Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[N:4][N:5]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[Cu][C:28]#[N:29].[OH-].[NH4+]>CN(C)C=O.C(OCC)(=O)C.O>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][N:5]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[C:2]([C:28]#[N:29])[C:3]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[N:4]1
Reactant: N#C[Cu]
Reactant: Fc1ccccc1Cn1nc(-c2ccccn2)c(Br)c1-c1ccccn1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1c(-c2ccccn2)nn(Cc2ccccc2F)c1-c1ccccn1
Temperature: 150 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
To a suspension of 2,2′-(4-bromo-1-(2-fluorobenzyl)-1H-pyrazole-3,5-diyl)dipyridine (200 mg, 0.489 mmol) in N,N-dimethylformamide (3.4 mL) was added copper (I) cyanide (253 mg, 2.69 mmol). The suspension was stirred at 150° C. for 2 h, at which point LC/MS indicated a complete reaction. The solution was cooled to 23° C. and 5 mL of water, 5 mL of ammonium hydroxide, and 5 mL of ethyl acetate were added. The blue heterogeneous mixture was stirred rapidly for 40 min, and then further diluted with ethyl acetate (150 mL) and water (75 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×75 mL). The organics were combined and washed with water (75 mL) and brine (75 mL), dried over magnesium sulfate, filtered, and the solvent was removed in vacuo to give the crude product as an oil. Purification by silica gel chromatography (hexanes/ethyl acetate) gave 1-(2-fluorobenzyl)-3,5-di(pyridin-2-yl)-1H-pyrazole-4-carbonitrile (161 mg, 0.453 mmol, 93% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.77-8.73 (m, 2H), 8.05-8.03 (m, 1H), 7.96-7.94 (m, 1H), 7.87 (dt, 1H), 7.78 (dt, 1H), 7.40-7.36 (m, 1H), 7.33-7.30 (m, 1H), 7.23-7.17 (m, 1H), 7.07-6.94 (m, 3H), 5.97 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[CH:23]1([CH2:26]O)[CH2:25][CH2:24]1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:26][CH:23]3[CH2:25][CH2:24]3)[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: OCC1CC1
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(-c3ccccc3)c12
Product: Clc1c(-c2ccccc2)nnc2c1c(-c1ccccc1)nn2CC1CC1

Procedure:
Compound IIi was synthesized from 4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine and cyclopropylmethanol following the general procedure for the Mitsunobu reaction as described above.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[NH:15][C:16](=O)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([O-])=O.C(O)C>C(O)(=O)C>[CH2:17]([C:16]1[NH:1][C:4]2[CH:5]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:12]=[CH:13][C:14]=2[N:15]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1ccc(NC(=O)Cc2ccccc2)c([N+](=O)[O-])c1
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1ccc2nc(Cc3ccccc3)[nH]c2c1
Reaction time: 40 h
Yield: 74.8 %

Procedure:
A mixture of 3.60 g of ethyl 3-nitro-4-phenylacetylaminobenzoate, 47 ml of ethanol, 23 ml of acetic acid and 6.4 g of reduced iron was heat-refluxed for 4 hours. The solid material was separated through filtration, and the filtrate was concentrated. To the residue were added 50 ml of ethanol and 5 g of 35% hydrochloric acid. The mixture was stirred for 40 hours while being heat-refluxed. The reaction solution was neutralized with sodium hydrogencarbonate, and was extracted with chloroform. The organic layer was concentrated under reduced pressure, and was purified through silica-gel column chromatography to give 2.30 g of 2-benzyl-5-ethoxycarbonylbenzimidazole (150).
Reaction SMILES: [C:1]([C:4]1[CH:20]=[CH:19][C:7]2[C:8](=[O:18])[C:9]3[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:10]=3[CH2:11][CH2:12][C:6]=2[CH:5]=1)([OH:3])=[O:2].[OH-].[K+].[CH:23](Br)([CH3:25])[CH3:24].Cl>C(O)C.O>[C:1]([C:4]1[CH:20]=[CH:19][C:7]2[C:8](=[O:18])[C:9]3[CH:16]=[C:15]([O:17][CH:23]([CH3:25])[CH3:24])[CH:14]=[CH:13][C:10]=3[CH2:11][CH2:12][C:6]=2[CH:5]=1)([OH:3])=[O:2]
Reactant: CC(C)Br
Reactant: O=C(O)c1ccc2c(c1)CCc1ccc(O)cc1C2=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)Oc1ccc2c(c1)C(=O)c1ccc(C(=O)O)cc1CC2

