Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][CH2:6][CH:7]1[O:12][CH2:11][CH2:10][NH:9][CH2:8]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:27]Cl>CN(C)C=O>[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:27][N:9]1[CH2:10][CH2:11][O:12][CH:7]([CH2:6][NH:5][C:3](=[O:4])[C:2]([F:13])([F:1])[F:14])[CH2:8]1
Reactant: O=C(NCC1CNCCO1)C(F)(F)F
Reactant: ClCc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)C(F)(F)F
Temperature: 22 °C
Reaction time: 18 h

Procedure:
To a stirred solution of Intermediate 19 (3.3 g) in N,N-dimethylformamide (50 ml) under nitrogen was added potassium carbonate (2.46 g) and sodium iodide (2.12 g). A solution of 3,4-dichlorobenzyl chloride (2 ml) in N,N-dimethylformamide (10 ml) was added dropwise to the mixture. The mixture was stirred at 22° C. for 18 h before the volatiles were removed in vacuo. The residue was partitioned between dichloromethane (100 ml) and saturated aqueous sodium carbonate solution (50 ml). The organic phase was subsequently washed with additional saturated aqueous sodium carbonate solution (2×50 ml) and water (50 ml) before drying over magnesium sulphate, filtering and evaporation of the solventin vacuo to give a pale yellow oil. The oil was purified by Biotage flash chromatography on a 90 g silica cartridge eluting with 25% ethyl acetate in cyclohexane, to give the title compound as a colourless oil (2.97 g).
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:6]([N:7]2[CH:11]=[CH:10][N:9]=[N:8]2)[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1>FC(F)(F)C(O)=O>[NH2:1][C@H:2]1[C@@H:6]([N:7]2[CH:11]=[CH:10][N:9]=[N:8]2)[CH2:5][NH:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)[C@@H](n2ccnn2)C1
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1CNC[C@@H]1n1ccnn1

Procedure:
A solution of compound of example K (1.0 g) in trifluoroacetic acid (4 ml) was stirred at room temperature under nitrogen for 10 minutes and concentrated. The residue was dissolved in methanol and treated with basic resin (ANGA-316) and filtered. The filtrate was concentrated and purified by column chromatography over neutral alumina using methanol/CHCl3 mixture as solvent. Yield 670 mg. 1H NMR (CD3OD) δ: 2.80 (m, 1H), 3.20-3.80 (m, 5H), 5.10 (m, 1H), 7.75 (s, 1H), 8.0 (S, 1H).
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[CH2:5]([NH2:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CCOC(C)=O>[CH2:5]([NH:12][CH2:2][C:3]#[N:4])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NCc1ccccc1
Reactant: N#CCCl
Solvent: CCOC(C)=O
Product: N#CCNCc1ccccc1
Temperature: 45 °C
Yield: 98.9 %

Procedure:
A solution of the ClCH2CN (316 g, 4.19 mol) in EtOAc (200 mL) was added dropwise to benzylamine (900 g, 8.40 mol) while the mixture was vigorously stirred. The mixture was warmed gently to 45° C. for 0.5 h and a white precipitate was removed by filtration. The filtrate was concentrated in vacuo to give the title compound (606 g, 99%) as yellow oil; 1H NMR: (CDCl3) 3.56 (2H, s), 3.94 (2H, s), 7.28-7.40 (5H, m).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[O:13][CH3:14].[C:15]([N:22]1[CH2:28][CH2:27][CH2:26][C@H:23]1[CH2:24]O)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:14][O:13][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=1[O:1][CH2:24][C@@H:23]1[CH2:26][CH2:27][CH2:28][N:22]1[C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: CCOC(=O)c1ccc(O)c(OC)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)c(OC)c1
Temperature: 25 °C

