Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([BH3-])#N.[Na+].[NH2:5][C:6]1[CH:7]=[C:8]([OH:13])[CH:9]=[CH:10][C:11]=1[F:12].[CH2:14]=[O:15].[C:16]([OH:19])(=O)C>C(#N)C.O>[CH3:14][O:15][N:5]([O:19][CH3:16])[C:6]1[CH:7]=[C:8]([OH:13])[CH:9]=[CH:10][C:11]=1[F:12]
Reactant: CC(=O)O
Reactant: Nc1cc(O)ccc1F
Reactant: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CON(OC)c1cc(O)ccc1F
Reaction time: 2 h
Yield: 91 %

Procedure:
Sodium cyanoborohydride (0.81 g, 12.7 mmol) is added to a solution of 3-amino-4-fluorophenol (0.66 g, 4.6 mmol), formaldehyde (37% solution, 2.0 g, 24.6 mmol) and acetic acid (0.5 mL) in 20 mL acetonitrile. The reaction is stirred for 2 hour and then poured into 100 mL water. The product is then extracted into diethyl ether (50 mL×3) and the combined organic fractions are washed with brine (40 mL), and dried over anhydrous sodium sulfate. The resulting solution is concentrated in vacuo, and the residue is chromatographed on silica gel using CHCl3 :ethyl acetate as eluant (99:1 to 90:10 gradient) to yield 0.72 g (91%) of Compound 22 as a brown solid. 1H-NMR (CDCl3) 6.85 (dd, 1H); 6.40 (m, 1H); 6.27 (m, 1H); 2.84 (s, 6H). 19F-NMR (CDCl3) 133.25 (t, J=9.5 Hz).
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[C:14]2[CH2:13][CH2:12][N:11]([C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:10][CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1>C(#N)C>[Br:1][C:7]1[C:8]2[CH2:9][CH2:10][N:11]([C:15](=[O:20])[C:16]([F:19])([F:17])[F:18])[CH2:12][CH2:13][C:14]=2[C:4]([OH:3])=[CH:5][CH:6]=1
Reactant: O=C(N1CCc2cccc(O)c2CC1)C(F)(F)F
Reactant: BrBr
Solvent: CC#N
Product: O=C(N1CCc2c(O)ccc(Br)c2CC1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
Add dropwise bromine (10.8 mL, 0.21 mol) in acetonitrile (260 mL) to a slurry of 6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (51.8 g, 0.2 mol) in acetonitrile (400 mL) at 0° C. cooling with ice-water to keep the temperature between 2-5° C. Warm the reaction to ambient temperature and stir for 30 min. Pour the mixture into ice-cold water (2 L) to obtain a white precipitate. Collect the solid by vacuum filtration, wash with water and dry under vacuum at 105° C. Recrystallize the crude material in toluene/heptane and cool the mixture in an ice bath. Collect the solid by vacuum filtration, wash with heptane and dry under vacuum at 105° C. to obtain the desired intermediate as a white solid (54.63 g, 81%). MS (ES+) m/z: 338 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([F:17])([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH:18]1(N)CC1.C(OC(N1CCC(C(=O)[NH:36][CH:37]2[CH2:42]CCC[CH2:38]2)CC1)=O)(C)(C)C>>[C:37]([NH:36][C:14]([C:11]1([F:17])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:16])([CH3:42])([CH3:18])[CH3:38]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NC2CCCCC2)CC1
Reactant: NC1CC1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(C(=O)O)CC1
Product: CC(C)(C)NC(=O)C1(F)CCNCC1