Procedure:
0.82 G. of 2-carboxy-7-hydroxy-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cycloheptene was dissolved in 30 ml of ethanol and a solution of 1.0 g of potassium hydroxide in 5 ml of water was added, followed by 2.0 ml of isopropyl bromide. The reaction was refluxed for 3 hours, then diluted with water and acidified with dilute hydrochloric acid. The product was filtered off and recrystallized from aqueous dimethylformamide to give 2-carboxy-7-isopropoxy-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cycloheptene, m.p. 174°-177°. By substituting other alkylbromides or iodides such as ethyl bromide, m-propyl bromide, isobutyl bromide, n-amyl bromide, n-hexyl bromide and the like, the corresponding 2-carboxy-7-alkoxy-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cycloheptenes are obtained. The 8- and 9- alkoxy compounds are similarly prepared.
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](O)=[O:31])[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].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[F:70][C:71]1[CH:77]=[CH:76][C:74]([NH2:75])=[CH:73][CH:72]=1>CN(C=O)C>[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]([NH:75][C:74]2[CH:76]=[CH:77][C:71]([F:70])=[CH:72][CH:73]=2)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:2]
Reactant: Nc1ccc(F)cc1
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)Nc3ccc(F)cc3)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.1 %

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 (31.3 mg, 0.06 mmol) in DMF (0.5 mL) were added HBTU (27.3 mg, 0.072 mmol), triethylamine (16.9 uL, 0.12 mmol) and 4-fluoroaniline (8.64 uL, 0.08 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (10 mg, 27%). LC-MS m/z 615 (M+H)+.
Reaction SMILES: C([NH:4][C@@H:5]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][C:8]=1[F:17])[CH3:6])(=O)C.[ClH:18]>>[ClH:18].[NH2:4][C@@H:5]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[F:17])[CH3:6]
Reactant: COC(=O)c1ccc([C@@H](C)NC(C)=O)c(F)c1
Agent: Cl
Product: C[C@@H](N)c1ccc(C(=O)O)cc1F

Procedure:
Methyl (R)-4-(1-acetamidoethyl)-3-fluorobenzoate (690 mg) was added to 2N hydrochloric acid (15 ml), and the mixture was refluxed for 3 hours. After the reaction, the reaction mixture was evaporated under reduced pressure, further boiled with toluene, and dried to give (R)-4-(1-aminoethyl)-3-fluorobenzoic acid hydrochloride (620 mg).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].S(Cl)(Cl)=O.[CH3:18]O>>[NH2:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([O:10][CH3:18])=[O:9])(=[O:3])=[O:4]
Reactant: CO
Reactant: NS(=O)(=O)c1cccc(C(=O)O)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(S(N)(=O)=O)c1
Yield: 73 %

Procedure:
To a solution of 3-(aminosulfonyl)benzoic acid (22 g, 0.109 mol) in MeOH (250 ml) is added thionyl chloride (25 ml, 0.328 mol) and the mixture is refluxed for 16 h. The solvent is removed and the residue is diluted with EtOAc (200 ml), washed with a 10% solution of sodium bicarbonate, water and brine. The solvent was removed under vacuum to afford 17 g (73%) of the title compound as a solid. 1H NMR (DMSO-d6) δ 8.39 (t, J=1.5 Hz, 1H), 8.16-8.13 (m, 1H), 8.09-8.05 (m, 1H), 7.76 (t, J=7.9 Hz, 1H), 7.53 (s, 2H), 3.90 (s, 3H). HPLC (max plot) 99%; Rt 1.49 min. LC/MS: (ES+):215.9, (ES−):214.1.
Reaction SMILES: Cl[Si](C)(C)C.Br[C:7]([F:14])([F:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9].N1([CH2:24][NH:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)C2C=CC=CC=2N=N1>O1CCCC1.[Zn]>[CH2:11]([O:10][C:8](=[O:9])[C:7]([F:14])([F:13])[CH2:24][NH:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:12]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: c1ccc(CCNCn2nnc3ccccc32)cc1
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)CNCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 11.1 %

