:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH:31][CH:32]5[C:34]([C:40](O)=[O:41])([NH:35][C:36]4=[O:39])[CH2:33]5)[CH2:22]3)[C:17]3[C:12](=[C:13]([CH3:47])[C:14]([O:45][CH3:46])=[CH:15][CH:16]=3)[N:11]=2)[CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(Cl)CCl.[CH:52]1([S:55]([NH2:58])(=[O:57])=[O:56])[CH2:54][CH2:53]1.C1CCN2C(=NCCC2)CC1>CN(C1C=CN=CC=1)C.CN(C=O)C.C(O)(=O)C>[CH:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:19]=[C:18]([O:20][CH:21]3[CH2:38][CH:37]4[CH:23]([C:24](=[O:44])[N:25]([CH3:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH:31][CH:32]5[C:34]([C:40]([NH:58][S:55]([CH:52]6[CH2:54][CH2:53]6)(=[O:57])=[O:56])=[O:41])([NH:35][C:36]4=[O:39])[CH2:33]5)[CH2:22]3)[C:17]3[C:12](=[C:13]([CH3:47])[C:14]([O:45][CH3:46])=[CH:15][CH:16]=3)[N:11]=2)[CH:7]=[CH:6][CH:5]=1)([CH3:2])[CH3:3]
Reactant: NS(=O)(=O)C1CC1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3cccc(C(C)C)n3)nc2c1C
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3cccc(C(C)C)n3)nc2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
A solution of 17-[2-(6-isopropyl-2-pyridyl)-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (113, 200 mg, 0.31 mmol), DMAP (76.5 mg, 0.62 mmol), and EDC (151 mg, 0.78 mmol) in DMF (5 mL) was stirred at room temperature overnight (the activation of the acid was monitored by LC-MS). Then, cyclopropylsulfonamide (191 mg, 1.56 mmol) was added, followed by DBU (228 μL, 1.56 mmol). The resulting solution was stirred overnight at room temperature, then neutralized with acetic acid and evaporated. The residue was re-dissolved in MeOH and purified by preparative HPLC to give 90 mg (39%) of the title compound 114: m/z=744 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[CH2:17][CH2:16][CH:15]([OH:18])[C:11]=3[CH:12]=[N:13][CH:14]=2)=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].OP([O-])(O)=O.[K+]>CN(C=O)C>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:10]3[CH2:17][CH2:16][CH:15]([O:18][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:11]=3[CH:12]=[N:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: OC1CCc2c(-c3ccc(C(F)(F)F)cc3)cncc21
Agent: O=P([O-])(O)O
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COC1CCc2c(-c3ccc(C(F)(F)F)cc3)cncc21
Temperature: 25 °C
Yield: 70.1 %

Procedure:
A cooled (0° C.) solution of (rac)-4-(4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (example 83) (400 mg, 1.43 mmol) in DMF (4 mL) was treated with NaH (55% in oil, 100 mg, 2.29 mmol) and after ½ h with tert-butyl 2-bromoacetate (201 μL, 1.36 mmol) in DMF (4 mL). After warming up to room temperature overnight, the reaction mixture was poured on aq. 10% KH2PO4 solution followed by extraction with Et2O (3×). The organic phases were washed once with aq. 10% NaCl solution. The combined organic phases were dried (Na2SO4), filtered and purified by flash chromatography (50 g SiO2, Telos-cartridge, 2% 2-propanol in CH2Cl2) to give the title compound (375 mg, 53%) as dark brown oil. MS: 394.2 (M+H+).
Reaction SMILES: CCN(CC)CC.I[C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18].CCCCCC.CC(C)=O>C1COCC1.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.[Cu]I>[CH3:16][Si:17]([CH3:19])([CH3:18])[C:20]#[C:21][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1
Reactant: C#C[Si](C)(C)C
Reactant: Oc1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: CCCCCC
Product: C[Si](C)(C)C#Cc1cccc(O)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred solution of PdCl2(PPh3)2 (46 mg, 0.04 mmol), CuI (15 mg, 0.08 mmol), and Et3N (0.303 g, 0.42 mL, 3 mmol) in 10 mL of THF under nitrogen was added 3-iodophenol (0.440 g, 2 mmol) by syringe. The reaction mixture was cooled to 0° C., and trimethylsilylacetylene (0.206 g, 0.30 mL, 2.1 mmol) was added dropwise over 30 min. The reaction mixture was stirred at room temperature overnight and was filtered through Celite to remove Pd and Cu catalysts. Column chromatography (n-hexane/Acetone 6:1) yielded 3-(2-(trimethylsilyl)ethynyl)phenol (380 mg, 2.0 mmol, >99%) as a light brown oil. This compound was diluted with THF (6 mL) and MeOH (6 mL), and 10% aqueous KOH (6 mL) was added. After stirring for 2 hr, the reaction mixture was neutralized by 1 N HCl and evaporated, extracted with CH2Cl2, and dried (Na2SO4). Column chromatography (n-hexane/acetone 5:1) yielded 3-ethynylphenol (162.8 mg, 70%) as a yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)=[CH:20][CH:19]=1)[CH2:9][C:10]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[O:11])(C)(C)C.Cl.[C:33]1(=[O:39])[O:38][C:36](=[O:37])[CH2:35][CH2:34]1.C(N(CC)CC)C>O1CCOCC1.C(Cl)Cl.CCOC(C)=O>[Cl:30][C:26]1[CH:25]=[C:24]([C:21]2[CH:20]=[CH:19][C:18]([CH2:17][C@@H:8]([NH:7][C:33](=[O:39])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])[CH2:9][C:10]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[O:11])=[CH:23][CH:22]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)NS(C)(=O)=O)Cc1ccc(-c2cccc(Cl)c2)cc1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)NC(=O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)CCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
[(R)-1-(3′-Chloro-biphenyl-4-ylmethyl)-3-methanesulfonylamino-3-oxo-propyl]-carbamic acid tert-butyl ester (150 mg, 0.321 mmol) is treated with 4M HCl in dioxane. After being stirred at room temperature for 1 h, the reaction mixture is concentrated in vacuo. To this residue in DCM (2 mL) are added succinic anhydride (48.2 mg, 0.482 mmol) and triethylamine (0.112 mL, 0.803 mmol). After being stirred at room temperature for 2 h, the reaction mixture is diluted with EtOAc and washed with 1M HCl and brine. The organic layer is dried over Na2SO4 and concentrated. The residue is purified by reverse phase HPLC (SunFire C18, 0.1% TFA in H2O/CH3CN) to give N—[(R)-1-(3′-chloro-biphenyl-4-ylmethyl)-3-methanesulfonylamino-3-oxo-propyl]-succinamic acid (63 mg). HPLC retentions time=1.32 minutes (condition A); MS (m+1)=467; 1H NMR (400 Mz, DMSO-d6) δ ppm 2.22-2.29 (m, 2H), 2.32-2.54 (m, 4H), 2.77 (d, 2H, J=6.82 Hz), 3.17 (s, 3H), 4.31 (dt, 1H, J=7.33, 13.9 Hz), 7.28 (d, 2H, J=8.08 Hz), 7.38-7.43 (m, 1H), 7.48 (t, 1H, J=7.83 Hz), 7.62 (d, 3H, J=8.34 Hz), 7.70 (t, 1H, J=2.02 Hz), 7.89 (d, 1H, J=8.34 Hz), 11.70 (s, 1H), 12.04 (s, 1H).