Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[NH:9][CH2:8][CH2:7]2.[CH3:16][N:17]([CH3:23])[C@H:18]([C:20](O)=[O:21])[CH3:19].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C)C=O>[CH3:16][N:17]([CH3:23])[C@@H:18]([CH3:19])[C:20]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([O:3][CH3:2])=[C:12]([N+:13]([O-:15])=[O:14])[CH:11]=2)[CH2:7][CH2:8]1)=[O:21]
Reactant: C[C@@H](C(=O)O)N(C)C
Reactant: COc1cc2c(cc1[N+](=O)[O-])NCC2
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)[C@H](C)N(C)C)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
To a solution of 5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole hydrogen chloride (2 g, 8.67 mmol) in N,N-dimethylformamide (100 mL) was added N,N-dimethyl-L-alanine (1.524 g, 13.01 mmol), PyBOP (13.54 g, 26.0 mmol), and DIPEA (15.14 mL, 87 mmol). After stirring overnight at rt, the solvent removed, residue suspended in dichloromethane (150 mL), washed with water (100 mL), concentrated on the rotovap, and purified by column chromatography (DCM to 5% MeOH/DCM) to give (2S)-N,N-dimethyl-1-[5-(methyloxy)-6-nitro-2,3-dihydro-1H-indol-1-yl]-1-oxo-2-propanamine (2.2 g, 86%). ESIMS (M+H)+=294.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:26]=[CH:27][CH:28]=2)[CH:12]=[C:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[N:6][CH:7]=1.[CH2:29](I)[CH3:30].C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CC(C)=O.O>[CH2:29]([O:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:26]=[CH:27][CH:28]=2)[CH:12]=[C:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:15][CH2:14]2)=[N:6][CH:7]=1)[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(O)cn3)c2)CC1
Reactant: CCI
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOc1ccc(Oc2cccc(C=C3CCN(C(=O)OC(C)(C)C)CC3)c2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
To a stirred solution of tert-butyl 4-(3-(5-hydroxypyridin-2-yloxy)benzylidene)piperidine-1-carboxylate (0.6 g, 1.56 mmol) in acetone (5 mL) was added ethyl iodide (0.304 g, 1.96 mmol), K2CO3 (0.431 g, 3.12 mmol) and 18-crown-6 (0.824 g, 3.12 mmol) at 0° C. The reaction mixture was stirred at RT overnight. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate three times. The organic layer was washed with fresh water and brine solution, dried over Na2SO4 and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (1:19 acetone:hexanes) to give the title compound (610 mg, 95%). 1H NMR (500 MHz, CDCl3): δ 7.86 (d, J=2.5 Hz, 1H), 7.27 (m, 2H), 6.96 (d, J=7.5 Hz, 1H), 6.90 (m, 2H), 6.85 (d, J=9 Hz, 1H), 6.32 (s, 1H), 4.02 (q, 2H, J=6.8), 3.49 (s, 2H), 3.38 (s, 2H), 2.45 (s, 2H), 2.30 (s, 2H), 1.47 (s 9H) 1.40 (t, J=6.92 Hz, 3H); m/z (411.51, M+ H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:33])=[C:14]([C:28](OCC)=[O:29])[C:15](=[O:27])[N:16]3[CH2:19][C:20](=[O:26])[N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:33])=[C:14]([C:28]([NH:34][CH2:35][CH2:36][N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[O:29])[C:15](=[O:27])[N:16]3[CH2:19][C:20](=[O:26])[N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCC2)c1=O
Reactant: NCCN1CCOCC1
Product: O=C(NCCN1CCOCC1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCC2)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-oxo-2-(1-pyrrolidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 4-(2-aminoethyl)morpholine employing methods similar to those those described in Example 9 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as a white rigid foam: 1H NMR (CDCl3) δ 10.39 (1H, br m), 8.55 (1H, s), 7.15 (3H, m), 7.02 (2H, t, J=9 Hz), 4.85 (2H, s), 4.12 (2H, s), 3.98 (4H, br), 3.88 (2H, q, J=6 Hz), 3.72 (2H, br), 3.54 (2H, t, J=7 Hz), 3.45 (2H, t, J=7 Hz), 3.35 (2H, t, J=6 Hz), 2.92 (2H, br), 2.06 (2H, m, J=7 Hz), 1.90 (2H, m, J=7 Hz); HRMS calcd for C28H32FN5O5+H+: 538.2466. Found: 538.2460.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[Br:10][C:11]1[S:25][C:14]2[S:15][CH2:16][CH2:17][C:18]3[C:19](=[N:20][NH:21][C:22](=[O:24])[CH:23]=3)[C:13]=2[CH:12]=1>>[Br:10][C:11]1[S:25][C:14]2[S:15][CH2:16][CH2:17][C:18]3[C:19](=[N:20][N:21]([CH2:6][C:5]4[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=4)[C:22](=[O:24])[CH:23]=3)[C:13]=2[CH:12]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: O=c1cc2c(n[nH]1)-c1cc(Br)sc1SCC2
Product: O=c1cc2c(nn1Cc1ccc(Cl)cc1)-c1cc(Br)sc1SCC2

