Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([S:23][CH2:24][CH2:25][CH2:26][C:27](O)=[O:28])[N:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[CH:11]=[C:5]2[N:4]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:3]1=[O:34].C([N:37](CC)CC)C.ClC(OCC)=O>O1CCCC1>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([S:23][CH2:24][CH2:25][CH2:26][C:27]([NH2:37])=[O:28])[N:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[CH:11]=[C:5]2[N:4]([CH2:30][CH:31]([CH3:32])[CH3:33])[C:3]1=[O:34]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCC(=O)O)n(Cc3cccc4ccccc34)cc21
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCC(N)=O)n(Cc3cccc4ccccc34)cc21
Reaction time: 0.25 h

Procedure:
The compound of Example 5, 4-[(2,3,4,6-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxo-1H-pyrrolo[3,4-d]pyrimidin-5-yl)thio]butanoic acid (100 mg), was dissolved in tetrahydrofuran (3 ml) and the solution was cooled in ice. Triethylamine (30 μl) was added followed by ethyl chloroformate (21 μl); the ice bath was removed and the solution was allowed to stir for 15 minutes and was then cooled in ice again. Aqueous ammonia (0.88 specific gravity, 1 ml) was added and the mixture was stirred for 3 days. The mixture was poured onto water and extracted thrice with dichloromethane. The organic extracts were combined, washed with brine, dried, filtered and evaporated to give an oil which was purified by chromatography, eluting first with ethyl acetate:isohexane: acetic acid (75:25:1) and then with ethyl acetate:acetic acid (199:1) to give the title compound (70 mg).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[S:8][C:9]=1[CH2:10][OH:11])[CH2:2][CH2:3][CH3:4].[CH3:22][O:23][C:24](=[O:33])[C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][C:26]=1[Cl:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl>[CH3:22][O:23][C:24](=[O:33])[C:25]1[CH:30]=[CH:29][C:28]([O:11][CH2:10][C:9]2[S:8][C:7]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:14][CH:13]=3)=[N:6][C:5]=2[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:27][C:26]=1[Cl:32]
Reactant: COC(=O)c1ccc(O)cc1Cl
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(C(=O)OC)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.1 %

Procedure:
To an ice-cold solution of [4-butyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-yl]-methanol (1.0 g, 3.17 mmol), 2-chloro-4-hydroxy-benzoic acid methyl ester (592 mg, 3.17 mmol) and triphenylphosphine (832 mg, 3.17 mmol) in dichloromethane add diethyl azodicarboxylate (0.567 mL, 3.17 mmol). Stir the reaction mixture for 2 hours while allowing it to warm to room temperature. Remove the solvent under reduced pressure and purify the residue by flash chromatography on silica gel to give 4-[4-butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-chloro-benzoic acid methyl ester (600 mg).
Reaction SMILES: [CH3:1][C:2]1([C:18](OC)=[O:19])[CH2:17][CH2:16][CH2:15][C:4]2([O:8][C:7](=[O:9])[N:6]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:5]2)[CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:19][CH2:18][C:2]1([CH3:1])[CH2:17][CH2:16][CH2:15][C:4]2([O:8][C:7](=[O:9])[N:6]([CH2:10][C:11]([CH3:13])([CH3:14])[CH3:12])[CH2:5]2)[CH2:3]1
Reactant: COC(=O)C1(C)CCCC2(CN(CC(C)(C)C)C(=O)O2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)CN1CC2(CCCC(C)(CO)C2)OC1=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 66.5 %

