Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[CH:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][CH2:17][CH3:18])[CH:11]=[C:10]2[CH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:21]=1[O:30][CH3:31])=[O:6].[Cl-].[NH4+].C(OCC)(=O)C>O1CCCC1>[OH:6][CH:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][CH2:17][CH3:18])[CH:11]=[C:10]2[CH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:21]=1[O:30][CH3:31])[CH:1]=[CH2:2]
Reactant: C=C[Mg]Br
Reactant: CCCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(C=O)ccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CC(O)c1ccc2c(c1)c(Cc1ccc(C(=O)OC)cc1OC)cn2CCC
Reaction time: 0.25 h
Yield: 95 %

Procedure:
Vinyl magnesium bromide (3.05 ml of a 1 molar solution in tetrahydrofuran) was added dropwise to a stirred solution of methyl 4-(5-formyl-1-propylindol-3-ylmethyl)-3-methoxybenzoate (1 g, prepared as described in Example 61, part a) in dry tetrahydrofuran (50 ml), at 0° under an atmosphere of nitrogen. The mixture was stirred at 0° for 15 min, and then poured rapidly into a stirred mixture of saturated aqueous ammonium chloride (100 ml) and ethyl acetate (150 ml). The aqueous layer was further extracted with ethyl acetate (75 ml), and the combined organic layers washed (water (twice), brine), dried (MgSO4) and evaporated to give methyl 4-[5-(1-hydroxyallyl)-1-propylindol-3-ylmethyl]-3-methoxybenzoate (1.03 g, 95%) as a yellow oil; partial NMR (250 MHz, DMSO-d6): 0.80(t, 3H, CH2CH3), 1.75(m, 2H, CH2CH3), 3.83(s, 3H, OCH3), 3.91(s, 3H, OCH3), 4.0(m, 4H, ArCH2Ar', NCH2), 5.0-5.3(m, 4H, H2C=CH, CH(OH)), 5.9(m, 1H, CH=CH2).
Reaction SMILES: [H-].[Na+].CC(C)(C)CC1N=[C:8](C(O)CC2C=CC(C3C=CC=CN=3)=CC=2)[N:9]([S:11](N(C)C)(=[O:13])=[O:12])[CH:10]=1.[CH3:34]I.[CH3:36][C:37]([CH3:62])([CH2:60][CH3:61])[CH2:38][C:39]1[N:40]=[C:41]([CH:44]([OH:59])[CH2:45][C:46]2[CH:51]=[CH:50][C:49]([C:52]3[CH:57]=[CH:56][C:55]([F:58])=[CH:54][N:53]=3)=[CH:48][CH:47]=2)[NH:42][CH:43]=1>>[CH3:36][C:37]([CH3:62])([CH2:60][CH3:61])[CH2:38][C:39]1[N:40]=[C:41]([CH:44]([O:59][CH3:34])[CH2:45][C:46]2[CH:51]=[CH:50][C:49]([C:52]3[CH:57]=[CH:56][C:55]([F:58])=[CH:54][N:53]=3)=[CH:48][CH:47]=2)[N:42]([S:11]([N:9]([CH3:10])[CH3:8])(=[O:13])=[O:12])[CH:43]=1
Reactant: CCC(C)(C)Cc1c[nH]c(C(O)Cc2ccc(-c3ccc(F)cn3)cc2)n1
Reactant: CI
Reactant: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(O)Cc1ccc(-c2ccccn2)cc1
Agent: [H-]
Agent: [Na+]
Product: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(Cc2ccc(-c3ccc(F)cn3)cc2)OC)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride (60 wt % in mineral oil) (50 mg, 1.25 mmol) was added to an ambient temperature solution of 4-(2,2-dimethylpropyl)-2-[1-hydroxy-2-(4-pyridin-2-ylphenyl)ethyl]-N,N-dimethyl-1H-imidazole-1-sulfonamide in N,N-dimethylformamide (for synthesis see example 11) (2 mL). After stirring at ambient temperature for 20 min, methyl iodide (50 μL, 0.8 mmol) was added. After stirring at ambient temperature for a further 2 h, the reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with diethyl ether. The combined ethereal layers were dried (magnesium sulfate) and concentrated in vacuo to afford 4-(2,2-dimethylbutyl)-2-{2-[4-(5-fluoropyridin-2-yl)phenyl]-1-methoxyethyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide which was used in the subsequent step without further purification.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:22]([C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1)#[N:23].O>CN(C)C=O>[C:22]([C:24]1[CH:25]=[C:26]([NH:30][C:31]([NH:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)=[O:32])[CH:27]=[CH:28][CH:29]=1)#[N:23]
Reactant: N#Cc1cccc(N=C=O)c1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)Nc2cccc(C#N)c2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 4-amino-N-(t-butoxycarbonyl)piperidine (0.133 mol, 30.5 g, prepared by the method of Mach, R. H. et al., J. Med. Chem. (1993) 36(23), 3707-20) and triethylamine (1.5 equivilents, 0.2 mol, 20.2 g, 27.8 ml) in dimethylformamide (230 ml) was cooled to 0° C. and m-cyanophenylisocyanate (1.1 equivilents, 0.146 mmol, 21.1 g) in dimethylformamide (70 ml) was added dropwise. The reaction was stirred at ambient temperature for 18 h. It was poured into water and extracted with ethyl acetate (3×). The ethyl acetate extracts were washed with 1N HCl and brine, then dried (Na2SO4) and evaporated to give 43.56 g of crude material. Pure N-(3-cyanophenyl)-N′-(1-(t-butoxycarbonyl)piperidin-4-yl)urea was isolated by flash chromatography on silica gel (1.2 kg) eluted with 2:1 hexane:ethyl acetate (6 L) then 1:1 heaxane ethyl acetate collected in 800 ml fractions. Fractions 9 thru 14 contained pure product, yield 21.69 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[C:5]2O[C:13]3[NH:12][CH:11](C(OC(C)(C)C)=O)[CH2:10][CH:9](C)[C:8]=3[C:6]=2[CH:7]=1.[ClH:32].[OH-:33].[Na+].O1CCC[CH2:36]1>CO>[ClH:1].[Cl:32][C:2]1[C:7]2[O:33][C:9]3[CH:10]([CH3:36])[CH2:11][NH:12][CH2:13][C:8]=3[C:6]=2[CH:5]=[C:4]([S:23]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)(=[O:24])=[O:25])[CH:3]=1
Reactant: CC1CC(C(=O)OC(C)(C)C)Nc2oc3c(S(=O)(=O)c4ccccc4)cc(Cl)cc3c21
Reactant: C1CCOC1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC1CNCc2c1oc1c(Cl)cc(S(=O)(=O)c3ccccc3)cc21
Reaction time: 15 h

