Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@@H:5]([C@H:7]([CH2:9][OH:10])[OH:8])[OH:6])O.OC1S[C@H](CO)[C@@H](O)[C@H]1O.OC1S[C@@H](CO)[C@@H](O)[C@H]1O>>[OH:1][CH:2]1[O:8][C@H:7]([CH2:9][OH:10])[C@@H:5]([OH:6])[CH2:3]1
Reactant: O=C[C@H](O)[C@H](O)[C@@H](O)CO
Agent: OC[C@@H]1SC(O)[C@H](O)[C@@H]1O
Agent: OC[C@H]1SC(O)[C@H](O)[C@@H]1O
Product: OC[C@H]1OC(O)C[C@@H]1O

Procedure:
The synthesis of L-thioLyxofuranose and D-thioRibofuranose was carried out in 7 steps from D-ribose and L-lyxose respectively with 29 and 21% yield respectively. This synthesis is illustrated in Scheme 6. ##STR27## The synthesis in order to obtain the thio-D-ribofuranose uses L-lyxose as starting product as in the Whistler synthesis (page 19). This strategy is called strategy C1-C4. Indeed, the sulfur atom is first introduced in the anomeric position and an NS2 nucleophilic substitution between the sulfur atom carried by the anomeric carbon (C1) and the C4 carbon carrying an OH activated by a Mesyl (Ms) group is then carried out. This strategy applied to the synthesis of 4-thio-D-ribofuranose and 4-thio-L-lyxofuranose resembles that which Walker used to obtain the 2-deoxy-D-ribofuranose series (Patent Eur. Pat. 0421 777 A 1 page 6). For example, WALKER's product 5 (Scheme 5) is similar to our product 10 (Scheme 6) in L-lyxofuranose series. ##STR28## The synthesis of the thionucleosides of uracil, thymine and cytosine was carried out using bis-trimethylsilyl acetamide (BSA) as silylating agent and trimethylsilyl trifluoromethanesulfonate (TMSTf) as coupling agent. The O and β nucleosides were obtained with 74, 77 and 70% yields respectively. The synthesis of the thionucleosides of adenine was carried out with SnCl4 in acetonitrile. The O and β nucleosides are obtained with 58% yield (Scheme 7).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C:11](=[N:13]O)[CH:10]([C:15](OCC)=[O:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].COCCO[Al+]OCCOC.[Na+].[H-].O>C1(C)C=CC=CC=1>[NH2:13][CH:11]1[CH:10]([CH2:15][OH:16])[CH2:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12]1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CC1=NO
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: NC1CN(Cc2ccccc2)CC1CO
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52.4 %

Procedure:
A solution of 5.24 g (0.02 mole) of 1-benzyl-3-ethoxycarbonyl-4-hydroxyiminopyrrolidine [prepared as described in step (a) above] in 10 ml of toluene was added dropwise to 28 ml of a 3.4M solution of sodium bis(2-methoxyethoxy)aluminum hydride in toluene over a period of 1 hour. The mixture was stirred at room temperature for 1.5 hours and was then heated under reflux for 2 hours. At the end of this time, the reaction mixture was allowed to cool to room temperature, after which ice and water were added to it to form a precipitate, which was removed by filtration. The filtrate was concentrated by evaporation under reduced pressure, and the residue was purified by column chromatography through silica gel using methanol as the eluent, to afford 2.16 g of 3-amino-1-benzyl-4-hydroxymethylpyrrolidine as a brown oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[H-].[Na+].[C:31](Cl)(=[O:33])[CH3:32].O>CN(C=O)C.C1COCC1.CN(C=O)C>[C:31]([N:21]1[C:22]2[C:18](=[CH:17][C:16]([NH:15][C:13]([C:10]3([C:8]4[CH:7]=[CH:6][C:5]5[O:1][CH2:2][O:3][C:4]=5[CH:9]=4)[CH2:12][CH2:11]3)=[O:14])=[CH:24][CH:23]=2)[CH:19]=[C:20]1[C:25]([CH3:28])([CH3:27])[CH3:26])(=[O:33])[CH3:32]
