Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11](=[O:26])[NH:12][C:13]1[C:14]([CH3:25])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=1)[CH3:9].[CH2:27]([O:29][C:30](=[O:48])[CH:31]([C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=1)[CH3:32])[CH3:28]>>[CH2:27]([O:29][C:30](=[O:48])[CH:31]([C:33]1[CH:38]=[CH:37][C:36]([C:21]2[CH:22]=[CH:23][C:18]([C:17]3[O:16][N:15]=[C:14]([CH3:25])[C:13]=3[NH:12][C:11]([O:10][C@@H:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH3:9])=[O:26])=[CH:19][CH:20]=2)=[CH:35][CH:34]=1)[CH3:32])[CH3:28]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)O[C@H](C)c1ccccc1Cl
Reactant: CCOC(=O)C(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCOC(=O)C(C)c1ccc(-c2ccc(-c3onc(C)c3NC(=O)O[C@H](C)c3ccccc3Cl)cc2)cc1

Procedure:
Following the procedure described in Example 36, Step 6, [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-chloro-phenyl)-ethyl ester and 2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propionic acid ethyl ester were reacted to provide 2-(4′-{4-[(R)-1-(2-chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-propionic acid ethyl ester, which was hydrolyzed to the acid as described in Example 17, Step 3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14](SC)[N:15]=[CH:16][C:11]=2[CH:10]=1.[NH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14]([NH:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: NCCc1ccccn1
Reactant: CSc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(C)c2n1
Product: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(NCCc3ccccn3)nc21

Procedure:
This compound was prepared by a procedure similar to that described in Example 49 starting with 0.165 g (0.47 mmol) of 6-(2,6-dichlorophenyl)-8-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 37 and 1.00 g (8.20 mmol) of 2-(2-aminoethyl)-pyridine yielding 0.082 g of pure product; mp 173°-174° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23]Br)=[CH:19][CH:18]=1.C(N(CC)CC)C>CC#N.O>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:13]2[CH2:14][CH2:15][N:10]([C:4]3[CH:5]=[CH:6][CH:7]=[C:8]([Cl:9])[C:3]=3[Cl:2])[CH2:11][CH2:12]2)=[CH:19][CH:18]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: Clc1cccc(N2CCN(Cc3ccc(Br)cc3)CC2)c1Cl
Yield: 55 %

Procedure:
A mixture of intermediate 41 (294 mg, 1.1 mmol), 1-bromo-4-(bromomethyl)benzene (250 mg, 1.0 mmol) and anhydrous triethylamine (253 mg, 2.5 mmol) was dissolved in CH3CN and the solution was heated to reflux for 4 h. The solution was diluted with water and extracted with EtOAc. The combined organic layers were washed with saturated aq NaHCO3, brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with PE/EtOAc=8:1) to give 1-(4-bromobenzyl)-4-(2,3-dichlorophenyl)piperazine (intermediate 54) (220 mg, 74%) as a white solid.
