Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:13]([NH2:15])=[O:14])[C:6](=[O:12])[NH:7]2.O.[NH2:17]N.O>C(O)(=O)C>[CH3:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:13]([NH:15][NH2:17])=[O:14])[C:6](=[O:12])[NH:7]2
Reactant: NN
Reactant: Cc1nccc2[nH]c(=O)c(C(N)=O)cc12
Solvent: CC(=O)O
Solvent: O
Product: Cc1nccc2[nH]c(=O)c(C(=O)NN)cc12

Procedure:
E-3. 1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridine-3-carboxylic acid hydrazide--A mixture containing 34 g of 1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridine-3-carboxamide and 150 ml of hydrazine hydrate was heated on a steam bath for 18 hours and then stripped to dryness on a steam bath. To the residue was added 100 ml of water and the aqueous mixture was neutralized by adding acetic acid. The fine yellow needles were collected, washed successively with water and methanol, and then dried at 90° C. to produce 32.6 g of 1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridine-3-carboxylic acid hydrazide, m.p.>310° C.
Reaction SMILES: Br[C:2]1[C:3]([OH:12])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[NH:13]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[CH3:20]C(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[N:13]1([C:2]2[C:3]([O:12][CH3:20])=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: CC(C)(C)[O-]
Reactant: Oc1ccc2cccnc2c1Br
Reactant: C1CNCCNC1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc2cccnc2c1N1CCCNCC1
Temperature: 25 °C
Yield: 78 %

Procedure:
A mixture of 8-bromo-7-hydroxyquinoline (126 g, 0.488 mol), homopiperazine (201 g, 2.0 mol), (±)-BINAP (19.8 g, 31.8 mmol), and sodium tert-butoxide (75.6 g, 0.786 mol) was suspended in 900 mL of toluene and purged with nitrogen gas for an hour. Tris-benzylidineacetone dipalladium(0) (9.7 g, 10.6 mmol) was added. The mixture was purged for another hour, heated to reflux under nitrogen for 4 hr, cooled to rt, carefully diluted with 1300 mL of 20% AcOH in water and filtered through 100 g of celite. The celite pad was washed with 20% AcOH in water (1 L×2) and ethyl acetate (1 L×1). The aqueous phase was extracted with ethyl acetate (1 L×4), adjusted to pH 10-11 with NaOH (10 N, 500 mL), and then extracted with a mixture of CH2Cl2 and iPrOH (80:20, 1 L×2 and 0.5 L×4). The combined organic phase was washed with saline (400 mL), dried over Mg2SO4 and evaporated to give the desired product (98 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:28](O)=[O:29])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:31]([O:38][CH2:39][CH2:40][NH:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].CCCP(=O)=O.O>CN(C)C=O>[Si:31]([O:38][CH2:39][CH2:40][N:41]([CH2:42][C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=1)[C:28]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:14]([OH:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]=1)=[O:29])([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)OCCNCc1ccc(F)cc1
Reactant: O=C(O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1
Agent: CCCP(=O)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCN(Cc1ccc(F)cc1)C(=O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 23.1 %

Procedure:
To a stirred solution mixture of 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (283) (250 mg, 0.62 mmol) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-(4-fluoro-benzyl)-amine (8k) (210 mg, 0.74 mmol) in dimethylformamide (5 mL) was added propylphosphonic anhydride (50 wt % in ethyl acetate) (1.3 g, 1.85 mmol) at 0° C. After stirring at room temperature for 20 h, water (20 mL) was added and the mixture was extracted with ethyl acetate (3×20 mL). The combined organic part was washed with water (3×50 mL) and brine (2×30 mL) and dried and concentrated. The crude product was purified by Combi-Flash column (eluted at 20-30% ethyl acetate in hexane) to yield 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-(4-fluoro-benzyl)-amide (312) (96 mg, 23.18%) as a colourless sticky solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[N:30]1([CH2:36][B-](F)(F)F)[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.[K+]>>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:36][N:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Br)ccc21
Reactant: F[B-](F)(F)CN1CCOCC1
Agent: [K+]
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCOCC3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-acetic acid methyl ester and potassium (morpholin-4-yl)methyltrifluoroborate following a procedure analogous to that described in Step 1 of Intermediate 9.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[N:22]([C:29]4[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=4[Cl:36])[N:23]=[N:24][C:25]=3[CH:26]([CH3:28])[CH3:27])=[CH:15][C:14]=2[CH3:37])[CH:6]=1)[CH3:2].[H-].[Na+].I[CH3:42]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:38])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[N:22]([C:29]4[C:30]([Cl:36])=[CH:31][CH:32]=[CH:33][C:34]=4[Cl:35])[N:23]=[N:24][C:25]=3[CH:26]([CH3:27])[CH3:28])=[CH:15][C:14]=2[CH3:37])[CH3:42])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(NCc2ccc(OCc3c(C(C)C)nnn3-c3c(Cl)cccc3Cl)cc2C)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(N(C)Cc2ccc(OCc3c(C(C)C)nnn3-c3c(Cl)cccc3Cl)cc2C)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 12.2 %

