Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]([NH:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=12.C(C1C=C(C(F)(F)F)C=CC=1)#C.CC(C)=[O:41].C(=O)=O.[Li]CCCC.N([C@@H](C1C2C(=CC=CC=2)C=CC=1)C)=C=O.[Cl-].[NH4+]>C1COCC1.CCCCCC>[C:3]1([C@H:2]([NH:13][C:14](=[O:41])[C:15]#[C:16][C:17]2[CH:18]=[CH:19][CH:20]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:22]=2)[CH3:1])[C:8]2[C:7](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)=O
Reactant: C[C@@H](NCCCc1cccc(C(F)(F)F)c1)c1cccc2ccccc12
Agent: C#Cc1cccc(C(F)(F)F)c1
Agent: C[C@@H](N=C=O)c1cccc2ccccc12
Agent: O=C=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)C#Cc1cccc(C(F)(F)F)c1)c1cccc2ccccc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 89.2 %

Procedure:
The invention also provides, in another embodiment, an alternative route for synthesizing cinacalcet via the reduction of an alkyne precursor. The precursor is obtained by reacting an aryl acetylene with an appropriately substituted isocyanate. For example, a solution of 3-ethynyl-α,α,α-trifluorotoluene (0.73 mL; 5.06 mmol; 2.0 equiv.) in anhydrous THF (20 mL) was cooled to −78° C. (acetone/dry ice bath). A hexane solution of n-BuLi (1.6M, 2.69 mL; 4.30 mmol; 1.7 equiv.). is then added and the reaction mixture stirred at −78° C. for 30 minutes. A solution of (R)-1-(1-isocyanatoethyl)naphthalene (1.0 equiv.; 2.53 mmol; 0.447 mL) in THF is then added to the reaction mixture which is stirred for an additional 30 minutes at −78° C. The reaction is stopped by the addition of an aqueous solution of ammonium chloride to the organic mixture. The organic layer is repeatedly extracted with water, dried over magnesium sulfate and the solvent removed in vacuo to afford 3-(3-Trifluoromethyl-phenyl)-propynoic acid ((R)-1-naphthalen-1-yl-ethyl)-amide as product. Isolated 830 mg, 89.2% yield. The identity of the product is confirmed by 1H NMR and high resolution mass spectrometry. (300 MHz, CDCl3) δ ppm 1.77 (d, 3H) 5.97-6.08 (m, 1H) 6.15 (br. S., 1H) 7.42-7.70 (m, 7H) 7.75 (s, 1H) 7.81-7.94 (m, 2H) 8.12 (d, 1H) and HRMS (M+1): 368.1
Reaction SMILES: Cl.[O:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.[C:11]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[C:11]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([N:7]2[CH2:8][CH2:9][C:10]3[O:2][CH:3]=[CH:4][C:5]=3[CH2:6]2)=[O:24])=[CH:26][CH:27]=1)(=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: c1cc2c(o1)CCNC2
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(c1ccccc1)c1ccc(C(=O)N2CCc3occc3C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[3,2-c]pyridine hydrochloride, 0.27 g (1.2 mmol) of 4-benzoylbenzoic acid and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.24 g (1.5 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. This solution was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=5/1 to 3/1); the resulting solid was washed with diethyl ether to yield the desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:12][OH:13].C(=O)([O-])[O-].[K+].[K+].O.[NH2:21][C:22]1[N:31]=[C:30]([C:32]([N:34]2[CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:35]2)=[O:33])[C:29]2[C:24](=[CH:25][CH:26]=[C:27](B3OC(C)(C)C(C)(C)O3)[CH:28]=2)[N:23]=1>C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:21][C:22]1[N:31]=[C:30]([C:32]([N:34]2[CH2:35][C:36]3[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:42]2)=[O:33])[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:2]3[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=3[CH2:12][OH:13])[CH:28]=2)[N:23]=1
Reactant: COc1cc(Br)c(CO)cc1OC
Reactant: CC1(C)OB(c2ccc3nc(N)nc(C(=O)N4Cc5ccccc5C4)c3c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Product: COc1cc(CO)c(-c2ccc3nc(N)nc(C(=O)N4Cc5ccccc5C4)c3c2)cc1OC
Temperature: 120 °C