Procedure:
To a −78° C. solution of methyl 7-methyl-3-neopentyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-carboxylate (24.2 g, 82.0 mmol) in THF (204 mL) under N2 was slowly added lithium aluminium hydride, 1 M in THF (122 mL, 122 mmol). After stirring 1 h at −78° C., additional lithium aluminum hydride, 1 M in THF (0.061 mL, 61.0 mmol) was added. After 3 h the reaction was quenched with water (5 mL) and diluted with 4 N HCl (500 mL). The product was extracted into EtOAc (3×300 mL). The combined organics were dried over MgSO4, filtered, and concentrated onto florisil for purification on a 330 g silica gel column (10-50% EtOAc/hexanes, 30 min gradient; 50% EtOAc/hexanes, 15 min; 50-75% EtOAc/hexanes, 10 min gradient; 75% EtOAc/hexanes, 10 min; 100 mL/min elution; 254 nm detection) to provide the title compound (14.7 g) as an orange oil and the intermediate aldehyde product (7.19 g) as a yellow solid.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>ClCCl.Cl>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: C1COCCN1
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(CBr)cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirring solution of commercially-available 4-bromomethyl benzenesulfonyl chloride (1.0 g, 3.71 mmol) in dichloromethane (8 ml) at 0° C. under an argon atmosphere, is added triethylamine (0.575 ml, 4.1 mmol), in one portion, followed by morpholine (0.359 ml, 4.1 mmol). The reaction mixture is stirred for 20 h, warming up slowly to room temperature. The reaction mixture is then diluted with 2N HCl aq (40 ml) and extracted in dichloromethane (20 ml), dried (MgSO4) and evaporated to dryness in vacuo to afford the title compound. No mass ion detected.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[C:5]([Cl:21])=[CH:4][C:3]=1[Cl:22].C(O)(C(F)(F)F)=O.C(Cl)Cl>>[Cl:22][C:3]1[C:2]([NH2:1])=[N:7][C:6]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[C:5]([Cl:21])[CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(N)c(Cl)cc2Cl)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc(N2CCNCC2)c(Cl)cc1Cl
Yield: 100 %

Procedure:
tert-butyl 4-(6-amino-3,5-dichloropyridin-2-yl)piperazine-1-carboxylate (110 mg, 0.305 mmol,) was treated with 50% TFA/DCM for 1 h, then drained and dried in vacuum to give 3,5-dichloro-6-(piperazin-1-yl)pyridin-2-amine (110 mg, 0.305 mmol). 1H-NMR (CD3OD-d4, 500 MHz): δ7.51 (1H, s), 3.51 (4H, m), 3.31 (4H, m).
Reaction SMILES: [F:1][C:2](=[CH2:6])[C:3](Cl)=[O:4].[C:7]1([O-:18])[C:12]([Cl:13])=[C:11]([Cl:14])[C:10]([Cl:15])=[C:9]([Cl:16])[C:8]=1[Cl:17].[K+]>C(#N)C>[F:1][C:2](=[CH2:6])[C:3]([O:18][C:7]1[C:8]([Cl:17])=[C:9]([Cl:16])[C:10]([Cl:15])=[C:11]([Cl:14])[C:12]=1[Cl:13])=[O:4]
Reactant: [O-]c1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: C=C(F)C(=O)Cl
Agent: [K+]
Solvent: CC#N
Product: C=C(F)C(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reaction time: 1.5 h
Yield: 51 %

Procedure:
13.9 g (0.128 mol) of α-fluoroacryloyl chloride (obtained in accordance with example 1c) were added dropwise, at a temperature of 25° C., with stirring and in the course of 30 minutes, to a solution of 30 g (0.0985 mol) of potassium pentachlorophenate in 400 ml of anhydrous acetonitrile, and the reaction mixture was then stirred for a further 90 minutes at the same temperature. The solid formed was filtered off and washed with 20 ml of anhydrous acetonitrile. After 0.01 g of hydroquinone monomethyl ether had been added, the volatile constituents in the mixture of filtrate and washing liquor were distilled off and the residue was recrystallized from boiling n-hexane. 17 g (51% of theory) of pentachlorophenyl α-fluoroacrylate were obtained, melting point 90° to 92° C.
Reaction SMILES: [CH:1]1([C:4]2([C:14]3[C:22]4[C:17](=[C:18]([CH2:24][S:25][CH3:26])[CH:19]=[C:20]([F:23])[CH:21]=4)[NH:16][CH:15]=3)[C:12]3[C:7](=[CH:8][C:9]([F:13])=[CH:10][CH:11]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.ClCCl.ClC1C=CC=C(C(OO)=[O:38])C=1>CO>[CH:1]1([C:4]2([C:14]3[C:22]4[C:17](=[C:18]([CH2:24][S:25]([CH3:26])=[O:38])[CH:19]=[C:20]([F:23])[CH:21]=4)[NH:16][CH:15]=3)[C:12]3[C:7](=[CH:8][C:9]([F:13])=[CH:10][CH:11]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: CSCc1cc(F)cc2c(C3(C4CC4)CCc4cc(F)ccc43)c[nH]c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: CS(=O)Cc1cc(F)cc2c(C3(C4CC4)CCc4cc(F)ccc43)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
80.0 mg (0.22 mmol) of the compound from Example 94 were introduced into 6 ml of dichloromethane at 0° C., 56.1 mg (0.23 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT overnight. Methanol was added, and the residue after concentration was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 43.6 mg (52% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: C[O:2][C:3](=[O:44])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14]/[N:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=2)=[CH:6][C:5]=1[NH:27][C:28](=[O:43])/[CH:29]=[CH:30]/[C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:33][CH:32]=1.[OH-].[K+]>C1COCC1.CO>[C:34]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:33]=[CH:32][C:31](/[CH:30]=[CH:29]/[C:28]([NH:27][C:5]2[CH:6]=[C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14]/[N:15]=[CH:16]/[C:17]3[CH:18]=[CH:19][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:21][CH:22]=3)[CH:8]=[CH:9][C:4]=2[C:3]([OH:44])=[O:2])=[O:43])=[CH:36][CH:35]=1
Reactant: COC(=O)c1ccc(OCCCO/N=C/c2ccc(C(C)(C)C)cc2)cc1NC(=O)/C=C/c1ccc(-c2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(/C=N/OCCCOc2ccc(C(=O)O)c(NC(=O)/C=C/c3ccc(-c4ccccc4)cc3)c2)cc1
Yield: 68.5 %