Procedure:
To a mixture of 3-{4-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-benzylamino}-benzoic acid ethyl ester (160 mg, 0.29 mmol) and sodium hydride (13 mg, 0.33 mmol) in anhydrous N,N-dimethyl formamide is added iodomethane (50 mg, 0.35 mmol). After three hours, more iodomethane (50 mg, 0.35 mmol) is added and the mixture is heated to 60° C. After three hours, more iodomethane (50 mg, 0.35 mmol) is added and the mixture is stirred at room temperature over night. The mixture is then partitioned between diethylether and water. The aqueous layer is extracted three times with diethylether. The combined ether layers are dried (MgSO4) and concentrated under reduced pressure. The crude residue is purified on 12 g of silica with ethyl acetate in heptane gradient to provide 3-({4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-benzyl}-methyl-amino)-benzoic acid ethyl ester (20 mg, 12%) LC-MS: 567.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:7][CH:6]=[CH:5][C:4]=1CC#N.Cl.[C:21]([OH:24])(=[O:23])[CH3:22]>>[CH3:1][O:2][C:3]1[C:8]([O:9][C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:22][C:21]([OH:24])=[O:23]
Reactant: CC(=O)O
Reactant: COc1c(CC#N)cccc1Oc1ccc(Cl)cc1
Agent: Cl
Product: COc1c(CC(=O)O)cccc1Oc1ccc(Cl)cc1

Procedure:
2-[2-Methoxy-3-(4-chlorophenoxy)phenyl]acetonitrile (11.8 g), glacial acetic acid (50 ml) and conc. hydrochloric acid (25 ml) were treated in a similar manner to that of Example 5-(4) to give oily 2-[2-methoxy-3-(4-chlorophenoxy)phenyl]acetic acid (6.7 g).
Reaction SMILES: Cl.[F:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][S:8][C:9]2[NH:10][C@H:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:13]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:35](OC(=O)C)(=[O:37])[CH3:36]>CN(C)C1C=CN=CC=1.ClCCl>[F:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][S:8][C:9]2[N:13]([C:35](=[O:37])[CH3:36])[C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C@H:11]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:10]=2)=[CH:5][CH:4]=1
Reactant: Fc1ccc(CSC2=N[C@@H](c3ccccc3)[C@@H](c3ccccc3)N2)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1C(SCc2ccc(F)cc2)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.2 %

Procedure:
To a solution of 2-[(4-fluorobenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole hydrochloride (197) (0.50 g, 1.25 mmol), triethylamine (0.384 mL, 2.75 mmol), 4-dimethylaminopyridine (20 mg) in dichloromethane (20 mL) is added acetic anhydride (0.130 mL, 1.38 mmol), and the mixture is stirred at rt for 3 h. Additional acetic anhydride (0.100 mL, 1.06 mmol) is added, and the mixture is stirred at rt overnight. The reaction mixture is diluted with dichloromethane and washed with water, brine, and the organic layer is dried (MgSO4), filtered, and evaporated. The residue is recrystallized from heptane:dichloromethane (95:5) to give 0.37 g of the product 549. 1H NMR (CDCl3) δ 7.60-7.40 (m, 2H), 7.10-6.90 (m, 8H), 6.90-6.75 (m, 2H), 6.75-6.65 (m, 2H), 5.65 (d, 1H), 5.43 (d, 1H), 4.33 (q, 2H), 1.91 (s, 3H). MS: m/z 405 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[OH:9].C([O-])(O)=O.[Na+].Cl[CH2:16][C:17](Cl)=[O:18]>C(C(C)=O)C(C)C.O.C(OCC)(=O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:17](=[O:18])[CH2:16][O:9][C:3]=2[CH:4]=1
Reactant: Nc1ccc(Br)cc1O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)CC(C)C
Product: O=C1COc2cc(Br)ccc2N1
Temperature: 25 °C
Yield: 77 %