Reactant: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)n1c(C(C)(C)C)cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc21
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1H-indol-5-yl)cyclopropanecarboxamide (120 mg, 0.31 mmol) in anhydrous DMF-THF (3.3 mL, 1:9) was added NaH (60% in mineral oil, 49 mg, 1.2 mmol) at room temperature. After 30 min under N2, the suspension was cooled down to −15° C. and a solution of acetyl chloride (1.1 eq.) in DMF (0.5 mL) was added dropwise. The reaction mixture was stirred for 30 min at −15° C. then for 6 h at room temperature. Water (0.5 mL) was added at 0° C., solvent was removed, and the residue was diluted with MeOH, filtrated and purified by preparative HPLC to give N-(1-acetyl-2-tert-butyl-1H-indol-5-yl)-1-(benzo[d][1,3]diox ol-5-yl)cyclo-propanecarboxamide. 1 H NMR (400 MHz, DMSO) δ 8.9(s, 1H), 7.74(d, J=2.1 Hz, 1H), 7.54(d, J=9.0 Hz, 1H), 7.28(dd, J1=2.1 Hz, J2=9.0 Hz, 1H), 7.01(d, J=1.5 Hz, 1H), 6.93(dd, J1=1.7 Hz, J2=8.0 Hz, 1H), 6.89(d, J=8.0 Hz, 1H), 6.54(bs, 1H), 6.02(s, 2H), 2.80(s, 3H), 1.42-1.40(m, 11H), 1.06-1.05(m, 2H). MS (ESI) m/e (M+H+) 419.3.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])[CH:6]=[O:7])[CH3:2].[O-:13]Cl=O.[Na+].Cl>CS(C)=O.O>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])[C:6]([OH:13])=[O:7])[CH3:2]
Reactant: [O-][Cl+][O-]
Reactant: CCc1cc(C=O)cc(C)c1O
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCc1cc(C(=O)O)cc(C)c1O
Temperature: 25 °C
Yield: 92.8 %

Procedure:
To a solution of 3-ethyl-4-hydroxy-5-methyl-benzaldehyde (78.8 g, 0.48 mol) in DMSO (585 mL), a solution of NaH2PO4 dihydrate (17.3 g, 0.144 mol) in water (160 mL) is added over a period of 13 min. The mixture is stirred at rt and a solution of NaClO2 (65.17 g, 0.577 mol) in water (160 mL) is added while the mixture is cooled with an ice-bath. The mixture is stirred for 1 h before a second portion of NaClO2 (43.44 g, 0.480 mol) in water (100 mL) is added while the temperature is kept between 25 and 40° C. with an ice-bath. The yellow suspension is stirred at rt for 24 h before it is acidified with 32% aq. HCl to pH 2-3. The mixture is extracted with TBME (250 mL), the org. extract is washed with water, and the washings are extracted back with TBME. The solvent of the combined org. extracts is evaporated to give crude 3-ethyl-4-hydroxy-5-methyl-benzoic acid (80.3 g) as a yellow solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[O:11]1[C:15]2([CH2:20][CH2:19][CH2:18][CH:17]([C:21]([N:23]3[CH2:28][CH:27]=[C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:25][CH2:24]3)=O)[CH2:16]2)[O:14][CH2:13][CH2:12]1>C(OCC)C.O1CCCC1>[O:14]1[C:15]2([CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][N:23]3[CH2:24][CH:25]=[C:26]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:27][CH2:28]3)[CH2:16]2)[O:11][CH2:12][CH2:13]1
