Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:16][CH2:15][CH2:14][CH:13]2[C:17](O)=[O:18])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.C(OCC)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:16][CH2:15][CH2:14][CH:13]2[CH2:17][OH:18])(=[O:10])=[O:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)N2CCCC2C(=O)O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N2CCCC2CO)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Part B: To a solution of 4.00 g (14 mmol) of 1-[(4-methoxyphenyl)sulfonyl]-2-carboxypyrrolidine from part A in 50 mL of anhydrous tetrahydrofuran at 0 C under a nitrogen atmosphere, was slowly added over 15 minutes, 20 mL (20 mmol) of a 1M solution of lithium aluminum hydride in diethyl ether. After stirring at room temperature for 2 hours, the solution was cooled in an ice bath, and quenched by the slow sequential addition of 0.8 mL of water, 0.8 mL of 10% sodium hydroxide and 2.4 mL of water. The resulting suspension was filtered through celite and the celite washed with ethyl acetate. The combined organic filtrates were stripped, the residue disolved in ethyl acetate, which was washed with 5% KHSO4, saturated sodium bicarbonate, brine, dried with sodium sulfate, filtered and stripped to afford 3.66 g of crude material. This was chromatographed on 200 g of silica gel using 40%-75% ethyl acetate/hexane to yield pure 1-[(4-methoxyphenyl)sulfonyl]-2-(hydroxymethyl)pyrrolidine, m/e=278 (M+Li).
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:9](=[O:16])[N:10]([CH2:11][C:12](OC)=[O:13])[C:6]=2[C:5]([N+:22]([O-])=O)=[C:4](Cl)[N:3]=1>CO.[Pd]>[O:16]=[C:9]1[N:10]2[C:6]3[C:5]([NH:22][C:12](=[O:13])[CH2:11]2)=[CH:4][N:3]=[CH:2][C:7]=3[N:8]1[CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)Cn1c(=O)n(CC(=O)OC)c2c([N+](=O)[O-])c(Cl)nc(Cl)c21
Agent: [Pd]
Solvent: CO
Product: COC(=O)Cn1c(=O)n2c3c(cncc31)NC(=O)C2
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A mixture of dimethyl 2,2′-(4,6-dichloro-7-nitro-2-oxo-1H-imidazo[4,5-c]pyridine-1,3-diyl)diacetate (40 mg, 0.10 mmol) from Step E and 10% Pd/C (12 mg) in MeOH (2 mL) was stirred under an atmosphere of hydrogen (ca. 1 atm) for 6 h. The reaction mixture was filtered through a pad of Celite and concentrated in vacuo. The crude material was heated at 80° C. for 2 h in toluene (2 mL) and AcOH (2 mL) then concentrated to give the title compound. MS: m/z=263 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:19]([O:26][C:27](=[O:32])[C@H:28]([CH2:30][OH:31])[NH2:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.C(OCC)(=O)C>[CH2:19]([O:26][C:27](=[O:32])[C@H:28]([CH2:30][OH:31])[NH:29][C:11](=[O:13])[C:10]1[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)c1ccccc1OCc1ccccc1
Reactant: N[C@@H](CO)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(N[C@@H](CO)C(=O)OCc1ccccc1)c1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-(benzyloxy)benzoic acid (2.0 g, 8.7 mmol), L-serine benzyl ester hydrochloride (2.0 g, 8.7 mmol, 1 equiv.) and HOAt (1.2 g, 8.7 mmol, 1 equiv.) in DMF (200 mL) was added triethylamine (0.98 mL, 9.6 mmol, 1.1 equiv.) and EDC HCl (2.02 g, 4.8 mmol, 1.2 equiv.). After being stirred overnight at room temperature under nitrogen, the reaction mixture was diluted with ethyl acetate (200 mL), washed with 1N HCl (60 mL), saturated NaHCO3, saturated NH4Cl (60 mL), and brine (60 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated and chromatographed