Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH:10]([OH:14])[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][Si](C=[N+]=[N-])(C)C>C1C=CC=CC=1.CO>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:15][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)[CH:10]([OH:14])[C:11]([O:13][CH3:22])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@H](CC1CCCCC1)C(O)C(=O)O
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)C(O)[C@@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of Example 3C (10.234 g, 34 mmol), and trimethylsilyldiazomethane (2.0M in hexanes, 25 mL) in 3.5:1 benzene/methanol (232 mL) at room temperature was stirred at 0° C. for 1 hour, warmed to ambient temperature, stirred for 1 hour, quenched by the dropwise addition of acetic acid, concentrated to provide the desired product. MS (ESI) m/e 316 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:20])[CH2:7][C:8]1([C:17]([OH:19])=[O:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)(C)(C)C.Cl>CCOC(C)=O>[C:6]([CH2:7][C:8]1([C:17]([OH:19])=[O:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)([OH:20])=[O:5]
Reactant: CC(C)(C)OC(=O)CC1(C(=O)O)Cc2ccccc2C1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(O)CC1(C(=O)O)Cc2ccccc2C1
Reaction time: 1 h

Procedure:
A solution of 2-(2-tert-butoxy-2-oxoethyl)indane-2-carboxylic acid from Step B (1.50 g, 5.43 mmol) in EtOAc (100 mL) was saturated with HCl (g) and stood at ambient temperature for 1 h, then concentrated to dryness in vacuo, to give the title compound. MS: m/z=284 (M+Na+CH3CN).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[Br:15]Br>C(Cl)Cl>[Br:15][CH2:9][C:8](=[O:10])[C:7]([O:6][C:5]1[CH:13]=[CH:14][C:2]([Cl:1])=[CH:3][CH:4]=1)([CH3:11])[CH3:12]
Reactant: BrBr
Reactant: CC(=O)C(C)(C)Oc1ccc(Cl)cc1
Solvent: ClCCl
Product: CC(C)(Oc1ccc(Cl)cc1)C(=O)CBr
Reaction time: 0.5 h
Yield: 72.6 %

Procedure:
110.2 g (0.5 mol) of 3-(4-chlorophenoxy)-3-methyl-butan-2-one were dissolved in 500 ml of methylene chloride, and 83 g (0.52 mol) of bromine were added dropwise at room temperature in a manner such that continuous decoloration occurred. When the addition had ended, the mixture was subsequently stirred for 30 minutes, the organic phase was washed twice with 300 ml of water and twice with 300 ml of saturated sodium bicarbonate solution and was dried over sodium sulphate and distilled. 105.9 g (70% of theory) of 1-bromo-3-(4-chlorophenoxy)-3-methyl-butan-2-one of boiling point 115° to 118° C./0.1 mm Hg were obtained. ##STR811##
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[N:15]1([C:21]2[CH:26]=[CH:25][C:24]([C:27]34[CH2:32][CH:31]3[CH2:30][NH:29][CH2:28]4)=[CH:23][CH:22]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.CCN(C(C)C)C(C)C.[CH3:42][O:43][CH2:44][CH2:45]Cl>CN(C=O)C>[CH3:42][O:43][CH2:44][CH2:45][N:29]1[CH2:30][CH:31]2[C:27]([C:24]3[CH:23]=[CH:22][C:21]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[CH:26][CH:25]=3)([CH2:32]2)[CH2:28]1
Reactant: c1cc(C23CNCC2C3)ccc1N1CCOCC1
Reactant: COCCCl
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCN1CC2CC2(c2ccc(N3CCOCC3)cc2)C1
Temperature: 100 °C
Reaction time: 16 h
Yield: 37.2 %

