Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6](=O)[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[N:15][C:16]([NH:19][C:20]3[N:21]=[CH:22][C:23]4[C:29]([CH3:30])=[C:28]([C:31]([O:33]CC)=[CH2:32])[C:27](=[O:36])[N:26]([CH:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)[C:24]=4[N:25]=3)=[CH:17][CH:18]=2)[CH2:9]1)(C)(C)C.Cl>C(Cl)(Cl)Cl>[C:31]([C:28]1[C:27](=[O:36])[N:26]([CH:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)[C:24]2[N:25]=[C:20]([NH:19][C:16]3[CH:17]=[CH:18][C:13]([N:10]4[CH2:11][CH2:12][N:7]([CH3:6])[CH2:8][CH2:9]4)=[CH:14][N:15]=3)[N:21]=[CH:22][C:23]=2[C:29]=1[CH3:30])(=[O:33])[CH3:32]
Reactant: C=C(OCC)c1c(C)c2cnc(Nc3ccc(N4CCC(NC(=O)OC(C)(C)C)C4)cn3)nc2n(C2CCCC2)c1=O
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC(=O)c1c(C)c2cnc(Nc3ccc(N4CCN(C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 76.5 %

Procedure:
To a solution of (1-{6-[8-cyclopentyl-6-(1-ethoxy-vinyl)-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-pyrrolidin-3-yl)-carbamic acid tert-butyl ester (394 mg, 0.68 mmol) in chloroform (5 ml) was added hydrogen chloride (2 M ethereal solution, 2.0 ml, 4.0 mmol). The reaction mixture was stirred at RT for 12 h. The solvents were evaporated and the residue was dissolved in ethanol. The ethanol was evaporated to give 6-acetyl-8-cyclopentyl-5-methyl-2-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-8H-pyrido[2,3-d]pyrimidin-7-one (239 mg, 0.52 mmol). MS (APCI+) 487, 391, 279 (100); 1H NMR δ(400 MHz, DMSOd6) 8.98 (s, 1H), 8.34 (br, 2H), 7.78-7.73 (m, 2H), 7.51 (br, 1H), 5.89-5.80 (m, 1H), 3.98 (br, 2H), 3.62-3.51 (m, 4H), 2.40-3.23 (m, 2H), 2.44 (s, 3H), 3.34 (s, 3H), 2.25-2.20 (m, 2H), 2.16-2.13 (m, 1H), 1.93 (br, 2H), 1.80-1.78 (m, 2H), 1.61-1.58 (m, 2H); Anal. Calc'd for C24H29N7O2, 2.10HCl, 2.85H2O, 0.45C2H5OH: C, 50.16; H, 6.68; N, 16.45; Cl−, 12.49. Found: C, 50.37; H, 6.90; N, 16.45; Cl−, 12.61.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[N:16]([CH2:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[N:15]=[CH:14]3)=[CH:5][CH:4]=1>CO.O.[Pd]>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[N:16]([CH2:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[N:15]=[CH:14]3)=[CH:5][CH:4]=1
Reactant: CN(C)CCCn1ncc2cc(/C=C/c3ccc(O)cc3)ccc2c1=O
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: CN(C)CCCn1ncc2cc(CCc3ccc(O)cc3)ccc2c1=O
Yield: 94.4 %

Procedure:
Trans-6-[2-(4-Hydroxyphenyl)ethenyl]-2-(3-dimethylaminopropyl)-1(2H)-phthalazinone hydrochloride (5 g) in methanol (100 ml) and water (10 ml) was hydrogenated at 50 psi over 10% Pd/C (0.5 g). After 6 hours the catalyst was filtered and the filtrate was diluted with ether (600 ml). The precipitated product was filtered to give 4.3 g of the saturated product as the hydrochloride mp. 234°-236° C.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:12]1[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=1)[N:6]2[CH3:11].[N:18]1([C:24]2[CH:25]=[C:26]([CH:37]=[CH:38][CH:39]=2)[O:27][CH2:28][C:29]([N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:30])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(N(CC)CC)C>C(O)(C)C>[CH3:11][N:6]1[C:5]([C:12]2[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=2)=[N:4][C:3]2[C:7]1=[N:8][CH:9]=[N:10][C:2]=2[N:21]1[CH2:22][CH2:23][N:18]([C:24]2[CH:39]=[CH:38][CH:37]=[C:26]([O:27][CH2:28][C:29](=[O:30])[N:31]3[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]3)[CH:25]=2)[CH2:19][CH2:20]1