on silica gel eluting with CH2Cl2/MeOH (95/5) to give the title compound, N-[2-(benzyloxy)benzoyl]-L-serine benzyl ester, 92.5 g, 70%) as white crystals. Rf=0.5 (CH2Cl2/MeOH, 95/5); 1H NMR (300 MHz, CDCl3) δ8.80 (d, 1H, NH), 8.19 (dd,1H, ArH), 7.46-7.24 (m, 11H, ArH), 7.12-7.04 (m, 2H, ArH), 5.21-5.11 (m, 4H, 2{CH2phenyl}), 4.91-4.87 (m, 1H, CH), 3.93-3.90 (m, 2H, CH2OH), 2.2 (1H, OH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][S:8][C:9]2[C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[C:20](N1C=CN=C1)(N1C=CN=C1)=O.C[O-].[Na+]>CN(C)C=O.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C:9]2[C:14]([C:15]([O:17][CH3:20])=[O:16])=[CH:13][N:12]=[CH:11][CH:10]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(CSc2ccncc2C(=O)O)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1cnccc1SCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 2.2 g (0.008 mole) of 4-(4-methoxybenzylthio)--nicotinic acid in 30 mL of dry N,N-dimethylformamide was reacted with 1.78 g (0.011 mole) of 1,1'-carbonyldiimidazole. This was stirred at room temperature for 2 hours, then 0.5 mL of 4.3M sodium methoxide in methanol and 5 mL of methanol. The reaction was stirred for 1 hour at room temperature, then partitioned between 75 mL of ether and 30 mL of water. The ether layer was extracted with 2×30 mL of water, dried, concentrated to a small volume, and hexane added to crystallize methyl 4-(4-methoxybenzylthio) nicotinate; yield 1.66 g (72% of theory), m.p. 108°-110° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[NH:5][CH3:6].C(N(C(C)C)CC)(C)C.ClCCCl.[C:24]12([C:34](Cl)=[O:35])[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2>C(OCC)(=O)C>[Br:1][C:2]1[C:3]([CH3:10])=[C:4]([N:5]([CH3:6])[C:34]([C:24]23[CH2:33][CH:28]4[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]4)[CH2:25]2)[CH2:31]3)=[O:35])[CH:7]=[CH:8][CH:9]=1
Reactant: CNc1cccc(Br)c1C
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1c(Br)cccc1N(C)C(=O)C12CC3CC(CC(C3)C1)C2
Temperature: 50 °C

Procedure:
3-Bromo-N,2-dimethylaniline (300 mg) and diisopropylethylamine (581 mg) were added to 1,2-dichloroethane (5 mL). 1-Adamantanecarbonyl chloride (328 mg) was added and the solution was heated at 50° C. for three days. The solution was diluted with 70% ethyl acetate (hexanes), washed three times with 1M aqueous HCl, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by flash column chromatography on silica gel using 10% ethyl acetate (hexanes) to yield the title compound.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[N:5][N:4]=[CH:3]1.CS(C)=O.[H-].[Na+].F[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1>O>[C:18]([C:17]1[CH:20]=[CH:21][C:14]([NH:1][N:2]2[CH:6]=[N:5][N:4]=[CH:3]2)=[CH:15][CH:16]=1)#[N:19]
Reactant: N#Cc1ccc(F)cc1
Reactant: Nn1cnnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccc(Nn2cnnc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.52 Grams of 4-amino-1,2,4-triazole was added little by little to a dimethylsulfoxide suspension of 1.2 g of sodium hydride at room temperature. After stirred for 3 hours at room temperature, 1.21 g of 4-fluorobenzonitrile was added thereto all at a time, and stirring was continued for further one hour. Water was added to the reaction solution, and the mixture was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The crystals obtained were washed with ethyl acetate to give 1.09 g of 4-[(4-cyanophenyl)amino]-4H-1,2,4-triazole.
