Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)=[CH:17][CH:16]=2)[CH:7]=1.[S:27]1[CH:31]=[CH:30][N:29]=[C:28]1[S:32](Cl)(=[O:34])=[O:33]>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)=[CH:17][CH:16]=2)[S:32]([C:28]2[S:27][CH:31]=[CH:30][N:29]=2)(=[O:34])=[O:33])[CH:7]=1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-n3cccn3)cc2)c1
Reactant: O=S(=O)(Cl)c1nccs1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-n3cccn3)cc2)S(=O)(=O)c2nccs2)c1

Procedure:
The title compound of Step A was prepared following the method described in Step A of Example 1 from 3-{3-[(4-pyrazol-1-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, prepared in Step A of Example 11 h, and thiazole-2-sulfonyl chloride using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 7.95 (d, 1H), 7.88 (d, 1H), 7.69 (d, 1H), 7.60 (d, 1H), 7.54 (d, 2H), 7.19-7.12 (m, 3H), 7.04 (m, 1H), 6.93 (m, 2H), 6.44 (m, 1H), 4.49 (s, 2H), 4.46 (s, 2H), 3.64 (s, 3H), 2.82 (t, 2H), 2.51 (t, 2H); MS 497 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([CH:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)=[O:11])=[N:4][CH:5]=[CH:6][N:7]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([CH:12]2[CH2:17][CH2:16][CH:15]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[CH2:14][CH2:13]2)=[O:11])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: C1COCCN1
Reactant: O=C1CCC(C(=O)NCc2nccnc2Cl)CC1
Product: O=C(NCc1nccnc1Cl)C1CCC(N2CCOCC2)CC1

Procedure:
According to the procedure described in example 7 step 7a N-((3-chloropyrazin-2-yl)methyl)-4-oxocyclohexanecarboxamide (1 g) and morpholine (0.44 mL) gave after work-up N-((3-chloropyrazin-2-yl)methyl)-4-morpholinocyclohexanecarboxamide (1.28 g). This crude product was used in the next step without further purification.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C1C=CC=CC=1.[NH3:24]>ClC1C=CC=CC=1Cl>[C:1](=[NH:24])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: N
Agent: O=C(O)c1ccccc1
Solvent: Clc1ccccc1Cl
Product: N=C(c1ccccc1)c1ccccc1
Reaction time: 3 h
Yield: 26 %

Procedure:
36.2 Grams of benzophenone, 50 ml of o-dichlorobenzene and 0.5 g of benzoic acid were fed to a reactor. Ammonia gas was passed through the reaction mixture under 6 atmospheres at 160° C. of the reaction temperature at a feed rate of 0.2 l/min. (NTP) continuously. The reaction was conducted for 3 hours and benzophenoneimine was obtained in yield of 26%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH:12]2[C:16]([CH3:17])=[N:15][NH:14][N:13]2[CH3:18])=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:20]([O:22][CH2:23][CH2:24][N:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[C:26]1[N:34]1[CH2:40][CH2:39][CH2:38][N:37]([CH2:41][CH2:42][C:43]2([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH2:47][CH2:46][NH:45][CH2:44]2)[CH2:36][CH2:35]1)[CH3:21]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH:12]2[C:16]([CH3:17])=[N:15][NH:14][N:13]2[CH3:18])=[CH:8][C:4]=1[C:5]([N:45]1[CH2:46][CH2:47][C:43]([CH2:42][CH2:41][N:37]2[CH2:38][CH2:39][CH2:40][N:34]([C:26]3[N:25]([CH2:24][CH2:23][O:22][CH2:20][CH3:21])[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[N:27]=3)[CH2:35][CH2:36]2)([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:44]1)=[O:7]
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: COc1ccc(C2C(C)=NNN2C)cc1C(=O)O
Agent: Cl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(C5C(C)=NNN5C)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 56.1 using 2-methoxy-5-(3,5-dimethyl-4H-triazol-4-yl)benzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: C[N:2](/[CH:4]=[C:5]1/[C:6](=[O:15])[NH:7][CH2:8][C:9]2[C:14]/1=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:3].[NH:16]1[CH:20]=[C:19]([C:21]2[CH:27]=[CH:26]C(N)=[CH:23][CH:22]=2)[N:18]=[CH:17]1>C1(C)C=CC=CC=1>[NH:16]1[CH:20]=[C:19]([C:21]2[CH:27]=[CH:26][C:3]([NH:2]/[CH:4]=[C:5]3\[C:6](=[O:15])[NH:7][CH2:8][C:9]4[C:14]\3=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:23][CH:22]=2)[N:18]=[CH:17]1
Reactant: CN(C)/C=C1/C(=O)NCc2ccccc21
Reactant: Nc1ccc(-c2c[nH]cn2)cc1
Solvent: Cc1ccccc1
Product: O=C1NCc2ccccc2/C1=C/Nc1ccc(-c2c[nH]cn2)cc1
Temperature: 110 °C
Yield: 27.8 %