Reactant: O=C(C1CCCC2(C1)OCCO2)N1CC=C(c2ccccc2)CC1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C1=C(c2ccccc2)CCN(CC2CCCC3(C2)OCCO3)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of aluminum chloride (14.54 g) in 500 mL of anhydrous diethyl ether is added dropwise to a suspension of lithium aluminum hydride (12.41 g) in 500 mL of tetrahydrofuran. The mixture is stirred at room temperature for 30 minutes. A solution of 1-(1,4-dioxaspiro[4.5]dec-7-yl carbonyl)-1,2,3,6-tetrahydro-4-phenylpyridine (Step B) in 500 mL of tetrahydrofuran is added dropwise. The mixture is stirred at room temperature overnight, and it is quenched by careful addition of 13 mL of water, followed by 59 mL of 25% aqueous sodium hydroxide solution. The resulting mixture is stirred at room temperature for 2 hours, filtered through celite, and concentrated in vacuo. The title compound is obtained (90.40 g) as a light yellow oil (silica; Rf =0.2; 1% methanol, 99% chloroform).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([C:16]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])[CH:13]=[C:12]([C:23]([O:25]C)=[O:24])[CH:11]=1)#[N:2].[OH-].[Li+].CO>O>[C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([C:16]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])[CH:13]=[C:12]([C:23]([OH:25])=[O:24])[CH:11]=1)#[N:2]
Reactant: COC(=O)c1cc(C(=O)N2CCCC2)cc(-c2ccc(C)cc2C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N3CCCC3)c2)c(C#N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A round-bottom flask was charged with methyl 2′-cyano-4′-methyl-5-(pyrrolidine-1-carbonyl)biphenyl-3-carboxylate (0.17 g, 0.46 mmol), lithium hydroxide (17 mg, 0.70 mmol), methanol (5 mL), and water (1 mL). The mixture was stirred at room temperature overnight. The evolatiles were removed under reduced pressure and the residue was acidified with 1 N HCl, extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered, concentrated to afford the desired product as a white solid. LC-MS: 335.4 [M+1]+; 1H NMR (400 MHz, DMSO-d6): 8.14 (t, J=1.6 Hz, 1H), 8.10 (t, J=1.5 Hz, 1H), 7.93 (t, J=1.7 Hz, 1H), 7.83 (t, J=0.8 Hz, 1H), 7.66-7.60 (m, 2H), 3.51-3.42 (m, 4H), 2.42 (s, 3H), 1.91-1.83 (m, 4H).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][NH:11][C:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:32]/[CH:33]=[CH:34]/[C:35]([O:37][CH3:38])=[O:36].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH2:1]([N:8]([CH2:9][CH2:10][NH:11][C:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:32]/[CH:33]=[CH:34]/[C:35]([O:37][CH3:38])=[O:36])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CNCCNC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)/C=C/CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)/C=C/CN(CCNC(c1ccccc1)(c1ccccc1)c1ccccc1)Cc1ccccc1
Temperature: 50 °C

Procedure:
To a solution of Example 12A (128 g, 326 mmol) in acetonitrile (652 mL) was added (E)-methyl 4-bromobut-2-enoate (38.4 mL, 326 mmol) and potassium carbonate (90 g, 652 mmol), and the mixture was heated at 50° C. for 17 hours. A small amount of water was added, and the mixture was decanted into a separatory funnel. The solid left behind was washed three times with ethyl acetate, and the ethyl acetate washings were added to the separatory funnel followed by more water. The layers were separated and the organic layer was concentrated, then dissolved in dichloromethane and loaded onto a silica gel column packed in hexanes. The product was eluted with 15% ethyl acetate/hexanes to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.38 (d, J=7.3 Hz, 5H), 7.31-7.12 (m, 15H), 6.83 (dt, J=5.6 Hz, 15.7 Hz, 1H), 6.07 (d, J=15.7 Hz, 1H), 3.67 (s, 3H), 3.42 (s, 2H), 3.05 (d, J=4.4 Hz, 2H), 2.58-2.49 (m, 2H), 2.11 (dd, J=6.2 Hz, 12.9 Hz, 2H).
