Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH3:16])=[CH:6][C:5]([O:17][CH3:18])=[C:4]([C:19]([N:21]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[CH2:25][N:24]3[C:32]([C:35]([OH:37])=O)=[CH:33][CH:34]=[C:23]3[CH2:22]2)=[O:20])[CH:3]=1.[NH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH3:16])=[CH:6][C:5]([O:17][CH3:18])=[C:4]([C:19]([N:21]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[CH2:25][N:24]3[C:32]([C:35]([NH:38][CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=4)=[O:37])=[CH:33][CH:34]=[C:23]3[CH2:22]2)=[O:20])[CH:3]=1
Reactant: NCc1ccccn1
Reactant: CCOc1ccccc1-c1cc(OC)c(C(=O)N2Cc3ccc(C(=O)O)n3Cc3ccccc32)cc1Cl
Product: CCOc1ccccc1-c1cc(OC)c(C(=O)N2Cc3ccc(C(=O)NCc4ccccn4)n3Cc3ccccc32)cc1Cl

Procedure:
Prepared by coupling the 10-{[6-chloro-3-methoxy-2′-ethoxy-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Step C with 2-(aminomethyl)pyridine (1.25 equiv.) in the manner of Example 1.
Reaction SMILES: [OH-].[Na+].C([O:6][C:7]1[CH:31]=[CH:30][C:29]([O:32][CH:33]([CH3:35])[CH3:34])=[CH:28][C:8]=1[C:9]([NH:11][C:12]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:18][C:13]=1[C:14]([O:16]C)=[O:15])=[O:10])(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1>[OH:6][C:7]1[CH:31]=[CH:30][C:29]([O:32][CH:33]([CH3:35])[CH3:34])=[CH:28][C:8]=1[C:9]([NH:11][C:12]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:18][C:13]=1[C:14]([OH:16])=[O:15])=[O:10]
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OC(C)C)ccc1OC(C)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(O)c(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)O)c1
Temperature: 55 °C
Reaction time: 4 h
Yield: 61.9 %

Procedure:
Dioxane (5.0 mL) and a 4 mol/L aqueous solution of sodium hydroxide (0.20 mL) were added to the obtained methyl 2-(2-acetoxy-5-isopropoxybenzamido)-4-phenylbenzoate (0.072 g), followed by stirring at 50 to 60° C. for 4 hours. The reaction mixture was cooled to room temperature, and a 4 mol/L aqueous solution of sodium hydroxide (0.081 mL) was added thereto, followed by stirring at 55 to 60° C. for 2 hours. The reaction mixture was cooled to room temperature, and a 4 mol/L aqueous solution of sodium hydroxide (0.040 mL) was added thereto, followed by stirring at 60° C. for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, and a 10% aqueous solution of citric acid (9 mL) was added thereto. The solid substance was collected by filtration to obtain 0.039 g of 2-(2-hydroxy-5-isopropoxybenzamido)-4-phenylbenzoic acid as a white solid.
Reaction SMILES: [O:1]([CH2:9][CH:10]1[CH2:13][CH:12]([OH:14])[CH2:11]1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1>ClCCl.C1(C)C(S(O)(=O)=O)=CC=CC=1>[C:5]([Si:2]([CH3:4])([CH3:3])[O:1][CH2:9][CH:10]1[CH2:11][CH:12]([O:14][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][O:15]2)[CH2:13]1)([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)OCC1CC(O)C1
Reactant: C1=COCCC1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC1CC(OC2CCCCO2)C1
Yield: 79.9 %

Procedure:
3-(tert-Butyl dimethylsilanoxymethyl)-cyclobutanol (1.46 g) in dry dichloromethane was treated with dihydropyran (1.7 g) and toluenesulphonic acid (0.01 g) for 3 hours. The reaction mixture was diluted with dichloromethane, the organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate in cyclohexane (0 to 1:9 by volume) to give the title compound (1.62 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:24]1[S:25][C:26]([CH:29]=[O:30])=[CH:27][N:28]=1)[CH2:9][CH2:10][C@H:11]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:12]([O:14]C)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].ClCCCl.C[Sn](C)(C)O>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]([C:24]1[S:25][C:26]([CH:29]=[O:30])=[CH:27][N:28]=1)[CH2:9][CH2:10][C@H:11]([NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:12]([OH:14])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@H](CCN(C(=O)OC(C)(C)C)c1ncc(C=O)s1)NC(=O)OC(C)(C)C
Agent: C[Sn](C)(C)O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](CCN(C(=O)OC(C)(C)C)c1ncc(C=O)s1)C(=O)O
Temperature: 69 °C
Yield: 9.5 %