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17]C(C#N)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(O)CO[CH2:24][CH2:25][OH:26].[OH-:28].[Na+].Cl>O>[CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:24]([C:25]([OH:26])=[O:28])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc(-c2ccc(C#N)cc2)cc1
Reactant: [OH-]
Reactant: OCCOCCO
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCCCCCc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reaction time: 25 h

Procedure:
5 Gram of 4-n-hexyl-4'-cyanobiphenyl, 40 ml of diethylene glycol, 4 ml of water and 2 g of sodium hydroxide were introduced into 200 ml three neck flask and heated with stirring for 25 hours, followed by acidifying with hydrochloric acid, separating by filtration and recrystallizing with glacial acetic acid to give 4.1 g of 4-n-hexyl-biphenyl-4'-carboxylic acid (II), which was a colorless crystal having a molecular formula of C19H22O2 (composition: C 80.8%, H 7.9%, O 11.3% as calculated values and C 80.4%, H 8.1%, O 11.5% as observed values) and a melting point of 170° -171° C and formed a smectic liquid crystal at temperatures exceeding the melting point.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:26])([F:25])[CH:22]([F:24])[F:23])[CH:15]=1)[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[N:7]=1)[OH:5].[F:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([C:38](O)=[O:39])=[CH:30][CH:29]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(#N)C.O>[F:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([C:38]([NH:2][CH:3]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:25])([F:26])[CH:22]([F:23])[F:24])[CH:15]=2)[CH:4]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[N:7]=2)[OH:5])=[O:39])=[CH:30][CH:29]=1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(F)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(F)n1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2RS)-2-amino-1-(6-fluoropyridin-2-yl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol hydrochloride (300 mg, 0.75 mmol) in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (141 mg, 0.75 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (216 mg, 1.13 mmol), 1-hydroxybenzotriazole hydrate (115 mg, 0.75 mmol) and triethylamine (1.03 ml, 0.75 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1-ethyl acetate). Recrystallization from ethyl acetate-hexane gave the objective substance (306 mg, 76%).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][CH:11]=O)=O.C([O-])=O.[NH4+].C([NH2:19])=O>>[N:10]1[C:9]2[CH:8]=[CH:7][S:6][C:5]=2[C:3](=[O:2])[NH:19][CH:11]=1
Reactant: NC=O
Reactant: COC(=O)c1sccc1NC=O
Agent: O=C[O-]
Agent: [NH4+]
Product: O=c1[nH]cnc2ccsc12
Temperature: 140 °C
Yield: 72 %

Procedure:
In a 125 mL round-bottomed flask 3-formylamino-thiophene-2-carboxylic acid methyl ester (5 g, 27.0 mmol), ammonium formate (5.11 9, 81.0 mmol), and formamide (6.40 mL, 162 mmol) were combined and heated at 140° C. After 10 hours the reaction mixture was cooled to room temperature and filtered. The crystalline solid was washed with water and dried in vacuo to afford 2.96 g (72%) of 3H-thieno[3,2-d]pyrimidin-4-one. 1H NMR (400 MHz, DMSO) d 8.10 (m, 2H), 7.34 (m, 1H). LC-MS: 153 (MH′); HPLC RT: 1.21 minutes.
Reaction SMILES: C([Mg]Br)C.CO[C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#N.C1[CH2:19][O:18][CH2:17][CH2:16]1.[Cl-].[NH4+].C([O:24]CC)C>O>[CH3:19][O:18][CH2:17][CH2:16][C:10]([C:9]1[CH:8]=[CH:7][CH:14]=[CH:13][CH:12]=1)=[O:24]
Reactant: C1CCOC1
Reactant: COc1cccc(C#N)c1
Reactant: CCOCC
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: COCCC(=O)c1ccccc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
