Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1C(F)=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:9]1([NH:37][C:38]([NH:40][C:41](=[O:48])[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[S:39])[C@H:13]([CH2:14]O)[C@@H:12]([CH2:16][O:17][C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:11][CH2:10]1.N1C=CC=CC=1.F[C:56]([F:69])(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(Cl)Cl>[F:1][C:2]1[C:56]([F:69])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:10][O:11][C@H:12]([CH2:16][O:17][C:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:13]1[CH2:14][S:39][C:38]([NH:40][C:41](=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[N:37]2
Reactant: O=C(NC(=S)N[C@@]1(c2cccc(F)c2F)CO[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H]1CO)c1ccccc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(NC1=N[C@@]2(c3cccc(F)c3F)CO[C@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2CS1)c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
N-(((3S,4R,5S)-3-(2,3-difluorophenyl)-4-(hydroxymethyl)-5-((trityloxy)methyl)tetrahydrofuran-3-yl)carbamothioyl)benzamide, obtained in Preparation Example 1-(4), (19.06 g) was dissolved in DCM (75 mL). Pyridine (8.6 mL) was added, and the mixture cooled to 0° C. Trifluoromethanesulfonic anhydride (9.6 mL) was added dropwise and the reaction was allowed to stir at 0° C. After 90 min, the reaction was quenched by the careful addition of NaHCO3 (sat., aq., 250 mL) and extracted with EtOAc (3×250 mL). The combined organic extracts were dried over MgSO4, concentrated in vacuo and purified by silica gel column chromatography (0% to 30% EtOAc/hex) to obtain the title compound (14.52 g). 1H NMR (400 MHz, CDCl3) δ ppm 2.63-2.76 (m, 1H), 3.07-3.24 (m, 2H), 3.32-3.52 (m, 3H), 3.99-4.11 (m, 1H), 4.53-4.63 (m, 2H), 7.09-7.56 (m, 21H), 8.08-8.30 (m, 2H)
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([C:19](OC)=[O:20])[C:12](=[CH:17][CH:18]=2)[C:13](OC)=[O:14])[S:4][CH:3]=1.[BH4-].[Li+]>C1COCC1>[Br:1][C:2]1[CH:6]=[C:5]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][C:12]([CH2:13][OH:14])=[C:11]([CH2:19][OH:20])[CH:10]=2)[S:4][CH:3]=1
Reactant: COC(=O)c1ccc(OCc2cc(Br)cs2)cc1C(=O)OC
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(OCc2cc(Br)cs2)cc1CO
Temperature: 0 °C

Procedure:
27 g (76 mmol) of dimethyl 4-(3-bromo-5-thienylmethoxy)phthalate are dissolved in 200 mL of anhydrous THF. This solution is added dropwise to a suspension of 4 g (183 mmol) of lithium borohydride in 50 mL of THF. The reaction medium is refluxed for 24 h and then cooled and poured onto 200 g of ice. After extraction with ether and then chromatography on a column of silica (eluent: 5 heptane/5 ethyl acetate), the desired product is obtained in the form of a yellow oil (m=22.1 g; Y=88%).
Reaction SMILES: O[Li].O.O.[C:5]([O:9][C:10]([N:12]([CH3:54])[C@@H:13]([CH3:53])[C:14]([NH:16][C@H:17]1[CH2:23][O:22][C:21]2[C:24]([C:28](=[O:34])[N:29]([CH2:31][CH2:32][OH:33])[CH3:30])=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:35][C:36]2[C:45]([O:46][CH3:47])=[CH:44][CH:43]=[C:42]3[C:37]=2[CH:38]=[CH:39][C:40]([C:48]([O:50]C)=[O:49])=[CH:41]3)[C:18]1=[O:52])=[O:15])=[O:11])([CH3:8])([CH3:7])[CH3:6]>CO.C([O-])(O)=O.[Na+]>[C:5]([O:9][C:10]([N:12]([CH3:54])[C@@H:13]([CH3:53])[C:14]([NH:16][C@H:17]1[CH2:23][O:22][C:21]2[C:24]([C:28](=[O:34])[N:29]([CH2:31][CH2:32][OH:33])[CH3:30])=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:35][C:36]2[C:45]([O:46][CH3:47])=[CH:44][CH:43]=[C:42]3[C:37]=2[CH:38]=[CH:39][C:40]([C:48]([OH:50])=[O:49])=[CH:41]3)[C:18]1=[O:52])=[O:15])=[O:11])([CH3:7])([CH3:8])[CH3:6]
Reactant: COC(=O)c1ccc2c(CN3C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)COc4c(C(=O)N(C)CCO)cccc43)c(OC)ccc2c1
Agent: O=C([O-])O
Agent: [Li]O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc2cc(C(=O)O)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)COc2c(C(=O)N(C)CCO)cccc21
Temperature: 50 °C
Yield: 74.4 %