Procedure:
To a stirred solution of ethyl 4-hydroxy-3-methoxybenzoate (3.00 g, 15.29 mmol), (S)-N-Boc-prolinol (3.08 g, 15.30 mmol), Ph3P (4.81 g, 18.34 mmol) in THF (50 mL) was added DIAD (3.61 mL, 18.33 mmol) at 0° C. The resulting mixture was heated under reflux 6.5 hr. After cooling to room temp, the mixture was evaporated and purified by column chromatography on silica-gel with CHCl3—MeOH (50:1, v/v) as eluent to give ethyl (S)-3-methoxy-4-[1-(tert-butoxycarbonyl)-2-pyrrolidinyl methoxy]benzoate as a gum. The above ethyl (S)-3-methoxy-4-[1-(tert-butoxycarbonyl)-2-pyrrolidinylmethoxy]benzoate was dissolved in CH2Cl2 (50 mL) and TFA (45 mL). The mixture was stirred for 2 days at room temp. The resulting mixture was concentrated in vacuo and made basic with sat. NaHCO3. The mixture was extracted with CH2Cl2, washed with brine, and dried over MgSO4. The solvent was evaporated and the residue was purified by column chromatography on silica-gel with CHCl3—MeOH (20:1, v/v) as eluent to give 3.27 g (77% for 2 steps) ethyl (S)-3-methoxy-4-(2-pyrrolidinylmethoxy) benzoate as a yellow oil. 1H-NMR (CDCl3) δ1.39 (t, 3 H, J=7.1 Hz), 1.52-1.59 (m, 1 H), 1.76-1.88 (m, 2 H), 1.92-2.01 (m, 1H), 2.92-3.06 (m, 2 H), 3.56-3.63 (m, 1 H), 3.90 (s, 3 H), 3.9-4.02 (m, 2 H), 4.35 (q, 2, J=7.1 Hz), 6.89 (d, 1 H, J=8.3 Hz), 7.54 (d, 1 H, J=2.0 Hz), 7.65 (dd, 1 H, J=2.0, 8.3 Hz).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:13]=1[N+:26]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]([O:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:13]=1[NH2:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(NCCOCc2ccccc2)c([N+](=O)[O-])c(Oc2ccccc2)n1
Solvent: Cc1ccccc1
Product: Cc1cc(NCCOCc2ccccc2)c(N)c(Oc2ccccc2)n1
Yield: 108.7 %

Procedure:
Under a nitrogen purge, 5% platinum on carbon (1.0 g) and toluene (20 mL) were added to a Parr vessel. [2-(Benzyloxy)ethyl](6-methyl-3-nitro-2-phenoxy-pyridin-4-yl)amine (4.91 g, 12.9 mmol) and additional toluene (40 mL) were then added. The vessel was placed under hydrogen pressure (49 psi, 3.3×105 Pa) for three hours. The reaction mixture was filtered through a layer of CELITE filter aid, and the filtrate was concentrated under reduced pressure to yield 4.9 g of N4-[2-(benzyloxy)ethyl]-6-methyl-2-phenoxypyridine-3,4-diamine as a milky oil, contaminated with a small amount of toluene.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2].[C:18](OC)(=[O:26])[C:19]1[C:20](=[CH:22][CH:23]=[CH:24][CH:25]=1)[SH:21].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:26]=[C:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[S:21][C:1]([C:3]2[CH:4]=[C:5]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=2)=[N:2]1
Reactant: CC(C)(C)OC(=O)CCc1cccc(C#N)c1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCc1cccc(-c2nc(=O)c3ccccc3s2)c1
Yield: 16.2 %

Procedure:
A mixture of tert-butyl 3-(3-cyanophenyl)propionate (0.74 g, 3.2 mmol), methyl thiosalicylate (1.1 g, 6.4 mmol), triethylamine (0.67 ml, 4.8 mmol) and toluene (3 ml) was heated and refluxed for 27 hours under a nitrogen flow. The reaction mixture was applied to column chromatography using silica gel (50 g). Fractions eluted with hexane-ethyl acetate (2:1, v/v) were collected and concentrated to give the title compound (0.19 g, 16%) as crystals.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH2:10]O)=[CH:4][CH:3]=1.P(Br)(Br)[Br:18]>>[Br:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH2:10][Br:18])=[CH:4][CH:3]=1
Reactant: BrP(Br)Br
Reactant: OCc1cccc(Oc2ccc(Br)cc2)c1
Product: BrCc1cccc(Oc2ccc(Br)cc2)c1