Reactant: O=C(COc1cccc(N2CCNCC2)c1)N1CCCCC1
Reactant: Cn1cc(-c2nc3c(Cl)ncnc3n2C)cn1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cn1cc(-c2nc3c(N4CCN(c5cccc(OCC(=O)N6CCCCC6)c5)CC4)ncnc3n2C)cn1
Temperature: 25 °C
Yield: 9.9 %

Procedure:
A stirred solution of 6-chloro-9-methyl-8-(1-methyl-1H-pyrazol-4-yl)-9H-purine (30 mg, 0.12 mmol), 2-(3-(piperazin-1-yl)phenoxy)-1-(piperidin-1-yl)ethanone (45.5 mg, 0.15 mmol), and triethylamine (84.0 uL, 0.60 mmol) in isopropyl alcohol (2.0 mL) were heated to 80° C. for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The product was purified by preparatory HPLC (reverse-phase, acetonitrile/water with 0.1% formic acid) to give 6.1 mg (10% yield) of the title compound. 1H NMR (400 MHz, DMSO-d6): δ 8.44 (s, 1H), 8.27-8.25 (m, 1H), 8.05 (s, 1H), 7.12 (t, 1H), 6.62 (dd, 1H), 6.55 (t, 1H), 6.39-6.35 (m, 1H), 4.73 (s, 2H), 3.96 (s, 3H), 3.85 (s, 3H), 3.46-3.37 (m, 4H), 3.30-3.24 (m, 6H), 3.17 (d, 2H), 1.63-1.48 (m, 4H), 1.43 (s, 2H). MS (EI) for C27H33N9O2: 516.7 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][NH:12][CH2:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[C:20]([N:27]2[N:31]=[CH:30][CH:29]=[N:28]2)[CH:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH2:1]([N:8]1[CH2:9][CH:10]2[CH2:11][N:12]([C:22]([C:21]3[CH:25]=[CH:26][C:18]([O:17][CH3:16])=[CH:19][C:20]=3[N:27]3[N:31]=[CH:30][CH:29]=[N:28]3)=[O:23])[CH2:13][CH:14]2[CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CN2CC3CNCC3C2)cc1
Reactant: COc1ccc(C(=O)O)c(-n2nccn2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)N2CC3CN(Cc4ccccc4)CC3C2)c(-n2nccn2)c1
Reaction time: 1 h
Yield: 57.9 %

Procedure:
To a mixture of 2-benzyloctahydropyrrolo[3,4-c]pyrrole (282 mg, 1.4 mmol), 4-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid (306 mg, 1.4 mmol), and TEA (0.21 mL, 1.5 mmol) in DMF (7.5 mL) was added HATU (583 mg, 1.5 mmol). After 1 h, the reaction mixture was diluted with EtOAc and washed with water. The aqueous layer was then extracted with EtOAc (1×). The combined organics were dried (Na2SO4) and concentrated to give a residue. Purification via Agilent prep system (Basic) gave 327 mg (58%) of the title compound as a clear oil. 1H NMR (CDCl3): 7.79 (s, J=6.5 Hz, 2H), 7.50 (d, J=5.0 Hz, 1H), 7.36 (d, J=8.5 Hz, 1H), 7.34-7.21 (m, 5H), 6.95 (dd, J=8.5, 2.5 Hz, 1H), 3.93 (s, 3H), 3.86-3.72 (m, 1H), 3.65-3.46 (m, 3H), 3.13 (s, 1H), 2.90-2.74 (m, 2H), 2.74-2.59 (m, 2H), 2.57-2.39 (m, 2H), 2.16 (dd, J=9.2, 4.2 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][NH:12][CH2:11]3)[CH2:9][N:8]([C:15]([NH:17][C:18]3[S:19][C:20]([Cl:23])=[CH:21][N:22]=3)=[O:16])[C:5]2=[CH:6][CH:7]=1.[C:24](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([CH3:24])[CH2:11]3)[CH2:9][N:8]([C:15]([NH:17][C:18]3[S:19][C:20]([Cl:23])=[CH:21][N:22]=3)=[O:16])[C:5]2=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(Nc1ncc(Cl)s1)N1CC2(CCNC2)c2cc(Br)ccc21
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CN1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Br)cc12
Reaction time: 3 h
Yield: 24.5 %

Procedure:
The 5-bromo-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide (48.2 mg, 0.105 mmol) obtained in Example 2 was dissolved in N,N′-dimethylformamide (1.0 mL). Thereafter, potassium carbonate (43.5 mg, 0.315 mmol) and methyl iodide (30.0 mg, 0.210 mmol) were added to the above obtained solution at room temperature, and the obtained mixture was then stirred for 3 hours. Thereafter, the reaction solution was diluted with water, and was then extracted with methylene chloride. The organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to obtain the captioned compound (11.0 mg, 35%) in the form of a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:32][NH2:33].C([O-])(O)=O.[Na+]>C1COCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:32][NH2:33])=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: NN
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc(C(=O)NN)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
To a stirring solution of 4′-methyl-[1,1′-biphenyl]-4-carboxylic acid (240 mg, 1.13 mmol) and 4-methylmorpholine (131 μL, 1.19 mmol) in THF (3 mL) was added isobutyl chloroformate (147 μL, 1.13 mmol). After 1 h the reaction mixture was added through a syringe filter to a stirring solution of hydrazine (1.24 mL, 1.24 mmol, 1 M in THF) in THF (1 mL). After stirring a further 30 min at room temperature, the reaction mixture was poured into NaHCO3 (20 mL) and extracted with DCM (3×20 mL). The combined organic extracts were dried over MgSO4 and evaporated. The crude product was purified by column chromatography (MeOH/DCM) to give 152 mg (59%) of 4′-methyl-[1,1′-biphenyl]-4-carbohydrazide INT-50 as a white solid. LCMS-ESI (m/z) calculated for C14H14N2O: 226; found 227 [M+H]+, tR=1.62 min (Method 10).
Reaction SMILES: Br[CH2:2][CH:3]=[CH:4][C:5]([OH:7])=[O:6].[CH3:8][NH:9][CH3:10].C(Cl)CCl>C1COCC1.CN(C=O)C>[CH3:8][N:9]([CH3:10])[CH2:2][CH:3]=[CH:4][C:5]([OH:7])=[O:6]
Reactant: CNC
Reactant: O=C(O)C=CCBr
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(C)CC=CC(=O)O
Temperature: 25 °C
Yield: 40 %

Procedure:
100 mg of 4-dimethylamino-2-butenoic acid (0.63 mmol) which was prepared by reaction between 4-bromo-2-butenoic acid and dimethylamine in THF, was added in 2 ml DMF and 185 mg of 4 (0.53 mmol) was added followed by 0.6 mmol EDC. The mixture was stirred over night at room temperature and the final product was purified by preparative HPLC to give 120 mg product as light yellow solid, yield 40%. HPLC-MS: m/z: 496 [M+1]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:27]=[CH:26][C:7](/[CH:8]=[C:9]2/[C:10](=[O:25])[N:11]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)[C:12](=[O:14])[S:13]/2)=[CH:6][CH:5]=1)[CH3:2].[Sn](Cl)Cl>C(Cl)(Cl)Cl.C(O)C.ClCCl>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:11]2[C:10](=[O:25])/[C:9](=[CH:8]/[C:7]3[CH:26]=[CH:27][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=3)/[S:13][C:12]2=[O:14])=[CH:17][CH:18]=1
Reactant: CCOc1ccc(/C=C2\SC(=O)N(Cc3ccc([N+](=O)[O-])cc3)C2=O)cc1
Agent: Cl[Sn]Cl
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: ClCCl
Product: CCOc1ccc(/C=C2\SC(=O)N(Cc3ccc(N)cc3)C2=O)cc1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a solution of compound 28n (100 mg, 0.26 mol) in 10 mL of chloroform-ethanol co-solvent (ratio, 4:1) was added tin(II) chloride.dihydrate (293 mg, 1.30 mmol). The reaction mixture was stirred at 45° C. overnight. The reaction mixture was diluted with dichloromethane and washed with sat'd aqueous NaHCO3, collected the organic layer, dried over anhydrous Na2SO4, filtered, concentrated and purified by silica column chromatography (10% ethyl acetate in dichloromethane) to afford 88 mg (97.0%) of pure 28o as a yellow-orange solid.
