Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[CH2:10][CH2:9][C:8](=[O:13])[N:7]([CH2:14][CH2:15][CH2:16][N:17]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]3=[O:27])[C:6]=2[CH:28]=1.[CH3:29][N:30]([CH:32](OC)OC)[CH3:31]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10](=[CH:29][N:30]([CH3:32])[CH3:31])[CH2:9][C:8](=[O:13])[N:7]([CH2:14][CH2:15][CH2:16][N:17]3[C:18](=[O:27])[C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:25]3=[O:26])[C:6]=2[CH:28]=1
Reactant: O=C1CCC(=O)N(CCCN2C(=O)c3ccccc3C2=O)c2cc(Cl)ccc21
Reactant: COC(OC)N(C)C
Product: CN(C)C=C1CC(=O)N(CCCN2C(=O)c3ccccc3C2=O)c2cc(Cl)ccc2C1=O

Procedure:
In a manner similar to that described for method G, 8-chloro-1-(3-(1,3-dioxoisoindolin-2-yl)propyl)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (I-40-a) and DMF-DMA were converted to I-40-b and carried on crude: MS m/z=452 (M+H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][P:6]([CH2:11][P:12]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])=[O:13])([O:8][CH2:9][CH3:10])=[O:7])[CH3:4].[C:20]([C:26]([O:28][CH3:29])=[O:27])#[C:21][C:22]([O:24][CH3:25])=[O:23].C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:25][O:24][C:22](=[O:23])/[C:21](/[CH:11]([P:6]([O:8][CH2:9][CH3:10])([O:5][CH2:3][CH3:4])=[O:7])[P:12]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])=[O:13])=[CH:20]\[C:26]([O:28][CH3:29])=[O:27]
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: COC(=O)C#CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOP(=O)(OCC)C(/C(=C/C(=O)OC)C(=O)OC)P(=O)(OCC)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
In a suspension of 1.33 g of sodium hydride (60% in oil) in 120 ml of toluene are added dropwise 10 g of bis(diethoxyphosphoryl)methane dissolved in 20 ml of toluene. The reaction mixture is kept at room temperature under stirring for 1 hour, then it is cooled to 0° C. and added dropwise with a solution of dimethyl acetylenedicarboxylate (5.17 g) in 20 ml of toluene. After 1 hour under stirring the reaction mixture is added with ethyl acetate until dissolution of the formed gummy solid occurs and it is washed firstly with 1 N hydrochloric acid (30 ml) then with water (2×30 ml). The organic phase is dried over sodium sulfate and the solvent is evaporated under reduced pressure, to give a residue (12.9 g) which, after purification by silica gel chromatography (300 g; eluent:petroleum ether/isopropanol 7:3) furnishes 9.6 g of pure product.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:18]([S-:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].[Na+]>C(S)CCCCCCCCCCC>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]([S:30][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[NH:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Reactant: CCCCCCCCCCCC[S-]
Agent: CCCCCCCCCCCCS
Agent: [Na+]
Product: CCCCCCCCCCCCSC(=N)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and sodium dodecanethiolate in 1-dodecanethiol there is obtained dodecyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-thiocarboximidate, which is purified by flash chromatography on silica gel using n-hexane/ethyl acetate (1:1) as the eluent; 1H-NMR(CDCl3): 0.88 (t, CH3), 1.2-2.0 (20H), 2.5 (t, SCH2), 4.43 (s, 4H), 7.3-7.7 (8H);
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[S-:6][C:7]#[N:8].[K+].[C:10]1([NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16]>C(#N)C>[CH3:5][O:4][C:2]([NH:8][C:7]([NH:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH2:17])=[S:6])=[O:3]
Reactant: Nc1ccccc1N
Reactant: N#C[S-]
Reactant: COC(=O)Cl
Agent: [K+]
Solvent: CC#N
Product: COC(=O)NC(=S)Nc1ccccc1N
Reaction time: 2 h
Yield: 27.2 %

