Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:33]=[CH:32][C:25]([O:26][C:27]([CH3:31])([CH3:30])[CH2:28][OH:29])=[CH:24][CH:23]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>ClCCl.C(OCC)(=O)C>[Si:1]([O:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:33]=[CH:32][C:25]([O:26][C:27]([CH3:31])([CH3:30])[CH:28]=[O:29])=[CH:24][CH:23]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(CO)Oc1ccc(CCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C=O)Oc1ccc(CCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Temperature: 22 °C
Reaction time: 3 h
Yield: 63.6 %

Procedure:
A solution of 2-[4-[3-(tert-butyldiphenylsilyloxy)propyl]phenoxy]-2-methyl propanol (5.14 g, 11.1 mmol) in dry dichloromethane (150 ml) was treated with 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martin periodi-nane) (19.2 g, 45.3 mmol) and the resulting mixture was stirred at 22° C. for 3 hours. The reaction mixture was then diluted with ethyl acetate, washed with 5% sodium thiosulfate, saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent and chromatography of the residue on silica gel (elution toluene ethyl acetate, 99:1) gave 3.25 g (63%) of the title material as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([O:21]CC)=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:24])[N:10]1[CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[NH:31][S:32]([CH3:35])(=[O:34])=[O:33].CO.[OH-].[Na+].Cl>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([OH:21])=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:24])[N:10]1[CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[NH:31][S:32]([CH3:35])(=[O:33])=[O:34]
Reactant: CCOC(=O)C1c2ccccc2C(=O)N(C2CCCCC2NS(C)(=O)=O)C1c1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)O)C1c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To a mixture of 2.0 g of ethyl(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate, 10 ml of methanol, and 10 ml of THF was added 10 ml of a 1 M aqueous sodium hydroxide solution, followed by stirring at room temperature for 1 hour. The solution was acidified by the addition of 1 M hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 1.9 g of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid as a pale yellow crystal.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[NH:23]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[N:23]1([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][NH:2][CH:3]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: C1CCCNCCC1
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCCCCCC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with azocane (1.2 equiv) to give 155 (12.1 mg, M+1 409.1)
Reaction SMILES: [CH2:1]([P+:3]([CH2:8]O)([CH2:6]O)[CH2:4]O)O.[Cl-:10].[CH3:11][NH:12][C:13]([NH:15][CH3:16])=[O:14].C1(C)C=CC=CC=1>O>[Cl-:10].[CH3:11][N:12]([CH2:8][P+:3]([CH2:1][N:12]([CH3:11])[C:13]([NH:15][CH3:16])=[O:14])([CH2:4][N:12]([CH3:11])[C:13]([NH:15][CH3:16])=[O:14])[CH2:6][N:12]([CH3:11])[C:13]([NH:15][CH3:16])=[O:14])[C:13]([NH:15][CH3:16])=[O:14]
Reactant: OC[P+](CO)(CO)CO
Reactant: CNC(=O)NC
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: CNC(=O)N(C)C[P+](CN(C)C(=O)NC)(CN(C)C(=O)NC)CN(C)C(=O)NC
Yield: 97.2 %

Procedure:
A mixture of THPC (9.53 g, 0.05 mol), 1,3-dimethylurea (17.62 g, 0.20 mol), and toluene (75 ml) was heated to reflux in an apparatus fitted with a Dean-Stark trap for azeotropic removal of the water. The mixture was held at reflux until the evolution of water ceased; 3.7 ml (0.20 mol) was collected in 1 hr., and no more passed over in the next hr. The product, which had separated during the reaction as a mass of white solids, was broken up, triturated under toluene, filtered, and dried, giving 22.88 g (97.2%) of tetrakis(1,3-dimethylureidomethyl)phosphonium chloride (I, R=R'=CH3, R"=H, X=Cl) as a white crystalline solid, mp 187°-189° C. dec. Two recrystallizations from 2-propanol (8 ml/g), followed by drying under vacuum for 2 hr at 56° C. (acetone), gave a 1:1 solvate of the product and 2-propanol, mp 194°-194.5° C. dec.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8](=[CH2:12])[CH2:9][CH2:10][OH:11].[Cl:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[Cl:13][C:14]1[CH:19]=[C:18]([C:8](=[CH2:12])[CH2:9][CH2:10][OH:11])[CH:17]=[CH:16][CH:15]=1
Reactant: C=C(Br)CCO
Reactant: OB(O)c1cccc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: C=C(CCO)c1cccc(Cl)c1