Procedure:
To a solution of the product of step C (190 mg, 0.41 mmol) in tetrahydrofuran (10 mL) was added conc. hydrochloric acid (1.2 mL, 12.34 mmol) at ambient temperature. After 15 h, the reaction was basified with 10% NaOH solution and extracted with dichloromethane. The organic layer was concentrated in vacuo and the residue purified by flash column chromatography (SiO2, 95:5 dichloromethane/methanol) to provide the free base which was converted directly to the hydrochloride salt by dissolving in methanol and treating with 1.25 M HCl in methanol. Concentration in vacuo afforded 6-chloro-4-methyl-8-(phenylsulfonyl)-1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine hydrochloride (70 mg, 48%, AUC HPLC 96.8%) as a white solid: mp 291-292° C. dec; 1H NMR (DMSO-d6, 400 MHz) δ 9.72 (br s, 2H), 8.43 (s, 1H), 8.09-7.99 (m, 3H), 7.74-7.59 (m, 3H), 4.49-4.28 (m, 2H), 3.71-3.44 (m, 2H), 3.19-3.11 (m, 1H), 1.35 (d, J=4.8 Hz, 3H); APCI MS m/z 362 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.CN(C=O)C.O=S(Cl)Cl.[CH2:20]([CH:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:27]O)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:27][CH:26]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CCCCCCCCC(CO)CCCCCC
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1C
Product: CCCCCCCCC(CCCCCC)COC(=O)c1ccc(Cl)nc1
Temperature: 80 °C

Procedure:
A suspension of 6-chloronicotinic acid (47.4 g, 0.3 mol) in xylene (150 ml) containing DMF (1.5 ml) was stirred and heated at 80° C. whilst SOCl2 (26.1 ml, 0.36 mol) was added during 20 minutes. Stirring and heating at 80° C. was continued for 11/2 hours, when all had passed into solution. Excess SOCl2, HCl, and a little xylene were then removed by distillation at 20 mm pressure. The residual solution was cooled to 40° C., and 2-hexyldecanol (72.9 g, 0.3 mol) was added during 20 minutes, the temperature rising to 55° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[OH:14])=[N:11][CH:10]=[CH:9][CH:8]=2)([O-])=O.[N+:15]([C:18]1[CH:19]=[N:20][C:21]2[C:26]([C:27]=1[OH:28])=[CH:25][CH:24]=[CH:23][CH:22]=2)([O-])=O>>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[OH:14])=[N:11][CH:10]=[CH:9][CH:8]=2.[NH2:15][C:18]1[CH:19]=[N:20][C:21]2[C:26]([C:27]=1[OH:28])=[CH:25][CH:24]=[CH:23][CH:22]=2
Reactant: O=[N+]([O-])c1cnc2cccnc2c1O
Reactant: O=[N+]([O-])c1cnc2ccccc2c1O
Product: Nc1cnc2ccccc2c1O
Product: Nc1cnc2cccnc2c1O

