Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:37])=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[C@@H:26]([CH2:27][C:28]([O:30]C)=[O:29])[C@H:25]([CH3:32])[C:24]([C:33]([F:36])([F:35])[F:34])=[N:23]4)=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)[CH:8]=1.[Li+].[OH-].Cl>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:37])=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([O:15][C:16]3[CH:17]=[CH:18][C:19]([N:22]4[C@@H:26]([CH2:27][C:28]([OH:30])=[O:29])[C@H:25]([CH3:32])[C:24]([C:33]([F:36])([F:35])[F:34])=[N:23]4)=[CH:20][CH:21]=3)[CH2:11][CH2:10]2)[CH:8]=1
Reactant: COC(=O)C[C@H]1[C@H](C)C(C(F)(F)F)=NN1c1ccc(OC2CCN(c3cc(OC)ccc3C)CC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(C)c(N2CCC(Oc3ccc(N4N=C(C(F)(F)F)[C@@H](C)[C@@H]4CC(=O)O)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71.3 %

Procedure:
To a round bottom flask was added methyl 2-((4S,5S)-1-(4-((1-(5-methoxy-2-methylphenyl)piperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetate (45 mg, 0.087 mmol), 2M LiOH (0.26 mL, 0.52 mmol) and THF (1 mL). The reaction solution was stirred at rt for 1.5 h, and the solution was acidified with 1N HCl to pH<4. The mixture was extracted with EtOAc (10 mL). The organic layer was washed with water (10 mL) and brine (10 mL), and then it was dried over MgSO4, filtered and concentrated. The residue was purified by Prep-HPLC to give 2-((4S,5S)-1-(4-(1-(5-methoxy-2-methylphenyl)piperidin-4-yloxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetic acid (31 mg, 0.062 mmol, 71% yield). LC-MS Anal. Calc'd for C26H30F3N3O4: 505.2. found [M+H] 506.1. 1H NMR (500 MHz, DMSO-d6) δ 7.12-7.03 (m, 3H), 6.99 (d, J=9.1 Hz, 2H), 6.59 (br. s., 1H), 6.55 (dd, J=8.3, 1.9 Hz, 1H), 4.45 (d, J=3.9 Hz, 2H), 3.72 (s, 4H), 3.39-3.33 (m, 2H), 3.05 (d, J=4.4 Hz, 2H), 2.78 (t, J=9.9 Hz, 2H), 2.66 (dd, J=16.2, 3.0 Hz, 1H), 2.18 (s, 3H), 2.05 (br. s., 2H), 1.85-1.72 (m, 2H), 1.27 (d, J=6.9 Hz, 3H). hGPR40 EC50=161 nM.
Reaction SMILES: [S:1]([O:11][CH2:12]/[CH:13]=[CH:14]/[CH2:15]OS(C1C=CC(C)=CC=1)(=O)=O)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[N+](CCCC)(CCCC)(CCCC)CCCC.[F-:44]>C1COCC1>[F:44][CH2:15]/[CH:14]=[CH:13]/[CH2:12][O:11][S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: [F-]
Reactant: Cc1ccc(S(=O)(=O)OC/C=C/COS(=O)(=O)c2ccc(C)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OC/C=C/CF)cc1
Yield: 38.4 %

Procedure:
To a solution of (E)-1,4-ditosyloxy-2-butene (256 mg, 0.64 mmol) in 10 mL of THF was added Bu4NF (0.7 mL, 1M in THF, 0.7 mmol). The mixture was heated to reflux for 30 min. Evaporation and purification of the residue by flash column chromatography with hexane:ether/2:1 afforded the product as a colorless oil (60 mg, 38%). 1 H NMR (CDCl3, 300 MHz) δ 7.80 (d, J=8.4 Hz, 2H), 7.36 (d, J=8.4 Hz, 2H), 5.99-5.75 (m, 2H, 4.84 (ddd, JFCH=46.5 Hz, J=4.8, 1.2 Hz, 2H), 4.59-4.56 (m, 2H), 2.46 (s, 3H).
Reaction SMILES: [N:1]([CH2:10][C:11]([OH:13])=O)([CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]([OH:5])=[O:4].C(OC(=O)C)(=O)C.[I:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[CH3:29])[NH2:25]>N1C=CC=CC=1>[I:21][C:22]1[CH:23]=[C:24]([NH:25][C:11](=[O:13])[CH2:10][N:1]([CH2:2][C:3]([OH:5])=[O:4])[CH2:6][C:7]([OH:9])=[O:8])[CH:26]=[CH:27][C:28]=1[CH3:29]
Reactant: O=C(O)CN(CC(=O)O)CC(=O)O
Reactant: Cc1ccc(N)cc1I
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)CN(CC(=O)O)CC(=O)O)cc1I
Temperature: 100 °C
Reaction time: 16 h
Yield: 56.4 %