Procedure:
The desired product was prepared using a procedure similar to Step 7 of example 34. Thus, 2-{[(2E)-3-(1,1′-biphenyl-4-yl)prop-2-enoyl]amino}4-[3-({[(1E)-(4-tert-butylphenyl)methylidene]amino}oxy)propoxy]benzoic acid methyl ester (0.148 g, 0.251 mmol) was reacted with 1N KOH (0.50 ml) in THF/MeOH (6 ml/4 ml) to give 2-{[(2E)-3-(1,1′-biphenyl-4-yl)prop-2-enoyl]amino}-4-[3-({[(1E)-(4-tert-butylphenyl)methylidene]amino}oxy)propoxy]benzoic acid (0.099 g, 0.172 mmol, 68%) as a white solid, mp 169-171° C. 1H NMR (DMSO-d6) δ 1.26 (s, 9H), 2.13-2.17 (m, 2H), 4.18 (t, J=6.4 Hz, 2H), 4.27 (t, J=6.3 Hz, 2H), 6.75 (dd, J=2.6, 8.9 Hz, 1H), 6.89 (d, J=15.6 Hz, 1H), 7.38-7.43 (m, 3H), 7.46-7.54 (m, 4H), 7.67 (d, J=15.6 Hz, 1H), 7.70-7.76 (m, 4H), 7.83 (d, J=8.2 Hz, 2H), 7.96 (d, J=8.9 Hz, 1H), 8.23 (s, 1H), 8.38 (d, J=2.4 Hz, 1H), 11.75 (s, 1H), 13.3 (s, 1H); IR (solid) 2960, 1680, 1610, 1580, 1540 and 1200 cm−1; [ES(−)], m/z 575 (M−H)−; Anal. Calcd. for C36H36N2O5: C, 74.98; H, 6.29; N, 4.86, Found: C, 74.57; H, 6.32; N, 4.89.
Reaction SMILES: [O:1]=[C:2]([NH:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][C:19]1=[O:23])[CH2:3][CH2:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][C@H:8]1[CH2:9][OH:10])=[O:6]>C1C=CC=CC=1.CS(C)=O.C(N(CC)CC)C>[O:1]=[C:2]([NH:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][C:19]1=[O:23])[CH2:3][CH2:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][C@H:8]1[CH:9]=[O:10])=[O:6]
Reactant: O=C(CCC(=O)N1CCC[C@H]1CO)NCCCN1CCCC1=O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C[C@@H]1CCCN1C(=O)CCC(=O)NCCCN1CCCC1=O
Reaction time: 1 h
Yield: 65.1 %