Reaction SMILES: [F: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][C:12]([CH3:15])([OH:14])[CH3:13].[H-].[Na+].[NH2:18]OS(O)(=O)=O>CN(C=O)C.CCOC(C)=O>[NH2:18][N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)[C:5]([CH2:11][C:12]([CH3:15])([OH:14])[CH3:13])=[CH:6]1
Reactant: CC(C)(O)Cc1c[nH]c2ccc(F)cc12
Reactant: NOS(=O)(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(O)Cc1cn(N)c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-(5-fluoro-1H-indol-3-yl)-2-methyl-propan-2-ol (207 mg, 1 mmol) in DMF (10 mL) is cooled to 0° C., treated with NaH (600 mg, 15 mmol, 60% in mineral oil) and stirred for 30 min. H2NOSO3H (565 mg, 5 mmol) is added portion wise, and the mixture is warmed to rt over 2 h. The mixture is diluted with EtOAc (100 mL), quenched with water, extracted with EtOAc, dried (Na2SO4), filtered and concentrated in vacuo to afford 1-(1-amino-5-fluoroindol-3-yl)-2-methyl-propan-2-ol, which is used in the next step without further purification.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1>ClC(Cl)Cl>[ClH:3].[Cl:3][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: OCCOc1ccncc1
Solvent: ClC(Cl)Cl
Product: Cl
Product: ClCCOc1ccncc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 134 %

Procedure:
Thionyl chloride (0.75 ml, 10 mmol) was added to a solution of 4-(2-hydroxyethoxy)pyridine (0.9 g, 6.5 mmol), (J. Chem. Soc. Perkin II, 1987, 1867), in trichloromethane (20 ml) at 5° C. The mixture was stirred for 1 hour at 5° C., allowed to warm to ambient temperature and stirred for a further 2 hours. The volatiles were removed by evaporation and by azeotroping with toluene to give 4-(2-chloroethoxy)pyridine hydrochloride (1.3 g, 100%).
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([C:8]([CH2:12][C:13]#[CH:14])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[K].[CH3:16][O:17][C:18]([NH:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:22]=1[CH2:23]Cl)=[O:19].O>CN(C)C=O>[CH3:16][O:17][C:18]([NH:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:22]=1[CH2:23][O:1][C:2]1[C:3]2[N:4]([C:8]([CH2:12][C:13]#[CH:14])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1)=[O:19]
Reactant: COC(=O)Nc1cccc(C)c1CCl
Reactant: C#CCc1c(C)nc2c(O)cccn12
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCc1c(C)nc2c(OCc3c(C)cccc3NC(=O)OC)cccn12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 6.6 %

Procedure:
A mixture of 8-hydroxy-2-methyl-3-(2-propynyl)imidazo[ 1,2-a]pyridine (0.372 g) and potassium carbona (0.276 g) in N,N-dimethylformamide (7.4 ml) was stirred at room temperature for 20 minutes under a nitrogen atmosphere and then 2-methoxycarbonylamino-6-methylbenzylchloride (0.427 g) was added. After being stirred for 2 hours. The mixture was poured into water and the resulting precipitates were collected by filtration. The crude product was purified by column chromatography on silica gel (10 g) with chloroform as eluents to give 8-(2-methoxycarbonylamino-6-methylbenzyloxy)-2-methyl-3-(2-propynyl)imidazo[1,2-a]pyridine (0.048 g).