A solution of ethyl magnesium bromide in diethyl ether (58 ml, 3 M) was added dropwise at room temperature to a mixture of 3-methoxybenzonitrile (21.2 g, 0.159 mol) and dry THF (250 ml). When addition was complete the mixture was stirred for 1 h at room temperature, 3 h at 40° C. and finally stirred overnight at room temperature. Water (250 ml) was added followed by a saturated ammonium chloride solution (250 ml) and the mixture was stirred for 1 h at room temperature. The phases were separated and the aqueous phase was extracted with ethyl acetate (100 ml). The combined organic phases was dried (MgSO4) and the solvent evaporated in vacuo to give 25.9 g (99%) of 3-methoxypropiophenone.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]([NH2:9])=[NH:8].[Cl:10][C:11]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:12]=1[CH:13]=O.[CH3:20][C:21]1([CH3:29])[CH2:26][C:25](=[O:27])[CH2:24][C:23](=O)[CH2:22]1.C([O-])(=O)C.[Na+].Cl>C(O)C.O.C(OCC)(=O)C>[S:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]1[N:9]=[C:13]([C:12]2[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:11]=2[Cl:10])[C:24]2[C:25](=[O:27])[CH2:26][C:21]([CH3:29])([CH3:20])[CH2:22][C:23]=2[NH:8]1
Reactant: O=Cc1ccc(F)cc1Cl
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: N=C(N)c1nccs1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CC1(C)CC(=O)C2=C(C1)NC(c1nccs1)N=C2c1ccc(F)cc1Cl
Yield: 27.3 %

Procedure:
2-thiazolecarboxamidine hydrochloride (Schaefer F. C., Peters G. A., et al.) 2.164 mmol, 2-chloro-4-fluorobenzaldehyde 2.164 mmol, 5,5-dimethyl-1,3-cyclohexanedione 2.164 mmol and sodium acetate 3.2 mmol were reacted in 8 ml of anhydrous ethanol under refluxing for 18 hr, condensed, to which ethyl acetate and water and 1N HCl were added, and separated. The water layer was adjusted with concentrated NaOH solution until pH value to be basic, then ethyl acetate was added and extracted twice. The organic layers were combined, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain a yellow crystal 0.23 g (yield 28%); 1H-NMR (400 MHz, CDCl3-d1) δ 7.95-7.85 (m, 1H, ArH); 7.64-7.47 (m, 1H, ArH); 7, 34-7.24 (m, 1H, ArH); 7.13-7.11 (m, 1H, ArH); 6.11 (s, 1H, CH); 2.70-2.52 (m, 2H, CH2); 2.43-2.26 (m, 2H, CH2); 1.15 (s, 6H, CH3). HREI: 389.0765 (M+).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:20]1[CH:29]=[C:28]([O:30][CH2:31][CH3:32])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1.C([O-])(O)=O.[Na+]>Cl.O>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:20]2[CH:29]=[C:28]([O:30][CH2:31][CH3:32])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: CCOc1cc(Cl)nc2ccccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCOc1cc(NCCCOc2cccc(CN3CCCCC3)c2)nc2ccccc12
Temperature: 160 °C
Reaction time: 4 h
Yield: 94.5 %

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine (9.93 g) and 2-chloro-4-ethoxyquinoline (4.15 g) were heated, with stirring, at 160° C. for 41/4 hours. The reaction mixture was cooled to give a glass which was dissolved in dilute HCl to give a solution having a pH of 6. This solution was washed with diethyl ether (2×), taken to pH 5 and extracted continuously into chloroform. The chloroform extract was evaporated under reduced pressure to give a residue which was dissolved in water, taken to pH 9 with aqueous NaHCO3, and extracted into diethylether (7×) and chloroform (2×). These extracts were dried (MgSO4) and evaporated to give 2-[3-[3-(piperidinomethyl)phenoxy]propylamino]-4-ethoxyquinoline as an oil (7.92 g). This was dissolved in hot ethanol and treated with maleic acid in ethanol to give the dimaleate salt (7.53 g), m.p. 145.5°-147.5° C. (recrystallised from ethanol).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:4]([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([O:25]CC)=[O:24])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.CCO.[OH-].[Na+].Cl>C1COCC1>[CH3:1][C:2]1[C:3]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:4]([O:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:19][CH:20]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2