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7](O)=[O:8])[CH:2]=1.Cl.[NH2:17][OH:18]>>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([NH:17][OH:18])=[O:8])[CH:2]=1
Reactant: NO
Reactant: O=C(O)c1cccc(-c2ccccc2)c1
Agent: Cl
Product: O=C(NO)c1cccc(-c2ccccc2)c1

Procedure:
Using the procedure of Example 1 part (b), but using 3-biphenyl carboxylic acid and hydroxylamine hydrochloride, the desired compound was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:20])[CH:11]=[C:12]([C:15](OCC)=[O:16])[NH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:22][NH2:23]>>[CH2:1]([O:8][C:9]1[C:10](=[O:20])[CH:11]=[C:12]([C:15]([NH:22][NH2:23])=[O:16])[NH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)c1cc(=O)c(OCc2ccccc2)c[nH]1
Solvent: O
Product: NNC(=O)c1cc(=O)c(OCc2ccccc2)c[nH]1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
A suspension of 5-(benzyloxy)-1,4-dihydro-4-oxo-2-pyridinecarboxylic acid, ethyl ester (7.1 g, 26 mmole) in 99% hydrazine hydrate (15 ml) was heated until most of the solid dissolved. The resulting mixture was stirred for 25 minutes at ambient temperature, the excess hydrazine was removed under high vacuum and the solid residue was treated with methanol. The volatiles were removed in vacuo (repeat methanol treatment and evaporation twice), the solid residue was washed with methanol, hexane, and dried to afford 6 g of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:15][CH2:14][C@H:13]([CH3:16])[C@@H:9]1[C:10](O)=[O:11])=O)(C)(C)C.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([N:33]2[CH:37]=[N:36][N:35]=[N:34]2)=[C:22]([CH:32]=1)[CH2:23][NH:24][C:25](=[O:31])[C@@H:26]1[CH2:30][CH2:29][CH2:28][NH:27]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:16][C@H:13]1[CH2:14][CH2:15][NH:8][C@H:9]1[C:10]([N:27]1[CH2:28][CH2:29][CH2:30][C@H:26]1[C:25]([NH:24][CH2:23][C:22]1[CH:32]=[C:18]([Cl:17])[CH:19]=[CH:20][C:21]=1[N:33]1[CH:37]=[N:36][N:35]=[N:34]1)=[O:31])=[O:11]
Reactant: C[C@H]1CCN(C(=O)OC(C)(C)C)[C@H]1C(=O)O
Reactant: O=C(NCc1cc(Cl)ccc1-n1cnnn1)[C@@H]1CCCN1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1CCN[C@H]1C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1-n1cnnn1

Procedure:
The title compound was prepared from (3S)-1-(tert-butoxycarbonyl)-3-methyl-D-proline (15 mg, 0.07 mmol), N-[5-chloro-2-(1H-tetraazol-1-yl)benzyl]-L-prolinamide (Example 26, Step B, 20 mg, 0.07 mmol, 1.0 equiv), EDC (19 mg, 0.10 mmol, 1.5 equiv) and HOAt (5 mg, 0.03 mmol, 0.5 equiv) in DMF (1 mL) followed by deprotection in TFA-CH2Cl2 essentially according to the procedure described in Example 27, Step C. Purification by reverse phase chromatography [95:5 water (+0.1% TFA)/CH3CN (+0.1% TFA) to 50:50 water (+0.1% TFA)/CH3CN (+0.1% TFA)] afforded the compound as a clear oil. 1H NMR (400 MHz, CDCl3): δ 9.10 (s, 1 H), 8.07–8.01 (m, 1 H), 7.56 (app s, 1 H), 7.41 (dd, J=1.6, 8.4 Hz, 1 H), 7.23 (d, J=8.4 Hz, 1 H), 4.65 (br s, 1 H), 4.57–4.55 (m, 1 H), 4.29 (dd, J=6.0, 15.6 Hz, 1 H), 4.05 (dd, J=5.2, 15.2 Hz, 1 H), 3.83–3.77 (m, 1 H), 3.62 (br s, 1 H), 3.45–3.38 (m, 2 H), 2.97 (br s, 1 H), 2.41–1.88 (m, 7 H), 1.01 (d, J=7.2 Hz, 3 H). HRMS (APCI) M+H: calcd for (C19H24N7O2Cl)+ 418.1753, found 418.1741.