Procedure:
To a dry 2-5 mL microwave vial under N2 is added material from Example 116 (120 mg, 0.271 mmol) and anhydrous 1,2-dichloroethane (3 mL). The resulting solution is flushed with N2, treated with trimethylstannanol (60 mg, 0.332 mmol), securely capped and heated in a microwave heating unit at 60-78° C. for 6.5 h. The reaction is diluted with ethyl acetate (75 mL), and the organic layer is washed with 0.5N aqueous HCl (3×15 mL), brine (15 mL), dried over Na2SO4, filtered and evaporated to dryness to give 11 mg (95%) of the title compound as a pale yellow glass that contains 0.5 equivalents of the tin reagent. LC/MS (Condition A): ret. T=3.69 min, (M+Na) 452.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11](=[O:15])[N:12]([CH3:14])[CH3:13])[CH:6]=1)=[O:4].Cl.Br[CH2:18][C:19]([O:21][CH3:22])=[O:20].C([O-])([O-])=O.[K+].[K+]>CO.C1(C)C=CC=CC=1.[Pt]=O.O>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:7]([C:11](=[O:15])[N:12]([CH3:14])[CH3:13])[CH2:6]1)=[O:4]
Reactant: COC(=O)CBr
Reactant: COC(=O)c1ccnc(C(=O)N(C)C)c1
Agent: O=[Pt]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: COC(=O)CN1CCC(C(=O)OC)CC1C(=O)N(C)C
Temperature: 70 °C
Yield: 96296.3 %

Procedure:
A mixture of compound 28 (55.4 g, 0.27 mmole), conc. HCl (16 ml) in MeOH (62 ml) was hydrogenated over platinum oxide (1 g) at 8 kg/cm2 for 24 hours. The catalyst was removed by filtration. The filtrate was concentrated under reduced pressure and the resulting oil was used without further purification. A mixture of crude intermediate compound hydrochloride, methyl bromoacetate (61 g, 0.4 mole) and K2CO3 (73.5 g, 0.53 mole) in toluene (200 ml) was heated at 70° C. for 3 hours. After cooling the reaction mixture, H2O (200 ml) was added and extracted with EtOAc (200 ml×2). The combined organic extracts were dried over MgSO4 and concentrated down. The crude oil was purified by silica gel chromatography EtOAc as eluent to give 29 (69.8 g, 0.26 mole, 97%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>>[C:10]([NH:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: NCCc1ccccc1
Product: CC(=O)NCCc1ccccc1

Procedure:
acetylating 2-phenylethylamine of the formula II: ##STR2## with acetic anhydride to protect the amino group and obtain N-acetyl (2-phenyl)ethylamine of the formula III: ##STR3## (b) chlorosulfonating the compound of the formula III with chlorosulfonic acid to obtain 4-(N-acetylamino) ethyl benzenesulfonyl chloride of the formula IV: ##STR4## (c) treating the compound of the formula IV with ammonia to obtain 4-(2-acetylaminoethyl)benzene sulfonamide of the formula V: ##STR5## (d) hydrolysing the compound of the formula V by treating with sodium hydroxide to deprotect the amino group and obtain 4-(2-aminoethyl)benzene sulfonamide of the formula VI: ##STR6## (e) treating the compound of the formula VI with hydrochloric acid to obtain 4-(2-aminoethyl)benzenesulfonamide hydrochloride of the formula VII: ##STR7## (f) purifying the compound of the formula VII by crystallization from methanol.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[N:5]=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=1.Cl[CH2:19][CH2:20][CH2:21][OH:22].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(O)CCC.CCOC(C)=O.O>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=2)[O:13][CH2:19][CH2:20][CH2:21][OH:22])[N:5]=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=1
Reactant: CC(C)(C)c1cc(N)n(-c2cccc(O)c2)n1
Reactant: OCCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: CC(C)(C)c1cc(N)n(-c2cccc(OCCCO)c2)n1
Temperature: 60 °C
Yield: 79.9 %