Procedure:
The title compound is prepared according to the reaction sequence 3.01a-2.01b described above using 1-(tert-butoxycarbonyl)-4-fluoropiperidine-4-carboxylic acid instead of 1-(tert-butoxycarbonyl)-piperidine-4-carboxylic acid and cyclopropylamine instead of cyclohexylamine as in 3.01a: LC-MS A: tR=0.41 min; [M+H]+=197.35.
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[C@H:3]([NH2:27])[C:4]([N:6]1[CH2:11][C@@H:10]2[CH2:12][C@H:7]1[CH2:8][N:9]2[C:13]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][N:16]=1)=[O:14])=[O:5].[F:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][C:35]([C:40](O)=[O:41])=[CH:34]2.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl>[CH3:1][C:2]([CH3:29])([CH3:28])[C@H:3]([NH:27][C:40]([C:35]1[NH:36][C:37]2[C:33]([CH:34]=1)=[CH:32][C:31]([F:30])=[CH:39][CH:38]=2)=[O:41])[C:4]([N:6]1[CH2:11][C@@H:10]2[CH2:12][C@H:7]1[CH2:8][N:9]2[C:13]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][N:16]=1)=[O:14])=[O:5]
Reactant: CC(C)(C)[C@H](N)C(=O)N1C[C@@H]2C[C@H]1CN2C(=O)c1ccc(-c2ccccc2)cn1
Reactant: O=C(O)c1cc2cc(F)ccc2[nH]1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)[C@H](NC(=O)c1cc2cc(F)ccc2[nH]1)C(=O)N1C[C@@H]2C[C@H]1CN2C(=O)c1ccc(-c2ccccc2)cn1
Yield: 47.7 %

Procedure:
A solution of [(1S)-2,2-dimethyl-1-({(1S,4S)-5-[(5-phenyl-2-pyridinyl)carbonyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}carbonyl)propyl]amine (100 mg, 0.25 mmol), 5-fluoro-1H-indole-2-carboxylic acid (48 mg, 0.26 mmol), EDC (58 mg, 0.3 mmol), HOBt (7 mg, 0.05 mmol), NMM (77 mg, 0.76 mmol) in CH2Cl2 (3 mL) was stirred at room temperature for 2 h. The mixture was washed with 1N sodium hydroxide (2×3 mL), water (2×10 mL). The combined aqueous washes were extracted with CH2Cl2 (2×5 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered concentrated to give the crude product, which was purified by reverse phase HPLC. Concentration of the desired fractions containing product afforded the title compound (66 mg) as a pale yellow solid. LCMS (m/z): 554.3 (M+H). 1H NMR (400 MHz, CDCl3) δ ppm: 0.90-1.10 (m, 9H), 1.80-2.15 (m, 2H), 3.45-4.20 (m, 4H), 4.60-5.55 (m, 3H), 6.90-7.60 (m, 10H), 7.80-8.10 (m, 2H), 8.55-8.90 (m, 1H), 9.20-9.55 (m, 1H)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[CH2:13]([O:12][CH2:11][CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C1CCNCC1
Reactant: CCCCOCCCCl
Product: CCCCOCCCN1CCC(=O)CC1

Procedure:
1-(3-Butoxypropyl)-4-piperidone is prepared from 4-piperidone and 1-chloro-3-butoxypropane essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [F:1][C@@:2]1([C:14]([O:16]C)=[O:15])[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[OH-].[Na+]>CO>[C:10]([O:9][C:7]([N:4]1[CH2:5][CH2:6][C@@:2]([F:1])([C:14]([OH:16])=[O:15])[CH2:3]1)=[O:8])([CH3:13])([CH3:11])[CH3:12]
Reactant: COC(=O)[C@]1(F)CCN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@](F)(C(=O)O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.4 %