Reaction SMILES: [CH3:1][CH:2]([OH:11])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[Cl:10].Cl[O-].[Na+].S(=O)(O)[O-].[Na+]>C(O)(=O)C>[CH3:1][C:2]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[Cl:10])=[O:11]
Reactant: CC(O)c1cccc(Cl)c1Cl
Agent: O=S([O-])O
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC(=O)O
Product: CC(=O)c1cccc(Cl)c1Cl
Temperature: 20 °C
Yield: 65 %

Procedure:
α-Methyl-2,3-dichlorobenzyl alcohol (5.0 g, 0.026 mol was dissolved in acetic acid (24 ml) and 12% w/v sodium hypochlorite solution (23.26 ml, 0.0314 mol) was added slowly dropwise, with stirring, at a temperature of 15-25° C. When the addition was complete the reaction mixture was stirred at ambient temperature for approximately 11/2 hours until a starch/iodide test gave a positive result. Saturated sodium bisulphite solution was added to the reaction mixture until the starch/iodide test was negative. The mixture was poured onto ice/brine (100 ml) and extracted with diethyl ether (3×75 ml). The ether phases were combined and washed with 2N sodium hydroxide solution (3×75 ml) until the aqueous washes were alkaline. The ether phase was dried over anhydrous magnesium sulphate, filtered and evaporated down. 2,3-Dichloroacetophenone (3.2 g, 65% yield) was afforded as a pale-yellow oil. T.l.c. (SiO2 ;CHCl3) and nmr showed this material to contain no impurities.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[S:19](=[O:22])(=[O:21])[CH2:20][C:11]=3[C:10]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(CC(=O)C)(=O)C.C[N:45](C=O)C>>[N:25]1([C:23]([C:10]2[C:11]3[CH2:20][S:19](=[O:22])(=[O:21])[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[C:12]=3[N:8]([C:4]3[CH:3]=[C:2]([NH2:45])[CH:7]=[CH:6][CH:5]=3)[N:9]=2)=[O:24])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: O=C(c1nn(-c2cccc(Br)c2)c2c1CS(=O)(=O)c1ccccc1-2)N1CCOCC1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)CC(C)=O
Product: Nc1cccc(-n2nc(C(=O)N3CCOCC3)c3c2-c2ccccc2S(=O)(=O)C3)c1
Temperature: 90 °C

Procedure:
1-(3-bromophenyl)-3-(morpholin-4-ylcarbonyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole 5,5-dioxide (150 mg, 0.31 mmol), cupric acetate (6.1 mg, 0.031 mmol), cesium carbonate (200 mg, 0.616 mmol) and acetyl acetone (13 □L, 0.123 mmol) are taken in a sealed tube to which is added a solution of DMF purged with NH3 gas. The reaction mixture is heated to 90° C. for 24 h. After this time, reaction mixture is concentrated under reduced pressure and purified by silica gel column chromatography (100% EtOAc) to afford the title compound as a pale brown solid. 1H NMR (DMSO-d6, 400 MHz): δ 7.99-7.97 (m, 1H), 7.62-7.60 (m, 1H), 7.24-7.20 (t, J=7.8 Hz, 1H), 6.98-6.95 (m, 1H), 6.75-6.73 (d, J=9.3 Hz, 1H), 6.58-6.56 (m, 2H), 5.57 (s, 2H), 4.87 (s, 2H), 3.95 (m, 2H), 3.66 (m, 6H). MS (ESI+): 425.0.; HPLC (max plot) 94.69%; Rt 2.65 min.
Reaction SMILES: [F:1][C:2]1([F:31])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([C:24]5[CH:29]=[CH:28][C:27](=[O:30])[NH:26][CH:25]=5)[N:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.Br[CH2:33][CH2:34][NH:35]C(=O)OCCCC.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:35][CH2:34][CH2:33][N:26]1[C:27](=[O:30])[CH:28]=[CH:29][C:24]([C:19]2[N:18]=[C:17]([NH:16][C:14]([C:11]3([C:9]4[CH:8]=[CH:7][C:5]5[O:6][C:2]([F:1])([F:31])[O:3][C:4]=5[CH:10]=4)[CH2:13][CH2:12]3)=[O:15])[CH:22]=[CH:21][C:20]=2[CH3:23])=[CH:25]1
Reactant: CCCCOC(=O)NCCBr
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccc(=O)[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccc(=O)n(CCN)c1
Temperature: 100 °C
Yield: 17.1 %

Procedure:
To a flask containing 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(5-methyl-6-(6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide (0.13 g, 0.3 mmol), ten-butyl 2-bromoethylcarbamate (0.35 g, 1.6 mmol), and potassium carbonate (0.5 g, 3.1 mmol) was added N,N-dimethylformamide (5 mL) and the reaction mixture was heated to 100° C. for 2 hours. The reaction was purified by reverse-phase preparative liquid chromatography to give the product (24 mg, 17%). ESI-MS m/z calc. 468.16. found 469.5 (M+1)+ Retention time 1.37 minutes.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.Cl.[F:25][C:26]1([F:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[F:25][C:26]1([F:32])[CH2:31][CH2:30][N:29]([C:19]([C:18]2[CH:17]=[N:16][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[CH:23][CH:22]=2)=[O:21])[CH2:28][CH2:27]1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: FC1(F)CCNCC1
Agent: Cl
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N2CCC(F)(F)CC2)cn1
Yield: 98 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using 4,4-difluoropiperidine hydrochloride (1 M in DMF) instead of methylamine, to the title compound (131 mg, 98%) which was obtained as a light yellow gum. MS: m/e=414.4 [M+H]+.