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[C:22]([CH3:24])[C:21]([C:25]2[NH:29][C:28]([CH2:30]C3CCOC3)=[N:27][N:26]=2)=[CH:20][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[CH3:36][O:37][CH2:38]CC(NN)=O.O1CCC(CC(NN)=O)C1>>[CH3:36][O:37][CH2:38][CH2:30][C:28]1[NH:29][C:25]([C:21]2[C:22]([CH3:24])=[CH:23][C:2]([CH3:1])=[C:3]([CH:20]=2)[C:4]([N:6]2[CH2:7][CH2:8][CH:9]([C:12]3[CH:13]=[CH:14][C:15]([C:16]#[N:17])=[CH:18][CH:19]=3)[CH2:10][CH2:11]2)=[O:5])=[N:26][N:27]=1
Reactant: Cc1cc(C)c(-c2nnc(CC3CCOC3)[nH]2)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Reactant: COCCC(=O)NN
Agent: NNC(=O)CC1CCOC1
Product: COCCc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C)[nH]1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of 4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 130), using 3-methoxypropanehydrazide (compound 143.1) instead of 2-(tetrahydrofuran-3-yl)acetohydrazide (compound 130.4). m/z (ES+) 444 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:15]1[N:20]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[C:18]([O:25][CH2:26][CH:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]2)=[CH:17][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[CH3:38][CH:36]([O:35][C:33]([N:30]1[CH2:31][CH2:32][CH:27]([CH2:26][O:25][C:18]2[C:19]([C:21]([O:23][CH3:24])=[O:22])=[N:20][C:15]([C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)=[CH:16][CH:17]=2)[CH2:28][CH2:29]1)=[O:34])[CH3:37]
Reactant: COC(=O)c1nc(Br)ccc1OCC1CCN(C(=O)OC(C)C)CC1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1nc(-c2ccc(S(C)(=O)=O)cc2)ccc1OCC1CCN(C(=O)OC(C)C)CC1
Yield: 70.3 %

Procedure:
The title compound (0.785 g, 82%) was prepared as a light yellow solid from [4-(methylsulfonyl)phenyl]boronic acid (0.48 g, 2.36 mmol), methyl 6-bromo-3-{[(1-{[(1-methylethyl)oxy]carbonyl}-4-piperidinyl)methyl]oxy}-2-pyridinecarboxylate (0.945 g, 86% pure), Pd(PPh3)2Cl2 (0.14 g, 0.20 mmol), 2M Na2CO3 (6 mL) and DME (20 mL) in a manner similar to Example 21, Step 3. The crude material was purified by chromatography on a silica gel column eluted with 1:10 acetone/CH2Cl2 followed by trituration with hot hexanes containing 1% of MeOH to give the title compound. 1H NMR (400 MHz, CDCl3): δ 8.15 (d, 2H, J=8.3 Hz), 8.01 (d, 2H, J=8.5 Hz), 7.86 (d, 1H, J=8.8 Hz), 7.41 (d, 1H, J=8.8 Hz), 4.92 (septet, 1H, J=6.2 Hz), 4.30-4.10 (m, 2H), 3.99 (s, 3H), 3.94 (d, 2H, J=6.3 Hz), 3.06 (s, 3H), 2.85-2.70 (m, 2H), 2.15-2.00 (m, 1H), 1.90-1.80 (m, 2H), 1.40-1.20 (m, 8H); LRMS (ESI), m/z 491 (M+H).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]C)=[O:9].