Procedure:
A toluene (3 mL) solution containing (4E)-4-[(dimethylamino)methylene]-1,4-dihydro-3(2H)-isoquinolinone (300 mg, 1.48 mmol) and 4-(1H-imidazol-4-yl)aniline (265 mg, 1.66 mmol) is heated at 110° C. for 4 h. Using the same workup as example 1, 0.13 g (28%) orange solid is obtained: mp 151-152° C. (dec.); HRMS (ESI) m/z calcd for C19H16N4O 317.13969. found 317.13894 (M+H)+1.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][O:6][C:7]1[C:8]([N+:24]([O-:26])=[O:25])=[C:9]([C:19]([F:23])=[C:20]([F:22])[CH:21]=1)[NH:10][C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:12]=1[F:18])C.B(F)(F)F>C(Cl)Cl>[F:22][C:20]1[C:21]2[CH:4]=[CH:5][O:6][C:7]=2[C:8]([N+:24]([O-:26])=[O:25])=[C:9]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:12]=2[F:18])[C:19]=1[F:23]
Reactant: CCOC(COc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1[N+](=O)[O-])OCC
Agent: FB(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1c(Nc2ccc(I)cc2F)c(F)c(F)c2ccoc12
Reaction time: 2 h
Yield: 69.5 %

Procedure:
For scale up, a solution of 3-(2,2-diethoxyethoxy)-5,6-difluoro-N-(2-fluoro-4-iodophenyl)-2-nitroaniline (75 g) in 300 mL of DCM was added quickly into a solution of BF3.ET2O in 100 mL of DCM at 28-32° C. with further stirring for 15 minutes. After about 2 hours, analysis showed complete conversion. The solution was then quenched by 1N NaOH (dropwise) at a temperature below 30° C. to pH 10 before separating. DCM was then washed with water twice to a pH of about 7 and concentrated to dryness. 210 mL of MBTE was then added. The suspension was stirred for 30 minutes, filtered and dried to give 43 g of an orange solid. 1H NMR (CDCl3, 400 MHz): δ 8.80 (bs, 1H), 7.75 (d, 1H), 7.48 (dd, 1H), 7.41 (d; 1H); 6.97 (d, 1H), 6.75-6.80 (m, 1H).
Reaction SMILES: [C:1]([NH:11][CH2:12][C:13]([OH:15])=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[Cl:16][CH2:17]I.C(N(CC)CC)C>CN(C=O)C>[Cl:16][CH2:17][O:14][C:13](=[O:15])[CH2:12][NH:11][C:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: ClCI
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CNC(=O)OCc1ccccc1)OCCl

Procedure:
A solution of N-carbobenzoxy-glycine (4.2 g), chloroiodomethane (6.0 ml), and triethylamine (3.5 ml) in DMF (10 ml) was stirred for 2 hours at room temperature. The mixture was worked up and purified in the same way as described in Example 6A to yield the desired compound as a slightly yellowish oil.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][C:3](=O)[CH2:2]1.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.[Br:20][C:21]1[CH:22]=[C:23]2[C:27](=[C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:29]=1)[NH:26][CH:25]=[CH:24]2.C([SiH](CC)CC)C>ClCCl>[Br:20][C:21]1[CH:22]=[C:23]2[C:27](=[C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:29]=1)[NH:26][CH:25]=[C:24]2[CH:3]1[CH2:4][CH2:5][CH2:6][S:1][CH2:2]1
Reactant: CCOC(=O)c1cc(Br)cc2cc[nH]c12
Reactant: O=C1CCCSC1
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc(Br)cc2c(C3CCCSC3)c[nH]c12
Temperature: 0 °C
Yield: 40.7 %