Procedure:
Methyl chloroformate (23.6 g; 0.25 mole) was added dropwise to a stirred suspension of potassium thiocyanate (24.2 g; 0.25 mole) in dry acetonitrile (100 ml). The temperature of the reaction mixture rose spontaneously to 50° C. and stirring was continued for two hours at 45° C. to 50° C. The reaction mixture was then filtered and the clear filtrate was added dropwise during fifteen minutes to a suspension of o-phenylenediamine (27 g; 0.25 mole) in dry acetonitrile (20 ml), the temperature during the addition being maintained between 15° C. and 20° C. by external cooling. When the addition was complete, the reaction mixture was stirred at laboratory temperature for two hours, filtered, and the crude solid product was crystallised from ethanol to give colourless needles of 1-methoxycarbonyl-3-(2-aminophenyl)-thiourea (15.3 g), m.p. 183.5°-184.5° C. (with decomposition).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH2:13][Cl:14])(=O)=O)=CC=1.[CH3:16][O:17][C:18](=[O:28])[C:19]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([OH:27])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:16][O:17][C:18](=[O:28])[C:19]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH2:11][CH2:12][CH2:13][Cl:14])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCCl)cc1
Reactant: COC(=O)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCCCl)c(OC)c1
Yield: 99.5 %

Procedure:
A mixture of 102.4 g (411.7 mmol) of 3-chloropropyl p-toluene sulfonate, 75 g (411.7 mmol) of 4-hydroxy-5-methoxy -benzoic acid methyl ester, 75.7 g (547.5 mmol) of potassium carbonate, and 1.66 g (4.1 mmol) of methyl-tricapryl ammonium chloride in 900 ml of acetone was stirred rapidly at reflux for 18 hr. The mixture was filtered and the solvent was removed giving 106 g of the tile compound after recrystallization from a chloroform-hexane mixture.
Reaction SMILES: [CH:1]([N:4]1[C:8]([CH3:9])=[CH:7][C:6]([CH2:10]O)=[N:5]1)([CH3:3])[CH3:2].S(Cl)([Cl:14])=O>C(Cl)Cl>[ClH:14].[Cl:14][CH2:10][C:6]1[CH:7]=[C:8]([CH3:9])[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=1
Reactant: Cc1cc(CO)nn1C(C)C
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(CCl)nn1C(C)C
Product: Cl
Reaction time: 1 h
Yield: 99 %

Procedure:
To (1-isopropyl-5-methyl-1H-pyrazol-3-yl)methanol (5.3 g, 34 mmol) in DCM (20 mL) at 0° C. was added sulfurous dichloride (20 g, 172 mmol). The cold bath was removed and the reaction mixture was stirred for one hour. Solvent was removed under reduced pressure to give the desired product (99%).
Reaction SMILES: N[C:2]1[NH:7][C:6](=O)[CH:5]=[C:4](Cl)N=1.[C:10]1([O:16]C2C=CC=CC=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[NH:7]1[C:2]2[C:4](=[CH:15][CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:6]1.[C:10]1(=[O:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: Nc1nc(Cl)cc(=O)[nH]1
Reactant: c1ccc(Oc2ccccc2)cc1
Product: O=C1CCCCC1
Product: c1ccc2[nH]ccc2c1