Procedure:
A slurry of 4.78 g of nitrilotriacetic acid in 40 ml of dry pyridine (dried over molecular sieves) is heated to 60° C. Acetic anhydride (2.55 g) is added slowly and the solution is heated to 100° C. After heating for 0.5 hour, the solution is cooled to 40° C. and a solution of 5.8 g of 3-iodo-4-methylaniline in 20 ml of dry pyridine is added over 25 minutes. The solution is heated at 100° C. for 1.0 hour. The reaction is cooled and rotary evaporated to a residue which is dissolved in 65 ml of 10% sodium hydroxide. This solution is extracted twice with 50 ml portions of methylene chloride diluted with 100 ml of distilled water, and neutralized with concentrated HCl to pH 3.2. The crude product is refrigerated for about 16 hours, filtered, washed twice with 50 ml portions of distilled water, and dried under vacuum at 40° C. The crude product (8.0 g) is recrystallized after Darco treatment to yield 5.7 g of product, melting point 213.5°-215.0° C. (dec).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:17])([F:16])[C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([C:14]#[N:15])=[CH:9][CH:8]=2.I[CH3:19].O>CN(C=O)C>[CH3:19][N:6]1[C:7]2[C:12](=[CH:11][C:10]([C:14]#[N:15])=[CH:9][CH:8]=2)[CH:13]=[C:5]1[C:4]([F:3])([F:16])[F:17]
Reactant: N#Cc1ccc2[nH]c(C(F)(F)F)cc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(C(F)(F)F)cc2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 135.9 %

Procedure:
Sodium hydride (60% in mineral oil) (76 mg, 1.903 mmol) was added to 2-trifluoromethyl-1H-indole-5-carbonitrile (Intermediate 3, 200 mg, 0.952 mmol) stirred in DMF (5 ml) under argon at room temperature. The reaction mixture was stirred at room temperature for 30 min and iodomethane (0.119 ml, 1.903 mmol) was then added. The reaction mixture was left to stir for a further 1 h. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (50 ml). The organic extract was washed with 1:1 water:Brine (50 ml×2), dried (MgSO4), filtered and the solvent removed to give the title compound (290 mg) which was then used in the next reaction without further purification;
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:55](=[O:56])[N:14]2[C:15]([C:39]([O:41][CH:42]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:40])=[C:16]([CH:19]=P(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:57][C:58]1[N:59]=[CH:60][S:61][C:62]=1[CH:63]=O>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH:42]([O:41][C:39]([C:15]1[N:14]2[C:55](=[O:56])[CH:12]([NH:11][C:9](=[O:10])[CH2:8][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C@H:13]2[S:18][CH2:17][C:16]=1[CH:19]=[CH:63][C:62]1[S:61][CH:60]=[N:59][C:58]=1[CH3:57])=[O:40])([C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=P(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Reactant: Cc1ncsc1C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ncsc1C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Yield: 59.4 %