Procedure:
Dihydro-2H-thiopyran-3(4H)-one (0.217 g, 1.86 mmol) was dissolved in dichloromethane (23 mL) in an oven dried flask containing 3 Å molecular sieves and stirred under argon at 0° C. TMS-OTf (0.414 g, 1.86 mmol, 0.33 mL) was added slowly to the mixture over 10 min. Ethyl 5-bromo-1H-indole-7-carboxylate (0.5 g, 1.86 mmol) was dissolved in DCM (7 mL) and added to the reaction via syringe pump over 2 hours, after which it was stirred for 3 hours between 0 and 10° C. The reaction was cooled to 0° C. and triethylsilane (0.325 g, 0.44 mL, 2.8 mmol) was added all at once and the reaction was stirred at room temperature for 18 hours. The reaction was then quenched with a saturated sodium bicarbonate solution and extracted with DCM. The combined organics were washed with water. The combined aqueous layers were back-extracted with DCM. The combined organics were washed with brine, dried with MgSO4, and concentrated. The crude compound was purified on a Combiflash silica column with 5-25% EA/Hexane to give 0.279 g (40%) of the title compound.
Reaction SMILES: N1CCCCC1.[CH3:7][C:8]1([CH3:24])[O:12][CH:11]([CH2:13][O:14][CH2:15][C:16](=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:10][O:9]1.[Cl:25][C:26]1[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=O>CC(O)C>[Cl:25][C:26]1[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=[C:17]([C:16]([CH2:15][O:14][CH2:13][CH:11]1[CH2:10][O:9][C:8]([CH3:7])([CH3:24])[O:12]1)=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: CCOC(=O)CC(=O)COCC1COC(C)(C)O1
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: CCOC(=O)C(=Cc1cccc(Cl)c1Cl)C(=O)COCC1COC(C)(C)O1
Temperature: 25 °C
Yield: 41.5 %

Procedure:
Piperidine (1.0 g) was added dropwise over 5 minutes to a stirred, ice-cooled solution of ethyl 4-{(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy}acetoacetate (26.0 g) (see Preparation 5) and 2,3-dichlorobenzaldehyde (17.5 g) in 2-propanol (200 ml) and the mixture was stirred with ice-cooling for 2 hours and at room temperature for 14 hours. The mixture was evaporated and the residue twice taken up in toluene and evaporated. The residue was purified by chromatography on silica (150 g) using toluene plus 0-40% ethyl acetate as the eluant. Appropriate fractions were combined and evaporated to give essentially pure ethyl 2-(2,3-dichlorobenzylidene)-4-{(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy}acetoacetate (17.3 g) as an oil. A solution of this oil in 2-propanol (150 ml) was treated with methyl 3-aminocrotonate (5.0 g) and the mixture stirred at room temperature for 24 hours. The mixture was evaporated and the residue twice taken up in toluene and evaporated. The residue was purified by chromatography on SiO2 (110 g) using toluene plus 0-10% ethyl acetate as the eluant. Appropriate fractions were combined and evaporated to give the title compound (2.75 g), m.p. 135°-137° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([N:15]=[C:16]=[S:17])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[NH3:18]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:16]([NH2:18])=[S:17])=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccccc2N=C=S)cc1
Reactant: N
Solvent: CCO
Product: COc1ccc(-c2ccccc2NC(N)=S)cc1

Procedure:
Reaction of 4'-methoxy-2-biphenylylisothiocyanate (12.7 g) in ethanol (30 ml) with 28% aqueous ammonia (20 ml) at 0° C. for 2 hours gave N-(4'-methoxy-2-biphenylyl)thiourea (m.p. 158°-159° C.).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1.N([O-])=O.[Na+].[BrH:14]>O>[Br:14][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1
Reactant: Br
Reactant: Cc1ccc(N)cc1O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(Br)cc1O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 20 %