Procedure:
To a solution of dihydrochloride salt of 1-(4-morpholin-4-yl-phenyl)-3-aza-bicyclo[3.1.0]hexane (Example XXI) (250 mg, 0.89 mmol) in anhydrous DMF (5 mL) were added DIPEA (0.63 mL, 3.56 mmol) and 2-methoxyethyl chloride (0.12 mL, 1.3 mmol) at r.t. and reaction mixture was stirred at 100° C. for 16 h. Progress of the reaction was monitored by TLC. On completion, reaction mixture was then concentrated and the crude product was purified by column chromatography (silica gel, 0.25:9.75 MeOH:CHCl3) to afford the title compound as viscous liquid (100 mg, 37%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:8]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][N:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:8]=1
Reactant: Cc1ccc(-n2cc([N+](=O)[O-])cn2)cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(-n2cc(N)cn2)cc1
Yield: 85.5 %

Procedure:
Intermediate 6a (212 mg, 1.04 mmol) was dissolved in ethanol (20 mL) then hydrogenated over 10% palladium on carbon for 4 h under hydrogen atmosphere. The mixture was then filtered through Celite, washing with ethanol, and evaporated to dryness. The residue was purified by FCC, eluting with 0-10% MeOH in DCM, to give the title compound as a pale brown solid (154 mg, 86%). LCMS (Method 3): Rt 1.92 min, m/z 174.1 [MH−].
Reaction SMILES: [Cl:1][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[Cl:1][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][S:32]([CH3:31])(=[O:34])=[O:33])=[CH:21][CH:22]=2)=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(Cl)Cc1ccc(CCOc2ccc(O)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(Cl)Cc1ccc(CCOc2ccc(OS(C)(=O)=O)cc2)cc1
Temperature: -20 °C
Yield: 95.4 %

Procedure:
Methyl 2-chloro-3-{4-[2-(4-hydroxyphenoxy)ethyl]phenyl}propanoate (334 mg, 1.0 mmol) and triethylamine (303 mg, 3.0 mmol) was dissolved in 20 ml dichlormethane and cooled to −20° C. under nitrogen atmosphere. Methanesulfonyl chloride (114 mg, 1.0 mmol) was added dropwise. The mixture was allowed to reach room temperature. After 2 hours dichlormethane was added, the mixture was washed (water, brine), dried (Na2SO4) and evaporated under reduced pressure to yield 394 mg pure product (yield 96%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:6]=[CH:5]2.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH2:29])[CH:23]=1>O1CCOCC1>[O:15]([CH2:14][CH2:13][NH:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:29][CH2:28][C:24]3[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=3)[CH:3]=2)[N:8]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1cccnc1
Reactant: Clc1ccc2nc(NCCOc3ccccc3)ccc2c1
Solvent: C1COCCO1
Product: c1ccc(OCCNc2ccc3cc(NCc4cccnc4)ccc3n2)cc1
Temperature: 115 °C
Reaction time: 16 h

Procedure:
(6-Chloro-quinolin-2-yl)-(2-phenoxy-ethyl)-amine (150 mg, 0.503 mmol) was dissolved in 2 mL dioxane. Argon was bubbled through the solution for 2 minutes to remove oxygen. 3-Picolylamine (165 mg, 1.53 mmol), sodium tert.-butylate (119 mg, 1.24 mmol) and 1,1′-2-(dimethylamino)ferrocen-1-yl-palladium(II) chloride dinorbornylphosphine (16 mg, 0.03 mmol) were added. The reaction mixture was stirred in a sealed tube at 115° C. for 16 h. The solvent was evaporated and the residue purified by flash chromatography on silica gel (dichloromethane/methanol 100:0->90:10 gradient). The title compound was obtained as a light brown solid (108 mg, 58%), MS: m/e=371.1 (M+H+).
Reaction SMILES: C([Li])CCC.[C:6]([O:10][C:11]([N:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18](Br)[CH:19]=2)[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[CH3:23][N:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1>C1COCC1>[C:6]([O:10][C:11]([N:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:27]3([OH:30])[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]3)[CH:19]=2)[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CN1CCC(=O)CC1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(Br)cc2C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1CCC(O)(c2ccc3c(c2)CN(C(=O)OC(C)(C)C)C3)CC1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
0.69 ml of n-Butyl lithium (2.5M solution in hexane) was added dropwise to a stirred solution of 5-bromo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (429 mg; 1.44 mmol) in anhydrous THF (10 ml) at −78° C. under an atmosphere of nitrogen. The reaction was stirred for 50 minutes then 1-methyl-4-piperidone (212 μl; 1.2 equiv.) was added and stirred at −78° C. for a further 60 minutes then warmed to room temperature. The reaction was quenched with saturated ammonium chloride solution then extracted with EtOAc. The EtOAc layer was washed with saturated NaHCO3, brine, dried (MgSO4) and evaporated. Purification by flash column chromatography on SiO2, gradient elution from 0% to 10% 2M methanolic ammonia/DCM gave 111 mg of 5-(4-hydroxy-1-methyl-piperidin-4-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester as a colourless oil.
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:9]2[C:8](=O)[NH:7][C:6]([NH2:12])=[N:5][C:4]=2[N:3]=1.P(Cl)(Cl)([Cl:15])=O>C(N(CC)C1C=CC=CC=1)C>[NH2:12][C:6]1[N:5]=[C:4]2[C:9]([NH:10][C:2]([CH3:1])=[N:3]2)=[C:8]([Cl:15])[N:7]=1
Reactant: Cc1nc2nc(N)[nH]c(=O)c2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: Cc1nc2nc(N)nc(Cl)c2[nH]1

