Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[CH3:17][O:18][C:19](=[O:31])[CH2:20][C@H:21]1[C:25]2[CH:26]=[CH:27][C:28]([OH:30])=[CH:29][C:24]=2[O:23][CH2:22]1.[Br:32][C:33]1[CH:41]=[CH:40][C:39]([F:42])=[C:38]2[C:34]=1[CH2:35][CH2:36][C@@H:37]2O.C(P(CCCC)CCCC)CCC>O1CCCC1>[CH3:17][O:18][C:19](=[O:31])[CH2:20][C@H:21]1[C:25]2[CH:26]=[CH:27][C:28]([O:30][C@H:37]3[C:38]4[C:34](=[C:33]([Br:32])[CH:41]=[CH:40][C:39]=4[F:42])[CH2:35][CH2:36]3)=[CH:29][C:24]=2[O:23][CH2:22]1
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Reactant: O[C@H]1CCc2c(Br)ccc(F)c21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Reaction time: 0.5 h

Procedure:
A solution of di-tert-butyl azodicarboxylate (18.0 g) in tetrahydrofuran (80 mL) is added dropwise over 45 min to a solution of [(S)-6-hydroxy-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester (for preparation see WO 2008001931; 11.0 g), (S)-4-bromo-7-fluoro-indan-1-ol (11.95 g), and tri-n-butyl-phosphine (19.3 mL) in tetrahydrofuran (320 mL) at −10° C. The resulting solution is stirred for 30 min and then partitioned between saturated aqueous NaHCO3 solution and dichloromethane. The aqueous phase is separated and extracted with dichloromethane. The combined organic phases are dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10→70:30) to give the title compound. LC (method 1): tR=1.41 min; Mass spectrum (ESI+): m/z=421/423 (Br) [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([CH3:49])[CH:3]([NH:44][C:45](=[O:48])[O:46][CH3:47])[C:4]([N:6]1[C@H:10]([C:11]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([C:26]5[CH:31]=[CH:30][C:29]([C:32]6[NH:36][C:35]([C@@H:37]7[CH2:41][CH2:40][C@H:39]([CH3:42])[NH:38]7)=[N:34][CH:33]=6)=[CH:28][CH:27]=5)=[CH:22][CH:21]=4)[C:13]=3[N:12]=2)[CH2:9][CH2:8][C@@H:7]1[CH3:43])=[O:5].[CH3:50][O:51][C:52]([NH:54][C@@H:55]([CH:59]([CH3:61])[CH3:60])[C:56](O)=[O:57])=[O:53].N1C(C)=CC(C)=CC=1C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH3:47][O:46][C:45]([NH:44][CH:3]([CH:2]([CH3:49])[CH3:1])[C:4]([N:6]1[C@@H:7]([CH3:43])[CH2:8][CH2:9][C@H:10]1[C:11]1[NH:12][C:16]2[CH:17]=[CH:18][C:19]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][C:29]([C:32]5[N:36]=[C:35]([C@@H:37]6[CH2:41][CH2:40][C@H:39]([CH3:42])[N:38]6[C:56]([C@@H:55]([NH:54][C:52](=[O:53])[O:51][CH3:50])[CH:59]([CH3:61])[CH3:60])=[O:57])[NH:34][CH:33]=5)=[CH:28][CH:27]=4)=[CH:22][CH:21]=3)=[CH:13][C:14]=2[N:15]=1)=[O:5])=[O:48]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: COC(=O)NC(C(=O)N1[C@@H](C)CC[C@H]1c1nc2c(-c3ccc(-c4ccc(-c5cnc([C@@H]6CC[C@H](C)N6)[nH]5)cc4)cc3)cccc2[nH]1)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: Cc1cc(C)nc(C)c1
Solvent: CN(C)C=O
Product: COC(=O)NC(C(=O)N1[C@@H](C)CC[C@H]1c1nc2cc(-c3ccc(-c4ccc(-c5c[nH]c([C@@H]6CC[C@H](C)N6C(=O)[C@@H](NC(=O)OC)C(C)C)n5)cc4)cc3)ccc2[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 21.4 %