Reaction SMILES: C1C=CC=CC=1.[C:7]([C:11]1[CH:12]=[C:13]([OH:18])[CH:14]=[CH:15][C:16]=1[Cl:17])([CH3:10])([CH3:9])[CH3:8].[Cl:19][C:20](OC(Cl)(Cl)Cl)=[O:21].C(N(CC)CC)C>CCCCCC>[Cl:19][C:20]([O:18][C:13]1[CH:14]=[CH:15][C:16]([Cl:17])=[C:11]([C:7]([CH3:10])([CH3:8])[CH3:9])[CH:12]=1)=[O:21]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cc(O)ccc1Cl
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: c1ccccc1
Product: CC(C)(C)c1cc(OC(=O)Cl)ccc1Cl
Yield: 135.7 %

Procedure:
Into 50 ml of benzene were dissolved 9.2 g of 3-tert-butyl-4-chlorophenol and 5.5 g of trichloromethyl chloroformate, and a solution obtained by dissolving 5.8 g of triethylamine into 20 ml of benzene was added dropwise thereto with stirring and cooling by ice. After completion of this dropwise addition, the mixture was subjected to stirring for 12 hours at room temperature. To the reaction mixture were added 70 ml of hexane, and precipitated crystal was separated by filtration. The filtrate was washed with water and a saturated aqueous solution of sodium chloride in this order, and was dried over anhydrous calcium chloride. Thereafter, solvent was distilled off. The residue was distilled under reduced pressure to give 9.32 g of 3-tert-butyl-4-chlorophenyl chloroformate having boiling point of 105°-108° C./1 mmHg, of which properties are as follows.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[C:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:9][CH:10]=2)[C:5](=[O:21])[N:4]([CH2:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=2)[C:3]1=[O:32].CCN=C=NC[CH2:39][CH2:40][N:41]([CH3:43])[CH3:42].Cl.C1C=CC2N(O)N=NC=2C=1.C(CN)O>CN(C=O)C.O>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[C:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:9][CH:10]=2)[C:5](=[O:21])[N:4]([CH2:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([O:29][CH2:39][CH2:40][N:41]([CH3:43])[CH3:42])=[O:28])=[CH:25][CH:24]=2)[C:3]1=[O:32]
Reactant: Cn1c(=O)n(Cc2ccc(C(=O)O)cc2)c(=O)c2cc(C#CCc3ccccc3)ccc21
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: NCCO
Product: CN(C)CCOC(=O)c1ccc(Cn2c(=O)c3cc(C#CCc4ccccc4)ccc3n(C)c2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 0.72 g (1.7 mmol) 4-[1-Methyl-2,4-dioxo-6-(3-phenyl-prop-1-ynyl)-1,4-dihydro-2H-quinazolin-3-ylmethyl]-benzoic acid, 0.43 g (2.2 mmol) EDAC-HCl, 0.29 g (2.2 mmol) HOBT in 10 ml DMF is treated with 0.19 g (2.2 mmol) ethanolamine. The resulting mixture is stirred overnight at room temperature before diluting with water and extracting with 1:1 EtOAc/Et2O (2×). The combined organic extracts are washed with saturated aqueous NaCl (3×), dried (MgSO4). The resulting oil is dissolved in EtOAc and treated with saturated methanolic HCl. Concentration provided a solid which is triturated in EtOAc and filtered.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[C:10]2[CH:15]=[CH:14][C:13]([C:16]([N:18]3[CH2:23][CH2:22][C:21]4[CH:24]=[CH:25][O:26][C:20]=4[CH2:19]3)=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.[CH2:32]=O>C(O)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[C:10]2[CH:11]=[CH:12][C:13]([C:16]([N:18]3[CH2:23][CH2:22][C:21]4[CH:24]=[C:25]([CH2:32][N:27]5[CH2:31][CH2:30][CH2:29][CH2:28]5)[O:26][C:20]=4[CH2:19]3)=[O:17])=[CH:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: C=O