Procedure:
The reaction and procedure are conducted in the same manner as in Example 36 using 4-chlorobenzylchloride in place of methyl iodide and using 9-bromo-5,6-dihydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one in place of 9-ethyl-5,6-dihydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one as used in Example 36 to give 9-bromo-2-(4-chlorobenzyl)-5,6-dihydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one as white crystals, melting at 152°-154° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:33])([CH3:32])[C@@H:11]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:12]([O:14][CH2:15][CH2:16][O:17][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[O:13])(=[O:7])=[O:6].[N-:34]=[N+:35]=[N-:36].[Na+]>CS(C)=O>[N:34]([CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:33])([CH3:32])[C@@H:11]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:12]([O:14][CH2:15][CH2:16][O:17][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[O:13])(=[O:7])=[O:6])=[N+:35]=[N-:36]
Reactant: CC(C)OC(=O)OCCOC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCCl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)OC(=O)OCCOC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCN=[N+]=[N-]

Procedure:
Following the general procedure for the preparation of azides of Description 16, 23.0 g (45.3 mmol) of (methylethoxycarbonyloxy)ethyl (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoate (40a) dissolved in 210 mL of anhydrous dimethyl sulfoxide (DMSO) was reacted with 5.9 g (93.6 mmol) of sodium azide (NaN3). After work-up, the crude title compound (40b) was obtained and used in the next step without further purification. Rf=0.29 (EtOAc/Hxn=1:4). 1H NMR (400 MHz, CDCl3, both diastereomers): δ=1.06-1.08 (m, 6H), 1.24-1.35 (m, 6H), 1.57 (d, J=5.2 Hz, 3H), 2.03-2.10 (m, 2H), 3.10-3.16 (m, 2H), 3.44-3.48 (m, 2H), 3.84-3.85 (2s, 1H), 3.94-3.96 (2d, J=8.8, 9.2 Hz, 1H), 4.18-4.22 (2d, J=9.2, 9.6 Hz, 1H), 4.33-4.38 (2d, J=11.2, 11.2 Hz, 1H), 4.64 (t, J=11.2 Hz, 1H), 4.78-4.97 (m, 1H), 6.82-6.87 (m, 1H), 7.32-7.37 (m, 5H) ppm. MS (ESI) m/z 538.07 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: Cl.[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([OH:16])[CH:10]=1)=[O:8])([CH3:4])[CH3:3].[Cl:17][C:18]1[C:26]([O:27][CH3:28])=[C:25]([CH3:29])[CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>>[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][C:25]([CH3:29])=[C:26]([O:27][CH3:28])[C:18]=2[Cl:17])=[C:11]([OH:16])[CH:10]=1)=[O:8])([CH3:4])[CH3:3]
Reactant: COc1c(C)ccc(C(=O)Cl)c1Cl
Reactant: CC(C)NCC(=O)c1ccc(O)c(O)c1
Agent: Cl
Product: COc1c(C)ccc(C(=O)Oc2ccc(C(=O)CNC(C)C)cc2O)c1Cl