Procedure:
LiOH.H2O (7.15 mg, 170 μmol, Eq: 2.00) and H2O (200 μl) were added to a solution of methyl 5-(((S)-3-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-9-((2-hydroxyethyl)(methyl)carbamoyl)-4-oxo-3,4-dihydrobenzo[b][1,4]oxazepin-5(2H)-yl)methyl)-6-methoxy-2-naphthoate (59 mg, 85.2 μmol, Eq: 1.00) in MeOH (2 mL) and the mixture heated to 50° C. After 4 h an additional portion of LiOH.H2O (2 mg, 48 μmol, Eq. 0.65) was added. After 1 h the mixture was diluted with sat. NaHCO3 and extracted with Et2O. The aqueous mixture was acidified to pH 2.0 with 1 N HCl, extracted with EtOAc and the combined organic extracts were washed with brine, dried over Na2SO4 and concentrated to afford 5-(((S)-3-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-9-((2-hydroxyethyl)(methyl)carbamoyl)-4-oxo-3,4-dihydrobenzo[b][1,4]oxazepin-5(2H)-yl)methyl)-6-methoxy-2-naphthoic acid (43 mg, 74%) which was used without purification.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[CH:9]=[C:8]2[C:10]([CH3:16])=[CH:11][C:12]([CH3:15])([CH3:14])[NH:13][C:7]2=[CH:6][CH:5]=1.[C:17](Cl)([Cl:19])=[O:18]>C(OC(=O)C)C>[Cl:19][C:17]([N:13]1[C:7]2[C:8](=[CH:9][C:4]([O:3][CH2:2][CH3:1])=[CH:5][CH:6]=2)[C:10]([CH3:16])=[CH:11][C:12]1([CH3:15])[CH3:14])=[O:18]
Reactant: CCOc1ccc2c(c1)C(C)=CC(C)(C)N2
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOc1ccc2c(c1)C(C)=CC(C)(C)N2C(=O)Cl

Procedure:
A solution of ethoxyquin (30 g) in ethylacetate (300 ml) was added dropwise at room temperature to a stirred saturated solution of phosgene in ethylacetate (100 ml). Phosgene was rapidly and continuously bubbled into the stirred solution during the period of addition (2 hours). After the addition of the ethoxyquin solution was finished, phosgene bubbling was stopped and the solvent was gradually distilled (atmospheric pressure). At the end of the distillation, CCl4 (50 ml) was added and distillation continued under a slow stream of N2 (to eliminate traces of phosgene), another portion of CCl4 (50 ml) was added. Undesired ethoxyquin hydrochloride was filtered off (9.26 g), and the filtrate was evaporated to dryness under reduced pressure, yielding 1-Chlorocarbonyl-6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline as yellow, viscous syrup, which crystallised on standing (31.67 g). Recrystallisation from acetone. m.p.: 75.5°-76.5°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=3)[N:3]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: COc1ccc(-c2nc(Nc3cc(C)[nH]n3)cc3ccccc23)cc1OC