Reactant: CCOC(=O)COc1ccc(Oc2c(-c3ccccc3)c(C)cc3cc(OC)ccc23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc2c(Oc3ccc(OCC(=O)O)cc3)c(-c3ccccc3)c(C)cc2c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
Ethyl [(4-{[3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}phenyl)oxy]acetate (234) (0.170 g, 0.39 mmol) was dissolved in 1:1 THF:EtOH (6 mL). To the above mixture was added 1 N NaOH (0.5 mL) at room temperature and heated to 50° C. The reaction mixture was kept at that temperature for 0.5 h and cooled at RT. Reaction mixture was acidified with 25% aqueous HCl, and then extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), and concentrated under reduced pressure to afford 0.155 g (97%) the crude product (235). 1H NMR (400 MHz, CDCl3): δ 7.78 (d, J=10.0 Hz, 1H), 7.54 (s, 1H), 7.28-7.03 (m, 4H), 6.64 (d, J=9.0 Hz, 2H), 6.50 (d, J=8.9 Hz, 2H), 4.54 (s, 2H), 3.93 (s, 3H), 2.23 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1Br)[CH:12]([NH:17][C:18]1[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:20][CH:19]=1)[CH2:11][CH2:10]2)=[O:5].[Cu][C:32]#[N:33].N>CN1C(=O)CCC1>[CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[C:32]#[N:33])[CH:12]([NH:17][C:18]1[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:20][CH:19]=1)[CH2:11][CH2:10]2)=[O:5]
Reactant: COCC(=O)Nc1cc2c(cc1Br)C(Nc1ccc(C(=O)OC(C)(C)C)cc1)CC2
Reactant: N#C[Cu]
Agent: N
Solvent: CN1CCCC1=O
Product: COCC(=O)Nc1cc2c(cc1C#N)C(Nc1ccc(C(=O)OC(C)(C)C)cc1)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-[N-(5-methoxyacetamido-6-bromoindan-1-yl)-amino]benzoate (0.714 g, 1.50 mmol) in NMP (8 ml) [1-methyl-2-pyrrolidone] was added copper (I) cyanide (0.230 g, 2.55 mmol). The reaction mixture was placed in an oil-bath preheated to 140° C. and stirred at this temperature for 2 h. More copper (I) cyanide (0.100 g, 1.10 mmol) was then added and stirring was continued for a longer 3 hours. The reaction mixture was allowed to cool to room temperature, then poured into a mixture of aqueous ammonia (d=0.88, 7 ml) and ice (−20 ml) and the resulting brown mixture was stirred at room temperature for −5 min. The brown solid was collected by filtration washed with plenty of water, then suspended in dichloromethane (100 ml). The mixture was stirred at room temperature for 10 min, dried (Na2SO4), and concentrated in vacuo. Purification by column chromatography, on elution with 35% ethyl acetate in hexane, afforded an off white solid that was reprecipitated from dichloromethane-ethyl acetate/hexane: 0.328 g, (52%) m.p. 163-164° C. 1H-NMR (250 MHz, DMSO-d6, TMS) 1.50 (s, 9H, C(CH3)3), 1.85, 2.58 (2×m, 2H, indanyl 2-H), 2.89 (m, 2H, indanyl 3-H), 3.41 (s, 3H, OCH3), 4.05 (s, 2H, CH2OMe), 5.06 (m, 1H, indanyl 1-H), 6.73 (d, J=8.82 Hz, 2H, 3,5-H), 6.82 (d, J=8.37 Hz, 1H, N10—H), 7.59, 7.57 (2×s, each 1H, indanyl 4-H, 7-H), 7.66 (d, J=8.77 Hz, 2,6-H), 9.88 (s, 1H, CONH); MS (ESI, m/z) 444 {(M+Na)+, 100%}. Found: C, 68.21; H, 6.47; N, 9.81; C24H27N3O4 requires C, 68.39; H, 6.46; N, 9.97%.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:18]([Cl:19])=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[O:8])=[C:5]([O:20][CH3:21])[CH:4]=1.[C:22](=[O:25])([O-])[O-].[K+].[K+].BrCCCCCC[C:35]1[CH:45]=[CH:44][CH:43]=[C:37]2[C:38]([NH:40][C:41](=[O:42])[C:36]=12)=O>CN(C)C=O>[NH2:2][C:3]1[C:18]([Cl:19])=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH:11]2[CH2:12][CH2:13][N:14]([CH2:5][CH2:4][CH2:3][CH2:18][CH2:17][CH2:38][N:40]3[C:41](=[O:42])[C:36]4[C:35](=[CH:45][CH:44]=[CH:43][CH:37]=4)[C:22]3=[O:25])[CH2:15][CH2:16]2)=[O:8])=[C:5]([O:20][CH3:21])[CH:4]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: O=C([O-])[O-]
