Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[C:14]([OH:16])=O)=[O:7])=[CH:4][CH:3]=1.Cl.[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1)([O-:22])=[O:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2([OH:7])[C:8]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[C:14](=[O:16])[N:28]2[CH2:27][C:26]2[CH:25]=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:30][CH:29]=2)=[CH:17][CH:18]=1
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)C1=C(C(=O)c2ccc(Cl)cc2)CCCC1
Agent: Cl
Product: O=C1C2=C(CCCC2)C(O)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Yield: 44.4 %

Procedure:
The named compound was synthesised from 2-(4-chlorobenzoyl)cyclohex-1-enecarboxylic acid (1.00 g, 3.78 mmol) and 4-nitrobenzylamine hydrochloride (0.78 g, 4.16 mmol) using General Procedure B, purified by chromatography (Biotage SP4; 30% EtOAc/petrol) and obtained as a yellow solid (0.67 g, 44%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][C:11]([CH:13]=[O:14])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C[Mg+].[Br-].[CH3:18]COCC>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][C:11]([CH:13]([OH:14])[CH3:18])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOCC
Reactant: O=Cc1ccc(-c2cccc(Cl)c2)o1
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(O)c1ccc(-c2cccc(Cl)c2)o1
Reaction time: 0.75 h

Procedure:
To a solution of 5-(3-chlorophenyl)furan-2-carbaldehyde (1.0 equiv.) in THF at 0° C. was added MeMgBr in ether (3.0 equiv.) and stirred for 45 min. The reaction was quenched with water, diluted with ether and filtered through Celite. The organic layer was separated and washed with brine, dried over MgSO4, and concentrated to give the 1-[5-(3-chlorophenyl)-2-furyl]ethan-1-ol.
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][S:7]([N:10]1[CH2:15][CH2:14][CH2:13][S:12][C:11]1=[CH:16][N+:17]([O-:19])=[O:18])(=[O:9])=[O:8])=O>ClCCl.CO>[OH:3][CH2:4][CH2:5][CH2:6][S:7]([N:10]1[CH2:15][CH2:14][CH2:13][S:12][C:11]1=[CH:16][N+:17]([O-:19])=[O:18])(=[O:8])=[O:9]
Reactant: O=COCCCS(=O)(=O)N1CCCSC1=C[N+](=O)[O-]
Solvent: ClCCl
Solvent: CO
Product: O=[N+]([O-])C=C1SCCCN1S(=O)(=O)CCCO

Procedure:
2 g of 1 was elected through a column of 200 g of neutral alumina, using a 19:1 v:v mixture of dichloromethane and methanol as eluent. The fractions containing 2 were stripped of solvent under reduced pressure and the combined residue was triturated with ether, to give 2, as a solid, m.p.: 80°-83° C.
Reaction SMILES: C[Al](C)C.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Si:13]([O:20][CH2:21][CH2:22][CH2:23][C@H:24]([O:29][C:30]1[N:35]=[CH:34][N:33]=[C:32]2[N:36]([C:39]3[C:44]([Cl:45])=[CH:43][CH:42]=[CH:41][N:40]=3)[N:37]=[CH:38][C:31]=12)[C:25](OC)=[O:26])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>C1(C)C=CC=CC=1>[Si:13]([O:20][CH2:21][CH2:22][CH2:23][C@H:24]([O:29][C:30]1[N:35]=[CH:34][N:33]=[C:32]2[N:36]([C:39]3[C:44]([Cl:45])=[CH:43][CH:42]=[CH:41][N:40]=3)[N:37]=[CH:38][C:31]=12)[C:25]([NH:12][C:9]1[CH:8]=[CH:7][C:6]([Cl:5])=[CH:11][N:10]=1)=[O:26])([C:16]([CH3:18])([CH3:19])[CH3:17])([CH3:14])[CH3:15]
Reactant: COC(=O)[C@H](CCCO[Si](C)(C)C(C)(C)C)Oc1ncnc2c1cnn2-c1ncccc1Cl
Reactant: Nc1ccc(Cl)cn1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OCCC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)Nc1ccc(Cl)cn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of trimethylaluminium (2M in toluene) (0.795 mL, 1.59 mmol) was added dropwise to a stirred solution of 5-chloropyridin-2-amine (178 mg, 1.38 mmol) in toluene (5 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 15 minutes. A solution of (2S)-methyl 5-(tert-butyldimethylsilyloxy)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)pentanoate (Intermediate O2) (680 mg, 1.38 mmol) in toluene (5 mL) was added dropwise. The resulting solution was stirred at 0° C. for 10 minutes allowed to warm to ambient temperature and then heated at reflux for 18 hours. The reaction mixture was allowed to cool to r.t. and concentrated. The residue was diluted with ethyl acetate and treated with 1M citric acid (2ml). The layers were separated and the organics were washed with water and brine, dried (MgSO4) and concentrated to a yellow foam, (2S)-5-(tert-butyldimethylsilyloxy)-N-(5-chloropyridin-2-yl)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)pentanamide (693 mg, 85%). m/z (ES+) (M+H)+=588.46; HPLC tR=3.54 min.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][C:3]=1[F:10].C(=O)([O-])[O-].[K+].[K+].[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[CH2:18][SH:19]>CN(C=O)C>[CH2:22]([O:21][C:17]([C:18]1[S:19][C:2]2[C:3]([F:10])=[CH:4][N:5]=[CH:6][C:7]=2[C:8]=1[NH2:9])=[O:20])[CH3:23]
Reactant: N#Cc1cncc(F)c1Cl
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc2c(F)cncc2c1N
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 97.6 %