Procedure:
To a mixture of 3.63 g (0.056 g-atom) of zinc powder (−325 mesh) and 60 mL of anhydrous tetrahydrofuran was added 5.3 mL (0.042 mole) of chlorotrimethylsilane in one portion. After stirring for 20 minutes, a solution of 5.4 mL (0.042 mole) of ethyl bromodifluoroacetate in 5 mL of tetrahydrofuran was added dropwise at a rate to keep the internal temperature below 35 degrees. The mixture was stirred for 20 minutes and then cooled to −10 to 0 degrees. A solution of 7 g (0.028 mole) of benzotriazol-1-ylmethyl-phenethyl-amine in 30 mL of tetrahydrofuran was added dropwise at a rate to keep the internal temperature at −10 to 0 degrees. After 10 minutes the reaction mixture was warmed to room temperature and stirred for 3 hours at room temperature. The solution was cooled to −10 to 0 degrees and quenched by the addition of saturated aqueous sodium bicarbonate at a rate to maintain the internal temperature −10 to 0 degrees. Ether was added, the mixture was stirred for 15 minutes at room temperature and then filtered through Celite, washing with ether. The filtrate was extracted 3 times with ether. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Ether and hexane were added to the residue, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexane-ethyl acetate (gradient, 100:0-80:20) to give 0.8 g of 2,2-difluoro-3-phenethylamino-propionic acid ethyl ester as a oil.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:16]([C:17](O)=[O:18])[C:15]=3[C:23](O)=[O:24])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:27][CH:28]1[CH2:34][CH2:33][C:32](=[O:35])[NH:31][C:29]1=[O:30]>N1C=CC=CC=1>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:16]4[C:15]=3[C:23](=[O:24])[N:27]([CH:28]3[CH2:34][CH2:33][C:32](=[O:35])[NH:31][C:29]3=[O:30])[C:17]4=[O:18])=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cccc(Nc2ccc(C3CCCCC3)cc2)c1C(=O)O
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CCC(N2C(=O)c3cccc(Nc4ccc(C5CCCCC5)cc4)c3C2=O)C(=O)N1
Yield: 86 %

Procedure:
A mixture of 3-(4-cyclohexylphenylamino)phthalic acid (0.80 g, 2.4 mmol) and rac-α-aminoglutarimide hydrochloride (0.39 g, 2.4 mmol) in pyridine (10 mL) was heated to reflux for 16 hours. The mixture was cooled and evaporated under vacuum. The residue was dissolved in ethyl acetate (150 mL), washed with dilute aqueous HCl (2×100 mL) and water (2×100 mL), and evaporated. The residue was chromatographed in 1:1 hexanes-ethyl acetate, eluting 0.86 g of the product, in 86% yield: mp 219-221° C.; 1H NMR (DMSO-d6) δ 1.10-1.46 (m, 5H), 1.67-1.80 (m, 5H), 2.04-2.07 (m, 1H), 2.40-2.50 (m, 1H), 2.53-2.64 (m, 2H), 2.83-2.90 (m, 1H), 5.12 (dd, J=12.6 Hz, J=5.3 Hz, 1H), 7.19-7.24 (m, 5H), 7.35 (d, J=8.6 Hz, 1H), 7.58 (t, J=7.9 Hz, 1H), 8.34 (s, 1H), 11.14 (s, 1H); 13C NMR (DMSO-d6) δ 22.1, 25.6, 26.4, 31.0, 34.0, 43.2, 48.7, 111.3, 113.0, 119.0, 122.4, 127.6, 132.4, 136.2, 136.9, 143.3, 143.7, 167.1, 168.4, 170.0, 172.8; Anal. calcd for C25H25N3O4: C, 69.59; H, 5.84; N, 9.74. Found: C, 69.38; H, 5.85; N, 9.41.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([CH3:23])([CH3:22])[C:19]([OH:21])=[O:20])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[N:32]=[C:33]=[O:34].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[NH:32][C:33](=[O:34])[N:8]([CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18]([CH3:22])([CH3:23])[C:19]([OH:21])=[O:20])=[CH:15][CH:16]=1)[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: CCCCCCCNCCc1ccc(NC(C)(C)C(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCN(CCc1ccc(NC(C)(C)C(=O)O)cc1)C(=O)Nc1ccc(F)cc1F
Yield: 7.7 %