Procedure:
48 mg of (2-bromo-4,5-dimethoxyphenyl)methanol, 80 mg of potassium carbonate, 7 μl of water and 8 mg of [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride are added to a solution of 100 mg of [2-amino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone in 10 ml of ethanol under argon. The mixture is heated at 120° C. for 30 min. The solid is filtered off through kieselguhr with suction, and the filtrate is evaporated to dryness in vacuo. The residue is dissolved in 1 ml of DMSO and chromatographed by means of prep. HPLC (Agilent). The product fractions obtained are subsequently evaporated and freeze-dried.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([O:16][CH3:17])[CH:15]=2)[NH:12][C:11](=[O:18])[C:10]3=[O:19])=[C:5]([CH3:20])[O:4][N:3]=1.C1COCC1.[C:26]1([Mg]Br)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CC1CCCO1>CCOC(C)=O>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([O:16][CH3:17])[CH:15]=2)[NH:12][C:11](=[O:18])[C:10]3([OH:19])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: Br[Mg]c1ccccc1
Reactant: COc1cc(-c2c(C)noc2C)cc2c1NC(=O)C2=O
Solvent: CCOC(C)=O
Solvent: CC1CCCO1
Solvent: C1CCOC1
Product: COc1cc(-c2c(C)noc2C)cc2c1NC(=O)C2(O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
A suspension of 5-(3,5-dimethylisoxazol-4-yl)-7-methoxyindoline-2,3-dione (45 mg, 0.165 mmol) and anhydrous THF (1.5 mL) was added dropwise a solution of phenylmagnesium bromide in 2-methyltetrahydrofuran (2.9 M/L, 0.3 mL, 0.87 mmol). The reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was diluted with EtOAc (30 mL), washed with saturated aqueous NH4Cl (10 mL), brine (3×10 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo, purified by pre-TLC (CH2Cl2:EtOAc=3:2) to give the desired product as a light brown solid (28 mg, 48%). 1H NMR (400 MHz, DMSO-d6). δH 10.56 (s, 1H), 7.31-7.32 (m, 5H), 6.95-6.96 (m, 1H), 6.69-6.71 (m, 2H), 3.89 (s, 3H), 2.35 (s, 3H), 2.18 (s, 3H). MS (ESI) m/e [M+1]+ 351.
Reaction SMILES: O[CH2:2][C:3]1[S:11][C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[Cl:12])[CH:4]=1.[CH2:13]([N:15](CC)[CH2:16][CH3:17])[CH3:14].S(Cl)(C)(=O)=O.N1CCCC1.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>ClC(Cl)C.[Cl-].[Na+].O.ClCCl>[Cl:12][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[CH:4]=[C:3]([CH2:2][N:15]3[CH2:16][CH2:17][CH2:14][CH2:13]3)[S:11][C:10]=12
Reactant: CCN(CC)CC
Reactant: OCc1cc2nccc(Cl)c2s1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(Cl)Cl
Solvent: O
Solvent: C1CCNC1
Product: Clc1ccnc2cc(CN3CCCC3)sc12
Reaction time: 0.5 h
Yield: 56.2 %

Procedure:
A solution of 2-(hydroxymethyl)-7-chlorothieno[3,2-b]pyridine 114a (100 mg, 0.5 mmole) in dichloroethane was treated with triethylamine (0.08 mL, 0.55 mmole) and mesyl chloride (0.04 mL, 0.55 mmole). The clear solution was stirred for 30 minutes and treated with pyrrolidine (0.12 mL, 1.5 mmole). After one hour, the reaction mixture was poured into 5% sodium bicarbonate and the workup was performed with dichloromethane, brine and magnesium sulfate. The crude product (167 mg greenish oil) was purified over silica gel (1 mm plate) using 2% methanol-chloroform with 0.1% ammonium hydroxide, which provided the title compound as a clear oil (71 mg, 56%): 1H-NMR (DMSO-d6, 400 MHz) δ 8.58 (1H, d, J=5.1 Hz), 7.51–7.49 (2H, m), 3.96 (2H, s), 2.56 (4H, bs), 1.75–1.72 (4H, m); MS m/z 253 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][O:14][CH2:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:17])[N:12]=2)=[CH:4][CH:3]=1.[C:24](=O)([O:27]C)[O:25][CH3:26].[H-].[Na+].Cl>O1CCCC1.O.CO>[CH3:26][O:25][C:24]([CH:15]([O:14][CH2:13][C:11]1[N:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[S:9][CH:10]=1)[C:16]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:17])=[O:27]
Reactant: COC(=O)OC
Reactant: O=C(COCc1csc(-c2ccc(F)cc2)n1)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(OCc1csc(-c2ccc(F)cc2)n1)C(=O)c1ccccc1
Yield: 93.4 %