Procedure:
N-{4-Oxo-4-[3-(2-oxo-1-pyrrolidinyl)propylamino]butanoyl}-L-prolinol (85 mg) was dissolved in a mixed solvent of benzene (0.18 ml), DMSO (0.5 ml) and triethylamine (0.18 ml), and sulfur trioxide pyridine complex (200 mg) was added thereto under ice-cooling. After 1 hour's stirring at a temperature of 10°-15° C., the reaction mixture was treated in the same manner as in Example 10-C) to give 55 mg of N-{4-oxo-4-[3-(2-oxo-1-pyrrolidinyl)propylamino]butanoyl}-L-prolinal.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([OH:26])([C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1[O:17][CH3:18])([CH3:9])[CH3:8])C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[F:16][C:12]1[C:11]([O:17][CH3:18])=[C:10]([C:7]([CH3:8])([CH3:9])[CH2:6][C:5]([C:19]([F:24])([F:25])[C:20]([F:23])([F:22])[F:21])([OH:26])[CH2:4][OH:3])[CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)C(O)(CC(C)(C)c1cccc(F)c1OC)C(F)(F)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: COc1c(F)cccc1C(C)(C)CC(O)(CO)C(F)(F)C(F)(F)F
Temperature: 25 °C

Procedure:
1.0 g (3.54 mmol) of ethyl-4-(3-fluoro-2-methoxyphenyl)-2-oxo-4-methyl-valerate and 0.98 g (5.1 mmol) of (pentafluoroethyl)-trimethylsilane in 7 ml of THF are mixed with 65 mg (0.7 mmol) of tetramethylammonium fluoride at −40° C. The reaction mixture is heated to −25° C. and stirred at this temperature. After 4.5 hours, 1 ml of 2N hydrochloric acid is added, and the reaction mixture is added to water. It is extracted several times with ethyl acetate, washed with saturated sodium chloride solution, dried on sodium sulfate, and concentrated by evaporation in a vacuum. 1.65 g of ethyl-4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(pentafluoroethyl)valerate is obtained as a crude product. The ester is mixed in 80 ml of diethyl ether at 0° C. with 300 mg (8 mmol) of lithium aluminum hydride and stirred for 3.5 more hours at room temperature. A little water is carefully added to the batch at 0° C., and it is stirred vigorously for 15 more minutes. It is filtered through Celite, and the precipitate is rewashed thoroughly with ethyl acetate. The filtrate is dried with sodium sulfate and concentrated by evaporation in a vacuum. After chromatographic purification on silica gel (hexane/ethyl acetate 10%-15%), 800 mg of 4-(3-fluoro-2-methoxyphenyl)-4-methyl-2-(pentafluoroethyl)pentane-1,2-diol is obtained. 1.8 ml (13 mmol) of triethylamine is added to 800 mg (2.2 mmol) of diol in 25 ml of dichloromethane and 8.9 ml of DMSO, and 1.6 g (10 mmol) of pyridine SO3 complex is added in portions over 10 minutes. It is stirred over 2.5 hours, and saturated ammonium chloride solution is added. The mixture is stirred for another 15 minutes, the phases are separated, and it is extracted with dichloromethane. It is washed with water and dried on sodium sulfate. The solvent is removed in a vacuum, and the desired aldehyde is obtained quantitatively.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:10]2[CH2:11][C:12]3[C:17]([CH:9]12)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)(Cl)Cl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[CH2:18]([C:25]1[CH:26]=[CH:27][C:28]([O:31][C@@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C@@H:10]2[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Oc1ccc(Cc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1C2Cc3ccccc3C21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@H]1Cc2ccccc2[C@H]1Oc1ccc(Cc2ccccc2)cc1
Yield: 38.7 %

Procedure:
The title compound was prepared in a similar manner to Preparation 18 from (±)N-tert-butoxycarbonyl-1,2-iminoindane (2 g, 8.7 mmol), 4-benzylphenol (1.59 g, 8.7 mmol), pyridinium p-toluenesulfonate (30 mg) and chloroform (50 ml). After a reaction time of 3 h, the reaction was diluted with chloroform (50 ml) then washed sequentially with saturated aq. sodium bicarbonate, water and brine. After drying over Na2 SO4, volatiles were removed in vacuo and the residue subjected to column chromatography on neutral alumina eluting with 10% diethyl ether in hexanes to afford the title compound (1.4 g) as a foam
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:12].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].CCCCCC.C(OCC)(=O)C>CC(C)=O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: Oc1ccc2ccccc2c1Cl
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)NCCOc1ccc2ccccc2c1Cl
Yield: 77 %