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3,4-dimethoxy-phenylboronic acid to give [1-(3,4-dimethoxy-phenyl)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 361(MH+).
Reaction SMILES: COC1C=CC(C[N:8]([C:38]2[S:42][N:41]=[CH:40][N:39]=2)[S:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=2[C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)=[N:17][CH:16]=[CH:15]3)(=[O:11])=[O:10])=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:35]1[CH:34]=[CH:33][C:32]([C:23]2[CH:24]=[C:25]([C:28]([F:30])([F:29])[F:31])[CH:26]=[CH:27][C:22]=2[C:18]2[C:19]3[C:14](=[CH:13][C:12]([S:9]([NH:8][C:38]4[S:42][N:41]=[CH:40][N:39]=4)(=[O:11])=[O:10])=[CH:21][CH:20]=3)[CH:15]=[CH:16][N:17]=2)=[CH:37][CH:36]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4-c4ccncc4)nccc3c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1ncns1)c1ccc2c(-c3ccc(C(F)(F)F)cc3-c3ccncc3)nccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 7.6 %

Procedure:
To a solution of N-(4-methoxybenzyl)-1-(2-(pyridin-4-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (100 mg, 0.158 mmol) in DCM (1578 μl) was added TFA (60.8 μl, 0.789 mmol). The reaction mixture was stirred at room temperature. After 2 hours, LC/MS showed mainly product. Purification was done using a Phenomenex Gemini 5 μm, C18, 110 Å, 150×30 mm column with 0.1% TFA in ACN and water as mobile phase to afford 1-(2-(pyridin-4-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (6.2 mg, 0.012 mmol, 7.65%). MS (ESI): 514.0 [M+H]+; 1H NMR (500 MHz, DMSO-d6) δ ppm 7.19-7.22 (m, 2H), 7.80 (s, 2H), 7.85 (d, J=8.01 Hz, 1H), 8.01-8.06 (m, 2H), 8.11 (d, J=5.77 Hz, 1H), 8.37 (br. s., 2H), 8.47 (s, 1H), 8.54 (s, 1H), 8.61 (d, J=5.66 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]([CH2:28][OH:29])[N:19]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:29][CH2:28][C:20]2[N:19]=[CH:18][C:27]3[C:22]([CH:21]=2)=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1
Reactant: OCc1cc2ccccc2cn1
Reactant: CS(=O)c1nc(N)nc(-n2cccn2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(OCc2cc3ccccc3cn2)nc(N)nc1-n1cccn1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyrazol-1-yl-pyrimidine-5-carbonitrile, isoquinolin-3-yl-methanol and DBU in DME. ES-MS m/e (%): 366 (M+Na+, 60), 344 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28](Cl)[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:20][C:14]=3[N:13]=2)=[N:9][NH:10][CH:11]=1)=[O:5].ClC1C=CC=C([F:51])C=1C(NC1C(C(O)=O)=NNC=1)=O>>[Cl:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([F:51])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:20][C:14]=3[N:13]=2)=[N:9][NH:10][CH:11]=1)=[O:5]
Reactant: O=C(Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1)c1c(Cl)cccc1Cl
Reactant: O=C(O)c1n[nH]cc1NC(=O)c1c(F)cccc1Cl
Product: O=C(Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1)c1c(F)cccc1Cl

Procedure:
The compound was prepared in a manner analogous to 2,6-dichloro-N-[3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide (Example 94E), but using 4-(2-chloro-6-fluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid, to give 2-chloro-6-fluoro-N-[3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide (37 mg) as a pink solid. (LC/MS: Rt 2.04, [M+H]+ 455.18).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([C:12]2[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][N:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1.Br[CH2:20][CH3:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([S:9]([C:12]2[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][N:13]=2)(=[O:11])=[O:10])[CH2:20][CH3:21])=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cc1ccc(Cl)cc1)c1cc(Br)ccn1
Reactant: CCBr
Product: CCC(c1ccc(Cl)cc1)S(=O)(=O)c1cc(Br)ccn1
Yield: 93 %

Procedure:
3.2 mmoles of 2-[(4-chlorophenyl)methylsulfonyl]-4-bromopyridine was contacted with 7.0 mmoles bromoethane using essentially the conditions of Example 4 providing about 93% yield of 2-[1-(4-chlorophenyl)propylsulfonyl]-4-bromopyridine.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([NH:7][C:8](=[O:10])[CH3:9])=[CH:5][N:6]=1.[Br:11]Br>C(Cl)(Cl)Cl.OS([O-])=O.[Na+]>[Br:11][C:5]1[N:6]=[C:2]([CH3:1])[S:3][C:4]=1[NH:7][C:8](=[O:10])[CH3:9]
Reactant: CC(=O)Nc1cnc(C)s1
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1sc(C)nc1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.4 %

