Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8](=O)[NH:9][N:10]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(C)C(C)=CC=CC=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:29]>C(OCC)(=O)C>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8](=[S:29])[NH:9][N:10]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=c1[nH]n(-c2ccccc2)c2cc([N+](=O)[O-])ccc12
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc2c(=S)[nH]n(-c3ccccc3)c2c1
Temperature: 25 °C

Procedure:
Into a 250-mL 3-necked round-bottom flask, was placed 6-nitro-1-phenyl-1,2-dihydroindazol-3-one (15 g, 58.82 mmol, 1.00 equiv), xylene (150 mL), P2S5 (52.2 g, 235.14 mmol). The resulting solution was heated to reflux for 40 min in an oil bath. The resulting mixture was then cooled to 25° C. The resulting solution was diluted with ethyl acetate (50 mL). The solids were filtered out to yield 6-nitro-1-phenyl-1,2-dihydroindazole-3-thione as a yellow solid. MS: 272 (MH+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([C:10]3[N:11]=[C:12]([C:21]4[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=4)[NH:13][C:14]=3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[O:29]1C2C=C(C3N=C(C4C=CC(C#N)=CC=4)N(O)C=3C3C=CC=CN=3)C=CC=2CC1>>[O:1]1[C:5]2[CH:6]=[C:7]([C:10]3[N:11]=[C:12]([C:21]4[CH:22]=[CH:23][C:24]([C:25]([NH2:26])=[O:29])=[CH:27][CH:28]=4)[NH:13][C:14]=3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: N#Cc1ccc(-c2nc(-c3ccc4c(c3)OCC4)c(-c3ccccn3)n2O)cc1
Reactant: N#Cc1ccc(-c2nc(-c3ccc4c(c3)OCC4)c(-c3ccccn3)[nH]2)cc1
Product: NC(=O)c1ccc(-c2nc(-c3ccc4c(c3)OCC4)c(-c3ccccn3)[nH]2)cc1

Procedure:
Prepared according to the method of Example 14 from 4-[4-(2,3-dihydro-benzofuran-6-yl)-5-pyridin-2-yl-1H-imidazol-2-yl]-benzonitrile which was prepared from 4-[4-(2,3-dihydro-benzofuran-6-yl)-1-hydroxy-5-pyridin-2-yl-1H-imidazol-2-yl]-benzonitrile according to the method of Example 2. 1H NMR (250 MHz, CDCl3) δ: 3.27 (2H, brt, J=8.5 Hz), 4.63 (2H, brt, J=8.5 Hz), 5.50-5.90 (1H, brs), 6.05-6.35 (1H, brs), 7.08-7.20 (3H, m), 7.18-7.30 (3H, m) 7.56 (2H, brs), 8.86 (2H, d, J=8.3 Hz), 8.04 (2H, d, J=8.3 Hz), 8.54 (1H, brd, J=4.5 Hz); m/z (ESMS): 383.5 (MH+).
Reaction SMILES: C(Cl)Cl.[CH3:4][S:5][C:6]1[CH:16]=[C:15]2[C:10](=[C:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:12]([O:14]2)=[O:13])[CH:9]=[CH:8][CH:7]=1.C[OH:24]>>[CH3:4][S:5][C:6]1[CH:16]=[C:15]2[C:10](=[C:11]([C:17]3[CH:22]=[CH:21][C:20]([OH:24])=[CH:19][CH:18]=3)[C:12]([O:14]2)=[O:13])[CH:9]=[CH:8][CH:7]=1
Reactant: CSc1cccc2c(-c3ccccc3)c(=O)oc-2c1
Reactant: CO
Solvent: ClCCl
Product: CSc1cccc2c(-c3ccc(O)cc3)c(=O)oc-2c1

Procedure:
TLC(CH2Cl2:MeOH, 92:8 v/v): Rf=0.55; UV/vis λmax 262 nm, 432 nm; HRMS (m/z): [M]+ calculated for C16H12O3S, 285.0585. found 285.0578. See Table 2 for NMR data. Roseobacticide B. TLC(CH2Cl2:MeOH, 92:8 v/v): Rf=0.58; UV/vis λmax 262 nm, 316 nm, 430 nm; HRMS (m/z): [M]+calculated for C16H12O2S, 269.0637. found 269.0635. See Table 3 for NMR data.