Procedure:
A suspension of 8-methylguanine (Daves et al., J. Am. Chem. Soc., 82, 2633-2640 (1960)) (1.0 g, 6.1mmol) in phosphorous oxychloride (30 mL) and N,N-diethylaniline (1 mL) was refluxed for 3 h. The excess phosphorous oxychloride was evaporated under reduced pressure. The resulting brown oil was dissolved in ice-water and was neutralized with a concentrated aqueous NaOH solution. After evaporation of the solvent, the solid residue was suspended in 70 mL of H2O. Undissolved solid was filtered off, and the filtrate was loaded on a 3×80 cm Sephadex LH-20 column eluted with methanol/water (1:1) at 1 mL/min. Column eluent was continuously monitored at 280 nm and fractions (10 mL) were collected. Evaporation of pooled fractions 50-60 produced 2-amino-6-chloro-8-methylpurine as a crude solid. Crystallization from ethanol/water with charcoal treatment afforded 2-amino-6-chloro-8-methylpurine as a white solid: yield, 0.57 g (51%); mp >265° C. dec.; 1H NMR δ 2.39 (s, 3H, CH3), 6.62 (s, 2H, NH2, exchange with D2O), 12.56 (s, 1H, NH, exchanges with D2O); MS (EI) calcd. m/z for C6H6N535Cl 183.0312, found 183.0309; calcd. m/z for C6H6N537Cl 185.0283, found 185.0286.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:20][CH:19]([OH:21])[CH2:18]3)=[O:16])[CH2:12][CH:11]([C:22](O)=[O:23])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].O[N:26]=[C:27]([NH2:31])[CH:28]([CH3:30])[CH3:29]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][CH:11]([C:22]3[O:23][N:31]=[C:27]([CH:28]([CH3:30])[CH3:29])[N:26]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:20][CH:19]([OH:21])[CH2:18]3)=[O:16])[CH2:14]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CC(C)C(N)=NO
Reactant: Cc1ccc(C2CC(C(=O)O)CN(C(=O)N3CC(O)C3)C2)cc1C
Product: Cc1ccc(C2CC(c3nc(C(C)C)no3)CN(C(=O)N3CC(O)C3)C2)cc1C

Procedure:
72 mg (0.22 mmol) of the compound from Example 134A and 43 mg (0.33 mmol) of N′-hydroxy-2-methylpropanimidamide were reacted according to the General Method 2. Yield: 17 mg (19% of theory)
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[CH2:11]([N:13]([CH2:35][CH3:36])[CH2:14][CH:15]([N:17]1[C:30]2[CH:29]=[C:28]([C:31](=[NH:34])OC)[CH:27]=[CH:26][C:25]=2[S:24][C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH3:16])[CH3:12].O>CO>[CH2:1]([NH:8][C:31]([C:28]1[CH:27]=[CH:26][C:25]2[S:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH:15]([CH3:16])[CH2:14][N:13]([CH2:35][CH3:36])[CH2:11][CH3:12])[C:30]=2[CH:29]=1)=[NH:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CCN(CC)CC(C)N1c2ccccc2Sc2ccc(C(=N)OC)cc21
Agent: Cl
Solvent: CO
Solvent: O
Product: CCN(CC)CC(C)N1c2ccccc2Sc2ccc(C(=N)NCc3ccccc3)cc21
Temperature: 5 °C
Reaction time: 2 h