Reaction SMILES: [CH2:1](P(=O)(OCC)OCC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].C1OCCOCCOCCOCCOCCOC1.[Br:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][N:45]=1)[CH:41]=O>CN(C)C=O>[Br:37][C:38]1[CH:39]=[C:40](/[CH:41]=[CH:1]/[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:43]=[CH:44][N:45]=1
Reactant: O=Cc1ccnc(Br)c1
Reactant: CCOP(=O)(Cc1ccccc1)OCC
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cc(/C=C/c2ccccc2)ccn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of diethyl benzylphosphonate (4.57 mL, 21.91 mmol) in dimethylformamide (50 mL) at room temperature was added sodium methoxide (2.367 g, 43.8 mmol) and 18-Crown-6 (2.316 g, 8.76 mmol). After stirring at room temperature for 5 min, the reaction was cooled to 0° C. and treated with 2-bromoisonicotinaldehyde (4.89 g, 26.3 mmol) as a solid in one portion. The ice bath was removed and the reaction stirred at room temperature for 1 h. The reaction was gradually warmed to 120° C. and held there for 2 h. The reaction was cooled to room temperature and poured into water (500 mL) with vigorous stirring. The resulting suspension was extracted with diethyl ether (3×), washed with water, then brine, dried over magnesium sulfate, and concentrated to an oil. The resulting residue was purified by column chromatography (6% EtOAc/Hex-->12% EtOAc/Hex) to give 2.12 g (37%) as an oil. 1H-NMR (CDCl3, 500 MHz) δ 8.35 (d, J=5.2, 1H), 7.52-7.62 (m, 3H), 7.43 (m, 2H), 7.30-7.40 (m, 3H), 6.98 (d, J=16.2, 1H). 13C-NMR (CDCl3, 126 MHz) δ 150.4, 147.7, 143.1, 135.8, 134.8, 129.3, 129.0, 127.3, 125.0, 124.6, 120.1.
Reaction SMILES: [CH3:1][C:2]([N:9]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[N:10]1)([CH3:8])[C:3](OCC)=[O:4].[H-].C([Al+]C(C)C)(C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>O1CCCC1.C1(C)C=CC=CC=1>[CH3:8][C:2]([N:9]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[N:10]1)([CH3:1])[CH2:3][OH:4]
Reactant: CCOC(=O)C(C)(C)n1cc([N+](=O)[O-])cn1
Agent: CC(C)[Al+]C(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(CO)n1cc([N+](=O)[O-])cn1
Reaction time: 8 h
Yield: 98.2 %

Procedure:
To a solution of ethyl 2-methyl-2-(4-nitro-1H-pyrazol-1-yl)propanoate (45 g) obtained in Step F of Example 103 in tetrahydrofuran (400 mL) was added gradually dropwise diisopropylaluminium hydride in toluene (1.5 M in toluene, 400 mL) while maintaining the internal temperature of −20° C. or less, and the reaction mixture was stirred overnight while it was allowed to be warmed. To the reaction mixture was added aqueous potassium sodium tartrate solution in an ice bath, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the crude title compound (36 g).