Reaction SMILES: [CH3:1][N:2]([CH:4]([CH:7]1[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9][CH2:8]1)[C:5]#N)[CH3:3].[Cl:17][C:18]1[CH:23]=[CH:22]C([Mg]Br)=[CH:20][CH:19]=1.[Cl-].[NH4+]>C(OCC)C.O>[Cl:17][C:18]1[CH:23]=[CH:22][C:5]([CH:4]([N:2]([CH3:3])[CH3:1])[CH:7]2[CH2:16][CH2:15][C:10]3([O:14][CH2:13][CH2:12][O:11]3)[CH2:9][CH2:8]2)=[CH:20][CH:19]=1
Reactant: CN(C)C(C#N)C1CCC2(CC1)OCCO2
Reactant: Clc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: CN(C)C(c1ccc(Cl)cc1)C1CCC2(CC1)OCCO2
Reaction time: 20 h

Procedure:
A solution of the aminonitrile 3 (22.43 g, 100 mmol) in abs. ether (100 ml) was added dropwise, under argon and while cooling with ice, to a 1M solution of 4-chlorophenylmagnesium bromide in ether (200 ml, 200 mmol), and stirring was carried out for 20 h at RT. For working up the reaction mixture, saturated ammonium chloride solution (100 ml) and water (100 ml) were added, while cooling with ice, and extraction with diethyl ether (3×100 ml) was carried out. The organic phase was washed with water and saturated sodium chloride solution, dried and concentrated.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][OH:7])=[CH:2]1.[H-].[Na+].[Cl:10][C:11]1[CH:16]=[C:15]([NH:17][CH3:18])[CH:14]=[C:13](Cl)[N:12]=1>O1CCCC1>[Cl:10][C:11]1[CH:16]=[C:15]([NH:17][CH3:18])[CH:14]=[C:13]([O:7][CH2:6][C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[N:12]=1
Reactant: CNc1cc(Cl)nc(Cl)c1
Reactant: OCc1ccsc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CNc1cc(Cl)nc(OCc2ccsc2)c1

Procedure:
To a solution of 3-thiophenemethanol (1.42 g, 0.0113×1.1 mol) in 20 ml of dry tetrahydrofuran, sodium hydride (1.35 g (ca.60% in mineral oil), 0.0113×3.0 mol) was added. After the bubbling ceased, a solution of 2,6-dichloro-4-methylaminopyridine (2.0 g, 0.0113 mol) in 30 ml of dry tetrahydrofuran was added dropwise at room temperature.