Procedure:
To a mixture of methyl N-[2-methyl-1-[(2S,5S)-2-methyl-5-[4-[4-[4-[2-[(2S,5S)-5-methylpyrrolidin-2-yl]-1H-imidazol-5-yl]phenyl]phenyl]-1H-benzimidazol-2-yl]pyrro-lidine-1-carbonyl]propyl]carbamate (88 mg, 0.126 mmol), (2S)-2-(methoxycarbonylamino)-3-methyl-butanoic acid (22 mg, 0.126 mmol) and 2,4,6-collidine (50.11 μl, 0.38 mmol) in DMF (3.5 ml) is added HATU (52.8 mg, 0.14 mmol) at 0° C. The reaction mixture is stirred at rt for 5 hours, diluted with EtOAc, washed with H2O and brine. The organic phase is dried over Na2SO4, filtered and concentrated. The residue is purified by flash column chromatography on silica gel (1 to 20% MeOH in CH2Cl2) and repurified by reverse phase HPLC using a gradient of CH3CN/water to afford the methyl N-[(1S)-1-[(2S,5S)-2-[4-[4-[4-[2-[(2S,5S)-1-[2-(methoxycarbonylamino)-3-methyl-butanoyl]-5-methyl-pyrrolidin-2-yl]-1H-benzimidazol-5-yl]phenyl]phenyl]-1H-imidazol-2-yl]-5-methyl-pyrrolidine-1-carbonyl]-2-methyl-propyl]carbamate (22 mg, 19.9%) as a white fluffy powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12]([OH:14])[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:30])([F:29])[C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:27](=O)[NH:26][CH:25]=[N:24]2)=[CH:19][CH:18]=1.FC1C=C(F)C=CC=1[C@]1(OC1)[C@H](N1C=NN(C2C=CC(C(F)(F)F)=CC=2)C1=O)C>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@H:12]([O:14][C:27]2[N:23]([C:20]3[CH:19]=[CH:18][C:17]([C:16]([F:29])([F:15])[F:30])=[CH:22][CH:21]=3)[N:24]=[CH:25][N:26]=2)[CH3:13])[CH2:11][O:10]1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: O=c1[nH]cnn1-c1ccc(C(F)(F)F)cc1
Agent: C[C@@H](n1cnn(-c2ccc(C(F)(F)F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](Oc1ncnn1-c1ccc(C(F)(F)F)cc1)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 13.7 %

Procedure:
In the same manner as in Reference Example 5, starting from 2.49 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 2.52 g of 2-(4-trifluoromethylphenyl)-3(2H,4H)-1,2,4-triazolone, 4-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-2-(4-trifluoromethylphenyl)-3(2H,4H)-1,2,4-triazolone (1.13 g) and 618 mg of (2R)-2-(2,4-difluorophenyl)-2-[(1R}-1-[1-(4-trifluoromethylphenyl)-1H-1,2,4-triazol-5-yloxy]ethyl]oxirane were obtained.
Reaction SMILES: [Cl-:1].[Na+:2].[P:3]([O-:7])([O-:6])([O-:5])=[O:4].[K+:8].[K+].[K+]>O>[OH:5][P:3]([O-:7])([OH:6])=[O:4].[OH:5][P:3]([O-:7])([O-:6])=[O:4].[Na+:2].[Na+:2].[Na+:2].[Cl-:1].[Cl-:1].[K+:8].[K+:8]
Reactant: O=P([O-])([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: O=P([O-])(O)O
Product: O=P([O-])([O-])O

Procedure:
Sodium chloride was added to water to the final concentration of 9 g/l. To this solution was added 0.01 moles of potassium phosphate (monobasic). The pH was adjusted to 7.4 and the solution volume brought to exactly 1.00 liter by the addition of demineralized water.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34].CO>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:33]([NH:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[O:25][CH3:24])=[O:34])=[C:18]([F:23])[CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: COc1ccccc1N=C=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccccc1NC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1F
Temperature: 60 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
4-((6,7-Dimethoxy-4-quinazolinyl)oxy]-2-fluoroaniline (50 mg) was dissolved in chloroform (3 ml), and 2-methoxyphenyl isocyanate (32 μl) was then added to the solution. The mixture was stirred at 60° C. overnight. Methanol was added to the reaction solution, and the mixture was purified by HPLC by development with chloroform/methanol to give 22 mg (yield 30%) of the title compound.
Reaction SMILES: [Na].[CH3:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)=O.[CH:13](OCC)=O.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[N:20]=1.[OH-].[Na+]>>[NH2:18][C:19]1[CH:24]=[CH:23][C:22]2[C:21](=[N:25][C:3]([C:5]3[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=3)=[CH:2][CH:13]=2)[N:20]=1
Reactant: CCOC=O
Reactant: COc1cccc(C(C)=O)c1
Reactant: Nc1cccc(N)n1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Product: COc1cccc(-c2ccc3ccc(N)nc3n2)c1
Yield: 94.8 %