Procedure:
This compound was prepared from 3-(4-bromophenoxy)benzyl alcohol by a standard reaction with phosphorus tribromide.
Reaction SMILES: OP([O-])(O)=O.[Na+].[C:7]1([S:13]([CH2:16][C:17]2[C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[C:21]([OH:30])[C:20]([C:31]3[CH:35]=[CH:34][O:33][C:32]=3[CH:36]=[O:37])=[CH:19][CH:18]=2)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl([O-])=[O:39].[Na+]>O.C(#N)C.OO>[C:7]1([S:13]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:31]3[CH:35]=[CH:34][O:33][C:32]=3[C:36]([OH:39])=[O:37])=[C:21]([OH:30])[C:22]=2[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(=[O:15])=[O:14])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: [O-][Cl+][O-]
Reactant: CC(C)(C)OC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2C=O)c1O
Agent: O=P([O-])(O)O
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2C(=O)O)c1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.7 %

Procedure:
A solution of sodium phosphate monobasic (0.039 g) in water (1 mL) was added to a solution of tert-butyl 6-(benzenesulfonylmethyl)-3-(2-formylfuran-3-yl)-2-hydroxybenzoate (Intermediate 27, 0.105 g) in acetonitrile (2 mL) at 0° C. Hydrogen peroxide (50% wt. in water, 0.078 mL) and sodium chlorite (0.029 g) were added and the reaction mixture was warmed to room temperature and stirred for 18 hours. The mixture was cooled to 0° C. and further sodium phosphate monobasic (0.028 g) in water (0.5 mL), hydrogen peroxide (50% wt. in water, 0.038 mL) and sodium chlorite (0.052 g) were added and the mixture was warmed to room temperature and stirred for 18 hours. The mixture was poured onto sodium sulfite (10% in water) at 0° C., extracted into ethyl acetate, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of methanol and 1% acetic acid in methanol with a gradient of O-100%. The resultant product was triturated in cyclohexane and ethyl acetate and the solid was collected by filtration and dried in vacuo to give 3-[4-(benzenesulfonylmethyl)-3-tert-butoxycarbonyl-2-hydroxy-phenyl]-furan-2-carboxylic acid (0.028 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]([S:11]([CH3:14])(=[O:13])=[O:12])=[C:9]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:21])=O>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:10]([S:11]([CH3:14])(=[O:13])=[O:12])=[C:9]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:21])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1S(C)(=O)=O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Cl)ccc(S(C)(=O)=O)c1S(C)(=O)=O
Yield: 90.7 %

Procedure:
A few drops of dimethylformamide were added to a solution of 63 g (0.22 mol) of 2-methyl-3,4-di(methylsulfonyl)benzoic acid in 550 ml of toluene, and 36 g (0.3 mol) of thionyl chloride were then added dropwise. The reaction mixture was heated at reflux for 1.5 hours. After cooling, the reaction mixture was concentrated. This gave 62 g (93% yield) of 2-methyl-3,4-di(methylsulfonyl)benzoyl chloride as a beige solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1C=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:23][O:24][CH:25](OC)[O:26][CH3:27]>CO>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[CH:25]([O:26][CH3:27])[O:24][CH3:23]
Reactant: Cc1ccc(Br)c(C=O)c1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(OC)c1cc(C)ccc1Br
Yield: 99 %

Procedure:
Step AI (3): 2-Bromo-5-methylbenzaldehyde (500 mg, 2.51 mmol) was dissolved in methanol (5.0 mL). p-Toluenesulfonic acid monohydrate (90 mg, 0.52 mmol) and trimethoxymethane (5 mL) were added. The reaction mixture was heated at reflux for 5 h. The reaction mixture was extracted with DCM and washed with saturated aqueous sodium bicarbonate. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuum to yield 1-bromo-2-(dimethoxymethyl)-4-methylbenzene (615 mg, 99%) as a colorless oil. LC-MS (M−OCH3)+=213.25. 1H NMR (CD3OD, 500 MHz) δ 7.41-7.39 (m, 2H) 6.98 (d, J=10 Hz, 1H) 5.51 (s, 1H) 3.37 (s, 6H) 2.30 (s, 3H).
Reaction SMILES: [CH:1]1([CH2:6][C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[I:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]I.CN(C)P(N(C)C)(N(C)C)=O>C1COCC1>[CH:1]1([CH:6]([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][I:17])[C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ICCCCCCCCI
Reactant: O=C(CC1CCCC1)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(OCc1ccccc1)C(CCCCCCCCI)C1CCCC1
Reaction time: 0.5 h