Reaction SMILES: OO.[O:3]=[C:4]([CH3:19])[CH2:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[O:7].[Br-:20].[K+].Cl>C1(C)C=CC=CC=1.O>[Br:20][CH:5]([C:4](=[O:3])[CH3:19])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:11][CH:10]=1)=[O:7]
Reactant: CC(=O)CC(=O)Nc1ccc(C(F)(F)F)cc1
Reactant: [Br-]
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)C(Br)C(=O)Nc1ccc(C(F)(F)F)cc1
Yield: 48.5 %

Procedure:
Hydrogen peroxide (8.096 ml) was added dropwise to the well stirred solution of 3-oxo-N-[4-(trifluoromethyl)phenyl]butanamide (10 g) [obtained from above step-a], potassium bromide (4.85 g) and conc. HCl (7.446 ml) in toluene (100 ml) at room temperature. Reaction was monitored by TLC. D.M water was added to the reaction mixture and organic layer was separated. Aqueous layer was extracted with ethyl acetate (50 ml×2). Combined organic layer was washed with brine, dried over sodium sulfate and concentrated to give crude compound. The crude was purified by column chromatography to give pure 2-bromo-3-oxo-N-[4-(trifluoromethyl)phenyl]butanamide (6.4 g).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([F:7])([F:6])[F:5].CS(C)=O.C([N:20](CC1C=CC=CC=1)[CH2:21][CH2:22][NH2:23])C1C=CC=CC=1.[BH4-].[Na+]>C(O)C>[F:5][C:4]([F:7])([F:6])[CH:3]1[CH2:2][NH:23][CH2:22][CH2:21][NH:20]1
Reactant: NCCN(Cc1ccccc1)Cc1ccccc1
Reactant: O=C(CBr)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCO
Product: FC(F)(F)C1CNCCN1
Reaction time: 21 h

Procedure:
A 12.3 g portion of bromo-3,3,3-trifluoropropanone was slowly added to 50 ml of dimethyl sulfoxide and stirred under a dry atmosphere for 21 hours and then diluted to 100 ml with ethanol. A solution of 31 g of N,N-dibenzylethylenediamine in 100 ml of ethanol was added dropwise and the mixture was stirred for 8 hours. A 2.43 g portion of sodium borohydride was added over 30 minutes, this mixture was stirred overnight then the ethanol was removed. The dimethyl sulfoxide residue was dissolved in water and extracted with dichloromethane. The extracts were combined, washed with water and brine and then subjected to flash chromatography on a silica gel column, eluting with ether:hexane (3:7). The 2-(trifluoromethyl)dibenzylpiperazine was dissolved in 25 ml of ethanol in an argon flushed Parr bottle. A 0.63 g portion of 10% palladium on carbon was added and the mixture was shaken under 47 lbs. of hydrogen pressure overnight at 40° C. Filtration and evaporation of the solvent gave 0.55 g of 2-(trifluoromethyl)piperazine as a semi-solid.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][OH:11])[CH:7]=[CH:6][C:5]=1[C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1[F:20].[CH:23]1([CH:26]([C:33]2[C:38]([F:39])=[CH:37][N:36]=[C:35](O)[CH:34]=2)[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:25][CH2:24]1>C1(C)C=CC=CC=1.[Ag]=O>[CH:23]1([CH:26]([C:33]2[C:38]([F:39])=[CH:37][N:36]=[C:35]([O:11][CH2:10][C:8]3[CH:7]=[CH:6][C:5]([C:12]4[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=4[F:20])=[C:4]([CH2:3][C:2]([CH3:22])([CH3:21])[CH3:1])[N:9]=3)[CH:34]=2)[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:25][CH2:24]1
Reactant: COc1ccc(F)c(-c2ccc(CO)nc2CC(C)(C)C)c1
Reactant: CCOC(=O)CC(c1cc(O)ncc1F)C1CC1
Agent: O=[Ag]
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(c1cc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)ncc1F)C1CC1
Yield: 59.4 %

Procedure:
Silver oxide (327 mg) was added to a solution of (6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methanol (415 mg) and ethyl 3-cyclopropyl-3-(5-fluoro-2-hydroxypyridin-4-yl)propanoate (300 mg) in toluene (5 mL) at room temperature, and the mixture was heated under reflux for 2 hr. The reaction mixture was filtered, and the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (379 mg) as a pale-yellow oil.