Procedure:
To a mixture of 4-chloro-5-fluoro-nicotinonitrile (1.0 g, 6.4 mmol) and potassium carbonate (4.4 g, 32 mmol) in DMF (15 mL) at 0° C. was added ethyl thioglycolate (0.73 mL, 6.7 mmol) dropwise. The reaction mixture was stirred at 0° C. for 10 min, at room temperature for 20 min and then at 40° C. for 30 min. The reaction mixture was cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was separated and washed with water followed by brine, dried over sodium sulphate and concentrated in vacuo to give the title compound as a yellow solid (1.5 g, quant.). LCMS (method B): RT=3.41 min, M+H+=241.
Reaction SMILES: CO[C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:26][CH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[F:24][C:20]1[CH:19]=[C:18]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:26][CH:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[O:25])=[CH:5][N:6]=3)=[C:16]([CH3:17])[O:15][N:14]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: NC1CCOCC1
Reactant: COC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nc1
Product: Cc1onc(-c2cccc(F)c2)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Yield: 85 %

Procedure:
As described for example 92, 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (103 mg, 0.3 mmol) was converted, using 4-aminotetrahydropyran instead of cyclopropylamine, to the title compound (105 mg, 85%) which was obtained as a white solid. MS: m/e=412.5 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][C:5](=[O:7])[NH:4][C:3]2[N:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.[N+:12]([O-])([OH:14])=[O:13]>C(O)(=O)C.C(OC(=O)C)(=O)C>[N+:12]([C:9]1[CH:10]=[CH:11][C:2]2[O:1][CH2:6][C:5](=[O:7])[NH:4][C:3]=2[N:8]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: O=C1COc2cccnc2N1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1COc2ccc([N+](=O)[O-])nc2N1
Reaction time: 8 h