Procedure:
To a cooled (-78° C.) solution of lithium diisopropylamide (20 mmol) in a mixture of THF (20 mL) and hexane (8 mL) (obtained in situ from the corresponding diisopropylamine and n-BuLi) was added slowly the compound obtained in step 1(3.96 g, 18 mmol) in anhyd. THF(10 mL). The mixture was stirred for 30 minutes and 1,8-diiodooctane (7.19 g, 20 mmol) in hexamethylphosphoramide (3.50 g, 20 mmol), was added. The mixture was stirred at -78° C. for 30 minutes, slowly brought to 0° C. over a period of 2 h and quenched by the cautious addition of 50 mL of 12% aqueous sodium chloride solution. The mixture was extracted with ether, washed with brine, dried and the solvent was evaporated. The crude product was purified to an oil (3.23 g) by a flash chromatography over silica using hexane to 1% EtOAc in hexane as an eluant; 1H NMR (300 MHz, CDCl3) δ: 7.35(m, 5H), 5.15(s,2H), 3.20(t,8 Hz,2H), 2.20(m, 1H), 2.0(m, 1H), 1.2-1.8(m,22H)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6].Br[CH2:23][CH2:24][CH:25]=[CH2:26].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)CC=C>[CH2:26]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6])[CH2:25][CH:24]=[CH2:23]
Reactant: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Reactant: C=CCCBr
Agent: C=CCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: C=CCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Reaction time: 0.5 h
Yield: 35 %

Procedure:
A solution of 3-amino-4-phenoxy-5-sulfamylbenzoic acid (7.5 g), 4-bromo-1-butene (12 ml), and p-toluenesulfonic acid (500 mg) in 3-buten-1-ol (35 ml) was heated under reflux for 6 days. Most of the solvent was recovered by distillation. The concentrated solution was diluted with pet. ether and stirred for 1/2 hour. The ester of the product was collected (3.9 g) and hydrolyzed in 10% by weight methanolic KOH at room temperature. A second crop of 4.0 g was a mixture of the esters of starting material and product. These were not separated. The 3.9 g crop afforded 3.1 g (35%) of 3-(but-3-enylamino)-4-phenoxy-5-sulfamylbenzoic acid which was clean by tlc. Recrystallization from ether/pet. ether gave colorless crystals. The analytical sample was sublimed in vacuum. The product had mp 228°-32° (dec); ir (Nujol) 3350, 3200, 2600 (broad), 1680, 1610, 1585, 1540 and 1515 cm-1 ; nmr (CDCl3 /d6 -DMSO/D2O-washed) 2.17 (q, 2H), 3.13 (t, 2H), 3.13 (t, 2H), 4.6-6.0 (m, 3H, vinyl), 6.8-7.5 (m, C6H5), 7.55 (d, J=2, CH), and 7.95 ppm (d, CH); mass spectrum m/e 321 (100%) and 363 (M+).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[C:11]([CH3:20])=[CH:10][CH:9]=2)[C:4]([SH:7])=[N:5][N:6]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[NH:31][C:32](=[O:35])[CH2:33]Cl)[C:25]([OH:27])=[O:26].O>CN(C=O)C>[NH2:1][C:2]1[N:3]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[C:11]([CH3:20])=[CH:10][CH:9]=2)[C:4]([S:7][CH2:33][C:32]([NH:31][C:30]2[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=2[Cl:21])=[O:35])=[N:5][N:6]=1
Reactant: O=C(CCl)Nc1ccc(C(=O)O)cc1Cl
Reactant: COc1ccc2c(C)ccc(-n3c(N)nnc3S)c2c1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(C)ccc(-n3c(N)nnc3SCC(=O)Nc3ccc(C(=O)O)cc3Cl)c2c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 87.2 %