Procedure:
To a solution of #167 (238 mg, 0.963 mmol, 1 eq.) dissolved in methanol (2.6 mL) was added an aqueous solution of sodium hydroxide (2.5 M, 0.88 mL) and the reaction was stirred at room temperature for 3 hours. The reaction was then quenched with 10% aqueous citric acid (5 mL) and ethyl acetate (100 mL) was added, and the layers were separated. The organic layer was washed with 10% citric acid, water, and brine, then dried over sodium sulfate, filtered and concentrated in vacuo to afford #169 as a white solid (221 mg, 99%). 1H NMR (400 MHz, CDCl3), δ 3.96-3.69 (m, 3H), 3.59 (m, 1H), 2.59-2.33 (m, 2H), 1.51 (s, 9H). LC-MS (Protocol Q1): m/z 232.1 [M−H+], retention time=0.67 minutes. Chiral HPLC retention time: 3.95 min (purity=98%) (Column: Chiralpak AD-H, 4.6 mm×25 cm, mobile phase 5-60% CO2/Methanol, flow rate 3.0 mL/min); Optical rotation: [α]D25 −3.6 (c=0.55, MeOH)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[C:12]([O:18][CH2:19][CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15].C(O)(=O)C.N1CCCCC1>C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[C:13]([C:14]([CH3:16])=[O:15])[C:12]([O:18][CH2:19][CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:17])([O-:3])=[O:2]
Reactant: CC(=O)CC(=O)OCCOCc1ccccc1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: C1CCNCC1
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OCCOCc1ccccc1
Yield: 113.6 %

Procedure:
To a solution of 3-nitrobenzaldehyde (4.53 g), 2-benzyloxyethyl acetoacetate (7.79 g) and acetic acid (360 mg) in benzene (15 ml), was added a solution of piperidine (306 mg) in benzene (5 ml), in a similar manner to the aforementioned Example (1-i), and the mixture was heated to reflux for 2.5 hours under azeotropic dehydration. The reaction mixture was left to cool and diluted with benzene (50 ml), washed with water, diluted aqueous sodium bicarbonate solution and water, dried over magnesium sulfate and then evaporated to dryness under reduced pressure to give brown oily 2-benzyloxyethyl 2-(3-nitrobenzylidene)acetoacetate (12.58 g). The mixture of the above obtained oil (12.58 g) and ethyl 3-amino-4,4-diethoxycrotonate (8.47 g) was heated at 100° to 102° C. for 4 hours and at 110° to 115° C. for 6.5 hours. After cooling, the reaction mixture was dissolved in ethyl acetate, washed twice with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residual brown oil (19.04 g) was chromatographed on a column of silica-gel (570 g) and eluted with a mixture of benzene and ethyl acetate (13:1, v/v) to give oily 2-benzyloxyethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate (9.64 g).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([C@@H:14]([N:16]=[N+]=[N-])[CH3:15])[CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>C1C=CC=CC=1>[C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([C@@H:14]([NH2:16])[CH3:15])[CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](N=[N+]=[N-])c1cccc(C(=O)OC(C)(C)C)c1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: c1ccccc1
Product: C[C@H](N)c1cccc(C(=O)OC(C)(C)C)c1
Yield: 82.8 %

Procedure:
(S)-1-(3-Tert-butyloxycarbonylphenyl)-1-azidoethane (3.10 mmol) was dissolved in benzene (8 mL). Water (1 mL) was added followed by triphenylphosphine (6.18 mmol), and the resultant mixture heated to 80° C. for 2 h. The reaction was poured into 1N HCl solution, this solution then washed twice with diethyl ether. These ether washes were discarded and the aqueous phase made strongly basic (pH˜14) by the addition of 5N NaOH solution. This aqueous phase was then extracted 3× with diethyl ether. These ether extracts were combined, washed with brine, dried (MgSO4) and concentrated under reduced pressure to yield 568 mg of an oil which was used without further purification. 1H NMR (500 MHz, CDCl3): δ7.97 (m, 1H); 7.88 (m, 1H); 7.55 (d, J=7.5 Hz, 1H); 7.39 (t, J=7.8 Hz, 1H); 4.19 (q, J=6.6 Hz, 1H); 1.62 (s, 9H); 1.42 (d, J=6.7 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[CH2:20][CH2:21][CH2:22][CH3:23]>CN(C=O)C>[CH3:12][O:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([O:7][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:6])=[CH:3][C:2]=1[NH:1][CH2:9][CH2:10][CH2:2][CH2:3][CH3:4]
Reactant: CCCCCBr
Reactant: COc1ccc(C(=O)O)cc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCNc1cc(C(=O)OCCCCC)ccc1OC
Temperature: 100 °C
Reaction time: 10.5 h
Yield: 133.1 %