Procedure:
A solution of 9.8 g (0.03 mol) of 2-[2-(4-fluorophenyl)-4-thiazolylmethyloxy]acetophenone in 80 ml of tetrahydrofuran is added dropwise to 3.0 g (0.033 mol) of dimethyl carbonate and 0.8 g (0.033 mol) of sodium hydride in 20 ml of tetrahydrofuran at 60° C. with stirring under nitrogen, and the mixture is then stirred at 60° C. for 1 hour. After cooling, first 5 ml of methanol and then 500 ml of water are added, and the mixture is acidified with dilute hydrochloric acid and extracted with methyl tert-butyl ether. The organic phase is washed with sodium bicarbonate solution, dried and concentrated. The result is 10.8 g (93% yield) of ω-methoxycarbonyl-2-[2-(4-fluorophenyl)-4-thiazolylmethyloxy]acetophenone as an ocher solid of melting point 86°-89° C.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[NH2:11][C:12]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH2:31][CH3:32])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]#[N:22])[CH:19]=2)[NH:14][C:13]1=[O:23]>N1C=CC=CC=1>[C:5]1([O:4][C:2](=[O:3])[NH:11][C:12]2([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH2:31][CH3:32])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]#[N:22])[CH:19]=3)[NH:14][C:13]2=[O:23])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCOc1ccccc1C1(N)C(=O)Nc2ccc(C#N)cc21
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Product: CCOc1ccccc1C1(NC(=O)Oc2ccccc2)C(=O)Nc2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 111 %

Procedure:
1.2 ml (9.38 mmol) of phenyl chloroformate were added dropwise to 2.5 g (8.5 mmol) of product 10a dissolved in 50 ml of pyridine at 0° C. The reaction solution was then stirred at room temperature for 16 h. The solution was subsequently poured into ice-water, and the aqueous phase was extracted with ethyl acetate (AcOEt). The organic phase was washed several times with water, dried and concentrated in vacuo. 3.9 g of the product were obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([CH2:10][CH3:11])[C:7]([OH:12])=[C:6]([CH2:13][CH3:14])[CH:5]=1.[OH-].[Na+].O.S(OC)(O[CH3:23])(=O)=O>CCOCC>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([CH2:10][CH3:11])[C:7]([O:12][CH3:23])=[C:6]([CH2:13][CH3:14])[CH:5]=1
Reactant: COS(=O)(=O)OC
Reactant: CCc1cc(C(=O)OC)cc(CC)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CCc1cc(C(=O)OC)cc(CC)c1OC

Procedure:
To a cooled solution of 16.2 (0.078 mol.) of 3,5-diethyl-4-hydroxybenzoic acid methyl ester and 4.0 g. (0.1 mol.) of sodium hydroxide in 100 ml. of water is added 9.8 g. (7.3 ml., 0.079 mol.) of dimethyl sulfate. The reaction mixture is refluxed for two hours. After cooling, ether is added and the layers are separated. The organic phase is washed with water, dilute sulfuric acid and water, dried (Na2SO4) and concentrated to give 3,5-diethyl-4-methoxybenzoic acid methyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]([CH3:19])([CH3:18])[C:16]#N)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.[O:30]1CCCC1>CCCCCC>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]([CH3:19])([CH3:18])[CH:16]=[O:30])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C#N)c1cccc(OCc2ccccc2)c1
Reactant: C1CCOC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Product: CC(C)(C=O)c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a 15° C. solution of 325 g. (1.25 mole) of 2-(3-benzyloxyphenyl)-2-methylpropionitrile in 1.85 liters of tetrahydrofuran is added 1.6 moles of diisobutylaluminum hydride as a 1.3 M solution in hexane (reaction temperature is maintained at 15°-18° C.). The reaction mixture is allowed to warm to room temperature and is stirred 2 hours longer. It is then quenched by addition to a solution of 170 ml. of concentrated sulfuric acid in 670 ml. of water (temperature ≤30° C.). The resultant mixture is allowed to warm to room temperature and is then stirred an additional 2 hours. The organic layer is separated and the aqueous phase extracted once with one liter of ether. The combined organic phase is washed with 500 ml. of water and 500 ml. of saturated sodium chloride, dried over magnesium sulfate and evaporated to yield 315 g. (99%) of the title product.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.I[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1C(N)CCC(N)C1>[Cu](I)I.O.O1CCOCC1>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:4]=2[CH:3]=1
Reactant: Brc1ccc2c(c1)[nH]c1ccccc12
Reactant: Ic1ccccn1
Agent: I[Cu]I
Agent: NC1CCC(N)CC1
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Brc1ccc2c3ccccc3n(-c3ccccn3)c2c1
Temperature: 65 °C
Yield: 43.2 %