Procedure:
To a solution of 1-chloronaphthalen-2-ol (1.68 mmol) and K2CO3 (3.36 mmol) in acetone was added tert-butyl (2-bromoethyl)carbamate (1.85 mmol). The resulting mixture was heated at reflux overnight. After TLC control (n-hexane/ethyl acetate 7:3) showed the disappearance of 1-chloronaphthalen-2-ol, solvent was evaporated in vacuo and the residue was dissolved in 15 mL of ethyl acetate and washed with water (3×5 mL), brine (10 mL) and dried over Na2SO4. The evaporation of solvent afforded tert-butyl {2-[(1-chloronaphthalen-2-yl)oxy]ethyl}carbamate as a grey solid (77% yield) which was used without further purification.
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[Cl:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[O:10][CH2:11][CH2:12][OH:13]>>[Cl:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[O:10][CH2:11][CH2:12][O:13][S:1](=[O:4])(=[O:3])[NH2:2]
Reactant: NS(=O)(=O)Cl
Reactant: OCCOc1cccc(Cl)c1
Product: NS(=O)(=O)OCCOc1cccc(Cl)c1
Yield: 44 %

Procedure:
The title compound was prepared by procedures of Example 28 from sulfamoyl chloride and 2-(3-chlorophenoxy)ethanol. The oil obtained was further purified by chromatography and recrystallization as in Example 38 to give white solid, mp 66°-69° C., in 44% yield.
Reaction SMILES: [CH:1]1([CH2:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19].O>ClCCl>[CH3:17][S:18]([O:9][CH2:8][CH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:20])=[O:19]
Reactant: OCC1CCCCCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)OCC1CCCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103 %

Procedure:
To a solution of cycloheptylmethanol (1.0 g, 7.81 mmol) in dichloromethane (20 ml) at 0° C. under nitrogen was added triethylamine (1.63 ml, 1.5 mol. equiv.) Methanesulphonyl chloride (0.73 ml, 1.2 mol. equiv.) was added, dropwise, and the reaction allowed to stir for two hours at room temperature. Water (50 ml) and dichloromethane (50 ml) were added. The organic phase was separated, washed with water (2×50 ml) and then dried over anhydrous magnesium sulphate. The solution was then filtered and the solvent removed under reduced pressure to give the title compound as an oil (1.66 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[C:22](Br)[CH:23]=[C:18]3[N:17]=[CH:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[Cl-].[NH4+].[OH-].O.[CH3:30][N:31](C=O)C.O>[C-]#N.[C-]#N.[Zn+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[C:22]([C:30]#[N:31])[CH:23]=[C:18]3[N:17]=[CH:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cnc2c(c1)ncn2-c1ccc(OCc2ccccc2)cc1
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: N#Cc1cnc2c(c1)ncn2-c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-[4-(Benzyloxy)phenyl]-6-bromo-3H-imidazo[4,5-b]pyridine (2 g, 5.26 mmol), Zn(CN)2 (371 mg, 3.16 mmol), Pd2(dba)3 (101 mg, 0.11 mmol) and dppf (122 mg, 0.22 mmol) in degassed DMF/H2O (100:1) (15 mL) was stirred at 120° C. under N2 for 20 h. The mixture was then cooled to rt and treated with NH4Cl:NH4OH:H2O (4:1:4) (45 mL) and reheated to 80° C. for 30 min and then stirred at 0° C. for another 30 min. The precipitated solids were isolated by filtration and purified by chromatography over silica gel eluting with 50% EtOAc/hexane to give 3-[4-(benzyloxy)phenyl]-3H-imidazo[4,5-b]pyridine-6-carbonitrile. 1H NMR (400 MHz, D6-Acetone) δ 5.16 (s, 2H), 7.18 (d, J=8 Hz, 2H), 7.36-7.47 (m, 5H), 7.57 (d, J=8 Hz, 2H), 8.41 (s, 1H), 8.44 (d, J=2 Hz, 1H) and 8.70 (d, J=2 Hz, 1H); MS (ES+): m/z 327 [MH+].
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]1[O:18][CH3:19])=[O:10].[NH2:20][C:21]([C:23]1[S:27][C:26](Cl)=[N:25][C:24]=1[C:29]([O:31]CC)=[O:30])=[O:22].C([O-])([O-])=O.[K+].[K+].Cl>CN1C(=O)CCC1.O>[NH2:20][C:21]([C:23]1[S:27][C:26]([N:15]2[CH2:16][CH2:17][C@H:12]([NH:11][C:9]([C:3]3[NH:4][C:5]([CH3:8])=[C:6]([Cl:7])[C:2]=3[Cl:1])=[O:10])[C@H:13]([O:18][CH3:19])[CH2:14]2)=[N:25][C:24]=1[C:29]([OH:31])=[O:30])=[O:22]
Reactant: CO[C@@H]1CNCC[C@@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Reactant: CCOC(=O)c1nc(Cl)sc1C(N)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CO[C@@H]1CN(c2nc(C(=O)O)c(C(N)=O)s2)CC[C@@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Temperature: 150 °C
Yield: 37.4 %