Procedure:
A mixture of 3-(5-amino-3-tert-butyl-pyrazol-1-yl)-phenol (400 mg, 1.73 mmol), 3-chloropropanol (326 mg, 3.46 mmol), potassium carbonate (596 mg, 4.32 mmol) and sodium iodide (77 mg, 0.52 mmol) were combined in n-butanol (6 mL). The reaction mixture was heated at 60° C. for 4 days. The mixture was cooled to room temperature, water (100 mL) and EtOAc (100 mL) were added, and then the organic phase was washed with water and brine, dried (Na2SO4), and concentrated at reduced pressure. The residue was purified by MPLC (80:20 hexane/EtOAc) to give the product 3-[3-(5-amino-3-tert-butyl-pyrazol-1-yl)-phenoxy]-propan-1-ol (400 mg, 80%). 1H-NMR (DMSO-d6) δ 7.30 (t, 1H), 7.10 (m, 2H), 6.80 (d, 1H), 5.30 (s, 1H), 5.10 (bs, 2H), 4.0 (t, 2H), 3.60 (t, 3H), 1.80 (m, 2H), 1.30 (s, 9H); MS LC-MS [M+H]+=290.3, RT=1.05 min.
Reaction SMILES: [C:1]([CH:8]1[CH2:13][C:12]2([CH2:16][NH2:17])[CH2:14][CH2:15][C:9]1([C:18]#[N:19])[CH2:10][CH2:11]2)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>CO.CC(O)=O.O.O=[Pt]=O>[C:1]([CH:8]1[CH2:13][C:12]2([CH2:16][NH2:17])[CH2:11][CH2:10][C:9]1([CH2:18][NH2:19])[CH2:15][CH2:14]2)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)C1CC2(CN)CCC1(C#N)CC2
Agent: O=[Pt]=O
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)C1CC2(CN)CCC1(CN)CC2

Procedure:
A solution of 6.75 g (25.5 mmol) of the product from step D in 200 ml of CH3OH plus 4 ml of HOAc and 2 ml of H2O was hydrogenated over 1.63 g of PtO2 in a Parr shaker at 55 psi for 22 hr. The catalyst was removed by filtration through Celite, and the filtrate was concentrated in vacuo to an oily residue, which was flushed/evaporated with CH3OH (1×) and CH2Cl2 (2×). Product began to crystallize toward the end of the evaporation, and ether (up to 300 ml) was added to complete the precipitation. The white solid was triturated and isolated by filtration and washing with ether to give, after drying in vacuo, the title compound as the acetate salt.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([N:26](CC3C=CC=CC=3)CC3C=CC=CC=3)[CH:24]=2)[NH:19][CH:18]=1)=O)C1C=CC=CC=1.[OH-]>C(O)C.[Pd]>[NH2:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]=[C:17]2[CH2:16][C@H:12]1[CH2:13][CH2:14][CH2:15][NH:11]1
Reactant: O=C(OCc1ccccc1)N1CCC[C@@H]1Cc1c[nH]c2ccc(N(Cc3ccccc3)Cc3ccccc3)cc12
Agent: [Pd]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc2[nH]cc(C[C@H]3CCCN3)c2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.7 %

Procedure:
A mixture of (R)-3-(N-benzyloxycarbonylpyrrolidin-2-ylmethyl)-5-dibenzylamino-1H-indole (7.90 g, 14.91 mmol) and moist palladium (ll) hydroxide on carbon (Peariman's catalyst, 3.16 g) in absolute ethanol (100 mL) was shaken under a hydrogen atmosphere (3 arm) for 12 hours at room temperature. The resulting mixture was filtered through diatomaceous earth, and the filtrate was evaporated and dried under reduced pressure to afford the title compound as a white foam (3.20 g, 100%): 1H NMR (CD3OD) δ7.18 (d, J=8.5 Hz, 1H), 7.08 (s, 1H), 6.92 (d, J=2.0 Hz, 1H), 6.69 (dd, J=1.9 and 8.5 Hz, 1H),3.81-3.69(m, 1H),3.30-2.95(m,4H), 2.09-1.55(m, 4H); 13C NMR (CD3OD) δ140.1, 133.4, 129.1, 125.0, 114.6, 113.1, 109.8, 105.1, 62.1, 46.0, 31.1, 29.1, 24.3; LRMS (m/z, relative intensity) 215 (M+, 2), 198 (1), 146 (100), 128 (7), 117 (9), 70 (60).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][O:6][C:7](=[O:21])[C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([NH:15][C:16](=[O:18])[CH3:17])=[CH:10][C:9]=1[O:19][CH3:20]>CCOC(C)=O>[CH3:5][O:6][C:7](=[O:21])[C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([NH:15][C:16](=[O:18])[CH3:17])=[C:10]([N+:1]([O-:4])=[O:2])[C:9]=1[O:19][CH3:20]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1cc(Cl)c(NC(C)=O)cc1OC
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cl)c(NC(C)=O)c([N+](=O)[O-])c1OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 91 %