Procedure:
The procedure is analogous to that described in Example 11, but starting with sodium (2.3 g), 3-methoxyacetophenone (15 g) and ethyl formate (11 g). The solid obtained (20 g) is then added to 2,6-diaminopyridine (11 g). The product obtained after hydrolysis and neutralization with sodium hydroxide is separated by filtration, washed with distilled water (6×100 cc) at 50° C., and then air-dried. 2-Amino-7-(3-methoxyphenyl)-1,8-naphthyridine (23.8 g), m.p. 270°-275° C., is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[CH:10]([CH3:12])[CH3:11])[CH:7]=1.FC1N=CC(C(C)C)=CC=1[C:16]#[N:17]>>[CH3:11][CH:10]([CH3:12])/[CH:9]=[CH:8]/[C:6]1[CH:5]=[N:4][CH:3]=[C:2]([CH:7]=1)[C:16]#[N:17]
Reactant: CC(C)/C=C/c1cncc(Br)c1
Reactant: CC(C)c1cnc(F)c(C#N)c1
Product: CC(C)/C=C/c1cncc(C#N)c1

Procedure:
(E)-5-(3-methylbut-1-enyl)nicotinonitrile was synthesized from (E)-3-bromo-5-(3-methylbut-1-enyl)pyridine following the general procedure as described for the 2-fluoro-5-isopropylnicotinonitrile.
Reaction SMILES: [F:1][C:2]([F:56])([CH2:29][CH2:30][N:31]([S:46]([C:49]1[CH:54]=[CH:53][C:52]([CH3:55])=[CH:51][CH:50]=1)(=[O:48])=[O:47])[CH2:32][CH2:33][CH2:34][N:35]1C(=O)C2=CC=CC=C2C1=O)[CH2:3][N:4]([S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH2:5][CH2:6][CH2:7][N:8]1C(=O)C2=CC=CC=C2C1=O.O.NN>C(O)C.O.CO.Cl>[NH2:8][CH2:7][CH2:6][CH2:5][N:4]([S:19]([C:22]1[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=1)(=[O:21])=[O:20])[CH2:3][C:2]([F:56])([F:1])[CH2:29][CH2:30][N:31]([S:46]([C:49]1[CH:54]=[CH:53][C:52]([CH3:55])=[CH:51][CH:50]=1)(=[O:47])=[O:48])[CH2:32][CH2:33][CH2:34][NH2:35]
Reactant: Cc1ccc(S(=O)(=O)N(CCCN2C(=O)c3ccccc3C2=O)CCC(F)(F)CN(CCCN2C(=O)c3ccccc3C2=O)S(=O)(=O)c2ccc(C)cc2)cc1
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N(CCCN)CCC(F)(F)CN(CCCN)S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 90 °C

Procedure:
A mixture of 6,6-difluoro-1,12-diphthalimido-4,9-di-p-toluenesulfonyl-4,9-diaza-dodecane (3.4 g, 4.22 mM), ethanol (8.5 mL) and 8.5 mL of a 1N solution of hydrazine hydrate in ethanol is stirred and heated (bath temperature: 90° C.) overnight. Evaporation and stripping twice with methanol yields a residue which is dissolved in a mixture of water (20 mL), methanol (20 mL), and concentrated HCl (40 mL), and heated (bath temperature: 90° C.) under reflux for 3 hours. The reaction mixture is cooled, filtered and evaporated, and the residue is dissolved in hot 1N HCl. The solution is filtered, the filtrate is evaporated, and the residue is stripped with isopropanol (twice) and ethanol (twice). The residue is dissolved in ethanol, ether is added, and upon evaporation of the solvent, there is obtained 1,12-diamino-6,6-difluoro-4,9-di-p-toluenesulfonyl-4,9-diaza-dodecane as a white crystalline foam: 2.7 g (quantitative yield).
Reaction SMILES: [CH3:1][CH2:2][N:3]([C:6]([NH:8][C@@H:9]1[CH2:24][N:23]([CH3:25])[C@H:22]2[C@@H:11]([C:12]3[C:17]4[C:18]([CH2:21]2)=[CH:19][NH:20][C:16]=4[CH:15]=[CH:14][CH:13]=3)[CH2:10]1)=[O:7])[CH2:4][CH3:5].[CH2:26]([N:28](CC)CC)C.ClS(N=C=O)(=O)=O>C(#N)C>[C:26]([C:19]1[NH:20][C:16]2[C:17]3[C:18]=1[CH2:21][C@@H:22]1[C@@H:11]([C:12]=3[CH:13]=[CH:14][CH:15]=2)[CH2:10][C@H:9]([NH:8][C:6](=[O:7])[N:3]([CH2:2][CH3:1])[CH2:4][CH3:5])[CH2:24][N:23]1[CH3:25])#[N:28]
Reactant: CCN(CC)CC
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1
Agent: O=C=NS(=O)(=O)Cl
Solvent: CC#N
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]c(C#N)c(c34)C[C@H]2N(C)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 31 %