Procedure:
2H-Pyrido[3,2-b]-1,4-oxazin-3(4H)-one (2.5 g) was dissolved in acetic acid (6 mL) and acetic anhydride (30 mL). Fuming nitric acid (3 mL) was added dropwise to the reaction solution in ice-bath. The reaction solution was stirred in ice-bath overnight. Solution was poured into crashed ice. The light yellow precipitation was collected by filtration, washed with water and dried to give a mixture of nitrated products (regio-isomers). The mixture was crystallized from dichloromethane to give 6-nitro-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one (1 g) as a light yellow solid.
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[C:5]1([CH3:13])[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Mg]Br.[CH2:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][C:15]1=[O:23]>C1COCC1>[CH2:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][C:15]1=[O:23].[C:5]1([CH3:13])[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:15]1([OH:23])[CH2:16][C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14]1
Reactant: Cc1ccccc1[Mg]Br
Agent: O=C1Cc2ccccc2C1
Agent: [Ce+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1ccccc1C1(O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of anhydrous cerium chloride (40.60 g, 164.7 mmol) in THF(250 mL) was stirred at room temperature for 2 hours under nitrogen. o-Tolylmagnesium bromide (70.0 mL of 2.0M solution in diethyl ether, 140.0 mmol) was added at 0° C. and stirred for 3.5 h. A solution of 2-indanone (14.21 g, 107.7 mmol) in THF (20 mL) was added at the same temperature. After stirring at 0° C. for 3 h, the mixture was allowed to warm to room temperature and kept at ambient temperature overnight (12 h). It was then treated with 5% aqueous hydrochloric solution. The solution was extracted with diethyl ether (4*200 mL). All etheral layers were combined, washed with water (100 mL), dried over anhydrous magnesium sulphate and concentrated to give the crude product. Kugelrohr distillation (120° C./0.3 mm Hg) yielded 4.0 g of 2-indanone and 10.38 g of 2-(o-tolyl)-2-indanol in solid form. 1 H-N.M.R. (CDCl3) d 2.13 (br s, 1H), d 2.52(s, 3H), d 3.36 (d, J=16.2 Hz, 2H), d 3.63 (d, J=16.2 Hz, 2H), d 7.15-7.62 (m, 8H)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH3:12][O:13][C:14](=[O:28])[C:15]([O:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[CH:26]=O)([CH3:17])[CH3:16].N1CCCC1>CO>[CH3:12][O:13][C:14](=[O:28])[C:15]([O:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1/[CH:26]=[C:6]1\[C:7](=[O:11])[NH:8][C:9]2[C:5]\1=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)([CH3:17])[CH3:16]
Reactant: COC(=O)C(C)(C)Oc1ccc(Cl)cc1C=O
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: C1CCNC1
Solvent: CO
Product: COC(=O)C(C)(C)Oc1ccc(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Temperature: 70 °C
Yield: 72 %

Procedure:
To the mixture of 6-chloro-1,3-dihydro-indol-2-one (43 g, 0.26 mol) and 2-(4-chloro-2-formyl-phenoxy)-2-methyl-propionic acid methyl ester (66 g, 0.26 mol) in methanol (700 mL) was added pyrrolidine (22 g, 0.31 mol) dropwise. The mixture was then heated at 70° C. for 1 h. After cooled to room temperature, the mixture was filtered and resulting precipitate was collected, dried to give the title compound as a yellow solid (76 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[O:17]1[C:21]2[CH:22]=[CH:23][C:24]([O:26][C:27]3[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][C:28]=3[CH3:34])=[CH:25][C:20]=2[N:19]=[CH:18]1>C(O)(C)C.ClCCCl>[O:17]1[C:21]2[CH:22]=[CH:23][C:24]([O:26][C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:2]4[C:11]5[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=5)[N:5]=[CH:4][N:3]=4)=[CH:29][C:28]=3[CH3:34])=[CH:25][C:20]=2[N:19]=[CH:18]1
Reactant: Cc1cc(N)ccc1Oc1ccc2ocnc2c1
Reactant: COCCOc1ccc2ncnc(Cl)c2c1
Solvent: CC(C)O
Solvent: ClCCCl
Product: COCCOc1ccc2ncnc(Nc3ccc(Oc4ccc5ocnc5c4)c(C)c3)c2c1
Temperature: 80 °C
Yield: 27.2 %

Procedure:
To a solution of 4-chloro-6-(2-methoxyethoxy)quinazoline (0.199 g, 0.83 mmol) and 4-(benzo[d]oxazol-5-yloxy)-3-methylbenzenamine (0.200 g, 0.83 mmol) in isopropanol (2 mL) and DCE (2 mL). After heating to 80° C. for 12 hours, the mixture was concentrated under reduced pressure. The residue was partitioned between saturated NaHCO3 and EtOAc. The aqueous phase was extracted 2× with EtOAc, the combined organic phase was washed with brine, dried (Na2SO4), filtered and condensed. The residue was chromatographed to provide the product (0.100 g, 27%) as off-white solids. MS APCI (+) m/z 443 (M+1) detected; 1H NMR (400 MHz, DMSO-d6) δ 9.59 (s, 1H), 8.76 (s, 1H), 8.50 (s, 1H), 7.96 (s, 1H), 7.75 (m, 4H), 7.52 (dd, 1H), 7.26 (m, 1H), 7.10 (m, 1H), 6.97 (d, 1H), 4.30 (m, 2H), 3.76 (m, 2H), 3.36 (s, 3H), 2.24 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)[C:5]([Cl:22])=[CH:4][N:3]=1>CCN(C(C)C)C(C)C.CO.[Pt]=O>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:17][CH2:18]2)[C:5]([Cl:22])=[CH:4][N:3]=1
Reactant: NC(=O)C1(c2ccccc2C#Cc2nc(Cl)ncc2Cl)CC1
Agent: O=[Pt]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: NC(=O)C1(c2ccccc2CCc2nc(Cl)ncc2Cl)CC1
Reaction time: 58 h