Reactant: O=C1NC(=O)c2c(CCCCCCBr)cccc21
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCCN2C(=O)c3ccccc3C2=O)CC1
Temperature: 70 °C
Reaction time: 16 h
Yield: 62.7 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide hydrochloride (8.5 g) was dissolved in dimethylformamide (100 ml). Potassium carbonate (10.5 g) and 6-bromohexylphthalimide (7.2 g) were added, and the mixture was stirred at 70° C. for 16 hr. The reaction mixture was concentrated under reduced pressure and the residue was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to give 4.2 g of 4-amino-5-chloro-N-(1-(6-(2,3-dihydro-1,3-dioxo-1H-isoindol-2-yl)hexyl)-piperidin-4-ylmethyl)-2-methoxybenzamide.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:44][OH:45])=[C:19]([C:23]3[CH:24]=[C:25]([NH:31][C:32]4[N:37]=[CH:36][C:35]([C:38]([CH3:43])([CH3:42])[C:39](O)=[O:40])=[CH:34][CH:33]=4)[C:26](=[O:30])[N:27]([CH3:29])[CH:28]=3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[NH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1.C(Cl)CCl.[Cl-].[NH4+]>CN(C1C=CN=CC=1)C.C(Cl)Cl.C(OCC)(=O)C>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:24]=[C:25]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([C:38]([CH3:43])([CH3:42])[C:39]([N:46]5[CH2:51][CH2:50][O:49][CH2:48][CH2:47]5)=[O:40])=[CH:36][N:37]=4)[C:26](=[O:30])[N:27]([CH3:29])[CH:28]=3)[C:18]=1[CH2:44][OH:45])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: Cn1cc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2ccc(C(C)(C)C(=O)O)cn2)c1=O
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: ClCCl
Product: Cn1cc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2ccc(C(C)(C)C(=O)N3CCOCC3)cn2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
2-(6-{5-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-ylamino}-pyridin-3-yl)-2-methyl-propionic acid (50 mg, 0.08 mmol), morpholine (11 mg, 0.12 mmol), EDC (23 mg, 0.12 mmol), and DMAP (15 mg, 0.12 mmol) were dissolved in 1 ml of DCM and stirred at room temperature under nitrogen overnight. Ethyl acetate and saturated aqueous ammonium chloride were added and the layers were separated. The organic layer was washed with dilute ammonium chloride, then saturated aqueous sodium bicarbonate, dried, and concentrated. The crude product was purified by flash chromatography using a gradient of 0% to 10% methanol in DCM to give 40 mg (74%) of 6-tert-butyl-2-(3-{5-[5-(1,1-dimethyl-2-morpholin-4-yl-2-oxo-ethyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one. MS: (M+H)+=681. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.43 (s, 9 H) 1.53 (s, 6 H) 3.45 (br. s, 7 H) 3.71 (s, 3 H) 3.76 (br. s., 1H) 4.41 (br. s., 2 H) 6.85 (d, J=8.69 Hz, 1 H) 7.31-7.43 (m, 3 H) 7.48-7.61 (m, 4 H) 7.96 (s, 1 H) 8.15 (s, 1 H) 8.30 (s, 1 H) 8.69 (s, 1 H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:21][C@H:20]([CH2:22][OH:23])[O:19][C:18]4=[O:24])=[CH:13][C:12]=3[F:25])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.O[C:27]1[CH:31]=[CH:30][O:29][N:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1.CCOC(C)=O>[O:1]1[C:5]2([CH2:6][CH2:7][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:21][C@H:20]([CH2:22][O:23][C:27]5[CH:31]=[CH:30][O:29][N:28]=5)[O:19][C:18]4=[O:24])=[CH:13][C:12]=3[F:25])[CH2:9][CH2:10]2)[O:4][CH2:3][CH2:2]1
Reactant: Oc1ccon1
Reactant: O=C1O[C@@H](CO)CN1c1ccc(N2CCC3(CC2)OCCO3)c(F)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1O[C@@H](COc2ccon2)CN1c1ccc(N2CCC3(CC2)OCCO3)c(F)c1
Reaction time: 18 h
Yield: 85.4 %

Procedure:
3-(4-(1,4-Dioxa-8-azaspiro[4,5]decan-8-yl)-3-fluorophenyl)-5(R)-hydroxymethyloxazolidin-2-one (3.52 g, 10 mmol), 3-hydroxyisoxazole (893 mg, 10.05 mmol), and triphenylphosphine (3.03 g, 12 mmol) were dissolved by stirring in dry tetrahydrofuran (75 ml) under nitrogen. The mixture was cooled in an ice-bath, and diisopropylazodicarboxylate (2.33 g, 12 mmol) added dropwise over 10 minutes. The solution was stirred 18 hours, allowing the temperature to rise to ambient. The mixture was diluted with EtOAc (750 ml). the organic layer washed with water (3×500 ml), dried (magnesium sulfate) and evaporated. The residue was purified by MPLC on silica, eluting with a gradient between 0.25% and 1% MeOH in dichloromethane. Relevant fractions were combined and evaporated to give product (3.58 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][C:7]#[CH:8].[Cl:9][C:10]1[CH:15]=[CH:14][C:13](/[C:16](/[C:33]2[CH:38]=[CH:37]C(I)=[CH:35][CH:34]=2)=[CH:17]/[CH2:18][O:19][C:20]2[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[C:22]([CH3:32])[CH:21]=2)=[CH:12][CH:11]=1.O1CCC[CH2:41]1>C(N(CC)CC)C.C1C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[Cl:9][C:10]1[CH:11]=[CH:12][C:13](/[C:16](/[C:33]2[CH:38]=[CH:37][C:8]([C:7]#[C:6][CH2:5][N:4]([CH2:3][CH2:2][OH:1])[CH3:41])=[CH:35][CH:34]=2)=[CH:17]/[CH2:18][O:19][C:20]2[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[C:22]([CH3:32])[CH:21]=2)=[CH:14][CH:15]=1
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(Cl)cc2)c2ccc(I)cc2)cc1C
Reactant: C#CCCNCCO
Reactant: C1CCOC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(Cl)cc2)c2ccc(C#CCN(C)CCO)cc2)cc1C
Temperature: 0 °C
Reaction time: 48 h

Procedure:
N-(2-Hydroxyethyl)-N-propargylmethylamine (300 mg, 2.65 mmol) was added under nitrogen atmosphere to a degassed solution of methyl (Z)-[4-[3-(4-chlorophenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate (450 mg, 0.82 mmol; prepared as described in example 7) in a mixture of tetrahydrofuran (10 mL) and triethylamine (8 mL) The solution was cooled to 0° C., tetrakis(triphenylphosphine)palladium (85 mg, 0.073 mmol) and copper(I) iodide (22 mg, 0.115 mmol) were added. The reaction mixture was stirred at ambient temperature for 48 h, dissolved in benzene (100 mL), decanted and evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, benzene/ethyl acetate 1:0-0:1) yielding methyl (E)-[4-[3-(4-chlorophenyl)-3-[4-(3-[N-(2-hydroxyethyl)-N-methylamino]propynyl]-phenyl]allyloxy]-2-methylphenoxy]acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].C([O:14][C:15]1[C:16](=[O:27])[C:17](=O)[C:18]=1[NH:19][C@H:20]([CH3:25])[C:21]([CH3:24])([CH3:23])[CH3:22])C>C(O)C.C(OCC)C>[Cl:1][C:2]1[CH:9]=[C:8]([CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:17]1[C:16](=[O:27])[C:15](=[O:14])[C:18]=1[NH:19][C@H:20]([CH3:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[C:10]#[N:11]
Reactant: CCOc1c(N[C@H](C)C(C)(C)C)c(=O)c1=O
Reactant: N#Cc1ccc(CN)c(Cl)c1
Solvent: CCOCC
Solvent: CCO
Product: C[C@@H](Nc1c(NCc2ccc(C#N)cc2Cl)c(=O)c1=O)C(C)(C)C
Yield: 78.7 %

Procedure:
2-Chloro-4-cyano-benzylamine (0.30 g, 1.80 mmol, Example 2, Step 3) and (R)-3-ethoxy-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione (0.406 g, 1.80 mmol) were stirred in ethanol (10 mL) at 70° C. for 18 hours. The reaction was cooled and diluted with diethyl ether. Filtration afforded 0.49 g (79%) of (R)-3-chloro-4-{[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enylamino]-methyl]-benzonitrile which was collected as a white solid: mp 237°-241° C.; [α]25D =+27.30° (10.99 mg/mL, DMSO); 1H NMR (DMSO-d6) δ8.10 (d, 1H), 7.89 (dd, 1H), 7.68 (m, 1H), 7.69 (d, 1H), 7.36 (br d, 1H), 4.87 (m, 2H), 3.90 (m, 1H), 1.12 (d, 3H), 0.86 (s, 9H) ppm. IR (KBr): 3100, 2950, 2250, 1800 cm-1. MS (m/z) 345/347 (M+).