Procedure:
A 100 mL 3-neck flask was charged with copper iodide (0.057 g, 0.301 mmol), 2-bromo-9H-carbazole (7.4 g, 30.1 mmol), 2-iodopyridine (12.3 g, 60.1 mmol), potassium phosphate (12.8 g, 60.1 mmol), (1R,4R)-cyclohexane-1,4-diamine (0.343 g, 3.0 mmol), and dioxane (25 mL) and the reaction mixture was heated at 65° C. for 16 hours. The reaction mixture was then poured into deionized water and extracted with dichloromethane The organic layers were combined and subjected to a column chromatography (neutral Al2O3, 99/1 hexane/EtOAc) to yield 4.2 g (43%) of 2-bromo-9-(pyridin-2-yl)-9H-carbazole as a white solid. The product was confirmed by GC/MS and NMR.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:11]2[CH:7]1[CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10]2)=[O:5])C.[OH-].[Na+].CCCCCC.C(OCC)(=O)C>C(O)C>[C:15]([O:14][C:12]([N:9]1[CH2:8][CH:7]2[CH:11]([CH:6]2[C:4]([OH:5])=[O:3])[CH2:10]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)C1C2CN(C(=O)OC(C)(C)C)CC21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CC2C(C1)C2C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.5 %

Procedure:
The tert-butyl 6-ethoxycarbonyl-3-azabicyclo[3.1.0]hexane-3-carboxylate exo-isomer (613 mg, 2.40 mmol) prepared in Example 2 was dissolved in 6 mL of ethanol and 2N NaOH (2.40 mL, 4.80 mmol) was added dropwsie at 0° C. After stirring at room temperature for 3 hours, the completion of the reaction was confirmed by TLC (hexane:ethyl acetate=6:1). After the reaction was completed, the reaction mixture was concentrated under reduced pressure and then extracted by adding methylene chloride and water. After removing the organic layer containing byproducts, the aqueous layer was acidified with 1N HCl and extracted with methylene chloride. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain 527 mg (96.5%) of the target compound.
Reaction SMILES: N[C@H](C(O)=O)CS.[C:8]([C:10]1[CH:11]=[C:12]([CH:39]=[CH:40][C:41]=1[O:42][CH:43]([CH3:45])[CH3:44])[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:21]2[N:20]3[CH2:24][CH2:25][CH:26]([CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])[C:19]3=[C:18]([S:35]([CH3:38])(=[O:37])=[O:36])[C:17]=2[CH:16]=1)#[N:9].O.C(OCC)(=O)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:8]([C:10]1[CH:11]=[C:12]([CH:39]=[CH:40][C:41]=1[O:42][CH:43]([CH3:45])[CH3:44])[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:21]2[N:20]3[CH2:24][CH2:25][CH:26]([CH2:27][C:28]([OH:30])=[O:29])[C:19]3=[C:18]([S:35]([CH3:38])(=[O:37])=[O:36])[C:17]=2[CH:16]=1)#[N:9]
Reactant: CC(C)Oc1ccc(COc2ccc3c(c2)c(S(C)(=O)=O)c2n3CCC2CC(=O)OC(C)(C)C)cc1C#N
Agent: N[C@@H](CS)C(=O)O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)Oc1ccc(COc2ccc3c(c2)c(S(C)(=O)=O)c2n3CCC2CC(=O)O)cc1C#N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