Procedure:
Benzhydryl 7-(phenoxyacetamido)-3-(triphenylphosphoran-diylmethyl)-3-cephem-4-carboxylate (1.55 g ) and 4-methylthiazol-5-carboaldehyde (0.305 g) were dissolved in methylene chloride (20 ml), to which aqueous saturated sodium bicarbonate (20 ml) was added at ambient temperature. The resultant mixture was stirred for 17 hours at ambient temperature. The mixture was allowed to stand until it separated into the aqueous phase and organic solvent phase. The aqueous phase was removed and washed with methylene chloride (20 ml), and the washings (in methylene chloride) were combined with the organic solvent phase separated. The combined solution was dried over anhydrous magnesium sulfate and then concentrated to dryness under reduced pressure. The solid residue obtained was purified chromatographically on a column of silica gel (Wako gel C-300) (40 g) as developed with benzene-ethyl acetate (5:1) as the development solvent. The entitled compound, 7-(phenoxyacetamido)-3-[2-(4-methylthiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid benzhydryl ester (0.741 g) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:24][CH2:23][CH2:22][C:10]2([CH:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[NH:12][C:11]2=[O:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[CH3:26][Si]([N-][Si](C)(C)C)(C)C.IC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:24][CH2:23][CH2:22][C:10]2([CH:13]([C:14]3[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)[N:12]([CH3:26])[C:11]2=[O:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC2(C1)C(=O)NC2c1ccc(F)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CN1C(=O)C2(CCCN(C(=O)OC(C)(C)C)C2)C1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A stirred solution of rac-1-(4-Fluoro-phenyl)-3-oxo-2,6-diaza-spiro[3.5]nonane-6-carboxylic acid tert-butyl ester (850 mg, 2.54 mmol) in THF (15 ml) was treated with 1M LHMDS in THF (3.30 ml, 3.30 mmol) followed by the addition of iodomethane (0.238 ml, 3.81 mmol). The solution was stirred at RT. After 4 hours, the reaction was quenched with water (30 mL) and extracted with ethyl acetate. The organic layer was separated, dried (MgSO4) and concentrated in vacuo to yield the title compound as a yellow oil;
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:14]=[C:15]=[O:16])(=[O:13])=[O:12])=[O:4].[NH2:17][C:18]1[N:23]=[C:22]([F:24])[CH:21]=[C:20]([O:25][C:26]([F:29])([F:28])[F:27])[N:19]=1>ClCCCl>[F:24][C:22]1[CH:21]=[C:20]([O:25][C:26]([F:29])([F:27])[F:28])[N:19]=[C:18]([NH:17][C:15]([NH:14][S:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:3]([O:2][CH3:1])=[O:4])(=[O:12])=[O:13])=[O:16])[N:23]=1
Reactant: Nc1nc(F)cc(OC(F)(F)F)n1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: ClCCCl
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(F)cc(OC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3.6 g (0.015 mol) of 2-methoxycarbonylbenzenesulfonyl isocyanate in 15 ml of 1,2-dichloroethane were added over the course of 15 minutes to a stirred mixture of 2.95 g (0.015 mol) of 2-amino-4-fluoro-6-trifluoromethoxypyrimidine and 100 ml of 1,2-dichloroethane at 25° C., and the mixture was stirred at 25° C. for 12 hours. The solution was concentrated under reduced pressure, and the residue was stirred with 1:1 ether/petroleum ether. Filtration with suction and drying yielded 4.8 g (73.3% of theory) of the title compound of melting point 157-161° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20].C[O-].[Na+].Cl>O.CN(C)P(N(C)C)(N(C)C)=O>[O:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: O=C(O)CCCCCCCCCCBr
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: O=C(O)CCCCCCCCCCOc1ccccc1
Temperature: 100 °C

Procedure:
To a mixture of 9.4 g of phenol, 26.5 g of 11-bromoundecanoic acid and 250 ml of hexamethylphosphoramide chilled in an ice bath is added 10.5 g of sodium methoxide. A viscous mass developes and the mixture is stirred and heated at 100° C. for 20 hours. The mixture is diluted with cold water, acidified with concentrated hydrochloric acid, filtered and the solid washed with water to give gray crystals. Recrystallization from acetone gives pale gray crystals, mp 76°-78° C. A second crop of crystals is obtained from mother liquors, mp 75°-77° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[C:14]([CH3:17])[C@:13]([CH2:19][CH:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[OH:21])([CH3:18])[CH2:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.I[CH2:29][CH3:30]>>[CH2:29]([O:21][CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)[CH2:19][C@:13]1([CH3:18])[C:14]([CH3:17])=[CH:15][C:16]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=[CH:10][C:11]=2[CH2:12]1)[CH3:30]
Reactant: CC1=Cc2c(cnn2-c2ccc(F)cc2)C[C@]1(C)CC(O)c1ccccn1
Reactant: CCI
Product: CCOC(C[C@@]1(C)Cc2cnn(-c3ccc(F)cc3)c2C=C1C)c1ccccn1