Procedure:
To a solution of N-(2-methylthiazol-5-yl)acetamide (0.4 g, 2.6 mmol) in CHCl3 (30 mL) was added Br2 (0.15 mL, 2.8 mmol), then the solution was stirred at room temperature for 12 h to give a brown solution. The reaction mixture was diluted with saturated NaHSO3 solution. The aqueous layer was extracted with DCM (3×30 mL). The combined organic layers were dried with Na2SO4, filtered and concentrated to afford a yellow solid. The resulting mixture was deposited onto silica gel and loaded onto a silica gel column and eluted with PE/EA(1:1) to give the title compound (400 mg, yield 67%).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14]CC)=[O:13])=[CH:4][CH2:3]1.C[Si](C)(C)[O-].[K+]>C1COCC1>[CH3:1][C:2]1([CH3:17])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH2:3]1
Reactant: CCOC(=O)C1=CCC(C)(C)c2ccccc21
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1(C)CC=C(C(=O)O)c2ccccc21
Yield: 60 %

Procedure:
A solution of the compound from Example 41 (15.5 g, 71.7 mmol) and potassium trimethylsilanolate (17.4 g) in 100 ml of THF was refluxed for 24 hours. After workup the title compound (8.7 g, 52%) was obtained as a white solid.
Reaction SMILES: [N:1]1([C@@H:6]2[CH2:10][CH2:9][C@H:8](O)[CH2:7]2)[CH:5]=[CH:4][CH:3]=[N:2]1.[C:12]1(=[O:22])[NH:16][C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[N:1]1([C@H:6]2[CH2:10][CH2:9][C@H:8]([N:16]3[C:15](=[O:17])[C:14]4=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]4[C:12]3=[O:22])[CH2:7]2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O[C@H]1CC[C@@H](n2cccn2)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@H](n2cccn2)C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 52.4 %

Procedure:
A solution of cis-3-(1H-pyrazol-1-yl)cyclopentanol (5.01 g, 32.9 mmol) in THF (150 mL) was cooled to 0° C. and treated with phthalimide (5.33 g, 36.2 mmol), diisopropylazodicarboxylate (7.1 mL, 36.1 mmol) and triphenylphosphine (9.48 g, 36.1 mmol). The reaction mixture was stirred at 0° C. for 4 h. The reaction mixture was poured water and then extracted with EtOAc. The organic layer was dried over anhyd Na2SO4 followed by the removal of solvent. The crude product was purified by column chromatography (Chromatrex, Hexane/EtOAc=5/1) to yield trans-N-[3-(1H-pyrazol-1-yl)cyclopentyl]phthalimide (4.85 g, 52%) as a colorless powder.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([NH:10][C:11]2[N:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C:25](=O)[O:26]C4C=CC=CC=4)[CH:19]=3)=[CH:13][CH:12]=2)=[O:9])[C:4](=[O:34])[N:3]1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[NH2:41][CH2:42][CH2:43][OH:44]>CN1C(=O)CCC1>[OH:44][CH2:43][CH2:42][NH:41][C:25](=[O:26])[NH:24][C:20]1[CH:19]=[C:18]([O:17][C:14]2[CH:13]=[CH:12][C:11]([NH:10][C:8]([C:5]3[C:4](=[O:34])[N:3]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:2]([CH3:1])[C:6]=3[CH3:7])=[O:9])=[N:16][CH:15]=2)[CH:23]=[CH:22][N:21]=1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(NC(=O)Oc4ccccc4)c3)cn2)c(=O)n(-c2ccccc2)n1C
Reactant: NCCO
Solvent: CN1CCCC1=O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(NC(=O)NCCO)c3)cn2)c(=O)n(-c2ccccc2)n1C
Temperature: 40 °C
Yield: 97.7 %