D/L-Cysteine (40.5 mg, 0.334 mmol) was dissolved in TFA (1 mL) and cooled down to 0° C. The solution was added to a solution of tert-butyl 2-(7-(3-cyano-4-isopropoxybenzyloxy)-9-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (36 mg, 0.067 mmol) in DCM (1 mL) at 0° C. The reaction was stirred at this temperature for 1 h. Water was added, then ethyl acetate was added. The organic layer was separated, washed with water and brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by preparative HPLC. The combined fractions were partially concentrated in vacuo and diluted with ethyl acetate. The organic layer was separated, washed with water, and dried over anhydrous Na2SO4. The solvent was evaporated to give the title compound as white solid. LCMS m/z=483.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.41 (d, J=6.0 Hz, 6H), 2.46-2.55 (m, 1H), 2.84 (dd, J=16.7 and 9.5 Hz, 1H), 2.92-3.03 (m, 1H), 3.11 (s, 3H), 3.33 (dd, J=16.7, 3.4 Hz, 1H), 3.98-4.08 (m, 1H), 4.10-4.17 (m, 1H), 4.17-4.25 (m, 1H), 4.62-4.69 (m, 1H), 5.04 (s, 2H), 6.95-7.00 (m, 2H), 7.22 (d, J=8.8 Hz, 1H), 7.41 (d, J=2.4 Hz, 1H), 7.59 (dd, J=8.7, 2.2 Hz, 1H), 7.66 (d, J=2.2 Hz, 1H).
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][N:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)C.Cl.[OH:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[OH:33])[CH2:27][CH2:28][NH2:29].C(O)CCC.Cl>O>[ClH:13].[CH2:17]([O:16][C:14]([N:6]([CH2:5][CH:4]1[C:30]2[C:26](=[CH:25][C:24]([OH:23])=[C:32]([OH:33])[CH:31]=2)[CH2:27][CH2:28][NH:29]1)[C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=1)=[O:15])[CH3:18]
Reactant: NCCc1ccc(O)c(O)c1
Reactant: CCOC(=O)N(CC(OCC)OCC)c1ccc(Cl)cc1
Agent: Cl
Solvent: O
Solvent: CCCCO
Product: CCOC(=O)N(CC1NCCc2cc(O)c(O)cc21)c1ccc(Cl)cc1

Procedure:
N-ethoxycarbonyl-p-chloroanilinoacetaldehyde diethyl acetal (3.0 g) and 3,4-dihydroxyphenethylamine hydrochloride (1.5 g) were added to a mixture of n-butyl alcohol (30 ml), water (5 ml) and 10% hydrochloric acid (0.5 ml), and then the mixture was refluxed for 4 hours in a stream of nitrogen. Above mentioned acetal (0.8 g) was further added to the mixture and the resultant mixture was refluxed for 4 hours. The solvent was distilled off from the reaction mixture and the residue was washed with ethyl acetate and then recrystallized from water to give 1-(N-ethoxycarbonyl-p-chloroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride, mp 208° to 210° C. and mp 214° to 215° C. Analysis: Calcd. for C19H21N2O4Cl.HCl.3/10H2O: C 54.50, H 5.44, N 6.69, Cl 16.93. Measured: C 54.29, H 5.57, N 6.70, Cl 16.69.
Reaction SMILES: C([NH:5]C1C=C(B(O)O)C=CC=1)(=O)C=C.C([O-])([O-])=O.[Na+].[Na+].[CH3:21][C:22]1[C:30]2[C:25](=[N:26][CH:27]=[C:28]([C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:41])[CH:39]=[CH2:40])[CH:34]=[CH:35][CH:36]=3)C=2)[NH:24]N=1>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N:5]1[C:28]([C:31]2[CH:32]=[C:33]([NH:37][C:38](=[O:41])[CH:39]=[CH2:40])[CH:34]=[CH:35][CH:36]=2)=[CH:27][N:26]=[C:25]2[NH:24][CH:21]=[CH:22][C:30]=12
Reactant: C=CC(=O)Nc1cccc(-c2cnc3[nH]nc(C)c3c2)c1
Reactant: C=CC(=O)Nc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: C=CC(=O)Nc1cccc(-c2cnc3[nH]ccc3n2)c1
Temperature: 90 °C