Procedure:
A solution of benzylamine (3.18 cc) in methanol (5 cc) is added dropwise in the course of 5 minutes to a solution, cooled to 0°-5° C., of methyl 10-[(2RS)-1-diethylamino-2-propyl]-2-phenothiazinecarboximidate dihydrochloride (3.49 g) in methanol (21 cc). The mixture is stirred for 2 hours at 5° C. and is then concentrated to dryness at 50° C. under reduced pressure (30 mm Hg; 4 kPa) to give a residue which is taken up with distilled water (50 cc). The solution is washed with distilled water (50 cc) alkalinized to a pH in the region of 9 with N sodium hydroxide. The two phases are allowed to settle and the organic phase is separated and washed with half-saturated sodium chloride solution (50 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. The residue is purified by chromatography on a column of neutral alumina (height: 24 cm; diameter: 2.1 cm), eluting successively with mixtures of cyclohexane and ethyl acetate in proportions of 50:50 (500 cc) and 25:75 (500 cc), then with pure ethyl acetate (500 cc) and finally with mixtures of ethyl acetate and methanol in proportions of 95:5 (500 cc) and 90:10 (500 cc) and collecting 50-cc fractions. Fractions 35 to 53 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. to give N-benzyl-10-[ (2RS)-1-diethylamino-2-propyl]-2-phenothiazinecarboxamidine (0.96 g) in the form of a yellow product of meringue-like consistency.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]1([S:14](Cl)=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.S(=O)(=O)(O)O>CCOCC.N1C=CC=CC=1>[C:1]1([S:7][S:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: O=S(Cl)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=S(Sc1ccccc1)c1ccccc1
Reaction time: 0.17 h

Procedure:
To a solution of 2.2 g. (20 mmol) thiophenol in 30 ml. dry ether one adds 1.8 g. pyridine and adds dropwise thereto, with cooling, a solution of 3.2 g. (20 mmol) benzenesulphinic acid chloride in 20 ml. dry ether. One allows to stir further for 10 min., pours into dil. sulphuric acid, separates off the organic phase, dries and evaporates. There remain 3.2 g. of the title compound (68% of theory) of the m.p. 69°-70° C. (from ligroin).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=O.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.C(Cl)Cl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CCOC(C)=O>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: O=Cc1sccc1Br
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Brc1ccsc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
To a solution of 3-bromothiophene-2-carbaldehyde (500 mg, 2.62 mmol) and morpholine (0.68 mL, 7.85 mmol) and CH2Cl2 (10 mL) was added sodium triacetoxyborohydride (1.11 g, 5.24 mmol). The mixture was stirred at room temperature overnight. The resulting mixture was diluted with EtOAc (100 mL) and the organic layer was washed with brine then dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography (silica, 0-5% MeOH in CH2Cl2) to afford the sub-title compound (580 mg, 84%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:13])[CH:12]=1)[CH:5]([OH:9])[C:6]([OH:8])=O.Cl.N[C@H](C([C:20]1([NH2:43])[C:26](=[O:27])[N:25]([CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:24]2[CH:33]=[CH:34][CH:35]=[CH:36][C:23]=2[N:22]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:21]1=[O:42])=O)C>>[F:13][C:11]1[CH:10]=[C:4]([CH:5]([OH:9])[C:6]([NH:43][C@H:20]([C:26]([NH:43][CH:20]2[C:21](=[O:42])[N:22]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:23]3[CH:36]=[CH:35][CH:34]=[CH:33][C:24]=3[N:25]([CH2:28][C:29]([CH3:31])([CH3:30])[CH3:32])[C:26]2=[O:27])=[O:27])[CH3:21])=[O:8])[CH:3]=[C:2]([F:1])[CH:12]=1
Reactant: C[C@H](N)C(=O)C1(N)C(=O)N(CC(C)(C)C)c2ccccc2N(CC(C)(C)C)C1=O
Reactant: O=C(O)C(O)c1cc(F)cc(F)c1
Agent: Cl
Product: C[C@H](NC(=O)C(O)c1cc(F)cc(F)c1)C(=O)NC1C(=O)N(CC(C)(C)C)c2ccccc2N(CC(C)(C)C)C1=O