Procedure:
680 mg of terguride (2 mmol) is dissolved in 120 ml of acetonitrile and 5.5 ml of triethylamine and, under ice cooling, a solution of 3.5 ml of chlorosulfonyl isocyanate in 40 ml of acetonitrile is added dropwise thereto under an argon atmosphere. The ice bath is removed and the mixture allowed to stand for two days at room temperature. To facilitate isolation of the polar by-products, the mixture is combined with 20 ml of diethylamine and stirred for three hours at room temperature. Then the mixture is diluted with methylene chloride, extracted with 1N sodium hydroxide solution, and the water phase is once more extracted. The combined organic phases are dried with sodium sulfate and evaporated. The residue is chromatographed on silica gel with a mixture of methylene chloride and methanol, thus isolating 229 mg (31% of theory) of crude 3-(2-cyano-6-methyl-8α-ergolinyl)-1,1-diethylurea. Ater crystallizing from ethyl acetate, 92 mg is obtained as the pure compound.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:7]([C:24]3[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=3)[NH:8][C:9](=[O:23])[N:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[C:11]=2[CH3:12])=[O:5])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:39][C:40]1[O:44][C:43]([C:45]([O:47][CH3:48])=[O:46])=[CH:42][CH:41]=1>CN(C)C=O.CO>[C:28]([C:27]1[CH:26]=[CH:25][C:24]([CH:7]2[N:8]([CH2:39][C:40]3[O:44][C:43]([C:45]([O:47][CH3:48])=[O:46])=[CH:42][CH:41]=3)[C:9](=[O:23])[N:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=3)[C:11]([CH3:12])=[C:6]2[C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])=[CH:31][CH:30]=1)#[N:29]
Reactant: COC(=O)c1ccc(CCl)o1
Reactant: CC1=C(C(=O)C2CC2)C(c2ccc(C#N)cc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1ccc(CN2C(=O)N(c3cccc(C(F)(F)F)c3)C(C)=C(C(=O)C3CC3)C2c2ccc(C#N)cc2)o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred suspension of 4-{5-(cyclopropylcarbonyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzonitrile (Example 22) (150 mg, 0.35 mmol) and potassium carbonate (98 mg, 0.71 mmol) in dimethylformamide (3 ml) is added methyl 5-(chloromethyl)-2-furoate (92 mg, 0.53 mmol). The suspension is stirred at room temperature overnight (16 h), then additional methyl 5-(chloromethyl)-2-furoate (6.1 mg, 0.35 mmol) and potassium carbonate (49 mg, 0.35 mmol) are added, and the suspension is stirred an additional 72 hours. The reaction mixture is diluted with methanol (5 ml) and purified directly by preparative HPLC (RP 18 column; eluent: acetonitrile/water 10:90→90:10). The title compound is isolated as a brownish amorphous solid.
Reaction SMILES: CS(OS(C)(=O)=O)(=O)=O.[N:10]1([C:16]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[C:27]([C:29]4[C:37]5[C:32](=[CH:33][CH:34]=[C:35]([CH2:38][OH:39])[CH:36]=5)[N:31](C5CCCCO5)[N:30]=4)[N:26]=[N:25]3)=[CH:20][CH:19]=2)=[O:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.CCN(C(C)C)C(C)C.O[C@@H:56]1[CH2:61][O:60][C:58](=[O:59])[CH2:57]1>C(Cl)Cl>[N:10]1([C:16]([C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH:28]=[C:27]([C:29]4[C:37]5[C:32](=[CH:33][CH:34]=[C:35]([CH2:38][O:39][C@@H:56]6[CH2:61][O:60][C:58](=[O:59])[CH2:57]6)[CH:36]=5)[NH:31][N:30]=4)[N:26]=[N:25]3)=[CH:22][CH:23]=2)=[O:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: O=C1C[C@H](O)CO1
Reactant: O=C(c1ccc(-n2cc(-c3nn(C4CCCCO4)c4ccc(CO)cc34)nn2)cc1)N1CCOCC1
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1C[C@H](OCc2ccc3[nH]nc(-c4cn(-c5ccc(C(=O)N6CCOCC6)cc5)nn4)c3c2)CO1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 7.2 %