Procedure:
5-Amino-2-methylphenol (5 g, 0.04 mol) was dissolved in HBr (20 mL) and H2O (20 mL) was added dropwise maintaining a temperature below 0° C. The resulting mixture was stirred for 5 min and a solution of NaNO2 (2.76 g, 0.04 mol) in H2O (7.5 mL) was added dropwise. The mixture was stirred for 30 min below 0° C. Then a solution of cuprous bromide (5.73 g, 0.04 mol) in HBr (7.5 mL) cooled to 0° C. was added dropwise. The resulting mixture was warmed to RT and then refluxed for 2 h. The reaction was cooled and filtered through celite. The filtrate was diluted with water and extracted with EtOAc. The organic extract was dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (2.5% EtOAc-97.5% Hexane) to give the pure title compound (1.57 g, 20%). 1H NMR (500 MHz, CDCl3): δ 6.97 (s, 3H), 4.89 (s, 1H), 2.19 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1N.N([O-])=[O:11].[Na+].O>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[OH:11]
Reactant: O=N[O-]
Reactant: Nc1cc(Cl)ccc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Oc1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To 400 ml of concentrated sulfuric acid in a 2-liter flask was added 145 grams (0.895 mole) of solid 2,5-dichloroaniline over a 5-minute period. Over the addition period the solution exothermically reached a temperature of 60° C. The sulfate salt solution of 2,5-dichloroaniline was cooled in an ice bath to about 5° C. and a solution of 65.6 grams (0.95 mole) of vacuum dried sodium nitrite in 400 ml concentrated sulfuric acid was added at such rate as to cause no exotherm. The mixture was stirred at 0° C. to 5° C. for about 30 minutes, was warmed to ambient temperature and stirred for an additional one hour. 450 ml of water was slowly added to the stirred mixture and the diluted mixture was steam distilled for about 15 minutes. An additional 450 ml of water was slowly added and the mixture steam distilled for about 75 minutes. The head temperature at the start of distillation was 145° C., the head temperature at the completion of distillation was 125° C., and the final pot temperature was 157° C. The distillate was transferred to a separatory funnel and extracted with 300 ml, 200 ml and 100 ml portions of methylene chloride. The extracts were combined and concentrated on a rotary evaporator at 55° C. and 40 mm Hg to remove methylene chloride. 135 grams, corresponding to a 92 percent yield, of slightly orange-colored 2,5-dichlorophenol was thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[N:12](S(C2C=CC=CC=2)(=O)=O)[C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH2:10].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[NH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH2:10]
Reactant: C=C(c1ccc(Cl)cc1Cl)c1cc2ccccc2n1S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C=C(c1cc2ccccc2[nH]1)c1ccc(Cl)cc1Cl
Yield: 89.2 %

Procedure:
In 30 ml of ethanol was dissolved 2.5 g of 2-[1-(2,4-dichlorophenyl)vinyl]-1-phenylsulfonylindole. Thereto was added 20 ml of a 5 N aqueous sodium hydroxide solution. The mixture was refluxed for 20 hours. The solvent was removed by distillation under reduced pressure. The residue was mixed with 20 ml of water. The mixture was adjusted to pH 7.0 with diluted hydrochloric acid, and extracted with 100 ml of ethyl acetate. The extract was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 1.5 g of 2-[1-(2,4-dichlorophenyl)vinyl]indole as a light yellow oily material.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>CC(C)=O>[CH2:19]([O:18][C:16](=[O:17])[CH:15]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:21])[CH3:20]
Reactant: Oc1ccccc1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)Oc1ccccc1
Temperature: 25 °C
Yield: 103 %

Procedure:
Phenol (24.28 g, 0.25 mol), potassium carbonate (39.2 g 0.28 mol), and ethyl 2-bromoproionate (46.7 g, 0.25 mol) were combined in acetone (200 mL) and stirred at room temperature over night. The acetone was removed in vacuo, the residue was purified in silica to provide a golden oil (50 g, 90%), Rf=0.80 in 10:1 ethyl acetate: petroleum ether.
Reaction SMILES: C1(C)C=CC(S(O[CH:11](C)[C:12](OC)(OC)[C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH3:24])[CH:19]=3)[CH:14]=2)(=O)=O)=CC=1.CO.[C:33](=[O:36])(O)[O-:34].[Na+]>O>[CH3:24][O:23][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([CH:12]([CH3:11])[C:33]([OH:34])=[O:36])[CH:22]=[CH:21]2
Reactant: O=C([O-])O
Reactant: COc1ccc2cc(C(OC)(OC)C(C)OS(=O)(=O)c3ccc(C)cc3)ccc2c1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc2cc(C(C)C(=O)O)ccc2c1