Reaction SMILES: [CH:1](=O)[CH3:2].Cl.[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][N:16]([C:19]2[CH:20]=[CH:21][C:22]3[C:23]4[CH2:33][NH:32][CH2:31][CH2:30][CH2:29][C:24]=4[N:25]([CH3:28])[C:26]=3[CH:27]=2)[C:15](=[O:34])[CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.CC(O)=O>[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][N:16]([C:19]2[CH:20]=[CH:21][C:22]3[C:23]4[CH2:33][N:32]([CH2:1][CH3:2])[CH2:31][CH2:30][CH2:29][C:24]=4[N:25]([CH3:28])[C:26]=3[CH:27]=2)[C:15](=[O:34])[CH:14]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC=O
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CNCCC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCN1CCCc2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc3n2C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.2 %

Procedure:
Acetaldehyde (50 μL, 0.88 mmol) and picoline borane complex (47 mg, 0.43 mmol) were added to a suspension of 4-(benzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one hydrochloride (64 mg, 0.18 mmol) in 10:1 CH2Cl2/AcOH (5.0 mL), and the resulting solution was stirred at ambient temperature for 2 h. Additional acetaldehyde (50 μL, 0.88 mmol) was added to the solution, and the resulting mixture was stirred for 18 h. The mixture was neutralized with saturated NaHCO3 solution and extracted with CH2Cl2 (3×20 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated to dryness. Flash chromatography (12 g ISCO CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 2 column volumes to 0:100 over 20 column volumes) provided the title compound (34 mg, 54%) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 7.56 (d, J=7.5 Hz, 1H), 7.48-7.41 (m, 5H), 7.39-7.37 (m, 1H), 7.35 (d, J=2.0 Hz, 1H), 6.87 (dd, J=8.5, 2.0 Hz, 1H), 6.07 (dd, J=7.5, 3.0 Hz, 1H), 5.96 (d, J=3.0 Hz, 1H), 5.14 (s, 2H), 3.88 (s, 2H), 3.66 (s, 3H), 3.03-3.01 (m, 2H), 2.94 (t, J=5.5 Hz, 2H), 2.46-2.42 (m, 2H), 1.78-1.76 (m, 2H), 1.01 (t, J=7.0 Hz, 3H); ESI MS m/z 428 [M+H]+.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:25][CH3:26])[C@H:3]([N:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=2)[C:12]1=[O:24])[C:4]([O:6]C(C)(C)C)=[O:5].FC(F)(F)C(O)=O>ClCCl>[CH3:1][C@@H:2]([CH2:25][CH3:26])[C@H:3]([N:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=2)[C:12]1=[O:24])[C:4]([OH:6])=[O:5]
Reactant: CC[C@H](C)[C@@H](C(=O)OC(C)(C)C)N1CCN(Cc2cccc(C)n2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H](C(=O)O)N1CCN(Cc2cccc(C)n2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 115.6 %

Procedure:
A solution containing the product from Example 7A (6.15 g, 17.0 mmol) in dichloromethane (150 mL) was treated with trifluoracetic acid (50 mL), stirred at 25° C. for 2 hours and concentrated. The residue was purified by reversed phase chromatography on a C18 column, eluting with 5-100% acetonitrile in water (0.1% TFA) to give the title compound (6.0 g, 84% yield) as the trifluoroacetic acid salt.
Reaction SMILES: [N+:1]([C:4]1[S:8][CH:7]=[C:6]([C:9]#[N:10])[C:5]=1[C:11]1[N:12]=[CH:13][S:14][CH:15]=1)([O-])=O.O.O.[Sn](Cl)Cl>C(OCC)(=O)C>[NH2:1][C:4]1[S:8][CH:7]=[C:6]([C:9]#[N:10])[C:5]=1[C:11]1[N:12]=[CH:13][S:14][CH:15]=1
Reactant: N#Cc1csc([N+](=O)[O-])c1-c1cscn1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1csc(N)c1-c1cscn1
Temperature: 25 °C
Yield: 37.4 %

Procedure:
To a solution of 5-nitro-4-(thiazol-4-yl)thiophene-3-carbonitrile (0.071 g, 0.31 mmol) in ethyl acetate (3 mL) was added tin (II) chloride dihydrate (0.29 g, 1.27 mmol). The reaction mixture was heated in an oil bath set at 70° C. under condenser. After 20 min. the mixture was cooled to RT and concentrated under reduced pressure. Purification by flash chromatography (silica, 40:60 ethyl acetate/hexane) gave 5-amino-4-(thiazol-4-yl)thiophene-3-carbonitrile (24 mgs, 38%) Retention time (min)=1.837, method [4], MS(ESI) 208.0 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:15][CH3:16])[CH3:14])=[CH:9][CH:8]=1)=[O:5].[OH:21][CH2:22][CH2:23][O:24][C:25]1[C:32]([CH3:33])=[CH:31][C:28]([CH:29]=O)=[CH:27][C:26]=1[CH3:34].S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[CH:13]([C:10]1[CH:11]=[CH:12][C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:1]=[C:29]2[C:28]2[CH:31]=[C:32]([CH3:33])[C:25]([O:24][CH2:23][CH2:22][OH:21])=[C:26]([CH3:34])[CH:27]=2)=[CH:8][CH:9]=1)([CH2:15][CH3:16])[CH3:14]
Reactant: Cc1cc(C=O)cc(C)c1OCCO
Reactant: CCC(C)c1ccc(NC(=O)c2ccccc2N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCC(C)c1ccc(-n2c(-c3cc(C)c(OCCO)c(C)c3)nc3ccccc3c2=O)cc1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To a solution of 2-amino-N-(4-sec-butylphenyl)benzamide (1.27 g, 4.73 mmol) in N,N-dimethyl acetamide (20 mL) were added 4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde (D) (0.92 g, 4.7 mmol), sodium hydrogen sulphite (58.5 wt %) (0.95 g, 5.2 mmol) and p-toluenesulfonic acid (0.18 g, 0.95 mmol). The reaction mixture was stirred at 120° C. overnight, and cooled to room temperature. The solvent was removed under reduced pressure and water (100 mL) was added. The mixture was extracted with ethyl acetate (200 mL). The organic phase was washed with water (2×100 mL), then brine (100 mL), and dried over anhydrous Na2SO4. Removal of solvent gave crude compound, which was purified by the Simpliflash system (30% ethyl acetate in hexanes as eluent) to give the title compound (E) as a white solid. Yield: 0.34 g (16%). MP 152-153° C. 1H-NMR (400 MHz, CDCl3): δ 8.36-8.34 (m, 1H), 7.81-7.80 (m, 2H), 7.54-7.50 (m, 1H), 7.13 (d, J=6.26 Hz, 2H), 7.06 (d, J=8.21 Hz, 2H), 6.98 (s, 2H), 3.92-3.88 (m, 2H), 3.78-3.76 (m, 2H), 2.56-2.54 (m, 1H), 2.13 (s, 6H), 2.06 (t, J=6.26 Hz, 1H), 1.60-1.48 (m, 2H), 1.20 (d, J=7.04 Hz, 3H), 0.727 (t, J=7.43 Hz, 3H). MS (ES+) m/z: 443.01 (M+1) (100%).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[C:28]([N+:29]([O-])=O)=[CH:27][C:10]([O:11][CH2:12][C:13]2([NH:16][C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:15][CH2:14]2)=[C:9]([O:32][CH3:33])[CH:8]=1)=[O:6]>CC(O)=O.CCOC(C)=O.[Fe]>[OH:6][C:5]1[C:7]2[C:28](=[CH:27][C:10]([O:11][CH2:12][C:13]3([NH:16][C:17]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:14][CH2:15]3)=[C:9]([O:32][CH3:33])[CH:8]=2)[N:29]=[CH:3][CH:4]=1
Reactant: COc1cc(C(=O)C=CN(C)C)c([N+](=O)[O-])cc1OCC1(NC(=O)OCc2ccccc2)CC1
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1cc2c(O)ccnc2cc1OCC1(NC(=O)OCc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
A mixture of the compound of Example 3 (1.5 g, 3.2 mmol) and powder iron (1.8 g, 32 mmol) in AcOH (15 mL) was stirred a 80° C. for 2 h. The reaction mixture was cooled at room temperature, diluted with AcOEt (150 mL), filtered and washed with 50 ml of AcOEt. The filtration liquors were combined, washed with water (2×100 mL) and an NaHCO3 saturated solution (2×100 mL), dried and evaporated to give 1-[(4-hydroxy-6-methoxyquinolin-7-yloxy)methyl]-N-benzyloxycarbonyl-1-aminocyclopropane (1.2 g, yield: 95%) as a yellow solid.