Procedure:
Following General Procedure I above using 3,5-difluoromandelic acid (Lancaster) and 3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example 8-V), the title compound was prepared as a white solid (melting point=116-126° C.). Purification was by flash chromatography eluting with CH2Cl2/EtOAc (1:1 gradient to 2:3). Rf=0.54 and 0.40 (CH2Cl2/EtOAc, 1:1).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[F:12][C:13]1[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=1)[O:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.S([O-])(O)=O.[Na+]>C(Cl)Cl>[F:12][C:13]1[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=1)[O:16][C:17]1[CH:18]=[N+:19]([O-:9])[CH:20]=[CH:21][CH:22]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Fc1cccc(Oc2cccnc2)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: [O-][n+]1cccc(Oc2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
To a solution of 46.3 g of m-chloroperbenzoic acid in 460 ml of methylene chloride, 37.35 g of 3-(3-fluorophenoxy)pyridine was added at room temperature, and the mixture was stirred at room temperature for 1.5 hours. An aqueous sodium hydrogen sulfite solution (20%, 120 ml) was added to the mixture and then the mixture was stirred for a few minutes. The organic layer separated was washed with 10% aqueous sodium hydroxide solution and with water, dried over anhydrous sodium sulfate, and concentrated. The residue was crystallized by trituration with isopropyl ether. The crystals were collected by filtration and washed with isopropyl ether to yield 34.44 g of pale yellow crystals, which were recrystallized from ethyl acetate to give colorless needles, mp 59°-61° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[C:7]#[N:8])[CH:2]=[CH2:3].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]#[N:8])[CH:2]=[CH2:3]
Reactant: BrCc1ccccc1
Reactant: C=CCc1cc(C#N)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCc1cc(C#N)ccc1OCc1ccccc1