Procedure:
A solution of DME (20 mL) and 2M Na2CO3 (15 mL) containing 3-bromobut-3-en-1-ol (1.40 g, 7.66 mol), (3-chlorophenyl)boronic acid (2.3 g, 14.7 mmol) and Pd(PPh3)4 (0.4 g, 0.35 mmol) was refluxed under an argon atmosphere for 3 hours. The solution was concentrated (to remove excess DME) and partitioned between water and ethyl acetate. The organic phase was washed with 1N NaOH, water (2×) and brine. The solution was then dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography using a hexanes/ethyl acetate gradient to give the title compound. 1H NMR (500 MHz, CDCl3): δ 7.42 (s, 1H); 7.31-7.29 (m, 3H); 5.43 (s, 1H); 5.21 (s, 1H); 3.73 (t, J=6.5 Hz, 2H); 2.77 (t, J=6.3 Hz, 2H); 1.91 (s, 1H). LCMS1 2.95 min. (M-OH)=165.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[CH2:12][S:11][C:10]1=[S:15].C([O-])(=O)C.[Na+].[N+:21]([C:24]1[CH:25]=[C:26]([C:30]2[O:34][C:33]([CH:35]=O)=[CH:32][CH:31]=2)[CH:27]=[CH:28][CH:29]=1)([O-:23])=[O:22]>C(O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[C:12](=[CH:35][C:33]2[O:34][C:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([N+:21]([O-:23])=[O:22])[CH:25]=3)=[CH:31][CH:32]=2)[S:11][C:10]1=[S:15]
Reactant: O=Cc1ccc(-c2cccc([N+](=O)[O-])c2)o1
Reactant: Cc1ccc(N2C(=O)CSC2=S)c(C)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(N2C(=O)C(=Cc3ccc(-c4cccc([N+](=O)[O-])c4)o3)SC2=S)c(C)c1

Procedure:
In 4.7 mL of 0.2 M ethanol was dissolved 0.1 g of 3-(2,4-dimethyl-phenyl)-2-thioxo-thiazolidin-4-one (0.42 mmol) synthesized in 1. The solution was mixed with 0.11 g of sodium acetate (1.34 mmol) and 0.15 g of 5-(3-nitro-phenyl)-furan-2-carboaldehyde (0.69 mmol), synthesized in 2, with stirring, and then heated for 4 hrs. The resulting reaction mixture was washed with ethanol to afford the title compound as a solid. When a solid was not formed, purification by silica gel column chromatography afforded 0.54 g of the title compound (yield: 28.6%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:28]=[CH:27][C:12]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([O:25]C)=[O:24])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[CH:29]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH:38]([CH3:40])[CH3:39])[C:33]=1O)([CH3:31])[CH3:30].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[OH-].[Na+].Cl>C(OCC)(=O)C.O1CCCC1.CO.C(OCC)C>[CH:38]([C:34]1[CH:35]=[CH:36][CH:37]=[C:32]([CH:29]([CH3:31])[CH3:30])[C:33]=1[O:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:19][CH:20]=3)=[CH:27][CH:28]=2)[CH2:4][CH2:3]1)([CH3:40])[CH3:39]
Reactant: CC(C)c1cccc(C(C)C)c1O
Reactant: COC(=O)CCc1ccc(OCc2ccc(CN3CCC(O)CC3)cc2)cc1
Agent: CCCCP(CCCC)CCCC
Agent: Cl
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(C(C)C)c1OC1CCN(Cc2ccc(COc3ccc(CCC(=O)O)cc3)cc2)CC1
Temperature: 0 °C
Yield: 16.3 %