Procedure:
A suspension of 1-(2-((2,5-dichloropyrimidin-4-yl)ethynyl)phenyl)cyclopropanecarboxamide (A13) (0.536 g, 1.61 mmol) and platinum oxide (0.110 g, 0.484 mmol) in DIPEA (16 mL) and MeOH (3 mL) was stirred under a hydrogen atmosphere for 58 hours. The resulting mixture was filtered through a pad of Celite and the filtrate concentrated in vacuo. The residue was diluted with water and EtOAc and filtered through a pad of Celite. The filtrate was extracted with EtOAc (2×20 mL) and the combined organic fractions were washed with water (3×20 mL), brine, dried (magnesium sulfate), filtered and concentrated in vacuo. The residue was adsorbed onto silica gel and purified by column chromatography (CombiFlash Rf, 24 g SiO2 Cartridge, 30-60% EtOAc in cyclohexane) to give the title compound A14 as a white solid (375 mg, 69%); 1H NMR (300 MHz, CDCl3) δ 8.52 (s, 1H), 7.43 (d, J=7.2 Hz, 1H), 7.28-7.31 (m, 3H), 5.37 (d, J=17 Hz, 2H), 3.27 (brs, 4H), 1.76 (brs, 2H), 1.16 (brs, 2H). LCMS-B: rt 5.30 min; m/z 337 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]12([C:13]3[CH:14]=[C:15]([C:20]4[CH:21]=[C:22]5[C:27](=[CH:28][CH:29]=4)[CH:26]=[C:25]([C:30]([O:32][CH3:33])=[O:31])[CH:24]=[CH:23]5)[CH:16]=[CH:17][C:18]=3[OH:19])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.Br[CH:35]([OH:38])[CH2:36][CH3:37].Cl>CN(C=O)C.O>[C:3]12([C:13]3[CH:14]=[C:15]([C:20]4[CH:21]=[C:22]5[C:27](=[CH:28][CH:29]=4)[CH:26]=[C:25]([C:30]([O:32][CH3:33])=[O:31])[CH:24]=[CH:23]5)[CH:16]=[CH:17][C:18]=3[O:19][CH2:37][CH2:36][CH2:35][OH:38])[CH2:10][CH:9]3[CH2:11][CH:5]([CH2:6][CH:7]([CH2:8]3)[CH2:12]1)[CH2:4]2
Reactant: CCC(O)Br
Reactant: COC(=O)c1ccc2cc(-c3ccc(O)c(C45CC6CC(CC(C6)C4)C5)c3)ccc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2cc(-c3ccc(OCCCO)c(C45CC6CC(CC(C6)C4)C5)c3)ccc2c1
Reaction time: 0.5 h

Procedure:
77 mg (2.55 retool) of 80% sodium hydride in oil are added to 1 g (2.42 mmol) of methyl 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthoate in solution in 10 ml of DMF. After 1 h 30 min of stirring, 230 ml (2.42 mmol) of bromopropanol are added to this reaction medium which is left stirring for 12 hours at room temperature, under nitrogen. The reaction medium is poured into water, acidified to pH=1 with concentrated HCl and extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulphate, filtered and evaporated. The residue is chromatographed on silica in dichloromethane, and crystallized from the dichloromethane/hexane mixture to give 600 mg (53%) of the expected derivative which melts at 201.9° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:11][CH3:12])[C:5]([O:9][CH3:10])=[C:6]([Cl:8])[CH:7]=1.[CH:13]1([CH:18]([OH:21])[CH:19]=[CH2:20])[CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[Cl:8][C:6]1[CH:7]=[C:2]([CH2:20][CH2:19][C:18]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:21])[CH:3]=[C:4]([CH2:11][CH3:12])[C:5]=1[O:9][CH3:10]
Reactant: CCc1cc(Br)cc(Cl)c1OC
Reactant: C=CC(O)C1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCc1cc(CCC(=O)C2CCCC2)cc(Cl)c1OC
Temperature: 140 °C
Yield: 80.6 %