Reaction SMILES: [CH3:1]C(=C)C[Mg]Cl.[Cl:7][C:8]1[CH:31]=[CH:30][C:11]([CH2:12][N:13]2[C:17]3([CH2:21][CH2:20][N:19]([CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[C:18]3=[O:28])[CH2:16][C:15](=[O:29])[CH2:14]2)=[CH:10][CH:9]=1>C1COCC1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][N:13]2[C:17]3([CH2:21][CH2:20][N:19]([CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[C:18]3=[O:28])[CH2:16][C:15]([OH:29])([CH3:1])[CH2:14]2)=[CH:30][CH:31]=1
Reactant: O=C1CN(Cc2ccc(Cl)cc2)C2(CCN(C3CCCCC3)C2=O)C1
Reactant: C=C(C)C[Mg]Cl
Solvent: C1CCOC1
Product: CC1(O)CN(Cc2ccc(Cl)cc2)C2(CCN(C3CCCCC3)C2=O)C1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
2-Methylallylmagnesium chloride in THF (3.0 M, 0.074 mL) was added to a solution of 1-(4-chlorobenzyl)-7-cyclohexyl-1,7-diazaspiro[4.4]nonane-3,6-dione (0.040 g, 0.00011 mol) in THF (1.0 mL, 0.012 mol) and the resulting mixture was stirred at 50° C. for 1 h. The reaction mixture was then allowed to cool to RT and was then quenched by the addition of saturated NH4Cl. The crude reaction mixture was purified by prep. HPLC to afford the desired product. LC/MS: 377.2 (M+1H)+.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[C:6]1([N+:12]2[C:17](Cl)=[CH:16][C:15]([NH2:19])=[CH:14][N:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.[NH2:21][NH2:22]>O>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[C:6]1([N+:12]2[C:17]([NH:21][NH2:22])=[CH:16][C:15]([NH2:19])=[CH:14][N:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NN
Reactant: Nc1cn[n+](-c2ccccc2)c(Cl)c1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Product: NNc1cc(N)cn[n+]1-c1ccccc1
Reaction time: 3 h

Procedure:
15.3 parts of 1-phenyl-4-amino-6-chloropyridazinium perchlorate is dissolved in 200 parts of water at 80° to 90° C; 5 parts of hydrazine hydrate is added and the whole is boiled for 3 hours. The reaction solution is concentrated to about half its volume and cooled. 13 parts (81.3% of theory, as hydrate) of 1-phenyl-4-amino-6-hydrazinopyridazinium perchlorate is obtained; C10H12O4N5Cl. H2O, obtained with 1 mole of water of crystallization when recrystallized from water. Melting point 63° to 65° C.
Reaction SMILES: Cl[CH2:2][C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[CH3:11][CH:12]([CH3:28])[C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:17]=1)=[O:14]>>[OH:4][C@@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:2][N:25]1[CH2:26][CH2:27][CH:22]([C:18]2[CH:17]=[C:16]([NH:15][C:13](=[O:14])[CH:12]([CH3:11])[CH3:28])[CH:21]=[CH:20][CH:19]=2)[CH2:23][CH2:24]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O[C@H](CCl)c1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(C[C@@H](O)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using (1S)-2-chloro-1-phenylethanol and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 367.2 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[NH2:8][C:9]1[C:14]([Cl:15])=[CH:13][C:12]([Cl:16])=[C:11]([NH2:17])[CH:10]=1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[NH2:8][C:9]1[CH:10]=[C:11]([NH:17][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][Cl:1])[C:12]([Cl:16])=[CH:13][C:14]=1[Cl:15]
Reactant: O=C(Cl)CCCCl
Reactant: Nc1cc(N)c(Cl)cc1Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Nc1cc(NC(=O)CCCCl)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
14.1 g (0.10 mol) of γ-chlorobutyryl chloride in 50 ml of chloroform are added dropwise in the course of 1 hour, at 10°-15° C., to a solution of 17.7 g (0.10 mol) of 1,3-diamino-4,6-dichlorobenzene and 8.7 g (0.11 mol) of pyridine in 500 ml of chloroform. The mixture is then stirred for 2 hours at room temperature, the solution is washed with water and filtered through 40 g of silica gel and the filtrate is concentrated. The resulting product is recrystallised from hexane/toluene. Yield: 13.5 g; melting point 125°-128° C.