Reaction SMILES: [C:1]1([C:7]2([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)(=O)C.O.[O-2].[O-2].[O-2].[Cr+6]>[C:1]1([C:7]2([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:8][CH2:9][C:10](=[O:13])[CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC1CCC(c2ccccc2)(N2CCCCC2)CC1
Agent: [Cr+6]
Agent: [Na+]
Agent: [O-2]
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCC(c2ccccc2)(N2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
4-Phenyl-4-piperidinocyclohexanol (1.2 g, 4.6 mmoles) was dissolved in 50 ml of glacial acetic acid. The solution was cooled with an external ice-bath. Chromium trioxide (1 g, 10 mmole) was dissolved in 10 ml of water and 15 ml of glacial acetic acid, and was slowly added to the solution. After completion, the solution was stirred at room temperature for 4 hours. TLC analysis indicated no starting material was left. The solution was cooled with an ice-bath and was carefully made basic with sodium hydroxide solution. The greenish solution was extracted with 5×60 ml of ethyl ether. The combined ethereal solutions were dried over sodium sulfate and were concentrated under reduced pressure to give a white solid residue. Recrystallization from hexane gave 1.1 g of slightly brown crystalline solid (mp: 116°-117° C.) in 93% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15]Br)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+].[S:26]1[C:30]2[CH2:31][C@@H:32]([NH2:35])[CH2:33][CH2:34][C:29]=2[N:28]=[C:27]1[NH2:36]>C(#N)C>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][NH:35][C@H:32]2[CH2:33][CH2:34][C:29]3[N:28]=[C:27]([NH2:36])[S:26][C:30]=3[CH2:31]2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1nc2c(s1)C[C@@H](N)CC2
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCBr)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN[C@H]2CCc3nc(N)sc3C2)CC1

Procedure:
Bromide 17 (1.1 g, 3.6 mmol), cesium carbonate (1.47 g, 4.5 mmol), and sodium iodide (0.68 g, 4.5 mmol) were added to a solution of compound 19 (0.63 g, 3.0 mmol) in acetonitrile (40 mL). After refluxing for 48 hours, the mixture was evaporated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, and dried over anhydrous sodium sulfate (Na2SO4). Flash column chromatography (MeOH/EtOAc, 1:6) gave compound 20 as a colorless oil (0.8 g, 61%). 1H NMR (CDCl3, 300 MHz) δ 4.93 (s, 2H), 4.02 (d, J=7.4 Hz, 1H), 3.50-3.30 (m, 1H), 3.10-2.95 (m, 1H), 2.80-2.35 (m, 8H), 2.05-1.90 (m, 3H), 1.85-1.60 (m, 3H), 1.55-1.00 (m, 9H), 1.44 (s, 9H), 0.87 (t, J=7.2 Hz, 3H).
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][C:6]2[S:7][C:8]([C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH:17]([CH3:20])[CH2:18][CH3:19])=[O:12])=[CH:9][N:10]=2)[CH2:2]1.[NH3:21]>C(O)C>[NH2:21][CH:2]([OH:1])[CH2:3][CH2:4][O:5][C:6]1[S:7][C:8]([C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH:17]([CH3:20])[CH2:18][CH3:19])=[O:12])=[CH:9][N:10]=1
Reactant: CCC(C)CCCNC(=O)c1cnc(OCC2CO2)s1
Reactant: N
Solvent: CCO
Product: CCC(C)CCCNC(=O)c1cnc(OCCC(N)O)s1
Reaction time: 20 h

Procedure:
This example illustrates methods according to the invention of converting the compounds of formula II to the corresponding compounds of formula I of the invention. In this example, 350 mg. of 1,2-epoxy-3-(5-4'-methylhexylaminocarbonylthiazol -2-oxy)-propane is dissolved in 6 ml. of anhydrous ethanol saturated with ammonia and allowed to stand at room temperature for 20 hours. The mixture is then evaporated to remove ethanol and the resulting residue purified by thin-layer chromatography on preparative silica plates using a developing system of 1% triethylamine, 1.5% methanol and the remainder ethyl acetate, yielding 1-amino- 3-(5-4'-methylhexylaminocarbonylthiazol-2-oxy)-propanol.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C:5](=[O:13])[N:4]([CH3:14])[CH:3]=1.[CH:15]1([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])=[CH:22][C:21]=2B2OC(C)(C)C(C)(C)O2)[CH2:17][CH2:16]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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.Cl[Pd]Cl.[Fe+2]>[CH:15]1([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])=[CH:22][C:21]=2[C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=3)[C:5](=[O:13])[N:4]([CH3:14])[CH:3]=2)[CH2:16][CH2:17]1