Procedure:
A mixture of 5-bromo-1-chloro-3-ethyl-2-methoxy-benzene (2 g, 8 mmol), 1-Cyclopentyl-2-propen-1-ol (1.3 g, 10.4 mmol), dichlorobis (triphenylphosphine) palladium (II) (110 mg, 0.16 mmol), and sodium bicarbonate (0.81 g, 9.6 mmol) in N-methylpyrrolidinone (15 mL) was heated to 140° C. under N2 for 5 h. The reaction mixture was partitioned between 1N HCl and EtOAc. The organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated to black oil. The oil was purified by flash column chromatography (0% to 10% EtOAc in hexanes) to give the desired product (1.9 g, 82%). 1H NMR (400 MHz, CDCl3): δ 1.20 (t, J=7.6 Hz, 3 H), 1.53–1.81 (m, 8 H), 2.65 (q, J=7.6 Hz, 2 H), 2.74 (m, 2 H), 2.79–2.87 (m, 3 H), 3.81 (s, 3 H), 6.90 (s, 1 H), 7.03 (m, 1 H).
Reaction SMILES: [Na].C(S)C.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:18][C:19]([OH:21])=[O:20])[CH2:14][C:15]([OH:17])=[O:16])=[CH:9][CH:8]=1>CN(C)C=O>[OH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:18][C:19]([OH:21])=[O:20])[CH2:14][C:15]([OH:17])=[O:16])=[CH:9][CH:8]=1
Reactant: COc1ccc(C(CC(=O)O)CC(=O)O)cc1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCS
Product: O=C(O)CC(CC(=O)O)c1ccc(O)cc1
Reaction time: 0.25 h
Yield: 81.5 %

Procedure:
To a stirred suspension of 57% sodium hydrideparaffin (6.45 g), in dry dimethylformamide (70 ml) is slowly added ethanethiol (11.89 ml) in dry dimethylformamide (20 ml). After stirring the resultant slurry for 15 minutes, a solution of 3-(4-methoxyphenyl)glutaric acid (3.0 g) in dry dimethylformamide (20 ml) is added. The slurry is heated in a bath at 165°to C. for 5.0 hours and most of the solvent is removed by distillation in vacuo. The residue is diluted with water, acidified with concentrated hydrochloric acid and extracted twice with ether (the extracts are discarded). The solution is saturated with sodium chloride and extracted with ethyl acetate. The ethyl acetate solution is washed once with brine, dried, and the residue crystallized from chloroform-hexane to afford 2.3g of 3-(4-hydroxyphenyl)glutaric acid, melting point 168-170° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:14]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N[C@@H:27]1[CH2:32][CH2:31][CH2:30]C[C@H:28]1[NH2:33].BrC1C=NC=CC=1>[Cu]I.O1CCOCC1>[NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([C:27]3[CH:28]=[N:33][CH:30]=[CH:31][CH:32]=3)[C:6]=2[N:14]=1
Reactant: NC(=O)c1cc2c(nc1N)[nH]c1ccccc12
Reactant: N[C@@H]1CCCC[C@H]1N
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Brc1cccnc1
Solvent: C1COCCO1
Product: NC(=O)c1cc2c3ccccc3n(-c3cccnc3)c2nc1N
Temperature: 110 °C
Yield: 164.8 %

Procedure:
To a stirred mixture of 2-amino-9H-pyrido[2,3-b]indole-3-carboxamide (5, 100 mg, 0.44 mmol), Copper(I) iodide (8 mg, 0.045 mmol) and potassium phosphate (190 mg, 0.88 mmol) under dry nitrogen was added (±)-trans-1,2-diaminocyclohexane (5 μL, 0.04 mmol) and 3-bromopyridine (43 μL, 0.442 mmol), followed by 1,4-dioxane (2 mL). The mixture was heated at 110° C. for 2 days. The reaction mixture was cooled to room temperature, extracted with methylene chloride (3×30 ml) and washed with water. The extracts were combined, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (12 g silica, methylene chloride to 90/10 methylene chloride/methanol gradient) to yield 2-amino-9-pyridin-3-yl-9H-pyrido[2,3-b]indole-3-carboxamide (67, 20 mg, 10%). NH4OAc standard conditions. DAD Retention time =5.99 min. M+H=310. 1H NMR (300 MHz, MeOD): δ 8.86 (d, J=2.4 Hz, 1H), 8.74 (s, 1H), 8.66-8.63 (m, 1H), 8.14 (d, J=8.2 Hz, 1H), 7.96 (d, J=7.0 Hz, 1H), 7.70 (dd, J=4.7, 8.2 Hz, 1H), 7.36-7.28 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[N:9]=[C:10]1[NH:14][CH2:13][CH2:12][NH:11]1.Cl[CH2:16][C:17](=O)[CH3:18].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[N:9]1[C:10]2=[N:11][CH2:12][CH2:13][N:14]2[C:17]([CH3:18])=[CH:16]1
Reactant: Brc1cccc(Br)c1N=C1NCCN1
Reactant: CC(=O)CCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC1=CN(c2c(Br)cccc2Br)C2=NCCN12
Temperature: 150 °C