Procedure:
A solution of of 2-[4-(2-heptylamino-ethyl)-phenylamino]-2-methyl-propionic acid (75 mg, 234 μmol), 2,4-difluorophenyl isocyanate (33 μL, 281 μmol), N,N-diisopropylethylamine (82 μL, 468 μmol) and methylene chloride (0.5 mL) was stirred at ambient temperature for 18 h, concentrated under reduced pressure and purified by flash column chromatography (3% methanol/chloroform) to provide 8.6 mg (8%) of 2-(4-{2-[3-(2,4-difluoro-phenyl)-1-heptyl-ureido]-ethyl}-phenylamino)-2-methyl-propionic acid as a white foam.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:9]1)=[O:7].[F:18][C:19]([Si](C)(C)C)([F:21])[F:20].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1.C(OCC)(=O)C>[F:18][C:19]([F:21])([F:20])[C:6]([C@H:8]1[CH2:9][CH2:10][C@H:11]([C:14]([O:16][CH3:17])=[O:15])[CH2:12][CH2:13]1)([OH:7])[C:2]1[S:1][CH:5]=[CH:4][N:3]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)c2nccs2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](C(O)(c2nccs2)C(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To the solution of methyl trans-4-(thiazole-2-carbonyl)cyclohexanecarboxylate (1.1 g, 4.34 mmol) in THF (20 mL) at 0° C. was added trifluoromethyltrimethylsilane (1.286 mL, 8.68 mmol). Tetrabutylammonium fluoride trihydrate (1M in THF, 17.37 mL, 17.37 mmol) was added slowly maintaining the temperature at 0° C. The reaction was allowed to stir for 1 hr and then water (30 mL) and ethyl acetate (30 mL) was added to quench the reaction. The organic layer was removed, washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-20% ethyl acetate in hexane) to afford methyl trans-4-[2,2,2-trifluoro-1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]cyclohexanecarboxylate. MS ESI calcd. for C13H17F3NO3S [M+H]+ 324. found 324. 1H NMR (500 MHz, CDCl3) δ 7.79 (d, J=3.2 Hz, 1H), 7.49 (d, J=3.2 Hz, 1H), 4.77 (s, 1H), 3.65 (s, 3H), 2.40 (m, 1H), 2.30-1.90 (m, 3H), 1.50-1.20 (m, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][CH:10]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([OH:35])=[O:34])=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:38][OH:39].C([O-])(O)=O.[Na+]>>[OH:39]/[N:38]=[C:8](/[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1)\[CH2:9][CH:10]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([OH:35])=[O:34])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([F:19])([F:20])[F:18]
Reactant: NO
Reactant: Cc1cc(C(=O)CC(c2ccc(-c3ccc(C(=O)O)cc3)cc2)c2ccccc2C(F)(F)F)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(CC(c2ccc(-c3ccc(C(=O)O)cc3)cc2)c2ccccc2C(F)(F)F)=N/O)ccn1