Procedure:
Following the procedure described above in Example 58A but using 3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride and 2-chloro-3-methoxy-4-methylbenzoyl chloride instead of isovaleryl chloride, there is obtained 3-hydroxy-4-(2-chloro-3-methoxy-4-methylbenzoyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3-hydroxy-4-(2-chloro-3-methoxy-4-methylbenzoyloxy)-apha-(isopropylaminomethyl)benzyl alcohol hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:8]([CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[S:9]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:25][CH:26]=[CH:27][N:28]=4)=[CH:20][C:19]=3[CH:29]=[O:30])=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])=[N:4][O:5][C:6]=1[CH3:7].[BH4-].[Na+]>CO>[CH3:1][C:2]1[C:3]([N:8]([CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[S:9]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:25][CH:26]=[CH:27][N:28]=4)=[CH:20][C:19]=3[CH2:29][OH:30])=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])=[N:4][O:5][C:6]=1[CH3:7]
Reactant: COCCOCN(c1noc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncco2)cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COCCOCN(c1noc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncco2)cc1CO
Reaction time: 2 h
Yield: 76.9 %

Procedure:
To a solution of the title compound of step D (0.37 g, 0.76 mmol) in 10 mL of MeOH at room temperature, sodium borohydride (0.035 g, 0.93 mmol) was added and the mixture stirred for 2 hours. The clear solution was then concentrated to 5 mL and diluted with 100 mL of water and the aqueous solution was extracted with 3×100 mL of EtOAc. The combined organic extracts were then washed once with water and dried and evaporated to provide 0.3 g (95%) of the title compound of this step as a colorless gum.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2][CH3:3].[F:13][C:14]1[CH:15]=[CH:16][C:17]2=[C:18]([CH:34]=1)[O:19][CH2:20][C:21]1[CH:31]=[C:30]([CH:32]=O)[CH:29]=[CH:28][C:22]=1/[C:23]/2=[C:24](/[CH3:27])\[C:25]#[N:26]>>[F:13][C:14]1[CH:15]=[CH:16][C:17]2=[C:18]([CH:34]=1)[O:19][CH2:20][C:21]1[CH:31]=[C:30]([CH2:32][C:12]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[NH:5][C:4]=3[CH2:1][CH2:2][CH3:3])[CH:29]=[CH:28][C:22]=1/[C:23]/2=[C:24](/[CH3:27])\[C:25]#[N:26]
Reactant: CCCc1cc2ccccc2[nH]1
Reactant: C/C(C#N)=C1/c2ccc(C=O)cc2COc2cc(F)ccc21
Product: CCCc1[nH]c2ccccc2c1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Yield: 55.1 %

Procedure:
[step 5] Using 2-propyl-1H-indole (100 mg, 0.64 mmol) obtained in step 4 and (E)-2-(3-fluoro-8-formyldibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (153 mg, 0.52 mmol) obtained in Reference Example 5, and in the same manner as in Reference Example 13A, the target compound (125 mg, 55%) was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:3]=1.[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1)([O-:20])=[O:19].N1C=CC=CC=1>O>[N+:18]([C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:32][CH2:31][N:30]([C:2]3[CH:7]=[C:6]([N:8]4[CH2:12][CH2:11][CH2:10][CH2:9]4)[N:5]=[C:4]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)[N:3]=3)[CH2:29][CH2:28]2)=[CH:25][CH:26]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: Clc1cc(N2CCCC2)nc(N2CCCC2)n1
Solvent: O
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(N2CCN(c3cc(N4CCCC4)nc(N4CCCC4)n3)CC2)cc1
Temperature: 100 °C
Yield: 49 %