Procedure:
To a mixture of methyl 3-[4-({4-[(4-hydroxypiperidin-1-yl)methyl]benzyl}oxy)phenyl]propanoate (0.20 g, 0.52 mmol), 2,6-diisopropylphenol (0.15 mL, 0.78 mmol), tributylphosphine (0.20 mL, 0.78 mmol) and tetrahydrofuran (6.0 mL) was added 1,1′-(azodicarbonyl)dipiperidine (0.20 g, 0.78 mmol) with stirring at 0° C., and the mixture was stirred at room temperature for 16 hr. Diethyl ether was added to the reaction mixture, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give an oil. Then, a mixture of the obtained oil, 1 N aqueous sodium hydroxide solution (1.0 mL), methanol (3.0 mL) and tetrahydrofuran (6.0 mL) was stirred at room temperature for 2 hr. The reaction mixture was neutralized with 1 N hydrochloric acid, and diluted with ethyl acetate. The mixture washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1-hexane/ethyl acetate=1/2) to give the title compound (45 mg, yield 16%) as colorless crystals. MS (APCI−): 528 (M−H).
Reaction SMILES: [C:1](/[CH:3]=[CH:4]\[S:5][CH2:6][C:7]([NH:9][CH:10]1[C:32](=[O:33])[N:12]2[C:13]([C:19]([O:21]CC3C=CC([N+]([O-])=O)=CC=3)=[S:20])=[C:14]([CH:17]=[CH2:18])[CH2:15][S:16][C@H:11]12)=[O:8])#[N:2].CO.C(O)(=O)C.[H][H]>[Pd].O1CCCC1>[C:1](/[CH:3]=[CH:4]\[S:5][CH2:6][C:7]([NH:9][CH:10]1[C:32](=[O:33])[N:12]2[C:13]([C:19]([OH:21])=[S:20])=[C:14]([CH:17]=[CH2:18])[CH2:15][S:16][C@H:11]12)=[O:8])#[N:2]
Reactant: [H][H]
Reactant: C=CC1=C(C(=S)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=O)CS/C=C\C#N)[C@H]2SC1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C=CC1=C(C(O)=S)N2C(=O)C(NC(=O)CS/C=C\C#N)[C@H]2SC1

Procedure:
p-Nitrobenzyl 7-[2-((Z)-2-cyanovinylthio)acetamido]-3-vinylthio-3-cephem-4-carboxylate (300 mg) was hydrogenated in the presence of 10% palladium on carbon (270 mg) in a mixture of tetrahydrofuran (9 ml), methanol (1.5 ml) and acetic acid (0.033 ml) at ambient temperature for 3 hours under 1 atmospheric pressure of hydrogen. The catalyst was filtered off and washed with methanol. The filtrate and washings were combined and concentrated in vacuo. The residue was dissolved in a mixture of ethyl acetate and water at pH 7. The aqueous layer was separated, adjusted to pH 7 with dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, concentrated in vacuo and triturated with diisopropyl ether to give 7-[2-((Z)-2-cyanovinylthio)acetamido]-3-vinylthio-3-cephem-4-carboxylic acid
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:25]([OH:32])[C:24]([OH:33])=[C:23]2[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:18][CH:17]=1.[CH2:39]([O:46][CH2:47][CH2:48]O)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH2:39]([O:46][CH2:47][CH2:48][O:33][C:24]1[C:25]([OH:32])=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:22]([C:19]2[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=2)[C:23]=1[C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: OCCOCc1ccccc1
Reactant: CCOC(=O)c1c(O)c(O)c(C(=O)OCC)n1-c1ccc(F)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)c1c(O)c(OCCOCc2ccccc2)c(C(=O)OCC)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.5 %