[CH:12]1([CH2:18][O:19][C:20]2[C:21]3[N:22]([C:26]([C:30](O)=[O:31])=[C:27]([CH3:29])[N:28]=3)[CH:23]=[CH:24][CH:25]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.F[B-](F)(F)F.N1(O[C+](N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[OH-].[Na+]>CS(C)=O>[CH:12]1([CH2:18][O:19][C:20]2[C:21]3[N:22]([C:26]([C:30]([NH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:31])=[C:27]([CH3:29])[N:28]=3)[CH:23]=[CH:24][CH:25]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)O
Reactant: COC(=O)CCCCCN
Agent: CN(C)[C+](On1nnc2ccccc21)N(C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)NCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
18 mg of methyl 6-aminohexanoate hydrochloride (0.1 mmol, 1.0 equivalent) were initially charged, and 29 mg of 8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid Example 6A (0.1 mmol, 1 equivalent) in 0.3 ml of DMSO, 41.7 mg of (benzotriazol-1-yloxy)bisdimethylaminomethyliumfluoroborate (TBTU, 0.13 mmol, 1.3 equivalents) in 0.3 ml of DMSO and 26 mg of N,N-diisopropylethylamine (0.2 mmol, 2 equivalents) were added in succession. The mixture was shaken at RT overnight, 0.4 ml of 2 N sodium hydroxide solution was added and the mixture was once more shaken at RT overnight. The solvent was then evaporated and the mixture was purified by preparative HPLC (Method 10). This gave 11 mg (26% of theory; purity: 100%) of the title compound.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:19]3[CH2:25][CH:24]4[N:26]([CH3:27])[CH:21]([CH2:22][CH2:23]4)[CH2:20]3)[C:10]3[C:15]([O:16][C:17]=2[CH:18]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[NH:4].[C:28](N1C=CN=C1)(N1C=CN=C1)=[O:29]>O1CCOCC1>[CH3:27][N:26]1[CH:21]2[CH2:22][CH2:23][CH:24]1[CH2:25][CH:19]([N:9]1[C:8]3[CH:7]=[CH:6][C:5]([C:3]4[NH:4][C:28](=[O:29])[O:1][N:2]=4)=[CH:18][C:17]=3[O:16][C:15]3[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:20]2
Reactant: CN1C2CCC1CC(N1c3ccccc3Oc3cc(C(=N)NO)ccc31)C2
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Product: CN1C2CCC1CC(N1c3ccccc3Oc3cc(-c4noc(=O)[nH]4)ccc31)C2
Temperature: 110 °C
Reaction time: 4 h
Yield: 17.6 %

Procedure:
To a solution of N-Hydroxy-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxamidine, 1 h (0.66 g; 1.81 mmol) in dioxane (20 mL) was added 1,1′-carbonyldiimidazole (0.44 g; 2.71 mmol), and the mixture was stirred at 110° C. for 4 h. The mixture was allowed to cool to rt, and the solvent was evaporated. The residue was purified via reverse phase HPLC (eluent gradient: 20 to 45% CH3CN in H2O containing 0.1% TFA) to yield 161 mg (17.6%) of title compound 3-[10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazin-3-yl]-4H-[1,2,4]oxadiazol-5-one, 2h as a TFA salt. MS m/z (MH+) 390.9.