Procedure:
A solution of methanesulfonic anhydride (113 mg; 0.65 mmol; 1.6 eq.) in DCM (3.0 mL) was added dropwise over 1 min to a solution of [3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl]methanol (194 mg; 0.40 mmol; 1.0 eq.) in DIEA (1.0 mL; 5.9 mmol; 15 eq.) and DCM (3.0 mL) containing activated molecular sieves. After 10 min, a solution of (S)-3-hydroxy-g-butyrolactone (160 mg; 1.57 mmol; 4 eq.) in DCM (1.0 mL) was added dropwise over 2 min. The reaction mixture was then stirred for 16 h at RT. It was filtered through a celite pad and the filtrate was concentrated under reduced pressure. The residue was redissolved in MeOH (2 mL) and hydrogen chloride (8 mL of a 4N solution in dioxane) was added. The reaction mixture was stirred at RT for 3 h and then concentrated under reduced pressure. Purification by preparative HPLC gave the title compound as a white solid (14 mg, 7%). 1H NMR (300 MHz, DMSO-d6) δ 13.41 (s, 1H), 9.38 (s, 1H), 8.33 (s, 1H), 8.15 (d, J=8.5 Hz, 2H), 7.69 (d, J=8.5 Hz, 2H), 7.61 (d, J=8.6 Hz, 1H), 7.49-7.37 (m, 1H), 4.69 (s, 2H), 4.47-4.34 (m, 3H), 3.82-3.40 (m, 8H), 2.88 (dd, J=17.8, 5.7 Hz, 1H), 2.56 (d, J=17.8 Hz, 1H). HPLC (max plot) 96.5%; Rt %2.59 min. UPLC/MS: (MS+) 489.5, (MS−) 487.6.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=O)[CH:18]=2)=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:18]=2)=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=1
Reactant: C1COCCN1
Reactant: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1cccc(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.8 %

Procedure:
To a solution of 2-(2,6-difluorophenyl)-5-(3-formylphenyl)oxazole-4-carboxamide(0.050 g, 0.152 mmol), morpholine (0.027 mL, 0.305 mmol) and sodium triacetoxyborohydride (0.014 g, 0.228 mmol) in 1,2-dichloroethane (6 mL) was added acetic acid (0.013 mL, 0.228 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h and then quenched with saturated sodium bicarbonate. The aqueous layer was extracted with ethyl acetate and the combined organic extracts dried over MgSO4 and concentrated in vacuo to give a residue that was purified by preparative HPLC to afford 2-(2,6-difluorophenyl)-5-(3-(morpholinomethyl)phenyl)oxazole-4-carboxamide (0.022 g, 0.056 mmol, 37%) as a white solid. 1H NMR (DMSO) δ 2.39 (4H, br m), 3.54 (2H, br m), 3.59 (4H, t), 7.38-7.45 (3H, m), 7.50 (1H, t), 7.71-7.78 (3H, m), 8.13-8.17 (2H, m). LCMS (2) Rt: 2.62 min; m/z (ES+) 400.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[C:14]1[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=1.[F:24][C:25]1[N:30]=[C:29](F)[CH:28]=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([S:20]([NH:23][C:27]2[CH:28]=[CH:29][N:30]=[C:25]([F:24])[N:26]=2)(=[O:21])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[C:14]1[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=1
Reactant: Cn1nccc1[C@H]1CCC[C@@H]1Oc1ccc(S(N)(=O)=O)cc1F
Reactant: Fc1ccnc(F)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1nccc1[C@H]1CCC[C@@H]1Oc1ccc(S(=O)(=O)Nc2ccnc(F)n2)cc1F
Yield: 44.3 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 16d by using 3-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}benzenesulfonamide (0.10 g, 0.29 mmol) prepared in Example 16c, 2,4-difluoropyrimidine (0.10 g, 0.88 mmol), potassium carbonate (0.16 g, 1.18 mmol) and DMF (3.0 mL), to yield the title compound (56 mg, 63%) as a colorless solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[Mg].[CH3:15][Si:16]([CH3:25])([CH3:24])[C:17]1[O:21][CH:20]=[C:19]([CH:22]=[O:23])[CH:18]=1.[CH3:26][O:27][CH2:28][CH2:29][O:30][CH2:31]Cl>O1CCCC1>[CH3:26][O:27][CH2:28][CH2:29][O:30][CH2:31][O:23][CH:22]([C:19]1[CH:18]=[C:17]([Si:16]([CH3:25])([CH3:24])[CH3:15])[O:21][CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: COCCOCCl
Reactant: C[Si](C)(C)c1cc(C=O)co1
Reactant: CCCCCCCCCCCCBr
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(OCOCCOC)c1coc([Si](C)(C)C)c1
Reaction time: 16 h