Procedure:
A solution of 21 (100 mg, 0.507 mmol) and 2 (84 mg, 0.507 mmol) in toluene and ethanol (4:1 mL) was added Na2CO3 (111.01 mg, 1.014 mmol). The reaction was degassed and purged with nitrogen for 10 min. Pd(dppf)Cl2 (20.7 mg, 0.025 mmol) was added to the reaction. The reaction was degassed and purged with nitrogen for another 10 min. The reaction was heated to 90° C. under sealed condition overnight, allowed to cool to RT, and diluted with chloroform. The organic layer was filtered through Celite and concentrated to get the crude, which was purified through flash chromatography by using 100-200 mesh silica gel. The compound was eluted in 40% ethyl acetate in hexane as an off-white solid 22. MS-ES+264.8; 1H NMR (400 MHz, DMSO-D6) 22: 9.99 (bs, 1H), 9.40 (bs, 1H), 7.25 (bs, 1H), 7.08 (m, 1H), 7.00 (d, 1H), 6.42 (m, 2H), 6.21 (m, 1H), 5.71 (m, 1H).
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].[CH3:39][N:40](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN>ClCCl.C1COCC1>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([NH:40][CH3:39])=[O:32])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:38]
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)NC)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (40 mg, 0.074 mmol) in dichloromethane (2 mL) were added HBTU (30 mg, 0.079 mmol) and methylamine (0.185 mL, 0.37 mmol, 2.0M soln in THF). The mixture was stirred at rt overnight. Solvent was removed by rotovap. Separation by chromatography (90% methylene chloride/7% MeOH/3% ammonia) afforded the title compound (32 mg, 78%). LC-MS m/z 535 (M+H)+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[O:10]=[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH2:21][C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:41])[CH2:30][CH:31]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:32]([OH:34])=O)[CH:25]=[CH:26][CH:27]=2)=[N:13][NH:12]1.O=C1C2C(=CC=CC=2)C(CC2C=C(NC(=O)C(C3C=CC=CC=3)CC(O)=O)C=CC=2)=NN1.O>CN(C)C=O>[O:10]=[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH2:21][C:22]2[CH:23]=[C:24]([N:28]3[C:29](=[O:41])[CH2:30][CH:31]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:32]3=[O:34])[CH:25]=[CH:26][CH:27]=2)=[N:13][NH:12]1
Reactant: O=C(CC(C(=O)O)c1ccccc1)Nc1cccc(Cc2n[nH]c(=O)c3ccccc23)c1
Agent: O=C(O)CC(C(=O)Nc1cccc(Cc2n[nH]c(=O)c3ccccc23)c1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C1CC(c2ccccc2)C(=O)N1c1cccc(Cc2n[nH]c(=O)c3ccccc23)c1
Temperature: 25 °C
Reaction time: 3.25 h

Procedure:
O-Benzotriazol-1-yl-N,N,N′N′-tetramethyluronium tetrafluoroborate (0.139 g, 0.429 mmol) and diisopropylethylamine (0.095 g, 0.726 mmol) were added sequentially at ambient temperature to a stirred solution of the above mixture of N-[3-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]-2-phenylsuccinamic acid and N-[3-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]-3-phenylsuccinamic acid (0.142 g, 0.33 mmol) in dimethylformamide (2 ml), the mixture was stirred at ambient temperature for 3.25 hours and allowed to stand at ambient temperature for 18 hours, then it was added dropwise to water (10 ml). The mixture was stirred at ambient temperature for 30 minutes, then the resulting solid was collected by filtration, washed with water (5 ml) and hexane (10 ml), and dried in vacuo to give 1-[3-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]-3-phenylpyrrolidine-2,5-dione (0.097 g) as an off-white solid, 250 MHz 1H-nmr (d6-DMSO) δ (ppm): 3.0 (m, 1H) (ring CH), 3.4 (m partially obscured by water peak, 1H) (ring CH), 4.4–4.55 (m, 3H) (ArCH2—+ring CH), 7.25–7.65 (m, 9H) (9×ArH), 7.9–8.15 (m, 3H) (3×ArH), 8.4 (d, 1H) (ArH), 12.8 (s, 1H) (CONH); m/z (M+H)+. 410, 94.2% purity.