Procedure:
In analogy to example 132, step 6, from 4′-[3-(2-methyl-pyridin-4-yl)-3-oxo-1-(2-trifluoromethyl-phenyl)-propyl]-biphenyl-4-carboxylic acid and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a light yellow solid, MS (ESI+): m/z=505.173 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([Cl:12])[CH:6]=1.[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][Br:14])=[C:7]([Cl:12])[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Nc1ccc(C)c(Cl)c1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)Nc1ccc(CBr)c(Cl)c1
Reaction time: 20 h
Yield: 55.5 %

Procedure:
To a stirred solution of 10.9 grams (0.055 mole) of methyl(3-chloro-4-methylphenyl)carbamate in 110 ml of carbon tetrachloride, under an argon atmosphere, was added 9.7 grams (0.055 mole) of N-bromosuccinimide. The reaction mixture was irradiated with a 250 watt brooder lamp, placed at such a distance as to cause a gentle reflux. The reflux was continued for 20 hours. The reaction mixture was cooled and a solid collected by filtration. The solid was slurried with water and the insoluble material collected by filtration. The filter cake was dried to give 8.5 grams of methyl(4-bromomethyl-3-chlorophenyl)carbamate; m.p. 128°-131° C.
Reaction SMILES: COC[O:4][C:5]1[C:17]([CH2:18][CH2:19][CH3:20])=[C:16]([O:21][CH3:22])[CH:15]=[CH:14][C:6]=1[C:7]([N:9]1[CH2:13][CH2:12][S:11][CH2:10]1)=[O:8].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.O>[OH:4][C:5]1[C:17]([CH2:18][CH2:19][CH3:20])=[C:16]([O:21][CH3:22])[CH:15]=[CH:14][C:6]=1[C:7]([N:9]1[CH2:13][CH2:12][S:11][CH2:10]1)=[O:8]
Reactant: CCCc1c(OC)ccc(C(=O)N2CCSC2)c1OCOC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CCCc1c(OC)ccc(C(=O)N2CCSC2)c1O
Temperature: 60 °C
Reaction time: 23 h
Yield: 93.8 %

Procedure:
The N-(2-methoxymethoxy-3-n-propyl-4-methoxybenzoyl)thiazolidine (9.0 g) was dissolved in a solution of methanol (100 ml)-water (20 ml). To the solution was added p-toluenesulfonic acid (2 spoonfuls in spatula) and the mixture was agitated at 60° C. for 23 hours. The reaction mixture was concentrated in evacuated atomosphere to about one fourth of the original volume. Saturated aqueous solution of sodium bicarbonate was added to the concentrate, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated in evacuated atomosphere. The residue was subjected to column chromatography using silica gel, and there was obtained N-(2-hydroxy-3-n-propyl-4-methoxybenzoyl)thiazolidine (7.3 g) from fractions eluted with n-hexane-ethyl acetate (5:1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH3:15]>>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH2:15])=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Clc1cc(-c2ccccc2)c(Cl)nn1
Reactant: N
Product: Nc1cc(-c2ccccc2)c(Cl)nn1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
36.5 g (162 mmol) 3,6-Dichloro-4-phenyl-pyridazine were suspended in 1000 mL aqueous ammonia solution (25%) and stirred in an autoclave for 18 hours at 100° C. The reaction mixture was transferred into a separating funnel and the phases were separated. The aqueous phase was washed twice with dichloromethane. The combined organic phases were washed twice with water, the solvent was evaporated and the crude residue (two regioisomers, 6-chloro-5-phenyl-pyridazin-3-yl-amine and 6-chloro-4-phenyl-pyridazin-3-yl-amine 20.2 g=60.6%) was used without further purification in the next step.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[C:38]3[C:33](=[CH:34][C:35]([Cl:39])=[CH:36][CH:37]=3)[N:32]=[CH:31][CH:30]=2)=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19]>CS(C)=O>[C:18]([C@@H:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][C:29]2[C:38]3[C:33](=[CH:34][C:35]([Cl:39])=[CH:36][CH:37]=3)[N:32]=[CH:31][CH:30]=2)=[CH:26][CH:27]=1)([OH:20])=[O:19]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: N[C@@H](Cc1ccc(Oc2ccnc3cc(Cl)ccc23)cc1)C(=O)O
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccc(Oc2ccnc3cc(Cl)ccc23)cc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 109c, 2,6-dichloroquinoline-3-carboxylic acid is reacted with (S)-2-amino-3-[4-(7-chloro-quinolin-4-yloxy)-phenyl]-propionic acid (prepared by analogy to Example 109a,b) in DMSO to provide the title compound in good, yield.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.[C:14](N1C=CN=C1)([N:16]1C=CN=C1)=[S:15].C(N(CC)CC)C.N>C(Cl)(Cl)Cl.O.CCCCCC.CO>[CH3:11][O:10][C:8]([C:7]1[CH:6]=[CH:5][C:4]([CH2:3][NH:2][C:14]([NH2:16])=[S:15])=[CH:13][CH:12]=1)=[O:9]
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: Cl
Agent: N
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CNC(N)=S)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.2 %