Procedure:
Part 2. A solution of 2-amino-5-bromophenol (2.53 g, 18.2 mmol, 1.0 equiv) in 15 mL of isobutylmethyl ketone and 15 mL of water was cooled to 0° C., NaHCO3 (3.67 g, 2.4 equiv) and then chloroacetyl chloride (2.36 g, 1.67 mL, 1.15 equiv) were added. The mixture was heated to reflux overnight, then cooled to room temperature. The mixture was diluted with ethyl acetate, washed with water, dried over MgSO4, and concentrated in vacuo. Flash chromatography on silica gel gave 7-bromo-3,4-dihydro-2H-1,4-benzoxazin-3-one in 77% yield. LRMS found for C9H10NO3 (M+H)+: 180.1.
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:8](=[O:9])[CH2:7][CH2:6][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:4]1.C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].C(O)(=O)C>O1CCCC1>[CH3:1][O:2][C@H:3]1[C@@H:8]([OH:9])[CH2:7][CH2:6][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:4]1
Reactant: COC1CN(Cc2ccccc2)CCC1=O
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CO[C@@H]1CN(Cc2ccccc2)CC[C@@H]1O
Temperature: -70 °C
Reaction time: 2 h
Yield: 29.3 %

Procedure:
a') A solution of 3-methoxy-1-(phenylmethyl)-4-piperidinone (4.4 g) in tetrahydrofuran was cooled to -75° C. Lithium tris-sec-butylborohydride was added dropwise and the reaction mixture was stirred for 2 hours at -70° C. Acetic acid 10% (100 ml) was added dropwise at room temperature. The organic solvent was evaporated. The aqueous residue was alkalized with NH4OH, then extracted twice with diisopropylether. The separated organic layer was washed with water, dried over MgSO4, filtered and the solvent was evaporated. The residue was purified by short column chromatography over silica gel (eluent: CH2Cl2 /CH3OH 95/5 upgrading to 98/2), yielding 1.3 g (29.4%) of cis-3-methoxy-1-(phenylmethyl)-4-piperidinol (intermediate 2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[C:4]([CH3:17])[CH:3]=1.C(N(CC)CC)C.[C:25](Cl)(Cl)=[S:26]>C(Cl)(Cl)Cl.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][CH2:11][N:12]([CH2:13][CH:14]([CH3:15])[CH3:16])[C:25]2=[S:26])=[C:4]([CH3:17])[CH:3]=1
Reactant: S=C(Cl)Cl
Reactant: Cc1cc(Cl)ccc1NCCCNCC(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1cc(Cl)ccc1N1CCCN(CC(C)C)C1=S
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 43 %

Procedure:
To an ice-cold solution of the diamine of Step A (4.8 g) and triethylamine (5.0 mL) in dry chloroform (75 mL) was added thiophosgene (2.2 mL). After 10 minutes at ambient temperature, the reaction was quenched with water and extracted with dichloromethane. The extracts were combined, dried over sodium sulfate and concentrated in vacuo to give a brown oil. The crude material was dissolved in dichloromethane and absorbed onto a column of Merck-60 flash silica gel. Elution with 11% ethyl acetate in hexane provided a yellow solid which was triturated with diethyl ether to give the title product (2.4 g, 43.0%) as a white solid, m.p. 88-90° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([OH:38])[C:19]3[CH:20]=[CH:21][C:22]([O:24][CH2:25][O:26][CH3:27])=[CH:23][C:18]=3[O:17][CH2:16][CH:15]2[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][O:36][CH3:37])=[CH:30][CH:29]=2)=[CH:10][CH:9]=1.[I-:39].[Na+].O>C(C(C)=O)C>[OH:38][C:14]1([C:11]2[CH:12]=[CH:13][C:8]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][I:39])=[CH:9][CH:10]=2)[C:19]2[CH:20]=[CH:21][C:22]([O:24][CH2:25][O:26][CH3:27])=[CH:23][C:18]=2[O:17][CH2:16][CH:15]1[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][O:36][CH3:37])=[CH:30][CH:29]=1
Reactant: [I-]
Reactant: COCOc1ccc(C2COc3cc(OCOC)ccc3C2(O)c2ccc(OCCCCCCl)cc2)cc1
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: O
Product: COCOc1ccc(C2COc3cc(OCOC)ccc3C2(O)c2ccc(OCCCCCI)cc2)cc1
Temperature: 25 °C
Yield: 74.6 %