Procedure:
Fuming nitric acid (33 mL) was added dropwise at 20° C. to compound 10 (13.0 g, 0.05 mol) over 15 min. After stirring for an additional 10 min at that temperature, the mixture was poured into ice water and EtOAc (100 mL) was added. After separating the organic phase, the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over MgSO4 and concentrated. Drying under hv yielded 14.0 g (91%) of 11 as a beige solid. 1H NMR (300 MHz, DMSO-d6): δ 2.01 (s, 3H), 3.84 (s, 3H), 3.87 (s, 3H), 8.12 (s, 1H), 10.30 (s, 1H).
Reaction SMILES: BrC1C=CC(N2CCN([CH:14]3[CH2:23][CH2:22][C:17]4[N:18]=[C:19](N)[S:20][C:16]=4[CH2:15]3)CC2)=NC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[O:30]1CCC[CH2:31]1>>[S:20]1[C:16]2[CH2:15][CH:14]([CH2:31][OH:30])[CH2:23][CH2:22][C:17]=2[N:18]=[CH:19]1
Reactant: C1CCOC1
Reactant: Nc1nc2c(s1)CC(N1CCN(c3ccc(Br)cn3)CC1)CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCC1CCc2ncsc2C1
Reaction time: 1 h

Procedure:
A solution of (±)-ethyl 2-amino-4,5,6,7-tetrahydro-6-benzothiazolecarboxylate (13.5 g) (Example C) in 700 ml of anhydrous tetrahydrofuran is cooled in an ice bath and lithium aluminum hydride (4.56 g) is added in small portions. A thick suspension forms which is kept at room temperature for one hour. The reaction mixture is quenched by careful addition of a 10% solution of hydrochloric acid. The volatile components are evaporated in vacuo and the residue is stirred with a 25% solution of sodium hydroxide and dichloromethane for 30 minutes. An emulsion forms which is filtered through Celite. The aqueous phase is extracted with dichloromethane several times. The pooled organic extracts are dried and evaporated. The residue is recrystallized from ethyl acetate to give (±)-4,5,6,7-tetrahydro-6-benzothiazolemethanol as a colorless solid, mp 176°-182° C. A solution of this compound (5.0 g) in 500 ml of chloroform is treated with 25 ml of a 1 M hydrochloric acid-diethyl ether solution, followed by 50 ml of thionyl chloride. The reaction mixture is refluxed under nitrogen for one hour until evolution of gas ceases. The mixture is concentrated in vacuo and the residue is taken up into 100 ml of dimethylformamide. To this solution is added 1-(2-pyridyl)piperazine (4.89 g) and sodium bicarbonate (5.0 g) and the mixture is heated at 85° C. for six hours. The solvent is evaporated in vacuo, and the residue is partitioned between dichloromethane and water. The organic layer is dried (magnesium sulfate) and purified by MPLC. The hydrochloride salt is prepared to give (±)-4,5,6,7-tetrahydro-6-[[4-(2-pyridinyl)-1-piperazinyl]methyl]benzothiazole containing 2.85 molecules of hydrochloric acid and 1.1 molecules of water; mp 251°-252° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([CH3:15])([CH3:14])[C:10]([O:12]C)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:16][C:17]1[CH:25]=[C:24]([O:26][CH2:27][C@@H:28]2[CH2:33][N:32]([CH3:34])[C:31]3[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=3[O:29]2)[C:23]([CH3:39])=[CH:22][C:18]=1[C:19](Cl)=[O:20].OC1C(C)=CC(C(OC)=O)=C(C)C=1>>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]([CH3:15])([CH3:14])[C:10]([OH:12])=[O:11])=[CH:3][C:2]=1[NH:1][C:19](=[O:20])[C:18]1[CH:22]=[C:23]([CH3:39])[C:24]([O:26][CH2:27][C@@H:28]2[CH2:33][N:32]([CH3:34])[C:31]3[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=3[O:29]2)=[CH:25][C:17]=1[CH3:16]
Reactant: COC(=O)C(C)(C)c1ccc(Cl)c(N)c1
Reactant: Cc1cc(C(=O)Cl)c(C)cc1OC[C@@H]1CN(C)c2ccccc2O1
Agent: COC(=O)c1cc(C)c(O)cc1C
Product: Cc1cc(C(=O)Nc2cc(C(C)(C)C(=O)O)ccc2Cl)c(C)cc1OC[C@@H]1CN(C)c2ccccc2O1
Yield: 66.1 %