Reactant: Cn1cc(Br)c2cc(F)ccc2c1=O
Reactant: CCS(=O)(=O)c1ccc(OCC2CC2)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)c1ccc(OCC2CC2)c(-c2cn(C)c(=O)c3ccc(F)cc23)c1
Temperature: 70 °C
Reaction time: 12 h
Yield: 16 %

Procedure:
A mixture of 4-bromo-6-fluoro-2-methylisoquinolin-1-one (500.00 mg, 1.95 mmol), 2-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.07 g, 2.92 mmol), K3PO4 (1.24 g, 5.85 mmol) and Pd(dppf)Cl2 (0.1 g, cat.) in dioxane/H2O (30 mL/4 mL) was stirred at 70° C. for 12 hrs under Ar. The mixture was concentrated and the residue purified by column chromatography (PE: EA=1:1) to give a pink solid. The pink solid was further purified by column chromatography (DCM: EA=4:1) to afford the title compound (0.13 g, 16%) as a light yellow solid. 1H NMR (CDCl3, 400 MHz) δ 8.54 (brs, 1H), 7.96 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H), 7.81 (d, J=2.0 Hz, 1H), 7.22-7.20 (m, 1H), 7.15-7.13 (m, 1H), 7.1 (d, J=8.8 Hz, 1H), 6.78 (dd, J1=10.4 Hz, J2=2.4 Hz, 1H), 3.90 (t, J=7.6 Hz, 2H), 3.68 (s, 3H), 3.15 (q, J=7.6 Hz, 2H), 1.33 (t, J=7.6 Hz, 3H), 1.06-1.02 (m, 1H), 0.50-0.43 (m, 2H), 0.15-0.14 (m, 2H). LCMS (M+H)+=416.0 (M+1)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[C:9]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[CH:10]N(C)C.[C:22]([CH2:24][C:25]([NH2:27])=[O:26])#[N:23].CO.[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:27][C:25](=[O:26])[C:24]([C:22]#[N:23])=[CH:10][C:9]=1[C:14]1[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=1
Reactant: CN(C)C=C(C(=O)c1ccccc1Cl)c1ccc(Cl)cc1
Reactant: N#CCC(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)[nH]c1=O
Temperature: 95 °C

Procedure:
To the product of step B was added 2-cyanoacetamide (1.912 g, 22.74 mmol), methanol (1.84 mL, 45.5 mmol) and DMF (50 mL). This solution was cannulated into a slurry of NaH (2.067 g, 51.7 mmol, 60% dispersion in mineral oil, washed with hexane) and DMF (24 mL) and then heated to 95° C. for 2.5 hours. The reaction was cooled and then concentrated in vacuo. The residue was diluted with ethyl acetate and then washed with 10% aq. NaHSO4 and water. The organic portion was dried (Na2SO4) and concentrated before suspending the solid in hot ethanol. After cooling, the solid was filtered and washed with ethanol and then hexane. This afforded product. MS (electrospray) m/e 341.1 MH+ (Rt=3.1 min LC/MS).
Reaction SMILES: C([O:8][CH2:9][C:10]1[N:11]([CH2:27][CH3:28])[C:12]([S:18][C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=2)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)C1C=CC=CC=1.Cl>C(O)C>[F:25][C:23]1[CH:24]=[C:19]([S:18][C:12]2[N:11]([CH2:27][CH3:28])[C:10]([CH2:9][OH:8])=[N:14][C:13]=2[CH:15]([CH3:16])[CH3:17])[CH:20]=[C:21]([F:26])[CH:22]=1
Reactant: CCn1c(COCc2ccccc2)nc(C(C)C)c1Sc1cc(F)cc(F)c1
Agent: Cl
Solvent: CCO
Product: CCn1c(CO)nc(C(C)C)c1Sc1cc(F)cc(F)c1
Yield: 68.3 %

Procedure:
In 5 ml of ethanol was dissolved 300 mg (0.75 mmol)of 2-benzyloxymethyl-5-(3,5-difluorophenylthio)-1-ethyl-4-isopropyl-1H-imidazole (17z), followed by addition of 5N-HCl (10 ml)at room temperature with stirring and the mixture was reacted on an oil bath at 130° C. for 3 hours during which time the mixture was concentrated. The reaction mixture was cooled, and a saturated aqueous sodium bicarbonate solution was added to be weakly alkali. The mixture was extracted with ethyl acetate, the ethyl acetate layer was washed with water and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residual oil was crystallized from n-hexane, and filtered to give 160 mg of Compound I-36 (yield 68%). mp 102-104° C.