Procedure:
A mixture consisting of 9.6 gm (0.03 mol) of 2-(2,6-dibromophenyl-imino)-imidazoline, 2.6 ml (110% of the stoichiometrically required amount) of chloroacetone, 3 ml of triethylamine and 30 ml of absolute toluene was heated in a closed tube at 150° C. for 17 hours. Thereafter, the toluene phase was decanted, and the residue was dissolved in dilute hydrochloric acid. The resulting solution was fractionally extracted with ether at stepwisely increasing pH values (addition of 2 N sodium hydroxide). The thin-layer chromatographically pure ethereal fractions were combined, dried over anhydrous calcium sulfate and evaporated in vacuo, leaving 1.65 gm (15.4% of theory) of the compound of the formula ##STR9## which had a melting point of 144°-147° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C[Si]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])(C)C.[O:21]1[C:25]([C:26]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][O:36]3)=[CH:30][CH:29]=2)=O)=[CH:24][N:23]=[CH:22]1>C1COCC1>[O:21]1[C:25]([C:26]([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][O:36]3)=[CH:32][CH:33]=2)=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:24][N:23]=[CH:22]1
Reactant: CCOC(=O)C[Si](C)(C)C
Reactant: O=C(c1ccc(OC2CCCCO2)cc1)c1cnco1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C=C(c1ccc(OC2CCCCO2)cc1)c1cnco1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 66.7 %

Procedure:
To a solution of lithium bis(trimethylsilyl)amide (31.5 mmol, 1 M in THF) was added ethyl trimethylsilylacetate (31.5 mmol) dropwise at −78° C. After 20 minutes at −78° C., a solution of 75.2 (21 mmol) in THF (60 mL) was added dropwise and the reaction was maintained at −78° C. for 1.5 hours. The reaction was quenched saturated NH4Cl (aq) and warmed to room temperature. The mixture was extracted with EtOAc (500 mL), the organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated with silica gel under reduced pressure. The residue was chromatographed (silica gel, 1:1 EtOAc/hexane) to afford compound 75.3 (4.83 g, 14 mmol). MS ESI (pos.) m/e 344.2 (M+H).
Reaction SMILES: I[C:2]1[CH:7]=[N:6][N:5](C2CCCCO2)[C:4](=[O:14])[CH:3]=1.[C:15]1([SH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([S:21][C:2]2[CH:7]=[N:6][NH:5][C:4](=[O:14])[CH:3]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=c1cc(I)cnn1C1CCCCO1
Reactant: Sc1ccccc1
Product: O=c1cc(Sc2ccccc2)cn[nH]1

Procedure:
In an analogous manner to the stepwise sequence outlined in Intermediate 18, starting from 5-iodo-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (Intermediate 18, step 2) and benzenethiol afforded 5-phenylsulfanyl-2H-pyridazin-3-one which was then reacted in an analogous manner to that outlined in the synthesis of intermediate 19 (steps 4 and 5) alkylating with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10) afforded the lithium salt of 3-cyclopentyl-2-(6-oxo-4-phenylsulfanyl-6H-pyridazin-1-yl)-propionic acid as a white solid (98 mg, quantitative for the final step); ES+-HRMS m/e calcd for C18H20N2O3SI [M+H+] 345.1268, found 345.1268. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.93-1.19 (m, 2H), 1.29-1.76 (m, 7H), 1.86-2.00 (m, 1H), 2.05-2.21 (m, 1H), 5.24 (dd, J=10.9, 3.9 Hz, 1H), 5.94 (d, J=2.1 Hz, 1H), 7.53-7.64 (m, 3H), 7.63-7.73 (m, 2H), 7.91 (d, J=2.1 Hz, 1H), 13.02 (br. s., 1H).