Procedure:
The synthesis of target compounds commenced from commercially available 2-amino-6-chloropyrimidin-4(3H)-one (1) using a method reported by Taylor et al1 to obtain 2 in 46% yield (Scheme 5). A thermal Fisher Indole-cyclization of 2 and cyclohexanone in diphenyl ether furnished the tricyclic scaffold 3. The partially saturated ring in 3 was oxidized using 10% Pd/C to provide 4 in 57% yield. Pivaloyl protection of 4 gave 5, and subsequent chlorination afforded the synthetic intermediate 6. Compound 6 was treated with various substituted anilines in isopropanal and three drops of concentrated HCl at reflux to provide the penultimate compounds 7-11 in yields of 37 to 80%. The pivaloyl group in 7-11 was removed by a basic hydrolysis of the 2-amide linkage in these compounds using 1N NaOH to give the desired target compounds—AAG103-AAG107 in yields ranging from 64-93%. AAG107 was also synthesized by treating 6 with 3-methoxy-N-methyl aniline, in n-butanol and three drops of conc. HCl at reflux, to afford 16 in a yield of 53%
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:11])([CH3:10])[C@@H:4]([C:6]([O:8][CH3:9])=[O:7])[NH2:5].N1C=CC=CC=1.[C:18](Cl)(Cl)=[O:19].Cl>C(Cl)Cl>[CH3:2][C:3]([CH3:11])([CH3:10])[C@@H:4]([C:6]([O:8][CH3:9])=[O:7])[N:5]=[C:18]=[O:19]
Reactant: COC(=O)[C@@H](N)C(C)(C)C
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@@H](N=C=O)C(C)(C)C
Reaction time: 1 h
Yield: 74 %

Procedure:
A solution of methyl 3-methyl-L-valinate hydrochloride (10.0 g, 54.9 mmol) and pyridine (22.3 mL, 276 mmol) in methylenechloride (300 mL) was cooled in an ice bath under nitrogen. Phosgene (20% in toluene, 41.1 mL, 83.0 mmol) was added dropwise over 0.5 h using an addition funnel. The resulting mixture was stirred 1 h then poured into cold 1M hydrochloric acid and extracted with methylenechloride (3×100 mL). The combined organic extracts were washed with brine, dried with anhydrous magnesium sulfate, filtered and concentrated. Flash column chromatography eluting with hexane/ethyl acetate 90/10 gave methyl 3-methyl-N-(oxomethylene)-L-valinate as an orange oil, 6.99 g (74% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19]Br>>[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Reactant: BrCc1ccccc1Br
Product: O=[N+]([O-])c1cc(OCc2ccccc2Br)ccc1Cl

Procedure:
A solution of 4-chloro-3-nitro-phenol was reacted with 1-Bromo-2-bromomethyl-benzene using the conditions described in Example 10C to provide 4-(2-Bromo-benzyloxy)-1-chloro-2-nitro-benzene which was treated sequentially using the procedures from Examples 10D and 10E to provide the title product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:15]([CH3:16])=[N:14][CH:13]=[CH:12][N:11]3[C:17]=2[C:18]2[CH:23]=[CH:22][N:21]=[C:20](S(C)(=O)=O)[N:19]=2)=[CH:4][CH:3]=1.[CH:28]1([NH2:31])[CH2:30][CH2:29]1>C(#N)C>[CH:28]1([NH:31][C:20]2[N:19]=[C:18]([C:17]3[N:11]4[CH:12]=[CH:13][N:14]=[C:15]([CH3:16])[C:10]4=[N:9][C:8]=3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH:23]=[CH:22][N:21]=2)[CH2:30][CH2:29]1
Reactant: NC1CC1
Reactant: Cc1nccn2c(-c3ccnc(S(C)(=O)=O)n3)c(-c3ccc(F)cc3)nc12
Solvent: CC#N
Product: Cc1nccn2c(-c3ccnc(NC4CC4)n3)c(-c3ccc(F)cc3)nc12
Temperature: 80 °C
Reaction time: 16 h
Yield: 82.8 %