Procedure:
4-[4-(5-Chloropentyloxy)phenyl]-4-hydroxy-7-methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-2,3-dihydro-4H-benzopyran (167 mg, 0.3 mmol) and sodium iodide (139 mg, 0.9 mmol) were dissolved in methyl ethyl ketone (5 ml) and then refluxed for 12 hours. The reaction solution was cooled to room temperature and, after adding water, extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure to remove the organic solvent. The concentrate was subjected to column chromatography (n-hexane:ethyl acetate=4:1) to obtain 142 mg (yield: 75%) of the title compound as a colorless oil.
Reaction SMILES: [Cl-].O[NH3+].[C:4](=[O:7])([O-])[OH:5].[Na+].[CH2:9]([C:11]1[S:43][C:14]2[N:15]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]4[C:36]([C:41]#[N:42])=[CH:37][CH:38]=[CH:39][CH:40]=4)=[CH:31][CH:30]=3)[C:16](=[O:27])[C:17]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:18][C:13]=2[CH:12]=1)[CH3:10].[N:44]12CCCN=C1CCCCC2>C(Cl)(Cl)Cl.C(Cl)Cl.CS(C)=O>[CH2:9]([C:11]1[S:43][C:14]2[N:15]([CH2:28][C:29]3[CH:30]=[CH:31][C:32]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[C:41]4[NH:44][C:4](=[O:7])[O:5][N:42]=4)=[CH:33][CH:34]=3)[C:16](=[O:27])[C:17]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:18][C:13]=2[CH:12]=1)[CH3:10]
Reactant: O=C([O-])O
Reactant: CCc1cc2cc(CCc3ccccc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Reactant: C1CCC2=NCCCN2CC1
Agent: [Cl-]
Agent: [NH3+]O
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: CCc1cc2cc(CCc3ccccc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
A mixture of hydroxylammonium chloride (0.41 g), sodium hydrogencarbonate (0.6 g) and dimethyl sulfoxide (20 mL) was stirred at 40° C. for 30 min, 4′-{[2-ethyl-6-oxo-5-(2-phenylethyl)thieno[2,3-b]pyridin-7(6H)-yl]methyl}biphenyl-2-carbonitrile (0.34 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained by silica gel column chromatography was dissolved in methylene chloride (40 mL), N,N′-carbonyldiimidazole (0.13 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.11 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was recrystallized from tetrahydrofuran to give the title compound as colorless crystals (0.23 g, 55%).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9]([NH:11][NH:12]C(=O)C1C=CC=CC=1)=[O:10])(C)(C)C.[ClH:29].[O:30]1[CH2:35][CH2:34]OCC1>>[NH2:7][C@@H:8]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:9]([N:11]([C:35](=[O:30])[C:34]1[CH:23]=[CH:22][CH:21]=[CH:8][CH:9]=1)[NH:12][Cl:29])=[O:10]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NNC(=O)c1ccccc1
Reactant: Cl
Reactant: C1COCCO1
Product: N[C@@H](Cc1ccccc1)C(=O)N(NCl)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
313 mg (818 μmol) of tert.-butyl-[(2S)-1-(2-benzoylhydrazino)-1-oxo-3-phenylpropan-2-yl]carbamate (intermediate 34) were stirred in 13 ml of a 4 N hydrogen chloride solution diluted in dioxane and stirred for 1 hour at RT. Then the reaction composition was evaporated and the residue vacuum dried. The yield was 255 mg (92% o. th.) of the title compound.
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]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:51]=[CH:50][C:35]5[N:36]([CH3:49])[C:37]([S:39][CH2:40][C:41]6[N:45]([CH2:46][CH2:47][CH3:48])[CH:44]=[N:43][CH:42]=6)=[N:38][C:34]=5[CH:33]=4)=[O:30])=[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.CSC.O>ClCCl>[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]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:51]=[CH:50][C:35]5[N:36]([CH3:49])[C:37]([S:39]([CH2:40][C:41]6[N:45]([CH2:46][CH2:47][CH3:48])[CH:44]=[N:43][CH:42]=6)=[O:61])=[N:38][C:34]=5[CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:52]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc4c(c2)nc(SCc2cncn2CCC)n4C)CCN3CC(C)C)cc1
Solvent: O
Solvent: ClCCl
Solvent: CSC
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc4c(c2)nc(S(=O)Cc2cncn2CCC)n4C)CCN3CC(C)C)cc1
Temperature: -13 °C
Reaction time: 2.5 h