Reactant: O=C(c1ccc(/C=C\c2ccc(Cl)cc2)cc1)N1CCc2ccoc2C1
Solvent: CC(=O)O
Product: Cl
Product: O=C(c1ccc(/C=C\c2ccc(Cl)cc2)cc1)N1CCc2cc(CN3CCCC3)oc2C1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 0.867 g (2.383 mmol) of (Z)-6-(4-chlorostilbene-4'-carbonyl)-4,5,6,7-tetrahydrofuro[2,3-c]pyridine in 10 ml of acetic acid, 0.30 ml (3.57 mmol) of pyrrolidine and 0.29 g (3.57 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 1 hour. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with ethyl acetate 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=4/1) to yield the desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.C([Li])CCC.CCCCCC.[CH3:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27](N(C)OC)=[O:28])[CH2:23][CH2:22]1.[OH-].[Na+]>ClCCl>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:27]([CH:24]2[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]2)=[O:28])[N:3]=1
Reactant: Brc1cccc(Br)n1
Reactant: CON(C)C(=O)C1CCN(C)CC1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCCCCC
Product: CN1CCC(C(=O)c2cccc(Br)n2)CC1
Temperature: -78 °C
Yield: 74 %

Procedure:
Dissolve 2,6-dibromopyridine (5.5 g, 23.2 mmol) in anhydrous dichloromethane (140 mL) under a nitrogen atmosphere. Cool the reaction mixture to −78° C. Add a solution of n-butyl lithium in hexane (1.6 M, 15.8 mL, 25.3 mmol) very slowly via a syringe. After the addition is complete, stir the reaction at −78° C. for 1 hr. Add a solution of 1-methyl-N-methyl-N-methoxy-piperidine-4-carboxamide (2 g, 11 mmol) in anhydrous dichloromethane (10 mL) dropwise to the reaction mixture. Stir the reaction at −78° C. for 2 hrs, and then allow the mixture to slowly warm to room temperature overnight. Quench the reaction with 0.1 N NaOH. Dilute the solution with dichloromethane (100 mL), transfer into a separatory funnel and shake with 2 N NaOH (50 mL). Separate the organic layer, dry it over anhydrous sodium sulfate, and then evaporate the solvent under reduced pressure. Further purify the residue by chromatography on asilica gel column (6%, 2M NH3 in methanol/CH2Cl2 ) to obtain 2-bromo-6-(1-methylpiperidin-4-ylcarbonyl)-pyridine e (2.3 g, 74% yield). Mass spectrum (ion spray): m/z 283 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH:5]=[CH:6][C:7]=1[C:8]([O:10]C)=[O:9].O.[OH-].[Li+].Cl>O1CCCC1.O.CO>[CH2:20]([O:19][C:17]([N:13]1[CH2:14][CH2:15][CH2:16][CH:12]1[C:4]1[CH:5]=[CH:6][C:7]([C:8]([OH:10])=[O:9])=[C:2]([F:1])[CH:3]=1)=[O:18])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)c1ccc(C2CCCN2C(=O)OCc2ccccc2)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(C2CCCN2C(=O)OCc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