Procedure:
To a mixture of 2-(4-fluorophenyl)-3-(2-methanesulfonylpyrimidin-4-yl)-8-methylimidazo[1,2-a]pyrazine (Example #G.1; 3.66 g, 9.55 mmol) in ACN (70 mL) was added cyclopropylamine (3.31 mL, 47.7 mmol). The mixture was heated to about 80° C. After about 16 h, the mixture was treated with additional cyclopropylamine (3.0 mL, 43 mmol) and heated at about 80° C. for about another 4 h. The mixture was cooled to ambient temperature and filtered. The resulting solid was washed with ACN and dried to yield the title compound as a white solid (2.85 g, 83%): LC/MS (Table 1, Method b) Rt=2.0 min; MS m/z: 361.2 (M+H)+.
Reaction SMILES: COC1C=CC(C(N(C)C2C=C(C=CC=2)CN[C:15]2[C:24]3[C:19](=[C:20]([C:25]([NH2:27])=[O:26])[CH:21]=[CH:22][CH:23]=3)[N:18]=[CH:17][N:16]=2)=O)=CC=1.[NH2:34][C:35]1[CH:36]=[CH:37][C:38]([CH3:43])=[C:39]([CH:42]=1)[C:40]#[N:41].[CH3:44][O:45][C:46]1[CH:54]=[CH:53][C:49]([C:50](O)=[O:51])=[CH:48][CH:47]=1>>[CH3:44][O:45][C:46]1[CH:54]=[CH:53][C:49]([C:50]([NH:34][C:35]2[CH:36]=[CH:37][C:38]([CH3:43])=[C:39]([CH:42]=2)[CH2:40][NH:41][C:15]2[C:24]3[C:19](=[C:20]([C:25]([NH2:27])=[O:26])[CH:21]=[CH:22][CH:23]=3)[N:18]=[CH:17][N:16]=2)=[O:51])=[CH:48][CH:47]=1
Reactant: COc1ccc(C(=O)O)cc1
Reactant: Cc1ccc(N)cc1C#N
Reactant: COc1ccc(C(=O)N(C)c2cccc(CNc3ncnc4c(C(N)=O)cccc34)c2)cc1
Product: COc1ccc(C(=O)Nc2ccc(C)c(CNc3ncnc4c(C(N)=O)cccc34)c2)cc1

Procedure:
4-[5-(4-Methoxy-benzoylamino)-2-methyl-benzylamino]-quinazoline-8-carboxylic acid amide was prepared according to example 4-{3-[(4-Methoxy-benzoyl)-methyl-amino]-benzylamino}-quinazoline-8-carboxylic acid amide, starting from 5-Amino-2-methyl-benzonitrile and 4-methoxy-benzoic acid:
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.Br[CH2:19][C:20](=[CH2:24])[C:21]([OH:23])=[O:22].[In].Cl>C1COCC1.O.C(OCC)(=O)C>[Cl:17][C:16]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]([OH:14])([C:10]([F:13])([F:11])[F:12])[CH2:24][C:20](=[CH2:19])[C:21]([OH:23])=[O:22])=[N:6][C:5]=2[CH:15]=1
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Reactant: C=C(CBr)C(=O)O
Agent: Cl
Agent: [In]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: C=C(CC(O)(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F)C(=O)O

Procedure:
1-(5,6-Dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (0.30 g; 1.05 mmol), 2-(bromomethyl)acrylic acid (1.80 g; 10.9 mmol) and indium (1.23 g; 10.7 mmol) were suspended in THF (10 mL) and 0.02 M HCl (15 mL) and stirred vigorously over 18 hours. The reaction mixture was then diluted with water (60 mL) and ethyl acetate (40 mL), the layers were separated and the aqueous layer was extracted with ethyl acetate (3×20 mL). The combined extracts were washed with brine (50 mL) and dried over Na2SO4 to yield a crude material. The crude material was purified by column chromatography (SiO2; 50% ethyl acetate/hexanes) to yield the title compound as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][C:11](O)([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:10]=[C:9]2[C:19]([C:22]2[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:29])([CH3:21])[CH3:20])=[C:4]([F:30])[CH:3]=1.C(O)(C(F)(F)F)=O.[OH-].[Na+]>CCO.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:10]=[C:9]2[C:19]([C:22]2[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:29])([CH3:20])[CH3:21])=[C:4]([F:30])[CH:3]=1
Reactant: CCOC(=O)C1(O)CN(c2ccc(Br)cc2F)C(C(C)(C)c2c(Cl)cccc2Cl)=N1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cn(-c2ccc(Br)cc2F)c(C(C)(C)c2c(Cl)cccc2Cl)n1
Temperature: 95 °C
Reaction time: 2.5 h
Yield: 87.6 %