Yield: 28.7 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[1-methyl-2-(((1-propylimidazol-5-yl)methyl)sulfanyl)benzimidazol-5-yl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (160 mg) in dichloromethane (10 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (82 mg) in dichloromethane (10 ml) at −78° C., and the mixture was stirred for 2.5 hours at −13° C. Dimethylsulfide (0.1 ml) was added to the mixture, and the mixture was allowed to be at room temperature and stirred for 30 minutes. To the mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was separated and purified by basic silica gel column chromatography (hexane:ethyl acetate=1:4→ethyl acetate), and was recrystallized from hexane-ethyl acetate, to give 7-[4-(2-butoxyethoxy) phenyl]-1-isobutyl-N-[1-methyl-2-(((1-propylimidazol-5-yl)methyl)sulfinyl)benzimidazol-5-yl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (47 mg) (Compound 445) as yellow crystals.
Reaction SMILES: COC1C=CC(C=[N:10][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])=CC=1.ClC1C=C(C=CC=1)C(OO)=[O:24].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl.ON>O1CCCC1.C(OCC)(=O)C.O>[C:13]1([C@@H:11]([NH:10][OH:24])[CH3:12])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(C=N[C@@H](C)c2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: NO
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@H](NO)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
A −78° C. solution of Example 2A (7.15 g, 30 mmole) in tetrahydrofuran (75 mL) was treated with a solution of 3-chloroperoxybenzoic acid (15 g, 60 mmol), warmed to 0 ° C., stirred for 2 hours, diluted with ethyl acetate (100 mL), washed sequentially with 10% (w/w) sodium thiosulfate, saturated sodium bicarbonate, and brine, dried (MgSO4), filtered, and concentrated. The concentrate was dissolved in tetrahydrofuran (100 mL), treated with p-toluene sulfonic acid monohydrate (8.15 g, 42.8 mmol), stirred for 2 hours, treated with a solution of N-hydroxylamine hydrochloride (8.7 g) in water (15 mL), and stirred for 16 hours. The mixture was diluted with ethyl acetate (100 mL), washed with saturated sodium bicarbonate and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 1:2 ethyl acetate/hexanes to provide 3.53g (86% yield) of the desired product. 1H NMR (300 MHz, CDCl3) δ 7.36-7.20 (m, 5H), 4.09 (q, 1H, J=6.6 Hz), 1.48 (d, 3H, J=6.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:15])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][C:27]([CH3:30])([CH3:29])[O:26][CH2:25][CH:24]1[C:31](O)=[O:32])=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[C@H:24]([C:31](=[O:32])[NH:15][C:13]2[CH:14]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:12]=2[NH:11][C:10]2[CH:9]=[N:8][CH:7]=[CH:6][C:5]3=2)[CH2:25][O:26][C:27]([CH3:30])([CH3:29])[CH2:28]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)OCC1C(=O)O
Reactant: Nc1cc(Cl)cc2c1[nH]c1cnccc12
Product: CC(C)(C)OC(=O)N1CC(C)(C)OC[C@H]1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12
Yield: 87 %

Procedure:
The desired compound was prepared according to Method C from 6-chloro-9H-β-carboline-8-ylamine and 6,6-dimethyl-morpholine-3,4-dicarboxylic acid 4-tert-butyl ester in 87% yield.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[CH:12]=1.[C:21](=O)([O-])[O-:22].[K+].[K+].CO>O>[CH3:21][O:22][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[CH:12]=1
Reactant: Fc1cnccc1-c1cc2cc(C(F)(F)F)ccc2o1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1cnccc1-c1cc2cc(C(F)(F)F)ccc2o1
Temperature: 25 °C
Yield: 80.8 %

Procedure:
A mixture of 0.19 g of 3-fluoro-4-[5-(trifluoromethyl)benzofuran-2-yl]pyridine, 0.19 g of potassium carbonate and 3 ml of methanol was heated under reflux for 27 hours. To this mixture was added 93 mg of potassium carbonate, and the mixture was further heated under reflux for 2 hours. The reaction mixture was cooled to room temperature. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined and washed with saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.16 g of 3-methoxy-4-[5-(trifluoromethyl)benzofuran-2-yl]pyridine (hereinafter, referred to as “Present Active Compound 9”).