Procedure:
Using a procedure analogous to Example 35, the diastereomer mixture of the alcohols from Examples 75 and 76 (53 mg, 0.146 mmol) was reacted with iodoethane to give Example 77 as a 1:2 mixture of two diastereomers (20 mg, 35%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([F:9])[C:3]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1C(=O)N([Br:24])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:24][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:4]=1[F:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Cl)c(Oc2ccccc2)c1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1c(CBr)ccc(Cl)c1Oc1ccccc1
Temperature: 25 °C
Yield: 8.7 %

Procedure:
A mixture of 1-chloro-3-fluoro-4-methyl-2-(phenyloxy)benzene (0.500 g, 2.113 mmol), NBS (0.414 g, 2.324 mmol) and AIBN (0.017 g, 0.106 mmol) in carbon tetrachloride (8 mL) was heated at reflux overnight. The reaction mixture was cooled to RT and filtered through Celite. The solvent was evaporated. Chromatography of the residue gave the desired product (0.058 g, 9%) as a white solid. 1H NMR (400 MHz, chloroform-d) δ ppm 7.27-7.35 (m, 3H), 7.18-7.27 (m, 2H), 7.05-7.11 (m, 1H), 6.89 (d, 2H), 4.30-4.59 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.[NH2:10][CH2:11][C@H:12]([N:14]1[CH:18]=[CH:17][C:16]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([Cl:27])[CH:20]=2)=[N:15]1)[CH3:13]>>[Cl:27][C:21]1[CH:20]=[C:19]([C:16]2[CH:17]=[CH:18][N:14]([C@H:12]([CH3:13])[CH2:11][NH:10][C:7]([C:5]3[N:6]=[C:2]([CH3:1])[NH:3][CH:4]=3)=[O:9])[N:15]=2)[CH:26]=[CH:25][C:22]=1[C:23]#[N:24]
Reactant: C[C@H](CN)n1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: Cc1nc(C(=O)O)c[nH]1
Product: Cc1nc(C(=O)NC[C@@H](C)n2ccc(-c3ccc(C#N)c(Cl)c3)n2)c[nH]1

Procedure:
(R)—N-{2-[3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propyl}-2-methyl-1H-imidazole-4-carboxamide was prepared using the method of Example 247 starting from 2-methyl-1H-imidazole-4-carboxylic acid and (R)-4-[1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl]-2-chlorobenzonitrile. The crude product was purified by flash chromatography on silica gel by using CH2Cl2-MeOH (98:2) as an eluent. The resulting product was triturated in DCM at RT to afford the title compound. 1H NMR (400 MHz, CDCl3): 1.61 (3H, d), 2.39 (3H, s), 3.74-3.81 (1H, m), 3.85-3.91 (1H, m), 4.63 (1H, m), 6.59 (1H, d), 7.45 (1H, d), 7.49 (1H, d), 7.62 (1H, t), 7.66 (1H, d), 7.84 (1H, dd), 8.00 (1H, d), 10.04 (1H, broad s).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].C(N(CC)CC)C.[C:18](Cl)(=[O:36])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][C:18](=[O:36])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: Nc1cccc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCC(=O)Nc1cccc([N+](=O)[O-])c1
Reaction time: 18 h
Yield: 95.5 %