Reaction SMILES: C(OC(=O)[N:7]([CH:25]([CH3:27])[CH3:26])[C:8]1[C:9]2[N:10]([C:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](SC)[N:18]=3)=[CH:15][N:16]=2)[CH:11]=[CH:12][N:13]=1)(C)(C)C.[NH2:29][CH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[CH:25]([NH:7][C:8]1[C:9]2[N:10]([C:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:29][CH:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[N:18]=3)=[CH:15][N:16]=2)[CH:11]=[CH:12][N:13]=1)([CH3:26])[CH3:27]
Reactant: CSc1nccc(-c2cnc3c(N(C(=O)OC(C)(C)C)C(C)C)nccn23)n1
Reactant: NC1CCOCC1
Product: CC(C)Nc1nccn2c(-c3ccnc(NC4CCOCC4)n3)cnc12

Procedure:
Isopropyl-{3-[2-(tetrahydro-pyran-4-ylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-amine was prepared by a process analogous to that described in Example 12 starting from isopropyl-[3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-carbamic acid tert-butyl ester (from Example 11 supra), and 4-amino-tetrahydropyran. LC-MS: [M+H]+ 354.3.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[NH2:8][C:9]1[N:14]=[C:13]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[C:12]([C:20]#[N:21])=[C:11](S(C)(=O)=O)[N:10]=1>COCCOC>[NH2:8][C:9]1[N:14]=[C:13]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[C:12]([C:20]#[N:21])=[C:11]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[N:10]=1
Reactant: CN1CCNCC1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Product: CN1CCN(c2nc(N)nc(-c3ccco3)c2C#N)CC1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile N-methylpiperazine in DME. ES-MS m/e (%): 2859 (M+H+, 100), 228 (35).
Reaction SMILES: [BH4-].[Na+].[CH3:3][CH:4]1[CH:9]([N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)[C:8](=[O:15])[C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=2[O:5]1.O>CO>[CH3:3][CH:4]1[CH:9]([N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)[CH:8]([OH:15])[C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=2[O:5]1
Reactant: CC1Oc2ccccc2C(=O)C1n1ccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1Oc2ccccc2C(O)C1n1ccnc1
Reaction time: 2 h
Yield: 99.1 %

Procedure:
NaBH4 (0.6 g) was added portionwise to a solution of 2-methyl-3-(1-imidazolyl)-2,3-dihydro-4H-1-benzopyran-4 one (1.3 g) in MeOH (70 ml) at room temperature. The mixture, stirred for 2 hours, added with water (300 ml), extracted with CHCl3, dried and evaporated to dryness gave 2-methyl-3-(1-imidazolyl)-2.3-dihydro-4H-1-benzopyran-4-ol (1.3 g);
Reaction SMILES: [OH-].[Na+].Cl.[Br:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:16][C:17]([OH:19])=[O:18])[CH2:12][C:13]([OH:15])=O)=[CH:7][CH:6]=1>C(Cl)(=O)C>[Br:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[CH2:12][C:13](=[O:15])[O:19][C:17](=[O:18])[CH2:16]2)=[CH:9][CH:10]=1
Reactant: O=C(O)CC(CC(=O)O)c1ccc(Br)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)Cl
Product: O=C1CC(c2ccc(Br)cc2)CC(=O)O1
Temperature: 25 °C

Procedure:
To a solution of commercial 4-bromobenzaldehyde (23.4 g) in ethyl acetoacetate (32.9 g) piperidine (3 ml) was added with stirring at rt. The yellowish solution slowly evolves strong heat. Ethanol (40 ml) was added to induce crystallisation and the mixture was kept at rt for 2 h. The precipitate was collected by suction filtration, washed with ethanol, and dried in vacuo to give 29.5 g of a faint yellowish solid (the bis-adduct of acetoacetate to the benzaldehyde). The powdered solid was added in portions to 50% NaOH (500 g) with stirring. The resulting yellow slurry was stirred at reflux for 2 h. After cooling in an ice bath the mixture was acidified by portionwise addition of conc. HCl (450 ml) to give a white, partly resinous precipitate. The solid was collected by suction filtration and washed with water. After drying in vacuo 3-(4-bromophenyl)glutaric acid (16.7 g) was obtained. The suspension of finely divided 3-(4-bromophenyl)-glutaric acid in acetyl chloride (20 ml) was heated to reflux with stirring for 1 h. After cooling to rt precipitation of the product is completed by addition of petrol ether (100 ml). The precipitate is isolated by suction filtration, washed with acetyl chloride (2×6 ml) and petrol ether, and dried in vacuo to give 3-(4-bromophenyl)-glutaric anhydride (12.3 g) as colourless crystals.