Procedure:
A mixture of phenyl (4-((6-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)pyridin-3-yl)oxy)pyridin-2-yl)carbamate (0.1 g, 0.187 mmol), NMP (10 mL) and 2-aminoethanol (14.0 mg, 0.224 mmol) was heated at 40° C. for 2 hours. The solvent was evaporated under reduced pressure at 40° C., and then diluted with EtOAc (20 mL). The precipitate was collected by filtration and washed with EtOAc (3 mL) to give the title compound as a white solid (92 mg, 98%).
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH2:8][C:9](=O)[CH3:10])[C:3]([O:5]C)=O.[CH2:12]([NH2:15])[CH2:13][NH2:14]>CCCCCCC>[CH3:10][CH:9]1[CH:8]2[N:15]([C:3](=[O:5])[CH:2]([CH3:1])[CH2:7]2)[CH2:12][CH2:13][NH:14]1
Reactant: COC(=O)C(C)CCC(C)=O
Reactant: NCCN
Solvent: CCCCCCC
Product: CC1CC2C(C)NCCN2C1=O
Temperature: 38 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
124.2 g (0.75 mole) of methyl 2-methyl-5-oxohexanoate in 450 ml of n-heptane are initially taken. 52.2 g (0.87 mole) of ethylenediamine are then added dropwise at room temperature in the course of 10 minutes. As a result of the exothermic reaction, the temperature increases to 38° C. 49 ml of the lower phase (aqueous methanol) are separated off. The mixture is cooled to 2° C. and stirred for 1 hour, and the product is filtered off under suction, washed with cold n-heptane and dried. 116.3 g of racemic 5,8-dimethyl-9-oxo-1,4-diazabicyclo[4.3.0]nonane are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:44]([NH2:45])=[CH:43][CH:42]=[CH:41][C:3]=1[C:4]([NH:6][C:7]1[CH:38]=[CH:37][C:10]([C:11]([N:13]([CH3:36])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])=[O:12])=[CH:9][C:8]=1[O:39][CH3:40])=[O:5].[CH3:46][O:47][C:48]([N:50]=[C:51]=S)=[O:49].C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C.C1C=CC=CC=1>[CH3:40][O:39][C:8]1[CH:9]=[C:10]([CH:37]=[CH:38][C:7]=1[NH:6][C:4]([C:3]1[C:2]2[N:1]=[C:51]([NH:50][C:48]([O:47][CH3:46])=[O:49])[NH:45][C:44]=2[CH:43]=[CH:42][CH:41]=1)=[O:5])[C:11]([N:13]([CH3:36])[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]1)=[O:28])=[O:12]
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc(N)c1N
Reactant: COC(=O)N=C=S
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccccc1
Solvent: CC#N
Product: COC(=O)Nc1nc2c(C(=O)Nc3ccc(C(=O)N(C)c4ccc(C)cc4OCCCCCC(=O)N4CCN(C)CC4)cc3OC)cccc2[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 49.8 %

Procedure:
To a stirred solution of 4-(2,3-diaminobenzoyl)amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (145 mg) in a mixture of acetonitrile and benzene [1:4(v/v)] was added methoxycarbonyl isothiocyanate (36 mg) and the reaction mixture was stirred at ambient temperature for 5 minutes. After being added 1,3-dicyclohexylcarbodiimide (73 mg) to the solution, the resulting mixture was stirred at reflux temperature for 5 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in chloroform. The solution was washed with saturated aqueous sodium bicarbonate solution, water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by chromatography on silica gel (chromatorex) eluting with chloroform and preparative thin-layer chromatography (chloroform-methanol=10:1) to give 3-methoxy-4-(2-methoxycarbonylamino-1H-benzimidazol-4-yl)carbonylamino-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (82 mg) as a powder.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl[C:18]1[CH:19]=[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:32]=3)[CH:25]=2)[CH:21]=[CH:22][CH:23]=1>[Cu].C1(C)C=CC=CC=1>[O:37]([C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=1)[O:30][C:26]1[CH:25]=[C:24]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([O:14][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:19]=2)[CH:29]=[CH:28][CH:27]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Oc1ccccc1Oc1ccccc1
Reactant: Clc1cccc(-c2cccc(Oc3cccc(Oc4ccccc4)c3)c2)c1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: c1ccc(Oc2cccc(Oc3cccc(-c4cccc(Oc5ccccc5Oc5ccccc5)c4)c3)c2)cc1
Yield: 61 %