Procedure:
Compound 8 (200 mg, 0.7 mmol) and 3-chloro-4-(2-chloroacetamido)benzoic acid (9) (174 mg, 0.7 mmol) were dissolved in DMF (3 mL) and the mixture was stirred at 50° C. for 18 hours. Water was then added and the mixture extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate and concentrated to give 304 mg of 4-(2-(5-amino-4-(7-methoxy-4-methylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetamido)-3-chlorobenzoic acid (10) which was used in the next step without further purification.
Reaction SMILES: [C:1]([NH:20][C@H:21]([C:25]([OH:27])=[O:26])[CH:22]([CH3:24])[CH3:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([CH:31]([CH2:34]O)[CH2:32][OH:33])[CH:29]=[CH2:30].C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[C:1]([NH:20][C@H:21]([C:25]([O:27][CH2:34][CH:31]([CH2:28][CH:29]=[CH2:30])[CH2:32][OH:33])=[O:26])[CH:22]([CH3:23])[CH3:24])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCC(CO)CO
Reactant: CC(C)[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: C=CCC(CO)COC(=O)[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)C
Yield: 66.1 %

Procedure:
To a solution of N-trityl-L-valine (5.5 g, 15.2 mmole), 2-allyl-1,3-propandiol (4.4 g, 38 mmol), N,N-dimethylamino pyridine (183 mg, 1.5 mmol) in dichloromethane (120 ml) was added DCC (3.5 g, 16.7 mmol). The reaction was kept under reflux overnight. After filtration through Celite, the organic phase was washed with sodium hydrogen carbonate aqueous solution and dried. Silica gel column chromatography gave 4.6 g intermediate 1-O-(N-trityl-L-valyl)-2-allyl-1,3-propandiol.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>C(O)C.C(OCC)(=O)C.[Pd]>[CH2:1]([O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCOc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCOc1ccc(N)cc1
Yield: 94.1 %

Procedure:
A solution of 30 g of product from Example 81 in 150 ml of ethyl alcohol and 20 ml of ethyl acetate is treated with 2 g of 10% palladium/carbon in a Parr Hydrogenator for 18 hours. The reaction solution is filtered and concentrated in vacuo. The residue is recrystallized from hexane to give 25.7 g of the desired product as a white solid.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]2[C:24]3[CH:25]=[CH:26][C:27]([C:29](=O)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:28][C:23]=3[S:22][C:21]2=[O:37])=[CH:13][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2].[CH3:38][O:39][NH2:40]>>[C:1]([NH:4][CH:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]2[C:24]3[CH:25]=[CH:26][C:27]([C:29](=[N:40][O:39][CH3:38])[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:28][C:23]=3[S:22][C:21]2=[O:37])=[CH:13][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2]
Reactant: CON
Reactant: COC(=O)C(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1)NC(C)=O
Product: CON=C(c1ccccc1)c1ccc2c(c1)sc(=O)n2CCOc1ccc(CC(NC(C)=O)C(=O)OC)cc1