Reaction SMILES: CN(C=O)C.[CH3:6][O:7][C:8](=[O:37])[N:9]=[C:10]([S:35][CH3:36])[C:11]([C:25]1[CH:30]=[C:29]([OH:31])[CH:28]=[C:27]([O:32][CH2:33][CH3:34])[CH:26]=1)=[N:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([CH3:24])[O:21][N:20]=2)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:45][CH2:46][O:47][CH:48]1[CH2:53][CH2:52][CH2:51][CH2:50][O:49]1>O>[CH3:6][O:7][C:8](=[O:37])[N:9]=[C:10]([S:35][CH3:36])[C:11]([C:25]1[CH:30]=[C:29]([O:31][CH2:45][CH2:46][O:47][CH:48]2[CH2:53][CH2:52][CH2:51][CH2:50][O:49]2)[CH:28]=[C:27]([O:32][CH2:33][CH3:34])[CH:26]=1)=[N:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([CH3:24])[O:21][N:20]=2)=[CH:15][CH:14]=1
Reactant: BrCCOC1CCCCO1
Reactant: CCOc1cc(O)cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(OCCOC2CCCCO2)cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1 ml of a DMF solution containing 80 mg of {2-(3-ethoxy-5-hydroxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester (Example (78a)), 200 mg of potassium carbonate and 0.1 ml of 2-(2-bromoethoxy)tetrahydro-2H-pyran were added. The resulting mixture was stirred at room temperature overnight, and then water was added thereto. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and then concentrated. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give {2-{3-ethoxy-5-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester (76 mg) as a yellow oil.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[C:13]([CH:17]([NH:23][C:24]([C@@H:26]2[CH2:31][CH2:30][CH2:29][N:28]([C:32](=[O:48])[CH2:33][CH2:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]3)[CH2:27]2)=[O:25])[CH2:18][C:19]([O:21]C)=[O:20])[CH:14]=[N:15][CH:16]=1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>CO>[C:44]([O:43][C:41]([N:38]1[CH2:39][CH2:40][CH:35]([CH2:34][CH2:33][C:32]([N:28]2[CH2:29][CH2:30][CH2:31][C@@H:26]([C:24]([NH:23][CH:17]([C:13]3[CH:14]=[N:15][CH:16]=[C:11]([C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[O:4][CH2:3][CH2:2][F:1])[CH:12]=3)[CH2:18][C:19]([OH:21])=[O:20])=[O:25])[CH2:27]2)=[O:48])[CH2:36][CH2:37]1)=[O:42])([CH3:47])([CH3:46])[CH3:45]
Reactant: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(-c2ccccc2OCCF)c1
Agent: [Ba+2]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CCC(=O)N2CCC[C@@H](C(=O)NC(CC(=O)O)c3cncc(-c4ccccc4OCCF)c3)C2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
73 mg (0.11 mmol) tert-butyl 4-(3-{(3R)-3-[(1-{5-[2-(2-fluoroethoxy)phenyl]pyridin-3-yl}-3-methoxy-3-oxopropyl)carbamoyl]piperidin-1-yl}-3-oxopropyl)piperidine-1-carboxylate were dissolved in 13 ml methanol. 344 mg (1.09 mmol) barium hydroxide octahydrate were added. The mixture was stirred at room temperature for 20 hours and then concentrated to give 3-({[(3R)-1-{3-[1-(tert-butoxycarbonyl)piperidin-4-yl]propanoyl}piperidin-3-yl]carbonyl}amino)-3-{5-[2-(2-fluoroethoxy)phenyl]pyridin-3-yl}propanoic acid.