Procedure:
To a mixture of ethyl 1-(4-bromo-2-fluorophenyl)-2-(2-(2,6-dichlorophenyl)propan-2-yl)-4-hydroxy-4,5-dihydro-1H-imidazole-4-carboxylate (38 g, 73 mmol) in EtOH (200 mL) was added TFA (25.0 g, 220 mmol). The mixture was subsequently heated to 95° C. HPLC analysis after 2.5 hours showed <1% of alcohol intermediate remaining The mixture was diluted with 300 mL of CH2Cl2 and cooled to approximately 5° C. with an ice bath. The mixture was neutralized with 1N NaOH (120 mL) and the organic layer was separated. The aqueous layer was extracted with CH2Cl2 (2×100 mL). The combined organic layers were concentrated on a rotary evaporator to give crude material. Recrystallization in EtOH (5 mL/1 g) provided 32 g of ethyl 1-(4-bromo-2-fluorophenyl)-2-(2-(2,6-dichlorophenyl)propan-2-yl)-1H-imidazole-4-carboxylate as an off-white solid (86% yield). 1H-NMR (DMSO-d6, 400 MHz) δ 7.92 (s, 1H), 7.16 (d, 1H, J=8.0 Hz), 7.22 (m, 3H), 7.11 (m, 1H), 7.04 (t, 1H, J=12.0 Hz), 4.25 (q, 2H, J=8.0 Hz), 1.94 (s, 6H), 1.27 (t, 3H, J=8.0 Hz); MS m/e 502.68 (M+H+); HPLC (XBridge 5μ C18 4.6×50 mm, 4 mL/min, Solvent A: 10% MeOH/water with 0.2% H3PO4, Solvent B: 90% MeOH/water with 0.2% H3PO4, gradient with 0-100% B over 4 minutes): 3.87 minutes.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9]2[CH:28]=[CH:27][CH:26]=[CH:25][C:10]=2[C:11]([NH:13][O:14][CH2:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=2)=[O:12])=[CH:3][CH:2]=1.Cl.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.O>CN(C=O)C>[N:30]1([C:20]([C:19]2[CH:18]=[CH:17][C:16]([CH2:15][O:14][NH:13][C:11](=[O:12])[C:10]3[CH:25]=[CH:26][CH:27]=[CH:28][C:9]=3[NH:8][CH2:7][C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)=[CH:24][CH:23]=2)=[O:21])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: O=C(O)c1ccc(CONC(=O)c2ccccc2NCc2ccncc2)cc1
Reactant: C1COCCN1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NOCc1ccc(C(=O)N2CCOCC2)cc1)c1ccccc1NCc1ccncc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirred mixture of 4-{2-[(pyridin-4-ylmethyl)-amino]-benzoylaminooxymethyl}-benzoic acid (see example 404, 220 mg) in DMF (3 ml) was added N,N′-carbonyldiimidazole (99 mg). The mixture was stirred at room temperature for 45 minutes and morpholine hydrochloride (79 mg) was added. The reaction mixture was stirred at room temperature for 18 hours and poured into water. The product was extracted several times with EtOAc and the combined organic layers were washed with water and brine, dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc as eluent) and gave the title compound. 13C-NMR (DMSO-d6) δ 168.7, 167.2, 149.5, 149.0, 148.3, 137.4, 135.3, 132.5, 128.8, 128.1, 127.0, 122.0, 114.8, 113.3, 111.5, 76.4, 66.0, 44.7
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:12]=1[C:13]([OH:15])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[O:43]=[C:44]([N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1)[CH2:45][NH:46][C:47]([C:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[CH:51][CH:50]=1)=[O:48]>CN(C=O)C.O>[F:10][C:11]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:12]=1[C:13]([N:64]1[CH2:63][CH2:62][N:61]([C:44](=[O:43])[CH2:45][NH:46][C:47]([C:49]2[CH:54]=[CH:53][C:52]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)=[CH:51][CH:50]=2)=[O:48])[CH2:66][CH2:65]1)=[O:15]
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1cc(F)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(F)ccc2F)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.5 %