Procedure:
3-Amino-4-methoxybenzoic acid (1.53 g, 6.45 mmol), DMF (15 ml), potassium carbonate (2.07 g, 15 mmol) and pentyl bromide (1.86 ml, 15 mmol) were mixed, and the solution was stirred at 100° C. for 10.5 hours. The reaction mixture was filtered to remove the inorganic salt, and DMF was evaporated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (hexane/ethyl acetate=10/1) to give pentyl 4-methoxy-3-pentylaminobenzoate (1.32 g, 67%) and pentyl 3-dimethylamino-4-methoybenzoate (334 mg, 14%) as colorless oils. pentyl 4-methoxy-3-pentylaminobenzoate
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:18]=[C:13]([C:14]([NH:16][OH:17])=[O:15])[C:12]([OH:19])=[CH:11][CH:10]=1.[CH3:20][N:21]([CH3:25])[C:22](Cl)=[O:23]>CN(C)C=O>[CH3:20][N:21]([CH3:25])[C:22](=[O:15])[OH:23].[Br:8][C:9]1[CH:18]=[C:13]([C:14]([NH:16][OH:17])=[O:15])[C:12]([OH:19])=[CH:11][CH:10]=1
Reactant: CN(C)C(=O)Cl
Agent: O=C(NO)c1cc(Br)ccc1O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)O
Temperature: 0 °C
Reaction time: 10 h