Procedure:
A mixture of the oil, 1,1-dimethoxy-1-(6-methoxy-2-naphthyl)prop-2-yl p-toluenesulfonate, from Example 30, 50 ml of water, 100 ml of methanol and 19.5 g of sodium bicarbonate is refluxed (70° C.) for 14 hours. After that time, the mixture is cooled, poured into 6 volumes of water and extracted twice with 100 ml of toluene. The aqueous layer is acidified with concentrated hydrochloric acid to a pH of about 3 to yield 4.8 g of 2-(6-methoxy-2-naphthyl)propionic acid (melting point: 151.5°-153° C.).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[C:8]([NH:13][C:14]2[C:19]([CH2:20]O)=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:9]=[C:10]([Cl:12])[CH:11]=1>C(Cl)Cl>[Cl:3][CH2:20][C:19]1[C:14]([NH:13][C:8]2[CH:7]=[C:6]([Cl:5])[CH:11]=[C:10]([Cl:12])[CH:9]=2)=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cccnc1Nc1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Product: ClCc1cccnc1Nc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Thionyl chloride (15 mL) was added slowly to a solution of 6.0 g of the above alcohol in 100 mL methylene chloride and the reaction stirred at room temperature for 18 hr. The reaction was concenterated, the residue dissolved in 150 mL methylene chloride and washed with 10% NaHCO3 solution. The organic layer was dried (Na2SO4) and concentrated to give 6.3 g of (3-chloromethylpyridin-2-yl) (3,5-dichlorophenyl)amine.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][CH:6]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH2:23][CH2:24][O:25][NH:26][C:27]3[NH:28][CH2:29][CH2:30][N:31]=3)=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.[OH-].[Li+].Cl>CO.O>[NH:28]1[CH2:29][CH2:30][N:31]=[C:27]1[NH:26][O:25][CH2:24][CH2:23][O:22][C:18]1[CH:17]=[C:16]2[C:21](=[CH:20][CH:19]=1)[N:13]([CH:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:5][C:4]([OH:32])=[O:3])[CH:14]=[CH:15]2
Reactant: CCOC(=O)CC(c1ccccc1)n1ccc2cc(OCCONC3=NCCN3)ccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CC(c1ccccc1)n1ccc2cc(OCCONC3=NCCN3)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
3-(5-{2-[N-(4,5-dihydro-1H-imidazol-2-yl)-aminooxy]-ethoxy}-indol-1-yl)-3-phenyl-propionic acid ethyl ester (0.24 g, 0.55 mmol) was dissolved in 70% methanol/water (4 mL). Lithium hydroxide monohydratate (0.70 g, 4.67 mmol) was added and the reaction was stirred for 16 h at room temperature under an argon atmosphere. The solution was neutralized with 1.0 N HCl (4.67 mL) and the solvent was evaporated under vacuum. The crude mixture was purified via column chromatography with silica gel, eluting with 10% methanol/dichloromethane to afford the title compound (74% yield). 1H NMR (DMSO-d6) δ 7.68 (d, 1H, J=3.2 Hz), 7.42 (d, 1H, J=9.0 Hz), 7.20–7.34 (m, 5H), 7.05 (d, 1H, J=2.5 Hz), 6.75 (dd, 1H, J=2.5, 9.0 Hz), 6.40 (d, 1H, J=3.0 Hz), 5.96 (m, 1H), 4.16 (m, 4H), 3.59 (br s, 4H), 3.36 (m, 2H). Mass Spectrum (LCMS, ESI) calculate for C22H25N4O4 409.2 (M+H); found 409.2.
Reaction SMILES: [O:1]=[C:2]1[C:10](=[C:11]([C:14]#[N:15])[C:12]#[N:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:16]([N:19]3[CH2:23][CH2:22][CH2:21][CH:20]3[CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:18])=[O:17])[CH:8]=2)[NH:3]1.[Br:32][C:33]1[CH:66]=[CH:65][C:36]([CH2:37]N2C3C(=CC(S(N4CCCC4COC4C=CC=CC=4)(=O)=O)=CC=3)C(=O)C2=O)=[CH:35][CH:34]=1>>[Br:32][C:33]1[CH:66]=[CH:65][C:36]([CH2:37][N:3]2[C:4]3[C:9](=[CH:8][C:7]([S:16]([N:19]4[CH2:23][CH2:22][CH2:21][CH:20]4[CH2:24][O:25][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)(=[O:17])=[O:18])=[CH:6][CH:5]=3)[C:10](=[C:11]([C:12]#[N:13])[C:14]#[N:15])[C:2]2=[O:1])=[CH:35][CH:34]=1
Reactant: O=C1C(=O)N(Cc2ccc(Br)cc2)c2ccc(S(=O)(=O)N3CCCC3COc3ccccc3)cc21
Reactant: N#CC(C#N)=C1C(=O)Nc2ccc(S(=O)(=O)N3CCCC3COc3ccccc3)cc21
Product: N#CC(C#N)=C1C(=O)N(Cc2ccc(Br)cc2)c2ccc(S(=O)(=O)N3CCCC3COc3ccccc3)cc21
Yield: 86 %