To a solution of benzyl 2-(3-fluoro-4-(methoxycarbonyl)phenyl)pyrrolidine-1-carboxylate (8.7 g, 24.4 mmol) in tetrahydrofuran (90 mL) was added lithium hydroxide monohydrate (2.05 g, 48.8 mmol) in 90 mL of water (90 mL) and methanol (90 mL) was added until a transparent solution formed. This mixture was stirred at ambient temperature for 2 hours and acidified with 2N hydrochloric acid to pH=2. The mixture was concentrated to about 90 mL, diluted with water and left to stand at ambient temperature overnight. The solid was collected by filtration, washed with water and dried to give 4-(1-(benzyloxycarbonyl)pyrrolidin-2-yl)-2-fluorobenzoic acid (8.4 g, yield 98%). LC-MS (ESI) m/z: 344 (M+1)+.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[SH:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:20]=[CH:21][CH:22]=1)[C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14])=[O:8].C(CN(CC([O-])=O)CC(O)=O)N(CC(O)=O)CC([O-])=O.[Na+].[Na+]>O1CCCC1.O>[OH:2][CH2:1][CH2:3][NH3+:4].[SH:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:20]=[CH:21][CH:22]=1)[C:13]([NH:15][CH2:16][C:17]([O-:19])=[O:18])=[O:14])=[O:8]
Reactant: O=C(O)CNC(=O)c1cccc(NC(=O)CS)c1
Reactant: NCCO
Agent: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)O)CC(=O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C([O-])CNC(=O)c1cccc(NC(=O)CS)c1
Product: [NH3+]CCO
Reaction time: 16 h
Yield: 93 %

Procedure:
A solution 1.13 ml. of ethanolamine (1.15 g., 0.0188 mole) and 10 ml. of tetrahydrofuran is added to a suspension of N-[3-(mercaptoacetylamino)benzoyl]glycine (5 g., 0.0186 mole), 5 mg. of disodium edetate, 6 ml. of water, and 40 ml. of tetrahydrofuran. Warming the mixture to 40°-45° C. provides a clear solution which is first diluted with 200 ml. of tetrahydrofuran, then cooled in a dry ice-acetone bath to promote crystallization and subsequently stirring for a period of 16 hrs. at room temperature. The precipitated material formed is collected, washed with tetrahydrofuran and dried over calcium chloride to afford 5.7 g., (93% yield) of N-[3-(mercaptoacetylamino)benzoyl]glycine 2-hydroxyethyl ammonium salt, m.p. 144.0°-160.0° C. (dec.).
Reaction SMILES: Cl[P:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2[C:12]3[C:17]([CH:18]=[CH:19][C:4]=2O1)=CC=CC=3.[F:20][C:21]1[CH:22]=[C:23]([Mg]Br)[CH:24]=[CH:25][CH:26]=1.[OH2:29].Cl>CC1C=CC=CC=1C>[F:20][C:21]1[CH:22]=[C:23]([P:2]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([F:20])[CH:22]=2)[C:7]2[CH:8]=[CH:9][C:10]3[C:11](=[CH:19][CH:4]=[CH:5][CH:6]=3)[C:6]=2[C:5]2[CH:12]=[CH:17][CH:18]=[CH:19][C:4]=2[OH:29])[CH:24]=[CH:25][CH:26]=1
Reactant: ClP1Oc2ccc3ccccc3c2-c2ccccc21
Reactant: Fc1cccc([Mg]Br)c1
Reactant: O
Agent: Cl
Solvent: Cc1ccccc1C
Product: Oc1ccccc1-c1c(P(c2cccc(F)c2)c2cccc(F)c2)ccc2ccccc12
Temperature: 25 °C

Procedure:
8.5 g (30 mmol) of 5-chloro-5H-benzo[c]naphth[1,2-e][1,2]-oxa-phosphorine in 50 ml of anhydrous o-xylene at 80° C. are introduced, in an argon atmosphere with stirring, and a solution of 70 mmol of 3-fluorophenylmagnesium bromide in 80 ml of o-xylene is added dropwise. The temperature increases in the course of this from 80° to 90° C. The mixture is then stirred for 1 hour at 110° C. The mixture is cooled to room temperature and 100 ml of water are added. The mixture is neutralized with dilute hydrochloric acid, the organic phase is separated off, dried with sodium sulfate and concentrated under reduced pressure. 19.0 g of colorless oil are obtained.