Procedure:
81 ml of triethylamine was gradually added to a dimethylformamide solution containing 136 g of 5-bromosalicylhydroxamic acid prepared as in (2-2) above and 54 ml of N,N-dimethylcarbamyl chloride at room temperature (about 20°-30° C.), then stirred for 10 hours. This solution was poured into ice-water to collect the precipitate by filtration followed by drying. Yield: 102 g; mp. 118°-119° C. (dec.)
Reaction SMILES: Cl.Cl.[CH2:3]([C:5]1[N:9]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15]([C:20]4([O:26][CH3:27])[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]4)[N:16]3[CH3:19])=[C:12]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:11]=2)[C:8]2[CH:34]=[CH:35][CH:36]=[CH:37][C:7]=2[N:6]=1)[CH3:4].[CH3:38][C:39]1([CH3:42])[CH2:41][O:40]1.CCN(C(C)C)C(C)C>CC#N>[CH2:3]([C:5]1[N:9]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15]([C:20]4([O:26][CH3:27])[CH2:25][CH2:24][CH2:23][N:22]([CH2:38][C:39]([CH3:42])([OH:40])[CH3:41])[CH2:21]4)[N:16]3[CH3:19])=[C:12]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[N:11]=2)[C:8]2[CH:34]=[CH:35][CH:36]=[CH:37][C:7]=2[N:6]=1)[CH3:4]
Reactant: CC1(C)CO1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CCCNC3)n(C)c2n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CCCN(CC(C)(C)O)C3)n(C)c2n1
Temperature: 90 °C
Yield: 34.4 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-8-(3-methoxypiperidin-3-yl)-9-methyl-6-morpholin-4-yl-9H-purine dihydrochloride (150 mg, 0.27 mmol), 2,2-dimethyloxirane (242 μL, 2.73 mmol) and DIPEA (187 μL, 1.09 mmol) in MeCN (3 mL) was heated at 70° C. r.t. for 3 h before further 2,2-dimethyloxirane (242 μL, 2.73 mmol) was added and the mixture heated at 90° C. for 6 h. The reaction mixture was concentrated in vacuo and the resulting residue purified by column chromatography (Si-PCC, MeOH:EtOAc, 0-20%) affording 791 (51 mg, 34%). LCMS (method I): RT 2.72 min, [M+H]+ 549.3. 1H NMR (DMSO, 400 MHz): δ 8.03-8.02 (1 H, m), 7.64-7.63 (1 H, m), 7.25-7.24 (2 H, m), 4.26 (4 H, brd s), 4.08 (1 H, s), 3.91 (3 H, s), 3.79 (4 H, t, J=4.72 Hz), 3.27-3.26 (2 H, m), 3.20-3.15 (1 H, m), 3.06 (3 H, s), 3.01-2.97 (1 H, m), 2.69-2.61 (1 H, m), 2.46-2.38 (1 H, m), 2.25 (2 H, s), 2.17-2.14 (1 H, m), 1.92-1.75 (3 H, m), 1.33 (3 H, t, J=7.43 Hz), 1.03 (3 H, s), 0.94 (3 H, s)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([NH2:13])[CH:3]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=O)=[CH:17][CH:16]=1.CN(C(ON1N=[N:40][C:35]2C=[CH:37][CH:38]=[N:39][C:34]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([N:39]3[CH2:34][CH2:35][N:40]([C:22](=[O:24])[CH2:21][C:18]4[CH:17]=[CH:16][C:15]([F:14])=[CH:20][CH:19]=4)[CH2:37][CH2:38]3)=[CH:3][C:4]([NH2:13])=[N:5]2)=[CH:10][CH:9]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: Nc1cc(Cl)c2ccc(Cl)cc2n1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: Nc1cc(N2CCN(C(=O)Cc3ccc(F)cc3)CC2)c2ccc(Cl)cc2n1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4,7-dichloro-2-quinolinamine (50 mg, 0.19 mmol) in DSMO (10 mL) was added 4-fluorobenzeneacetic acid (32 mg, 0.2 mmol) followed by HATU (94 mg, 0.25 mmol) and triethylamine (0.053 ml, 0.38 mmol) at rt. After stirring overnight, the reaction mixture was poured into ice-water (10 mL), extracted with EtOAc, washed with brine, and dried over Na2SO4. Concentration in vacuo followed by preemptive TLC afforded the product. LC-MS: 398 (M++1)). 1H NMR (DMSO-d6): 62.9–3.05 (m, 4H), 3.68–3.85 (m, 6H), 6.22 (s, 1H), 6.45 (s, 2H), 7.05–7.2 (m, 3H), 7.22–7.33 (m, 2H), 7.35–7.4 (m, 1H), 7.7–7.8 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[C:24]([CH3:26])[C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:8]=2)=[C:4]([CH3:27])[CH:3]=1.[C:28](OCC)(=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30]>>[CH2:32]([O:31][C:29](=[O:30])[C:28]([NH:1][C:2]1[CH:25]=[C:24]([CH3:26])[C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([S:14]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)(=[O:16])=[O:15])[CH:8]=2)=[C:4]([CH3:27])[CH:3]=1)=[O:34])[CH3:33]
Reactant: Cc1cc(N)cc(C)c1Oc1ccc(O)c(S(=O)(=O)c2ccc(F)cc2)c1
Reactant: CCOC(=O)C(=O)OCC
Product: CCOC(=O)C(=O)Nc1cc(C)c(Oc2ccc(O)c(S(=O)(=O)c3ccc(F)cc3)c2)c(C)c1
Temperature: 180 °C