Procedure:
Diisopropyl azodicarboxylate (317 μL, 1.63 mmol) was added to a solution of diethyl 1-(4-fluorophenyl)-3,4-dihydroxy-1H-pyrrole-2,5-dicarboxylate (UL2-003) (500 mg, 1.48 mmol), 2-(benzyloxy)ethanol (232 μL, 1.63 mmol) and triphenylphosphine (428 mg, 1.63 mmol) in DCM (5 ml), at 0° C. The reaction mixture was allowed to warm to RT and stirred for 1 h. The reaction was washed with water (5 mL) and the phases separated using a phase separation cartridge, the organic was concentrated in vacuo to afford a yellow oil. The residue was purified by silica gel chromatography (80 g, 0-25% EtOAc in isohexane) to afford diethyl 3-(2-(benzyloxy)ethoxy)-1-(4-fluorophenyl)-4-hydroxy-1H-pyrrole-2,5-dicarboxylate (22) (122 mg, 17%) as a yellow oil: m/z 472 (M+H)+ (ES+); 470 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 8.70 (s, 1H), 7.38-7.26 (m, 5H), 7.24-7.12 (m, 4H), 4.54 (s, 2H), 4.27-4.16 (m, 2H), 4.09-3.89 (m, 4H), 3.78-3.71 (m, 2H), 1.01-0.94 (m, 6H).
Reaction SMILES: CS(OCC(OCCC)(C)C(C1C=CC(Cl)=CC=1)=O)(=O)=O.C([O-])(=O)C.[Na+].C(O)(=O)C.O.NN.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[C:45]([CH3:50])([O:46][CH2:47][CH2:48][CH3:49])[CH2:44][N:43]([C:51]([NH2:53])=[O:52])[N:42]=2)=[CH:37][CH:36]=1.[F:54][C:55]([F:66])([F:65])[C:56]1[CH:61]=[CH:60][C:59](N=C=O)=[CH:58][CH:57]=1>CO>[F:54][C:55]([F:66])([F:65])[C:56]1[CH:61]=[CH:60][C:59]([NH:53][C:51]([N:43]2[CH2:44][C:45]([CH3:50])([O:46][CH2:47][CH2:48][CH3:49])[C:41]([C:38]3[CH:37]=[CH:36][C:35]([Cl:34])=[CH:40][CH:39]=3)=[N:42]2)=[O:52])=[CH:58][CH:57]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: CCCOC1(C)CN(C(N)=O)N=C1c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: CCCOC(C)(COS(C)(=O)=O)C(=O)c1ccc(Cl)cc1
Agent: NN
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CCCOC1(C)CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
To 3.5 g (10 mmole) of 2-methanesulfonyloxymethyl-2-propoxy-4'-chloropropiophenone (Example 96e) in 25 ml of methanol was added 1.5 g (18 mmole) of anhydrous sodium acetate, 2.5 g (41 mmole) of acetic acid and 1.0 g (20 mmole) of hydrazine monohydrate. The mixture was refluxed for one hour, concentrated in vacuo, partitioned between diethyl ether and water. The organic layer was washed with dilute aqueous sodium hydroxide and brine and then dried over anhydrous magnesium sulfate, filtered and concentrated to about 25 ml. To this solution of 3-(4-chlorophenyl)-4-methyl-4-propoxy-4,5-dihydro-1H-pyrazole-1-carboxamide was added 2.1 g (11 mmole) of 4-(trifluoromethyl)phenylisocyanate. After stirring for 1 hour the precipitated solid was filtered and washed with diethyl ether and hexanes yielding 3.3 g of the title compound, a white solid, mp 135°-138° C.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:8]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][C:32]=1[C:41](Cl)=[O:42].C(=O)(O)[O-].[Na+]>ClCCl>[CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][C:32]=1[C:41]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:8]=2)=[CH:22][CH:23]=1)=[O:42]
Reactant: CCOC(=O)Cn1nc(Cc2ccc(N)cc2)c2ccccc21
Reactant: O=C(Cl)c1ccc2ccccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cn1nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)c2ccccc21
Yield: 89.9 %

Procedure:
630 mg (2.04 mmol) ethyl 2-[3-(4-aminobenzyl)-1H-indazol-1-yl]acetate was dissolved in 20 mL dichloromethane. 0.85 mL (6.11 mmol) triethylamine was added, and in an ice bath a dichloromethane solution dissolving 428 mg (2.25 mmol) 2-naphthoyl chloride was added slowly, and reacted in an ice bath for 3 h. An aqueous solution of sodium bicarbonate was added to quench, extracted with ethyl acetate, rotate evaporated to dryness, chromatographed on a column to obtain a white solid 850 mg, at a yield of 89.7%.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH3:30])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([S:17]([NH:20][C:21]3[C:26]([O:27][CH3:28])=[N:25][C:24]([CH3:29])=[CH:23][N:22]=3)(=[O:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:7][CH:6]=1.C(=O)([O-])O.[Na+].[C:36](O)(=[O:38])[CH3:37]>C(OC(=O)C)(=O)C>[C:36]([O:1][CH2:2][CH:3]([CH3:30])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([S:17]([NH:20][C:21]3[C:26]([O:27][CH3:28])=[N:25][C:24]([CH3:29])=[CH:23][N:22]=3)(=[O:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:7][CH:6]=1)(=[O:38])[CH3:37]
Reactant: CC(=O)O
Reactant: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1-c1ccc(CC(C)CO)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1-c1ccc(CC(C)COC(C)=O)cc1
Temperature: 25 °C