Procedure:
A 500 ml. reaction flask equipped with stirrer, condenser, and Dean Stark trap was charged with 191 g. (1.03 moles) of o-phenoxyphenol, 50 ml. of toluene and 39.5 g. (0.70 mole) of potassium hydroxide. The mixture was heated to reflux and water azeotroped from the system. Diglyme (100 ml.) was then added followed by 20 g. (0.053 mole) of 3-chloro-3'-(m-phenoxyphenoxy)biphenyl over a 30 minute period. To this mixture 2.5 g. of cuprous chloride and 0.5 g. of copper powder was added and after removing the diglyme be distillation, the reaction mixture was heated at 230°-240° for 18 hours. The mixture was cooled, diluted with 500 ml. of ether and centrifuged to remove copper and potassium salts. The salts were washed with additional ether, and the ether fractions combined and washed with 25% potassium hydroxide solution followed by water washing to neutrality. After drying the ethereal solution over magnesium sulfate, and removing ether in vacuo, the resulting oil was distilled to give 16.9 g of the desired product, bp 255°-260°/0.02 mm.; nD25 1.6480.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:13]=[C:9]([C:10]([NH2:12])=[O:11])[C:8]([OH:14])=[CH:7][CH:6]=1)[OH:4].[Cl:15][C:16]1[CH:28]=[CH:27][C:19]([N:20]([CH2:22][CH2:23][C:24](=O)[CH3:25])[CH3:21])=[CH:18][CH:17]=1.[BH3-]C#N.[Na+]>CO>[Cl:15][C:16]1[CH:28]=[CH:27][C:19]([N:20]([CH2:22][CH2:23][CH:24]([NH:1][CH2:2][CH:3]([C:5]2[CH:13]=[C:9]([C:10]([NH2:12])=[O:11])[C:8]([OH:14])=[CH:7][CH:6]=2)[OH:4])[CH3:25])[CH3:21])=[CH:18][CH:17]=1
Reactant: CC(=O)CCN(C)c1ccc(Cl)cc1
Reactant: NCC(O)c1ccc(O)c(C(N)=O)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(CCN(C)c1ccc(Cl)cc1)NCC(O)c1ccc(O)c(C(N)=O)c1
Reaction time: 144 h

Procedure:
To a solution of 20 mmol 5-(2-amino-1-hydroxyethyl)salicylamide and 4.22 g (20 mmol) 4-(4-chloro-N-methylanilino)-2-butanone [mp 60°-1°, prepared by procedure of Craig, et al, J. Org. Chem., 29, 410 (1964)] in 100 ml methanol add 2.52 g (40 mmol) NaCNBH3. Stir 6 days, concentrate, and partition between EtOAc and 1.0 N NaHCO3 solution. Wash the organic layer with 1.0 N HCl. Neutralize the aqueous portion with NaHCO3 and extract with EtOAc. Dry, concentrate, and recrystallize the residue from EtOAc-hexane to give a white solid, mp 127°-9°.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:51])[C:41]5[C:46]([O:47][CH2:48][CH2:49][CH3:50])=[CH:45][CH:44]=[CH:43][N:42]=5)=[CH:36][CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:52]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:61])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:27])[F:28])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:35]=[CH:36][C:37]([CH:40]([OH:51])[C:41]5[C:46]([O:47][CH2:48][CH2:49][CH3:50])=[CH:45][CH:44]=[CH:43][N+:42]=5[O-:61])=[CH:38][CH:39]=4)=[O:32])=[CH:20][C:19]=3[CH:52]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4ncccc4OCCC)cc2)CCN3C(=O)C(F)(F)F)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4c(OCCC)ccc[n+]4[O-])cc2)CCN3C(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 30 h
Yield: 75.4 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(3-propoxypyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (480 mg) in dichloromethane (10 ml) was added 3-chloroperbenzoic acid (70%, 0.2 g) at 0° C. and the mixture was stirred for 30 hours at room temperature. To the reaction solution was added sodium thiosulfate solution and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:9) to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxido-3-propoxypyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 112) (370 mg) as colorless crystals.