Procedure:
A mixture of the title D compound, 4-(4-amino-2,6-dimethylphenoxy)-2-(4-fluoro-benzenesulfonyl)phenol (0.64 g, 1.65 mmol) and 2 mL of diethyl oxalate is heated at 180° C. for 3 h. The reaction is cooled to RT and diethyl oxalate is removed under vacuum. Chromatography on silica (eluant; EtOAc/hexane—1/3?2/3) affords N-{4-[3-(4-fluoro-benzenesulfonyl)-4-hydroxyphenoxy]-3,5-dimethylphenyl}oxamic acid ethyl ester: NMR (CDCl3) 1.46 (t, 3H, J=7.5), 2.06 (s, 6H), 4.42 (q, 2H, J=7.5), 6.90-6.98 (m, 3H), 7.22 (app t, 2H, J=8.3), 7.40 (s,2H), 7.87-7.93 (m, 2H), 8.87 (br s, 1H); ESI-MS 486 [M−1]−.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:14][CH3:15])=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:16]1[NH:17][C:18]2[CH:24]=[C:23]([C:25]([OH:27])=O)[CH:22]=[CH:21][C:19]=2[N:20]=1.[CH3:28][NH:29][CH3:30].C1COCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:28][N:29]([CH3:30])[C:25]([C:23]1[CH:22]=[CH:21][C:19]2[N:20]=[C:16]([C:3]3[CH:4]=[C:5]([C:8]4[C:9]([O:14][CH3:15])=[N:10][CH:11]=[CH:12][CH:13]=4)[CH:6]=[CH:7][C:2]=3[OH:1])[NH:17][C:18]=2[CH:24]=1)=[O:27]
Reactant: COc1ncccc1-c1ccc(O)c(-c2nc3ccc(C(=O)O)cc3[nH]2)c1
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncccc1-c1ccc(O)c(-c2nc3ccc(C(=O)N(C)C)cc3[nH]2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of 2-[2-hydroxy-5-(2-methoxy-pyridin-3-yl)-phenyl]-3H-benzoimidazole-5-carboxylic acid (containing 1 equivalent of DMA, 44 mg, 0.1 mmol), dimethylamine in THF (0.5 mL, 2 M, 1 mmol) and HATU (38 mg, 0.1 mmol) in DMF (1.5 mL) was added DIEA (26 mg, 0.2 mmol). The reaction mixture was stirred at room temperature for 1 h and heated at 65° C. for 15 h, and then evaporated under reduced pressure. The residue was purified by chromatography (500:10:1 CH2Cl2/MeOH/28% aqueous NH4OH) to afford the title compound (31 mg, 80%). 1H NMR (MeOH-d4) δ 3.05 (s, 3H), 3.12 (s, 3H), 3.95 (s, 3H), 7.00-7.06 (2H), 7.31 (d, J=9 Hz, 1H), 7.52-7.75 (4H), 8.08-8.14 (2H). ESI-MS m/z 389.5 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][NH:13]1.[C:17]([NH2:21])(=[O:20])[CH:18]=[CH2:19].C(N(CC)CC)C>COCCOC>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH2:19][CH2:18][C:17](=[O:20])[NH2:21]
Reactant: Brc1ccc2[nH]cc(C[C@H]3CCCN3)c2c1
Reactant: C=CC(N)=O
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: NC(=O)CCN1CCC[C@@H]1Cc1c[nH]c2ccc(Br)cc12

Procedure:
A stirred mixture of 5-bromo-3-(2(R)-pyrrolidinylmethyl)-1H-indole (Preparation 2; 600 mg, 2.1 mmol), acrylamide (168 mg, 2.4 mmol), triethylamine (0.60 ml) and 1,2-dimethoxyethane (11.9 ml), under nitrogen, was heated under reflux for 8 hours, allowed to cool, then partitioned between ethyl acetate (400 ml) and water (400 ml). The organic phase was separated, washed with water (400 ml), dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a solvent gradient of 0.880 aqueous ammonia:methanol: dichloromethane (0.1:10:90 to 0.4:10:90), to afford the required product as a foam. Rf 0.26 (SS 7). [α]D25 +59° (c=0.1, CH3OH).
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C:11](=[CH2:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>CO>[Si:1]([O:8][C@H:9]([CH3:10])[C@H:11]([CH2:17][NH:25][CH2:24][C:23]1[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: COc1ccc(CN)cc1
Reactant: C=C(C(=O)OCC)[C@@H](C)O[Si](C)(C)C(C)(C)C
Solvent: CO
Product: CCOC(=O)[C@@H](CNCc1ccc(OC)cc1)[C@@H](C)O[Si](C)(C)C(C)(C)C
Reaction time: 48 h
Yield: 109.5 %