Procedure:
2.52 g (10 mmol) of 4-chloro-2,6-di-pyrrolidin-1-yl-pyrimidine (J. Med. Chem. (1990) 33 (4), 1145-1151) and 2.07 g (10 mmol) of 4-nitrophenylpiperazine are dissolved in a 250 ml flask containing 20 ml of anhydrous pyridine, under an argon atmosphere. The reaction mixture is heated at 100° C. for 48 hours. After cooling down, the contents of the flask are poured into 250 ml of water and the product is extracted using twice 50 ml of CH2Cl2. The organic phase is then washed with 50 ml of brine, dried over magnesium sulphate, filtered and concentrated under vacuum. The residue is purified on a silica column (eluent: Heptane/AcOEt: 2/1). An orange solid is obtained with a yield of 49%. Melting point: 200-201° C.
Reaction SMILES: CO[C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11]([Cl:16])=[CH:10][CH:9]=2)=[O:4].[NH2:18][C@H:19]([C:21]([OH:23])=[O:22])[CH3:20].C[O-].[Na+]>COCCO>[Cl:16][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[S:7][C:6](=[O:17])[C:5]([C:3]([NH:18][C@@H:19]([CH3:20])[C:21]([OH:23])=[O:22])=[O:4])=[C:14]2[OH:15]
Reactant: C[C@H](N)C(=O)O
Reactant: COC(=O)c1c(O)c2cc(Cl)ccc2sc1=O
Agent: C[O-]
Agent: [Na+]
Solvent: COCCO
Product: C[C@H](NC(=O)c1c(O)c2cc(Cl)ccc2sc1=O)C(=O)O
Yield: 41.2 %

Procedure:
A mixture of 6-chloro-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Compound 58(b)) (100 mg, 0.37 mmol), L-alanine (165 mg, 1.85 mmol) and NaOMe (80 mg, 1.48 mmol) in 2-methoxyethanol (5.2 mL) was microwaved at 150° C. for 2 h and concentrated. Residue was dissolved in water (60 mL). Insoluble solid was filtered off. The Aqueous filtrate was acidified using 1 N HCl solution to pH=3-4. Precipitate was collected and dried. It was then triturated with MeOH (2 mL). Solid was collected and dried in vacuo to provide the title compound (50 mg). MS ESI(−) m/e: 325.93 (M−1).
Reaction SMILES: [NH:1]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[CH3:17]N(C=O)C>>[NH:1]([C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8])[C@H:2]([C:4]([O:6][CH3:17])=[O:5])[CH3:3]
Reactant: CN(C)C=O
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Product: COC(=O)[C@H](C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.8 %

Procedure:
CBZ-Ala (10, 0.165 g, 0.74 mmol) was added to 6 mL of dry DMF containing 1.1 g (500 mol % ) of 2 (R=Me) and the reaction mixture was stirred at 16 h a t room temperature. Following the general procedure gave 0.163 g of 19, 93%, as an oil: [α]25D -32.7° (c 1.3, MeOH) [Lit14 [α]25D -33.0° (c 1.0, MeOH )]; IR 3340, 3060, 3030, 1720; 1H NMR δ 7.34-7.26 (m, 5H), 5.53 (d, 1H, J=5.9), 5.10 (s, 2H), 4.39 (t, 1H, J=7.3), 3.73 (s, 3H), 1.40 (d, 3H, J=7.2).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[C:9]([O:19][CH3:20])=[C:10]([CH2:14][CH2:15][C:16](O)=[O:17])[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:25])=O>>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[C:9]([O:19][CH3:20])=[C:10]([CH2:14][CH2:15][C:16]([Cl:25])=[O:17])[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1c(CCC(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Product: COc1c(CCC(=O)Cl)cccc1C(=O)c1ccc(Cl)cc1