Procedure:
DIPEA (149.8 mg, 1.15 mmol) was added to a stirred solution of 2,5-difluoro-benzoic acid (40.7 mg, 0.26 mmol) in DMF (3 mL), HOBt (38.2 mg, 0.28 mmol) and EDCI.HCl (123.4 mg, 0.64 mmol) at room temperature. After 2 minutes biphenyl-4-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide (100 mg, 0.31 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added, and the resulting precipitate was filtered. The residue was purified by column chromatography (using 60-120 mesh silica gel and 50% EtOAc in hexane as eluent) to afford 56 mg (46.9% yield) of biphenyl-4-carboxylicacid {2-[4-(2,5-difluoro-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide, LC-MS purity: 97.42%, 1H NMR: (CDCl3) δ 7.98-7.88 (d, 2H), 7.74-7.58 (dd, 4H), 7.54-7.34 (m, 3H), 7.2-7.08 (s, 3H), 4.4-4.26 (d, 2H), 3.94-3.78 (m, 3H), 3.76-3.56 (d, 3H), 3.54-3.38 (d, 3H).
Reaction SMILES: B(O)(O)O.[OH:5]O.S(=O)(=O)(O)O.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][C:19]1[CH:26]=[CH:25][C:22](C=O)=[CH:21][CH:20]=1>O1CCCC1>[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][C:19]1[CH:26]=[CH:25][C:22]([OH:5])=[CH:21][CH:20]=1
Reactant: O=Cc1ccc(Oc2ccccn2)cc1
Reactant: OO
Agent: O=S(=O)(O)O
Agent: OB(O)O
Solvent: C1CCOC1
Product: Oc1ccc(Oc2ccccn2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 9.6 %

Procedure:
Following Scheme I: To a 100 mL round-bottomed flask equipped with condenser and N2 inlet were added 3.1 g (50.2 mmol) boric acid, 10 mL tetrahydrofuran, 2.3 mL (20 mmol) 30% hydrogen peroxide, and 1 mL concentrated sulfuric acid. To the reaction was added a solution of 2.0 g (10 mmol) 4-(pyridin-2-yloxy)-benzaldehyde in 10 mL tetrahydrofuran dropwise over 5 minutes. The reaction was stirred 3 hr at 60° C., cooled, filtered, and the filtrate neutralized with saturated aqueous sodium bicarbonate solution. The mixture was extracted into 2× ethyl acetate, and the organic layer washed with brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using hexane/ethyl acetate as eluant to afford 180 mg (9.6%) of the product as a solid.
Reaction SMILES: C[O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O.[CH2:22]([C:24]1[S:28][C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:26][C:25]=1[CH2:35]O)[CH3:23].C(O)(C(F)(F)F)=O.[OH-].[Na+]>O>[NH2:5][C@@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:35][C:25]2[N:26]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[S:28][C:24]=2[CH2:22][CH3:23])=[CH:18][CH:19]=1)[C:3]([OH:2])=[O:21]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: CCc1sc(-c2ccccc2)nc1CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCc1sc(-c2ccccc2)nc1COc1ccc(C[C@H](N)C(=O)O)cc1
Yield: 92 %