Procedure:
To a solution of ethyl 2-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]acrylate (15 g) in methanol (300 ml) was added 4-methoxybenzylamine (8.05 g) at room temperature. After stirring for 2 days, the solvent was removed by evaporation to give crude ethyl (2S,3R)-3-(t-butyldimethylsilyloxy)-2-(4-methoxybenzylaminomethyl)butanoate (25.14 g).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C:14]([CH2:19][OH:20])([CH3:18])[CH2:13]1.N1C=CC=CC=1.C(Cl)Cl.[C:30](OC(=O)C)(=[O:32])[CH3:31]>O>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C:14]([CH2:19][O:20][C:30](=[O:32])[CH3:31])([CH3:18])[CH2:13]1
Reactant: CC1(CO)CCCN(CC2COc3ccccc3O2)C1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCC1(C)CCCN(CC2COc3ccccc3O2)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of [1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-yl]methanol (0.5 g, 1.80 mmol), pyridine (0.29 ml) and DCM (40 ml) at 0° C. was added acetic anhydride (0.34 ml). The reaction mixture was stirred at RT for 6 h. Water was slowly added and the reaction mixture extracted with DCM (3×20 ml). The combined organic phases were dried over Na2SO4, filtered and the filtrate was evaporated to give the title compound.
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[CH:2]1.[C:13]1([S:19]([O-:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Na+]>C(OCC)(=O)C.C(O)(=O)C>[C:13]1([S:19]([C:3]2[CH:2]=[C:1]([OH:12])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]=2[OH:11])(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=S([O-])c1ccccc1
Reactant: O=C1C=CC(=O)c2ccccc21
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccccc1)c1cc(O)c2ccccc2c1O
Reaction time: 5 h

Procedure:
1,4-naphthoquinone (15.8 g) was dissolved in 100 ml of a mixture of ethyl acetate and acetic acid (9:1) and sodium benzenesulfinate (24.6 g) was added. The resulting mixture was stirred for 5 hours and the obtained crystals were filtered and washed with a small amount of acetone. (Yield: 22.5 g)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[SH:9].[K].[C:11]([NH:14][C:15]1[S:16][C:17](Cl)=[CH:18][N:19]=1)(=[O:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:11]([NH:14][C:15]1[S:16][C:17]([S:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[CH:18][N:19]=1)(=[O:13])[CH3:12]
Reactant: Fc1ccc(S)c(F)c1
Reactant: CC(=O)Nc1ncc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ncc(Sc2ccc(F)cc2F)s1
Temperature: 130 °C
Reaction time: 7 h
Yield: 38.5 %

Procedure:
A mixture of salt of potassium 2,4-difluorothiophenol (20 g), 2-acetamido-5-chlorothiazole (21 g) and potassium carbonate anhydrous (29.8 g) in N,N-dimethylformamide (400 ml) was stirred at 130° C. for 7 hours. The reaction mixture was concentrated under reduced pressure. The residue was triturated with water and the precipitates were collected by filtration, washed with water and dried in vacuo to give solid. The solid was subjected to column chromatography on silica gel (silica gel, 70-230 mesh; Merck: 750 g) and eluted with a mixture of chloroform and methanol (50:1). The fractions containing the objective compound were combined and evaporated to dryness in vacuo to give 2-acetamido-5-(2,4-difluorophenylthio)thiazole (11.91 g, yield: 38.5%). mp: 156°-170° C. (dec.) IR (Nujol): 3160, 3060, 1695, 1585, 1560, 1295 cm-1