Procedure:
A solution of 55 mg (23 mmol) of Cis(±)-3,4-dichloro-N-[3-methoxypiperidin-4-yl]-5-methyl-1H-pyrrole-2-carboxamide (Intermediate 50), 55 mg (0.23 mmol) of ethyl 5-(aminocarbonyl)-2-chloro-1,3-thiazole-4-carboxylate (Intermediate 220) and 33 mg (0.23 mmol) K2CO3 in 3 ml NMP was heated at 150° C. for 1 h in a microwave reactor. Water (0.1 ml) was added and the mixture was heated at 150° C. for another hour. The solution was diluted with water and acidified with 1N HCl before being extracted 2 times with EtOAc. The EtOAc extracts were washed with brine, dried (MgSO4) and concentrated to give a solid that was triturated with MeOH to give 41 mg of a white solid. MS (ES) MH+: 479 for C17H19Cl2N5O5S; NMR: 1.75 (m, 2H), 2.2 (s, 3H), 3.3 (s), 3.5 (s, 1H), 3.9 (m, 1H), 4.2 (m, 2H), 7.15 (d, 1H), 7.8 (s, 1H), 8.9 (s, 1H), 12.2 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][C:23]([C:25]4[CH:33]=[C:32]5[C:28]([CH:29]=[CH:30][NH:31]5)=[CH:27][CH:26]=4)=[N:22][C:21]=3[C:34](O)=[O:35])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.[N:44]1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.N.O1CCOCC1>CN(C=O)C>[C:34]([C:21]1[N:22]=[C:23]([C:25]2[CH:33]=[C:32]3[C:28]([CH:29]=[CH:30][NH:31]3)=[CH:27][CH:26]=2)[O:24][C:20]=1[C:17]1[CH:16]=[CH:15][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9][CH2:10]2)=[CH:19][CH:18]=1)(=[O:35])[NH2:44]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3oc(-c4ccc5cc[nH]c5c4)nc3C(=O)O)cc2)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3oc(-c4ccc5cc[nH]c5c4)nc3C(N)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 50 %

Procedure:
To a solution of 5-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)-2-(1H-indol-6-yl)oxazole-4-carboxylic acid (0.038 g, 0.08 mmol) in DMF (1 ml) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.036 g, 0.09 mmol) and diisopropylethylamine (0.016 ml, 0.09 mmol). The solution was stirred at room temperature for 5 minutes and then 0.5M ammonia in dioxane (0.31 ml, 0.16 mmol) was added and the resultant mixture stirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue purified by preparative HPLC to afford tert-butyl 4-(4-(4-carbamoyl-2-(1H-indol-6-yl)oxazol-5-yl)phenyl)piperazine-1-carboxylate (0.018 g, 0.04 mmol, 46%). LCMS (2) Rt: 3.39 min; m/z (ES+) 488.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Br:12][CH2:13][CH2:14]Br>>[Br:12][CH2:13][CH2:14][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: BrCCBr
Reactant: Oc1cccc2ncccc12
Product: BrCCOc1cccc2ncccc12
Yield: 11 %

Procedure:
Following the same procedure as in Example 32-(a), reaction and treatment were carried out using 1.05 g of 5-hydroxyquinoline and 2.04 g of 1,2-dibromoethane to obtain 0.2 g of 5-(2-bromoethoxy)quinoline.