Procedure:
Intermediate 62 was prepared as described above for the preparation of intermediate 52. From 3.27 g of N-(Boc)-L-Tyrosine methyl ester and 2.43 g of Intermediate 9C was prepared 5.07 g of BOC-protected intermediate methyl ester (92% yield; 1H NMR (CDCl3, 300 MHz) δ7.89-7.86 (m, 2H), 7.42-7.38 (m, 3H), 7.01 (d, 2H, J=6.3), 6.94 (d, 2H, J=6.3), 5.11 (s, 2H), 4.94 (d, 1H, J=6.0), 4.53-4.50 (m, 1H), 3.68 (s, 3H), 3.02-2.98 (m, 2H), 2.90 (q, 2H, J=5.7), 1.39 (s, 9H), 1.30 (t, 3H, J=5.7); From 5.05 g of BOC-protected ester intermediate was prepared the crude TFA salt of intermediate 62 as in example 52. The TFA salt was suspended into water and the pH adjusted to ˜7.0 with 10% NaOH. The resulting solids were filtered and dried to yield 4.28 g of intermediate 62; 1H NMR (DMSO-d6, 400 MHz) δ7.85-7.83 (m, 2H), 7.45-7.43 (m, 3H), 7.16-7.14 (m, 2H), 6.96-6.94 (m, 2H), 5.07 (s, 2H), 3.53 (s, 2H), 3.05-3.02 (m, 1H), 2.91-2.81(m, 4H), 1.21 (t, 3H, J=7.4); low resolution MS (ES+)m/e 382.94 (MH+); TLC Rf=0.33 (4/1, DCM/MeOH).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]#[CH:5].Br[CH2:7][C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[O:12][C:11]2[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=2[CH:9]=1.O>C1C=CC=CC=1.CO>[CH:22]1[C:10]2[CH:9]=[C:8]([CH2:7][N:2]([CH3:1])[CH2:3][C:4]#[CH:5])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[O:12][C:11]=2[CH:19]=[CH:20][CH:21]=1
Reactant: BrCC1=Cc2ccccc2Oc2ccccc21
Reactant: C#CCNC
Solvent: O
Solvent: c1ccccc1
Solvent: CO
Product: C#CCN(C)CC1=Cc2ccccc2Oc2ccccc21
Reaction time: 0.5 h
Yield: 77 %

Procedure:
Methylpropargylamine (4.5 g, 65 mmol) is dissolved in benzene (75 ml) and methanol (25 ml). At 40° C. a solution of 10-bromomethyldibenz[b,f]oxepine (7.0 g, 25 mmol) in benzene (25 ml) is added dropwise in the course of half an hour. When the addition is complete, the mixture is stirred for a further half hour at 40°-50° C., poured into water, washed three times with water and then extracted with 5% methanesulfonic acid. The acidic aqueous phase is rendered basic with concentrated ammonia and extracted with diethyl ether. The ethereal phase is dried over sodium sulfate and concentrated by evaporation. Crystallisation of the residue from petroleum ether yields N-(dibenz[b,f]oxepin-10-ylmethyl-N-methyl-N-prop-2-ynylamine alias 10-(N-propargyl-N-methyl-amino)methyldibenz[b,f]oxepine (5.3 g, 77%). Melting point: 66°-67° C.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5].[NH2:13][CH2:14][CH2:15][N:16]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(N(CC)CC)C.[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]\[C:33]([OH:35])=[O:34]>C(#N)C.CO>[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]\[C:33]([OH:35])=[O:34].[C:7]1([S:4]([CH2:3][CH2:2][NH:13][CH2:14][CH2:15][N:16]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:6])=[O:5])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCCN1CCCCCC1
Reactant: O=S(=O)(CCCl)c1ccccc1
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CC#N
Product: O=S(=O)(CCNCCN1CCCCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.7 %

Procedure:
A mixture of 20.06 g (0.098 mole) of [(2-chloroethyl)sulfonyl]benzene 15.44 g (0.109 mole) of N-(2-aminoethyl)homopiperidine, and 15.0 g (0.149 mole) of triethylamine in 800 ml of acetonitrile was stirred at room temperature for 18 hr. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and water. The methylene chloride solution was dried over magnesuim sulfate, and the solvent waas removed in vacuo to give an oil. This was dissolved in methanol, and the solution was treated with a solution of 2 equivalents of maleic acid (25.52 g, 0.22 mole) in methanol. A white solid precipitated at room temperature to give 32.3 g (60.7%) of title compound as a white solid; mp 144°-146° C.