Procedure:
2-[1-(4-Bromo-benzyl)-2-oxo-5-(2-phenoxymethyl-pyrrolidine-1-sulfonyl)-1,2-dihydro-indol-3-yl-idene]-malononitrile (27d) was prepared according to the same procedure for compound 26 except using 25d, to afford 52 mg (86%) of 27d as a purple solid, mp 237.0° C. (decomp). 1H NMR (300 MHz, CDCl3) δ 8.46 (s, 1H), 7.95 (d, J=8.1 Hz, 1H), 7.51 (d, J=8.4 Hz, 2H), 7.20-7.13 (m, 4H), 6.90 (t, J=7.5 Hz, 1H), 6.79 (d, J=8.4 Hz, 1H), 6.68 (d, J=7.8 Hz, 2H), 4.84 (m, 2H), 4.06 (m, 2H), 3.97 (m, 1H), 3.46 (m, 2H), 2.08-1.86 (m, 4H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH:6]1[CH:11]([NH:12]C(OC(C)(C)C)=O)[CH2:10][CH2:9][CH2:8][N:7]1[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])=[N+:2]=[N-:3].[ClH:30].O1CCOCC1>CO>[ClH:30].[NH2:12][CH:11]1[CH2:10][CH2:9][CH2:8][N:7]([C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21])[CH:6]1[CH2:5][CH2:4][N:1]=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)NC1CCCN(C(=O)OCc2ccccc2)C1CCN=[N+]=[N-]
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: [N-]=[N+]=NCCC1C(N)CCCN1C(=O)OCc1ccccc1

Procedure:
The compound 15 (125 mg), methanol (0.5 mL) and 4N hydrogen chloride-dioxane solution (2 mL) were stirred at room temperature for 1 hour. The reaction solution was concentrated and obtained the title compound (118 mg) having the following physical properties.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:6](=[N:7][S:8][N:9]=2)[C:5]([CH2:11][OH:12])=[CH:4][CH:3]=1>ClCCl.[O-2].[Mn+4].[O-2]>[Br:1][C:2]1[C:10]2[C:6](=[N:7][S:8][N:9]=2)[C:5]([CH:11]=[O:12])=[CH:4][CH:3]=1
Reactant: OCc1ccc(Br)c2nsnc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1ccc(Br)c2nsnc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
To a solution of (7-bromo-benzo[1,2,5]thiadiazol-4-yl)-methanol (Example 5.2) (20.22 g) in dichloromethane (185 ml) was added manganese(IV) oxide (71.7 g). The suspension was stirred at ambient temperature for 16 hours. The reaction mixture was filtered through a plug of Celite®. The filtrate was concentrated to give 7-bromo-benzo[1,2,5]thiadiazole-4-carbaldehyde (16.65 g) as an orange solid. 1H-NMR (400 MHz, CDCl3): 10.74 (s, 1H), 8.11-8.05 (m, 2H) ppm.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[S:7]1[CH:11]=[CH:10][N:9]=[C:8]1[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]([NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:20][C@H:21]([OH:37])[C@@H:22]([NH:30]C(=O)C(F)(F)F)[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:14][CH:13]=1>CO>[S:7]1[CH:11]=[CH:10][N:9]=[C:8]1[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]([NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:20][C@H:21]([OH:37])[C@@H:22]([NH2:30])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)NN(Cc1ccc(-c2nccs2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)NN(Cc1ccc(-c2nccs2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Temperature: 70 °C
Reaction time: 9 h

Procedure:
55 ml of a 1N K2CO3 solution are added dropwise to 3.12 g (5.5 mmol) of 1-[4-(thiazol-2-yl)-phenyl]-4(S)-hydroxy-2-(tert-butoxycarbonyl)amino-5(S)-(trifluoroacetyl)amino-6-phenyl-2-azahexane in 55 ml of methanol and the mixture is stirred at 70° C. for 9 hours. The mixture is cooled and ≈30 ml of methanol are evaporated off; methylene chloride and water are added and the aqueous phase is separated off and extracted with methylene chloride; the organic phases are washed with water, dried (Na2SO4) and concentrated by evaporation, yielding the title compound: HPLC20-100: tRet=1.9; FAB MS (M+H)+=469.