Procedure:
Starting from the compound obtained in Step A, the procedure is as in Step B of Example 2, replacing the hydroxylamine by O-methylhydroxylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](O)=[C:11]3[CH2:14][S:15][CH2:16][CH2:17][C:10]3=[N:9]2)=[CH:4][CH:3]=1.P(Br)(Br)([Br:20])=O.C(=O)(O)[O-].[Na+]>C1(C)C(C)=CC=CC=1>[Br:20][C:12]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=[C:10]2[CH2:17][CH2:16][S:15][CH2:14][C:11]=12
Reactant: Oc1c2c(nn1-c1ccc(Cl)cc1)CCSC2
Reactant: O=P(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: Clc1ccc(-n2nc3c(c2Br)CSCC3)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 10.6 parts of 2-(4-chlorophenyl)-3-hydroxy-2,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole, prepared according to the method of Example 1, and 12 parts of phosphorous oxybromide in 120 parts of xylene was refluxed for 7 hours and then stirred at room temperature for 12 hours. The suspension was neutralized with 5% sodium bicarbonate followed by extraction with chloroform (3 × 100 parts). The chloroform solution was washed with a saturated NaCl solution, dried over anhydrous magnesium sulfate and evaporated at a reduced pressure of 50 to 300 mm Hg, yielding a brown oil. This oil crystallized from acetone yielding 4.3 parts of the desired product, m.p. 138°-145° C.; a second recrystallization from acetone/methylene chloride gave 3.4 parts of pure 3-bromo-2-(4-chlorophenyl)-2,4,6,7-tetrahydrothiopyrano[4,3-c]pyrazole, m.p. 143.5°-145° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]2[N:14]([C:15](=[O:26])[C:16]=1[O:17]C(=O)C1C=CC=CC=1)[CH2:13][CH:12]1[CH2:27][CH2:28][C:9]2([O:29][CH2:30][CH2:31][O:32]C(=O)C2C=CC=CC=2)[CH2:10][CH2:11]1)=[O:5])[CH3:2].C([O-])C.[Na+]>C1COCC1.CCO.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]2[N:14]([C:15](=[O:26])[C:16]=1[OH:17])[CH2:13][CH:12]1[CH2:27][CH2:28][C:9]2([O:29][CH2:30][CH2:31][OH:32])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc2n(c(=O)c1OC(=O)c1ccccc1)CC1CCC2(OCCOC(=O)c2ccccc2)CC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1nc2n(c(=O)c1O)CC1CCC2(OCCO)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.9 %

Procedure:
At room temperature, to a cold (ice-cooling) and stirred solution of 5-benzoyloxy-1-(2-benzoyloxy-ethoxy)-6-oxo-3,7-diazatricyclo[7.2.2.02,7]trideca-2,4-diene-4-carboxylic acid ethyl ester (330 mg, 0.604 mmol) in THF (6 mL) and EtOH (3.00 mL) was added 21% sodium ethanolate in EtOH (0.676 mL, 1.81 mmol) diluted with EtOH (3 mL) and the mixture stirred under N2 for 1 h. The mixture was diluted with ethyl acetate (10 mL) and extracted with water (10 mL×2). The aqueous extracts were acidified with 1N-HCl (3 mL) and extracted with ethyl acetate (10 mL×5). The ethyl acetate extracts were washed with brine, dried (Na2SO4) and concentrated to provide the title compound (130 mg, 0.38 mmol; 64% yield) as an oil: HPLC: retention time=1.33 min (area percent=95%); LCMS: m/z 339 (M+H); 1H NMR (500 MHz, CDCl3) δ ppm 1.43 (3H, t, J=7.2 Hz), 1.65 (2H, dt, J=12.3, 6.2 Hz), 1.85-1.97 (2H, m), 1.99-2.17 (4H, m), 2.46 (1H, brs), 3.60 (2H, t, J=4 Hz), 3.75 (2H, d, J=4.1 Hz), 4.06-4.15 (2H, m), 4.45 (2H, q, J=7.0 Hz), 10.48 (1H, brs); 13C NMR (126 MHz, CDCl3) δ ppm 14.0, 23.2, 27.6, 30.5, 53.9, 62.0, 63.2, 65.3, 76.7, 124.1, 148.2, 154.3, 159.7, 169.1.
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][C:3]=2[O:2]1.[NH:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[N:29]=[C:28]([NH2:30])[CH:27]=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[CH2:14][CH2:13]1>>[CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6][N:12]3[CH2:17][CH2:16][CH:15]([C:18]4[CH:19]=[CH:20][C:21]([C:24]5[N:29]=[C:28]([NH2:30])[CH:27]=[CH:26][CH:25]=5)=[CH:22][CH:23]=4)[CH2:14][CH2:13]3)=[CH:4][C:3]=2[O:2]1
Reactant: Nc1cccc(-c2ccc(C3CCNCC3)cc2)n1
Reactant: BrCc1ccc2c(c1)OCO2
Product: Nc1cccc(-c2ccc(C3CCN(Cc4ccc5c(c4)OCO5)CC3)cc2)n1

Procedure:
Prepared from Example 13, using 3,4-methylenedioxybenzyl bromide to alkylate 6-[4-(piperidin-4-yl)-phenyl]-pyridin-2-ylamine, in 82%, mp 150-165° C. as the hydrochloride salt.