Procedure:
A solution of 5.1 g of 3-(3'-p-chlorobenzoyl-2'-methoxy-phenyl)-propionic acid in 25 ml of thionyl chloride was refluxed for 21/2 hours and the excess thionyl chloride was distilled off. The residue was taken up in benzene and was evaporated to dryness to obtain 5.6 g of 3-(3'-p-chlorobenzoyl-2'-methoxy-phenyl)-propionyl chloride which was used as is for the next step.
Reaction SMILES: N1C=CC=CC=1.C([N:10]1[C:14]([NH2:15])=[N:13][C:12]([S:16]([NH:19][C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:27])(=[O:18])=[O:17])=[N:11]1)(=O)C.Cl>[OH-].[Na+]>[NH2:15][C:14]1[NH:10][N:11]=[C:12]([S:16]([NH:19][C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:27])(=[O:18])=[O:17])[N:13]=1
Reactant: CC(=O)n1nc(S(=O)(=O)Nc2c(Cl)cccc2Cl)nc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: Nc1nc(S(=O)(=O)Nc2c(Cl)cccc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
53.6 g (0.12 mol) of the pyridine salt of 1-acetyl-5-amino-N-(2,6-dichlorophenyl)-1,2,4-triazole-3-sulphonamide was dissolved in 200 ml 2N aqueous sodium hydroxide and stirred at room temperature for 10 minutes. With ice cooling it was brought to pH 5 with 2N hydrochloric acid. The crystals were separated, washed with a small amount of water and ether and dried in vacuo.
Reaction SMILES: CS(C)=O.[C:5]([C:9]1[C:10](=[O:34])[CH2:11][CH:12]([C:16]2[CH:17]=[CH:18][C:19]3[O:24][CH2:23][C:22](=[O:25])[N:21]([CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:20]=3[CH:33]=2)[CH2:13][C:14]=1[OH:15])(=O)[CH2:6][CH3:7].Cl.[CH2:36]([O:38][NH2:39])[CH3:37].C([O-])(=O)C.[Na+]>Cl.CCOCC>[CH2:36]([O:38][N:39]=[C:5]([C:9]1[C:10](=[O:34])[CH2:11][CH:12]([C:16]2[CH:17]=[CH:18][C:19]3[O:24][CH2:23][C:22](=[O:25])[N:21]([CH2:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:20]=3[CH:33]=2)[CH2:13][C:14]=1[OH:15])[CH2:6][CH3:7])[CH3:37]
Reactant: CCC(=O)C1=C(O)CC(c2ccc3c(c2)N(Cc2ccccc2)C(=O)CO3)CC1=O
Reactant: CCON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CCON=C(CC)C1=C(O)CC(c2ccc3c(c2)N(Cc2ccccc2)C(=O)CO3)CC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 10 mL of methyl sulfoxide were added in sequence 1.4 g (3.5 mmol) of 2-propionyl-3-hydroxy-5-(N-benzyl-3-oxo-(2H)-1,4-benzoxazin-6-yl)cyclohex-2-en-1-one, 0.42 g (4.4 mmol) of ethoxyamine hydrochloride and 0.37 g (4.5 mmol) of anhydrous sodium acetate. The resulting mixture was stirred at ambient temperature for 3 hours. The reaction mixture was diluted with 50 mL of 0.5N HCl and extracted twice with 30 mL portions of ethyl acetate. The extracts were combined, dried over MgSO4 and filtered. Evaporation off of the solvent gave an oily residue. The residue was dissolved in 50 mL of ether, washed with water, then an aqueous NaCl solution, dried over MgSO4 and filtered. Evaporation off of the solvent gave a light amber glass which crystallized upon standing. The crude solid product was triturated in ether and the above-named product was isolated by filtration as a tan solid in a yield of 0.90 g (58 percent of theoretical). The product melted at 108°-110° C.; 1H NMR (CDCl3): d1.05-1.41 (m, 6H, both --CH2CH3 's), 2.42-3.45 (m, 7H), 4.12 (q, J=7 Hz, 2H, --OCH2CH3), 4.72 (2, 2H, --OCH2C=O), 5.20 (s, 2H, --CH2Ph), 6.75-7.08 (m, 3H, aromatic H's), 7.30 (s, 5H, --CH2Ph) ca. 14.7 (broad s, 1H, enol H); (Compound 7).
Reaction SMILES: [K].[OH:2][C:3]1[C:4]([N:15]2[S:19](=[O:21])(=[O:20])[NH:18][C:17](=[O:22])[CH2:16]2)=[CH:5][C:6]2[CH2:7][C:8]([CH3:14])([CH3:13])[CH2:9][CH2:10][C:11]=2[CH:12]=1.OC1C(N2S(=O)(=O)NC(=O)C2)=CC2CC(C)(C)CCC=2C=1.CC(C)([O-])C.[K+].[C:50](Cl)(=[O:57])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>CN(C=O)C>[CH3:13][C:8]1([CH3:14])[CH2:9][CH2:10][C:11]2[CH:12]=[C:3]([O:2][C:50](=[O:57])[C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:4]([N:15]3[CH2:16][C:17](=[O:22])[NH:18][S:19]3(=[O:21])=[O:20])=[CH:5][C:6]=2[CH2:7]1
Reactant: CC1(C)CCc2cc(O)c(N3CC(=O)NS3(=O)=O)cc2C1
Reactant: O=C(Cl)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Product: CC1(C)CCc2cc(OC(=O)c3ccccc3)c(N3CC(=O)NS3(=O)=O)cc2C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5-(3-hydroxy-7,7-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one potassium salt (47 mg, 0.14 mmol; prepared from the title compound of Example 49 analogously to procedure as described in Example 1, step I) in DMF (3 mL) at 0° C. is added potassium t-butoxide (1M in THF, 0.13 mL,). After 5 min, benzoyl chloride (0.016 mL, 0.14 mmol) is added. The mixture is stirred at 0° C. for 5 min. The mixture is partitioned between Et2O and aq. K2CO3. The ether layer is removed. The aqueous layer is acidified by adding 3M HCl solution, and Et2O is added to extract the product. The organic residue is purified by HPLC to give the title compound as a solid: 1H NMR (CD3OD) δ 1.02 (s, 6H), 1.62 (t, J=7 Hz, 2H), 2.59 (s, 2H), 2.88 (t, J=7 Hz, 2H), 4.43 (s, 2H), 7.11 (s, 1H), 7.23 (s, 1H), 7.52-7.55 (m, 2H), 7.65-7.69 (m, 1H), 8.16-8.19 (m, 2H); (M+H)+=413.
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]=[CH2:3].[CH:6]1([CH2:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=2)[CH2:8][CH2:7]1>C(OCC)C>[CH:6]1([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([CH:14]([OH:15])[CH2:3][CH:2]=[CH2:1])=[CH:16][CH:17]=2)[CH2:8][CH2:7]1
Reactant: O=Cc1ccc(CC2CC2)cc1
Reactant: C=CC[Mg]Br
Solvent: CCOCC
Product: C=CCC(O)c1ccc(CC2CC2)cc1
Reaction time: 0.25 h