Procedure:
By the same procedures as a series of Example 18 and Example 19 using the compound (139 mg) prepared in Example 16 and 2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoylchloride (211 mg) (the compound prepared by the same procedures as a series of Example 8→Example 9→Example 10 using methyl 4-hydroxy-2,5-dimethylbenzoate.), the title compound (211 mg) having the following physical data was obtained.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[C:8]([C:24]([O:26]C)=[O:25])[C:9]2[CH2:10][CH2:11][N:12]([CH:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[C:13](=[O:16])[C:14]=2[CH:15]=1.[OH-].[Na+]>O1CCOCC1>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[C:8]([C:24]([OH:26])=[O:25])[C:9]2[CH2:10][CH2:11][N:12]([CH:17]([CH2:18][CH2:19][CH3:20])[CH2:21][CH2:22][CH3:23])[C:13](=[O:16])[C:14]=2[CH:15]=1
Reactant: CCCC(CCC)N1CCc2c(C(=O)OC)cc(-c3ncco3)cc2C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCC(CCC)N1CCc2c(C(=O)O)cc(-c3ncco3)cc2C1=O
Yield: 93.9 %

Procedure:
320 mg of methyl 7-(2-oxazolyl]-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate are dissolved in 7 cm3 of dioxane at a temperature close to 20° C. 2.1 cm3 of a 1N aqueous solution of sodium hydroxide are added, then the reaction mixture is heated at a temperature close to 60° C. for 30 min. The dioxane contained in the reaction mixture is concentrated to dryness under reduced pressure (5 kPa). 2.5 cm3 of a 1N aqueous solution of hydrochloric acid, 20 cm3 of dichloromethane and 20 cm3 of water are added to the residue obtained. After decanting, the organic phase is dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (5 kPa). 289 mg of 7-(2-oxazolyl]-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid are obtained in the form of a beige powder.
Reaction SMILES: CO[C:3]([C:5]1[C:10](=[O:11])[N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:8]2[CH:23]=[C:24]([Cl:26])[CH:25]=[C:7]2[C:6]=1[OH:27])=[O:4].[NH2:28][CH2:29][C:30]([O-:32])=[O:31].[Na+]>>[Cl:26][C:24]1[CH:25]=[C:7]2[C:6]([OH:27])=[C:5]([C:3]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:4])[C:10](=[O:11])[N:9]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:22])[F:21])=[CH:17][CH:18]=3)[N:8]2[CH:23]=1
Reactant: COC(=O)c1c(O)c2cc(Cl)cn2n(Cc2ccc(C(F)(F)F)cc2)c1=O
Reactant: NCC(=O)[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1c(O)c2cc(Cl)cn2n(Cc2ccc(C(F)(F)F)cc2)c1=O

Procedure:
Prepared according to the glycinolysis condition used in Example 1 step d) from 6-chloro-4-hydroxy-2-oxo-1-(4-trifluoromethyl-benzyl)-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid methyl ester (1.0 eq.) and sodium glycinate (15 eq.). ESI (m/z): 444 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH2:28][S:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=[O:46])=CC=1.ClC1C=C(C=CC=1)C(OO)=O>ClCCl>[Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH2:28][S:29]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:46])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cn(CSc2ccccc2)c2ccc(CN3CCOCC3)cc2c1=O
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O
Product: O=C(NCc1ccc(Cl)cc1)c1cn(CS(=O)c2ccccc2)c2ccc(CN3CCOCC3)cc2c1=O
Reaction time: 1 h
Yield: 72.8 %

Procedure:
A solution of N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-1-[(phenylsulfanyl)methyl)-1,4-dihydro-3-quinolinecarboxamide (0.08 gm) from Example No. 76 in dichloromethane (2 mL) at 0° C. is added p-toluenesulfonic acid hydrate (0.03 gm) followed by m-chloroperoxybenzoic acid (˜85%) (0.03 gm). The mixture is stirred for 1 hr. The reaction mixture is diluted with dichloromethane, washed with saturated aqueous sodium sulfite, saturated aqueous sodium bicarbonate, brine, dried (Na2SO4) and concentrated under reduced pressure. The crude product is purified by recrystallization from acetonitrile to afford 0.06 gm of the title compound as a white solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C@@:11]([C:15]([F:18])([F:17])[F:16])([OH:14])[C@@H:10]([OH:19])[CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[F:18][C:15]([F:16])([F:17])[C@@:11]1([OH:14])[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]1[OH:19]
Reactant: [H][H]
Reactant: O[C@H]1CN(Cc2ccccc2)CC[C@]1(O)C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: O[C@H]1CNCC[C@]1(O)C(F)(F)F