Procedure:
A mixture of 1-bromododecane (222 mg, 0.89 mmol) and magnesium turnings (22 mg, 0.94 mmol) in tetrahydrofuran (5 ml) was refluxed under argon for 1 hour. After cooling to 0°, a solution of 5-trimethylsilyl-3-furaldehyde (150 mg, 0.89 mmol) in tetrahydrofuran (1 ml) was added and conditions maintained for 1 hour. 2-Methoxyethoxymethyl chloride (0.15 ml, 1.34 mmol) was added and stirring was continued at room temperature for 16 hours. The mixture was quenched with water and extracted with ethyl ether. Evaporation of the dried (magnesium sulphate) extracts gave an oil, which was purified by preparative TLC (silica plate; developed with 15% ethyl ether/petroleum ether). The title trimethylsilylfuran was obtained as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([C@@](O)([C@@H](O)[C@H](O)[C@H](O)CO)C(N)=O)=[CH:16][CH:15]=1.Cl.[OH:34][CH:35]1[O:43][C@H:42]([CH2:44][OH:45])[C@@H:40]([OH:41])[C@H:38]([OH:39])[C@H:36]1[NH2:37].C[N:47]([CH:49]=[O:50])C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[C:16]([NH:47][C:49]([NH:37][CH:36]2[C@@H:38]([OH:39])[C@H:40]([OH:41])[C@@H:42]([CH2:44][OH:45])[O:43][CH:35]2[OH:34])=[O:50])[CH:17]=[CH:18][CH:19]=1
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc([C@](O)(C(N)=O)[C@@H](O)[C@H](O)[C@H](O)CO)cc2)C1
Reactant: CN(C)C=O
Agent: Cl
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(NC(=O)NC3C(O)O[C@H](CO)[C@@H](O)[C@@H]3O)c2)C1

Procedure:
254 mg (0.5 mmol) of 4-nitrophenyl [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]carbamate hydrochloride (intermediate 1, Example 6) were initially charged in 7 ml of abs. DMF and admixed at 0° C. with a suspension of 119 mg (0.55 mol) of D-glucosamine hydrochloride in 5 ml of abs. DMF. A similar procedure to the method described in Example 6 afforded, after chromatography on silica gel, 87 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C@@H:8]([C:20](=O)[NH:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/[N:56]=[N:57]/C(OCC)=O)=O.C[Si]([N:67]=[N+]=[N-])(C)C.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[Ce]>C1COCC1.O>[C:1]([O:5][C:6](=[O:31])[NH:7][C@@H:8]([C:20]1[N:21]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:57]=[N:56][N:67]=1)[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)/N=N/C(=O)OCC
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc2ccccc2c1)C(=O)NCCc1ccccc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: [Ce]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: O=[N+]([O-])O
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc2ccccc2c1)c1nnnn1CCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.9 %

Procedure:
((1R)-2-(2-Naphthyl)-1-(phenethylcarbamoyl)ethyl)carbamic acid tert-butyl ester (2.20 g, 5.26 mmol) was dissolved in dry THF (50 ml). Triphenylphosphine (2.76 g; 10.52 mmol) diethylazodicarboxylate (1.66 g, 10.52 mmol) and trimethylsilyl azide (1.22 g; 10.52 mmol) were added. The mixture was stirred overnight at room temperature. Ammonium ceric nitrate (23.06 g; 21.04 mmol) was dissolved in water (400 ml) and added dropwise to the reation mixture. THF (120 ml) was added and the reaction mixture was extracted with methylene chloride (3×300 ml). The organic phase was dried (magnesium sulfate) and the solvent was removed in vacuo. The residue was chromatographed on silica (5×40 cm) using ethyl acetate/heptane as eluent (1:1) to afford 0.30 g of ((1R)-2-(2-naphthyl)-1-(1-phenethyl-1H-tetrazol-5-yl)ethyl)carbamic acid tert-butylester