Procedure:
Under an argon atmosphere, to a suspension of methyl 4-aminomethylbenzoate hydrochloride (170.0 g, 0.843 mol) in chloroform (850 ml, 5.0 v/w) were successively added 1,1′-thiocarbonyldiimidazole (purity 90%, 166.0 g, 0.843 mol) and triethylamine (123 ml, 0.885 mol). After stirring at room temperature for 3 hr, 28% aqueous ammonia (570 ml, 8.43 mol) and methanol (170 ml, 1.0 v/w) were added and the mixture was stirred overnight. n-Hexane (1700 ml, 10.0 v/w) and water (850 ml, 5.0 v/w) were successively added to the reaction mixture and the mixture was stirred at room temperature for 3 hrs. The precipitated crystals were collected by filtration, washed successively with n-hexane (500 ml) and water (500 ml) and dried in vacuo to give the title compound (172.5 g, yield 91.3%) as a colorless solid.
Reaction SMILES: N(C[C@@H](C1C=CC(OCC2C=CC=CC=2)=C2C=1C=CC(=O)N2)O)=[N+]=[N-].[Si]([O:33][CH2:34][C:35]1[CH:36]=[C:37]([C@@H:42]([OH:76])[CH2:43][NH:44][CH2:45][C:46]2[CH:47]=[C:48]([CH:73]=[CH:74][CH:75]=2)[C:49]([NH:51][CH2:52][C:53]2[C:54]([NH:66][CH:67]3[CH2:72][CH2:71][O:70][CH2:69][CH2:68]3)=[C:55]3[CH:63]=[N:62][N:61]([CH2:64][CH3:65])[C:56]3=[N:57][C:58]=2[CH2:59][CH3:60])=[O:50])[CH:38]=[CH:39][C:40]=1[OH:41])(C(C)(C)C)(C)C>N1C=CC=CC=1>[CH2:64]([N:61]1[C:56]2=[N:57][C:58]([CH2:59][CH3:60])=[C:53]([CH2:52][NH:51][C:49](=[O:50])[C:48]3[CH:73]=[CH:74][CH:75]=[C:46]([CH2:45][NH:44][CH2:43][C@H:42]([OH:76])[C:37]4[CH:38]=[CH:39][C:40]([OH:41])=[C:35]([CH2:34][OH:33])[CH:36]=4)[CH:47]=3)[C:54]([NH:66][CH:67]3[CH2:68][CH2:69][O:70][CH2:71][CH2:72]3)=[C:55]2[CH:63]=[N:62]1)[CH3:65]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(CNC[C@H](O)c2ccc(O)c(CO[Si](C)(C)C(C)(C)C)c2)c1
Agent: [N-]=[N+]=NC[C@H](O)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Solvent: c1ccncc1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(CNC[C@H](O)c2ccc(O)c(CO)c2)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 3, using HF pyridine in place of TBAF and Intermediate 45 as a substrate.