Procedure:
To a solution of allylmagnesium bromide (1.0M in diethyl ether, 3 ml) in diethyl ether (5 ml) was added dropwise 4-(cyclopropylmethyl)benzaldehyde (240 mg) in diethyl ether (2 ml) at 0° C. After 15 minutes, the reaction mixture was quenched by aqueous ammonium chloride and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel column eluting with a mixture of hexane and ethyl acetate (85:15) to give 1-[4-(cyclopropylmethyl)phenyl]-3-buten-1-ol (229 mg) as an oil.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:38])=[C:5]([C:29]([O:36]C)=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:33][O:32][C:31]1[C:3](=[O:2])[C:4]([CH3:38])=[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)=[C:11]([CH:20]=2)[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])[C:29](=[O:36])[C:30]=1[O:34][CH3:35]
Reactant: COc1c(C)c(Cc2ccc(OCc3ccncc3)c(C(=O)N3CCOCC3)c2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: COC1=C(OC)C(=O)C(Cc2ccc(OCc3ccncc3)c(C(=O)N3CCOCC3)c2)=C(C)C1=O
Yield: 61.9 %

Procedure:
N-[5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(4-pyridylmethyloxy)benzoyl]morpholine (0.460 g, 0.885 mmol) was dissolved in a mixed solution of acetonitrile (15 ml) and water (5 ml) and after adding thereto CAN (1.21 g, 2.21 mmol) at room temperature, the solution was stirred at room temperature for 1 hour. The reaction solution was diluted with water and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The residue was purified by silica gel column chromatography (chloroform:methanol=9:1) to obtain the titled compound (0.270 g, 0.548 mmol, 62%).
Reaction SMILES: [CH3:1][CH:2]([CH3:30])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22](=O)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].[CH3:31][N:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)N>>[CH3:1][CH:2]([CH3:30])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:32]([CH3:31])[C:22]=3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: CN(N)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccccc4)n(C)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-{3-[1-(5-oxo-5-phenylpentyl)-4-piperidinyl]phenyl}propanamide and 1-methyl-1-phenylhydrazine: ESMS m/e: 495.3 (M+H)+.