Procedure:
2-[4-(3-hydroxy-2-methylpropyl)phenyl]-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide from Example 19 (100 mg) was heated in a mixture of acetic acid (0.5 ml) and acetic anhydride (0.5 ml) to 80° C. for 10 minutes and allowed to cool to ambient temperature. After 16 hours excess saturated aqueous sodium hydrogen carbonate was added cautiously and the product extracted into ethyl acetate (3×20 ml). The combined organic extract was dried (MgSO4) and evaporated. The residue was purifed by elution with a gradient of 0-30% ethyl acetate/hexane through a silica gel Mega Bond Elut column (1 g) to give 2-[4-(3-acetoxy-2-methylpropyl)phenyl]-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (70 mg) as a white foam; 1H NMR (CDCl3): 0.98 (d, 3H), 1.58 (s, 3H), 2.11 (s, 3H), 2.1-2.3 (m, 1H), 2.51 (q, 1H), 2.85 (q, 1H), 3.80 (s, 3H), 3.97 (m, 2H), 6.69 (s, 1H), 7.2 (d, 2H), 7.29 (d, 2H), 8.67 (d, 1H), 8.80 (dd, 1H); mass spectrum (+ve ESP): 471.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:10]([CH3:12])[CH3:11])[C:7]([OH:9])=O)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(Cl)Cl.Cl.[OH:41][C@H:42]1[CH2:46][NH:45][C@H:44]([C:47]([O:49][CH3:50])=[O:48])[CH2:43]1>C([O-])(O)=O.[Na+]>[OH:41][C@H:42]1[CH2:46][N:45]([C:7](=[O:9])[C@@H:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[CH:10]([CH3:12])[CH3:11])[C@H:44]([C:47]([O:49][CH3:50])=[O:48])[CH2:43]1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)OC)C(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 79.7 %