Procedure:
A mixture of 1.50 g (5.45 mmol) of (3S,4R)-1-benzyl-4-trifluoromethylpiperidin-3,4-diol and 170 mg of Pd/C (10%) in 17 mL of MeOH was hydrogenated at RT and 3 bar hydrogen pressure for 5 hours. The catalyst was filtered off and the filtrate was evaporated down in vacuo. Yield: 910 mg (90% of theoretical); C6H10F3NO2 (M=185.144); calc.: molpeak (M+H)+: 186; found: molpeak (M+H)+: 186; Rf value: 0.35 (silica gel, EtOAc/MeOH/conc. aqueous ammonia 7:3:0.3).
Reaction SMILES: [CH:1](=[N:6][OH:7])[C:2]([CH3:5])([CH3:4])[CH3:3].ClN1C(=O)CCC1=O.[CH:16]([P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH2:17].C(N(CC)CC)C>ClCCl.N1C=CC=CC=1>[C:2]([C:1]1[CH2:17][CH:16]([P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])[O:7][N:6]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: C=CP(=O)(OCC)OCC
Reactant: CC(C)(C)C=NO
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOP(=O)(OCC)C1CC(C(C)(C)C)=NO1

Procedure:
The procedure is analogous to that of Example 25 using 15.2 g (0.15 mol) of pivalaldoxime, 22.0 g (0.165 mol) of N-chlorosuccinimide, 0.5 ml of pyridine, 27.1 g (0.165 mol) of diethyl vinylphosphonate and 22.9 ml (0.165 mol) of triethylamine in dichloromethane. The product is obtained as an oil after the usual working up.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:23][C:24]2[S:25][C:26]3[CH2:32][CH2:31][CH2:30][C:29](=[O:33])[C:27]=3[N:28]=2)[CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[N:20][C:19]([CH3:22])=[N:18]1>C(OCC)C>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:23][C:24]2[S:25][C:26]3[CH2:32][CH2:31][CH2:30][C:29]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)([OH:33])[C:27]=3[N:28]=2)[CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[N:20][C:19]([CH3:22])=[N:18]1
Reactant: COc1cc(Nc2nc3c(s2)CCCC3=O)ccc1-n1cnc(C)n1
Reactant: Br[Mg]c1ccccc1
Solvent: CCOCC
Product: COc1cc(Nc2nc3c(s2)CCCC3(O)c2ccccc2)ccc1-n1cnc(C)n1
Yield: 59.1 %

Procedure:
Phenylmagnesium bromide (1.0 M in THF, 0.118 mL, 0.118 mmol) was added to a rt solution of 2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenylamino)-6,7-dihydrobenzo[d]thiazol-4(5H)-one (14 mg, 0.039 mmol) in diethyl ether (0.13 mL). The reaction was quenched with saturated ammonium chloride and extracted with EtOAc. The organic layer was concentrated in vacuo. The crude product was purified using preparatory TLC (60% acetone/hexanes) to afford 10 mg (53% yield) of the titled compound as a oil. LC-MS (M+H)+ 434.3.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:8]2[O:12][C:11](=[O:13])[CH:10](O)[C:9]=2[CH:15]=1)([CH3:4])([CH3:3])[CH3:2].[Br:20]Br>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:8]2[O:12][C:11](=[O:13])[CH:10]([Br:20])[C:9]=2[CH:15]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2O
Reactant: BrBr
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2Br
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 1.5 %

Procedure:
12.9 g (0.052 mol) of 5,7-di-tert-butyl-3-hydroxybenzofuranone are dissolved in 50 ml of toluene and treated with 2.9 ml (0.052 mol) of bromine at 30° C. The mixture is subsequently stirred at 60° C. for 30 minutes. The solvent is distilled off by means of a rotary evaporator. 1 g of the crude product is purified by flash chromatography over silica gel (Merck Silicagel 60, 70-230 mesh ASTM; mobile phase: 1:1 hexane/dichloromethane) to leave 0.26 g (36% of theory) of 5,7-di-tert-butyl-3-bromobenzofuranone (XLVII).