Procedure:
Prepared analogously to Example 5d from 3-allyl-4-hydroxy-benzonitrile and benzylbromide/potassium carbonate in dimethylformamide.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[CH2:21][CH2:20][O:19][C:18]([OH:29])([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[CH2:17]2)[CH3:15])=[CH:9][CH:8]=1)(OC)=[O:2].[NH3:30]>>[NH2:30][C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[CH2:21][CH2:20][O:19][C:18]([OH:29])([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[CH2:17]2)[CH3:15])=[CH:9][CH:8]=1)=[O:2]
Reactant: N
Reactant: COC(=O)COc1ccc(CC(C)N2CCOC(O)(c3cccc(Cl)c3)C2)cc1
Product: CC(Cc1ccc(OCC(N)=O)cc1)N1CCOC(O)(c2cccc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2.03 g (4.76 mmol) of N-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(3-chlorophenyl)morpholine is dissolved in 20 ml of ammonia-saturated methanol and stirred for 24 hours at ambient temperature. The mixture is then evaporated down and the evaporation residue is purified by column chromatography on silica gel (eluant: ethyl acetate/cyclohexane=3:1).
Reaction SMILES: [F-].[K+].[Cl:3][C:4]1[C:12]([C:13]([F:16])([F:15])[F:14])=[C:11]([F:17])[C:10]([Si](C)(C)C)=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]>O.O1CCCC1>[Cl:3][C:4]1[C:12]([C:13]([F:14])([F:15])[F:16])=[C:11]([F:17])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: C[Si](C)(C)c1cc(C(=O)O)c(Cl)c(C(F)(F)F)c1F
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(F)c(C(F)(F)F)c1Cl
Temperature: 100 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
A solution of potassium fluoride (0.367 g, 9.55 mmol) in water (15 ml) was added to a solution of 2-chloro-4-fluoro-3-(trifluoromethyl)-5-(trimethylsilyl)benzoic acid (1 g, 3.18 mmol) in tetrahydrofuran (50 ml) and the mixture was stirred at 100° C. overnight. An additional aliquot of water (15 ml) and potassium fluoride (0.370 g, 9.62 mmol) was added and heating at 100° C. was continued for a further 4 hrs. The tetrahydrofuran was evaporated in vacuo and replaced with enough dimethylformamide to dissolve all solids. The mixture was heated overnight at 100° C. but starting material still remained so more potassium fluoride (0.367 g, 9.55 mmol) was added and heating at 100° C. continued for 7 days. At this stage almost all of the starting material had disappeared so the reaction was evaporated to dryness under vacuum and taken up in 2N aqueous hydrogen chloride (75 ml) and diethyl ether (50 ml). The aqueous layer was separated and extracted with more diethyl ether (2×50 ml) and then the combined organic fractions were dried over sodium sulphate and evaporated to give crude product as a white solid. This was purified by recrystallisation from toluene to give pure 2-chloro-4-fluoro-3-(trifluoromethyl)benzoic acid (0.566 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([OH:12])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:13].[F:14][C:15]([F:21])([F:20])[S:16](Cl)(=[O:18])=[O:17]>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][S:16]([C:15]([F:21])([F:20])[F:14])(=[O:18])=[O:17])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:13]
Reactant: O=C1CCc2c(Cl)cc(Cl)c(O)c21
Reactant: O=S(=O)(Cl)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C1CCc2c(Cl)cc(Cl)c(OS(=O)(=O)C(F)(F)F)c21
Temperature: 0 °C

Procedure:
4,6-Dichloro-7-hydroxyindan-1-one (21.71 g., 0.1 mole) was dissolved in DMF (80 ml) in a dry apparatus under nitrogen. Trifluormethanesulfonylchloride (21.60 g., 0.128 mole) was added with stirring, slowly, dropwise over a 20 minute period with occasional cooling to keep the internal temperature below 30° C. After the addition was complete, the reaction was stirred at room temperature for 30 minutes, then poured into ice-water with swirling. The green crystals were collected, washed with water, sucked dry, then dried in a vacuum oven at 50° C. to give 32.7 g. of the title compound mp 96°-100° C. Recrystallization from hexanes gave 22.4 g., mp 96°-98° C. A sublimed sample had mp 90°-96° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[C:5]([NH:7][CH2:8][CH2:9][CH2:10][C:11]([O:13]C)=[O:12])=[O:6].[OH:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].CCN(CC)CC.[OH-].[Na+].Cl>C(OCC)(=O)C>[OH:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[C:5]([NH:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:6])=[O:22]
Reactant: COC(=O)CCCNC(=O)c1cccc(N)c1
Reactant: O=C(Cl)c1ccccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(O)CCCNC(=O)c1cccc(NC(=O)c2ccccc2O)c1

Procedure:
To a solution of 2.60 g (11.00 mmol) of methyl 4-(3-aminobenzoylamino)butanoate dissolved in 25 ml of ethyl acetate, very slowly add 1.40 g (10.00 mmol) of 2-hydroxybenzoyl chloride dissolved in 5 ml of ethyl acetate. Then add 1.00 g (10.00 mmol) of Et3N (triethylamine) and keep the reaction mixture at room temperature for 24 hours. Eliminate the solvent at low pressure, add 40 ml of 10% NaOH to the crude product and continue stirring the mixture until the oil has completely disappeared. Immediately acidify with concentrated HCl, filter the resulting solid and wash several times with water. Purify the reaction product by recrystallization (EtOH/H2O). This yields 1.60 g (48%) of 4-[3-(2-hydroxybenzoylamino) benzoylamino]butanoic acid as a white solid.