Procedure:
To 2.0 g (14.5 mmol) of 3-nitroaniline and 4.5 ml (32 mmol) of triethylamine in 60 ml of methylene chloride stirred at room temperature was added 5.4 ml (16 mmol) of octadecanoyl chloride in 10 ml of methylene chloride. The reaction mixture was kept at room temperature for 18 hours and then was washed with 1N HCl, dried and concentrated at reduced pressure to a solid. Recrystallization from methanol gave 5.6 g (95% yield, mp 75°-76°) of N-(3-nitrophenyl) octadecanamide.
Reaction SMILES: Cl.CO.C(OC([NH:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]([CH3:30])[C:19]2[CH:23]([CH2:24][C:25]([OH:27])=[O:26])[O:22][B:21]([OH:28])[C:20]=2[CH:29]=1)=O)(C)(C)C.[Li+].[OH-]>O>[NH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]([CH3:30])[C:19]2[CH:23]([CH2:24][C:25]([OH:27])=[O:26])[O:22][B:21]([OH:28])[C:20]=2[CH:29]=1
Reactant: Cc1cc(OCCCNC(=O)OC(C)(C)C)cc2c1C(CC(=O)O)OB2O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(OCCCN)cc2c1C(CC(=O)O)OB2O
Reaction time: 18 h
Yield: 15.7 %

Procedure:
1.25M HCl in methanol (5 mL, 6.0 mmol) was added to [6-(3-tert-butoxycarbonylamino-propoxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid (0.345 g, 0.80 mmol) at room temperature and stirred for 18 hours then concentrated in vacuo. The residue was dissolved in THF (14 mL) and a solution of LiOH (0.229 g, 5.44 mmol) in water (5 mL) at 0° C. was added. The resulting mixture was stirred at room temperature for 3 hours then acidified to pH=2 with 6M HCl and extracted with EtOAc (3×25 mL). The organic extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give [6-(3-amino-propoxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid as a white solid (0.035 g, 14%). 1H NMR (400 MHz, methanol-d4) δ ppm 6.93 (br. s., 1H), 6.79 (br. s., 1H), 5.49 (d, J=5.86 Hz, 1H), 4.10 (t, J=5.47 Hz, 2H), 3.15 (t, J=7.03 Hz, 2H), 2.97 (d, J=14.85 Hz, 1H), 2.27 (s, 3H), 2.03-2.21 (m, 3H). MS (ESI) m/z: 280 [M+1]+. HPLC purity: 96.23% (Maxplot), 95.78% (220 nm).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[NH:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.Cl[C:17]1[N:22]=[C:21]([C:23]2[N:27]3[CH:28]=[CH:29][C:30]([C:32]([CH3:42])([O:34][Si:35]([CH2:40][CH3:41])([CH2:38][CH3:39])[CH2:36][CH3:37])[CH3:33])=[N:31][C:26]3=[N:25][CH:24]=2)[CH:20]=[CH:19][N:18]=1>C1COCC1>[N:11]1([C:17]2[N:22]=[C:21]([C:23]3[N:27]4[CH:28]=[CH:29][C:30]([C:32]([CH3:33])([O:34][Si:35]([CH2:36][CH3:37])([CH2:40][CH3:41])[CH2:38][CH3:39])[CH3:42])=[N:31][C:26]4=[N:25][CH:24]=3)[CH:20]=[CH:19][N:18]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: c1c[nH]cn1
Reactant: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(Cl)n3)cnc2n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(-n4ccnc4)n3)cnc2n1
Temperature: 25 °C
Yield: 45.3 %