Procedure:
In a 500 mL round-bottomed flask, (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (2.90 g, 16.6 mmol) and HATU (6.29 g, 16.6 mmol) were combined with CH2Cl2 (300 ml) to give a colorless suspension. TEA (5.03 g, 6.92 ml, 49.7 mmol) was added and stirred at rt for 30 min. (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate HCl (3.01 g, 16.6 mmol) was added and stirred at room temperature for 5 hr. It was diluted with NaHCO3 (sat. solution, 100 ml) and organic phase was separated. The aqueous layer was extracted with CH2Cl2 (2×100 ml) and the organic layer was dried with MgSO4, filtered and concentrated in vacuo. The crude material was purified by a silica gel column (CH2Cl2, 20%, 40%, 60%, 80% EtOAc/CH2Cl2) to afford (2S,4R)-methyl 4-hydroxy-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidine-2-carboxylate as an oil (4.0 g, 79.9%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.88 (dd, J=17.32, 6.78 Hz, 17H) 1.75-1.96 (m, 5H) 2.10 (br. s., 3H) 3.46-3.62 (m, 16H) 3.63-3.77 (m, 5H) 4.33 (d, J=8.03 Hz, 5H) 5.21 (d, J=3.76 Hz, 3H) 7.30 (d, J=8.78 Hz, 2H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[C:23]2[CH2:28][C:27]([CH3:30])([CH3:29])[O:26][C:25]([CH3:32])([CH3:31])[CH2:24]2)[C:10]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([O:20]CC)=[O:19])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[OH-].[Na+].Cl>CCO.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9](=[C:23]2[CH2:24][C:25]([CH3:32])([CH3:31])[O:26][C:27]([CH3:30])([CH3:29])[CH2:28]2)[C:10]2[CH:11]=[CH:12][C:13](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])=[CH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCOC(=O)/C=C/c1ccc(C(=C2CC(C)(C)OC(C)(C)C2)c2ccc(O)c(F)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CC(=C(c2ccc(/C=C/C(=O)O)cc2)c2ccc(O)c(F)c2)CC(C)(C)O1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl (2E)-3-{4-[(3-fluoro-4-hydroxyphenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]phenyl}-2-propenoate (137) (0.30 g, 0.68 mmol) in a mixture of EtOH (6 mL) and THF (6 mL) was added an aqueous solution of 1 N NaOH (7 mL). The mixture was stirred at 60° C. for 2 h. Upon cooling, the mixture was acidified to pH=2 with an aqueous solution of 2 N HCl. The mixture was extracted with EtOAc (2×50 mL). The combined organic extract was washed with brine and dried over Na2SO4. Upon concentration and adding hexanes, the title compound 138 was obtained as an off-white solid (0.227 g, 81%). mp 125-128° C. 1H NMR (400 MHz, DMSO-d6): δ 1.10 (s, 6H), 1.12 (s, 6H), 2.10 (s, 2H), 2.14 (s, 2H), 6.47 (d, J=15.9 Hz, 1H), 6.75-6.80 (m, 1H), 6.82-6.95 (m, 2H), 7.19 (d, J=8.2 Hz, 2H), 7.54 (d, J=15.9 Hz, 1H), 7.61 (d, J=8.2 Hz, 2H), 9.80 (s, 1H), 12.36 (s, 1H). LCMS (ES): m/z 409 (M−H)−. Anal. Calcd for C25H27FO4.0.4H2O: C, 71.89; H, 6.71; Found: C, 71.88; H, 6.92.
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:5]=1[O:6][CH2:7]C(O)=O)(=O)[CH3:2].C([O-])(=O)C.[Na+]>C(OC(=O)C)(=O)C>[Br:15][C:12]1[CH:13]=[CH:14][C:4]2[C:1]([CH3:2])=[CH:7][O:6][C:5]=2[CH:11]=1
Reactant: CC(=O)c1ccc(Br)cc1OCC(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: Cc1coc2cc(Br)ccc12
Temperature: 80 °C
Yield: 71.1 %

Procedure:
A 100 mL flask equipped with a magnetic stirbar, condenser, is charged with 2-(2-acetyl-5-bromophenoxy)acetic acid (1.14 g, 4.0 mmol) and (40 mL) of acetic anhydride and sodium acetate (860 mg, 10 mmol). The mixture was heated at 80° C. for 2 hours. After cooling the reaction mixture was evaporated to dryness. (40 mL) of methanol was added followed by concentrating under vacuum to give 6-bromo-3-methylbenzofuran (600 mg, 75%) as yellow oil. 1H NMR (300 MHz, CD3OD) δ 7.62 (s, 1H), 7.38-7.36 (m, 3H), 2.23 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.Br[C:19]1[C:28]2[C:23](=C[CH:25]=[C:26](OC)[N:27]=2)[N:22]=[CH:21]C=1N>CN(C)C=O>[CH3:19][C@H:28]1[CH2:23][N:22]([CH3:21])[CH2:25][CH2:26][N:27]1[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc2ncc(N)c(Br)c2n1
Reactant: Nc1ccnc(Cl)n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(C)CCN1c1nccc(N)n1
Temperature: 220 °C
Yield: 27.5 %

Procedure:
A mixture of 2-chloro-4-pyrimidinamine (200 mg, 1.544 mmol), Hunig's base (1348 μl, 7.72 mmol) and (3S)-1,3-dimethylpiperazine (Ref.: WO2009061879 (A1)) (318 mg, 1.698 mmol) in N,N-dimethylformamide (DMF) (1.7 ml) was heated to 220° C. via a microwave reactor for 15 min. The reaction mixture was purified by RP-HPLC to yield 2-[(2S)-2,4-dimethyl-1-piperazinyl]-4-pyrimidinamine (88 mg, 0.425 mmol, 28% yield). MS (ES+) m/z 208.0 (MH+).