Procedure:
A solution of LiHMDS (370 μl) in hexanes (1.0M, 370 μmol) was added to a stirred solution of imidazole (25 mg, 0.37 mmol) and 3-(2-chloropyrimidin-4-yl)-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine (from Example 34) (150 mg, 0.37 mmol) in THF (5 ml) at −78° C. under N2. The reaction was allowed to warm slowly to room temperature overnight and was then quenched with NH4Cl solution (10 ml). The organics were extracted with EtOAc (2×25 ml), washed with brine (10 ml) and concentrated under reduced pressure while dry loading onto silica. The residue was purified by column chromatography on silica using 100% EtOAc as the eluent to afford 3-[2-(imidazol-1-yl)pyrimidin-4-yl]-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine (73 mg, 45%): 1H NMR (400 MHz, d6-DMSO) δ 10.08 (1H, d, J 7.2), 8.93 (1H, s), 8.85-8.78 (2H, m), 8.13 (1H, d, J 1.1), 8.03 (1H, d, J 5.5), 7.72 (1H, d, J 7.2), 7.21 (1H, s), 1.64 (6H, s), 0.96 (9H, t, J 8.0), 0.65 (6H, q, J 8.0); m/z (ES+) 453 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@@H:6]1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=[O:4].[CH3:19][S:20]([NH:23][C:24]1[CH:39]=[CH:38][C:27]2[NH:28][C:29]([CH2:34][C:35](O)=[O:36])=[N:30][S:31](=[O:33])(=[O:32])[C:26]=2[CH:25]=1)(=[O:22])=[O:21].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C=O)C>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@@H:6]1[N:10]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[C:35](=[O:36])[CH2:34][C:29]1[NH:28][C:27]2[CH:38]=[CH:39][C:24]([NH:23][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:25][C:26]=2[S:31](=[O:32])(=[O:33])[N:30]=1)=[O:4]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: COC(=O)[C@@H]1CCC[C@@H]1NCc1ccc(F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCC[C@@H]1N(Cc1ccc(F)cc1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
(1R,2S)-2-(4-Fluoro-benzylamino)-cyclopentanecarboxylic acid methyl ester (106 mg, 0.42 mmol) and (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in U.S. Pat. No. 7,939,524 B2, 140 mg, 0.42 mmol) were dissolved in a 1:1 mixture of dichloromethane and N,N′-dimethylformamide (6 mL). A 1.0 M solution of N,N′-dicyclohexylcarbodiimide in dichloromethane (0.46 mL, 0.46 mmol) was added. The reaction was stirred at 25° C. for 16 h. The mixture was concentrated in vacuo and purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 0-85% ethyl acetate in hexanes) to afford the desired product, (1R,2S)-2-{(4-fluoro-benzyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclopentanecarboxylic acid methyl ester (127 mg, 0.22 mmol, 52%), as a white solid. 1H NMR (400 MHz, CDCl3) δ: 1.80-2.22 (6H, m), 3.07 (3H, s), 3.24 (1H, dd, J1=18.8 Hz, J2=8.0 Hz), 3.32 (1H, dd, J1=15.6 Hz, J2=8.0 Hz), 3.69 (1H, s), 4.63 (2H, d, J=4.8 Hz), 4.67-4.74 (1H, m), 4.82-4.89 (1H, m), 6.99-7.14 (5H, m), 7.51-7.64 (2H, m). LC-MS (ESI) calcd for C24H27FN4O7S2 566.62. found 567.1 [M+H+].
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].C(N(CC)CC)C.C[O:17][C:18](=O)[N:19]=[C:20](SC)[C:21]([C:35]1[CH:36]=[C:37]([O:46][CH3:47])[C:38]2[O:43][CH2:42][O:41][CH2:40][C:39]=2[C:44]=1[F:45])=[N:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:25][CH:24]=1>CN(C=O)C>[F:45][C:44]1[C:39]2[CH2:40][O:41][CH2:42][O:43][C:38]=2[C:37]([O:46][CH3:47])=[CH:36][C:35]=1[CH:21]([NH:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:27][CH:28]=1)[C:20]1[NH:19][C:18](=[O:17])[N:1]([C:3]2[N:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: NNc1ncccn1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c2c(c1F)COCO2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c(F)c2c1OCOC2
Temperature: 85 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
After adding 21 mg of 2-hydrazinopyrimidine and 50 μl of triethylamine to a solution of 105 mg of {2-(5-fluoro-8-methoxy-4H-benzo[1,3]dioxin-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in 2 ml of DMF, the mixture was stirred overnight at 85° C. under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of methanol and 0.3 ml of acetic acid. After adding 100 mg of sodium cyanotrihydroborate to the reaction mixture, the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give 5-{(5-fluoro-8-methoxy-4H-benzo[1,3]dioxin-6-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[1,2,4]triazol-3-one (74 mg) as a light brown solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=1.[ClH:37].C(O)C.C(=O)([O-])[O-].[NH4+:45].[NH4+]>ClCCl.C(O)C>[ClH:37].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:45])[NH2:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C#N)cc1)n2C)c1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)c1cccnc1
Yield: 91 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[2-(4-cyanophenyl)-ethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 91% of theory, C28H30N6O3 (498.6) Rf value: 0.19 (silica gel; dichloromethane/ethanol=4:1) EKA mass spectrum: (M+H)+ =499