Procedure:
In step (4) of Reaction Scheme II, a 3-nitro[1,5]naphthyridin-4-ol or 3-nitroquinolin-4-ol of Formula XXIX is reduced to provide a 3-amino[1,5]naphthyridin-4-ol or 3-aminoquinolin-4-ol of Formula XXX. The reduction can be carried out using the methods described in step (1) of Reaction Scheme I.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[NH:7][C:6]([C:12](Cl)=[O:13])=[CH:5]2.N1C=CC=CC=1.[CH:21]1[C:26]([NH2:27])=[CH:25][CH:24]=[C:23]([S:28]([NH:31][C:32]2[S:36][CH:35]=[CH:34][N:33]=2)(=[O:30])=[O:29])[CH:22]=1>C(Cl)Cl>[S:36]1[CH:35]=[CH:34][N:33]=[C:32]1[NH:31][S:28]([C:23]1[CH:22]=[CH:21][C:26]([NH:27][C:12]([C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([Cl:1])=[CH:10][C:9]=3[Cl:11])=[O:13])=[CH:25][CH:24]=1)(=[O:30])=[O:29]
Reactant: O=C(Cl)c1cc2cc(Cl)cc(Cl)c2[nH]1
Reactant: Nc1ccc(S(=O)(=O)Nc2nccs2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(S(=O)(=O)Nc2nccs2)cc1)c1cc2cc(Cl)cc(Cl)c2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
To a solution of 5,7-dichloro-indole-2-carbonylchloride (186 mg, 0.75 mmol) in pyridine (0.8 mL, 1 mmol) and DCM (5.2 mL) was added N′-(2-thiazolyl)sulfanilamide (128 mg, 0.5 mmol) and the reaction mixture stirred at rt for 16 h. The resulting solid was filtered, washed with DCM (3×5 mL), and dried under vacuum overnight to provide the product (0.21 g; yield=90%) as a white-green solid. 1H-NMR (DMSO-d6) 12.78 (s, 1H), 12.33 (s, 1H), 10.67 (s, 1H), 7.97 (d, J=7.0 Hz, 2H), 7.82 (d, J=7.0 Hz, 2H), 7.62 (d, J=1.5 Hz, 1H), 7.47 (s, 1H), 7.30 (d, J=1.7 Hz, 1H), 7.27 (d, J=4.6 Hz, 1H), 6.84 (d, J=4.6 Hz, 1H). LC/MS (10-99%) M/Z: obs=467.0; tR=3.12 min.
Reaction SMILES: C1(SC)C=CC=CC=1.C([O:16][C:17]1[CH:26]=[C:25]2[C:20]([C:21]([O:27][C:28]3[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=3)=[CH:22][CH:23]=[N:24]2)=[CH:19][C:18]=1[O:37][CH3:38])C1C=CC=CC=1>FC(F)(F)C(O)=O>[CH3:38][O:37][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:17]=1[OH:16])[N:24]=[CH:23][CH:22]=[C:21]2[O:27][C:28]1[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[CH:32][CH:33]=1
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2cc1OCc1ccccc1
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2cc1O
Temperature: 70 °C
Reaction time: 2 h
Yield: 128.9 %

Procedure:
After adding trifluoroacetic acid (30 ml) and thioanisole (3 ml) to 7-benzyloxy-6-methoxy-4-(4-nitrophenoxy)quinoline (4.0 g), the mixture was heated and stirred at 70° C. for 2 hours. After cooling the reaction solution, it was concentrated under reduced pressure, sodium bicarbonate water and methanol were added and the precipitated crystals were filtered out. They were then washed with diethyl ether to obtain 4.0 g of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].C(N(CC)CC)C.[CH3:24][CH:25]1[O:30][C:29](=[O:31])[CH2:28][C:27](=[O:32])[CH2:26]1.CC(C)(O)C#N>C(#N)C.ClCCl>[N+:1]([C:4]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:5]=1[C:6]([CH:28]1[C:27](=[O:32])[CH2:26][CH:25]([CH3:24])[O:30][C:29]1=[O:31])=[O:7])([O-:3])=[O:2]
Reactant: CC1CC(=O)CC(=O)O1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: CC(C)(O)C#N
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: ClCCl
Product: CC1CC(=O)C(C(=O)c2ccc(C(F)(F)F)cc2[N+](=O)[O-])C(=O)O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 40.8 %

Procedure:
2-Nitro-4-trifluoromethylbenzoyl chloride (4 g) was added at 0°-5° C. to a stirred solution of triethylamine (2.2 ml) and 6-methyltetrahydropyran-2,4-dione (2 g) in dry acetonitrile (25 ml) and the mixture was stirred at ambient temperature for 4 hours. Triethylamine (6.4 ml) and acetone cyanohydrin (0.3 ml) were added successively to the solution and the mixture stirred at ambient temperature for a further 2 hours. The mixture was diluted with dichloromethane (50 ml) and washed successively with 2N hydrochloric acid (20 ml) and water (3×20 ml). The dichloromethane solution was dried over sodium sulphate and evaporated under reduced pressure to give a brown gum which was triturated with a mixture of chloroform and hexane (1:1, 20 ml) to give 3-(2-nitro-4-trifluoromethylbenzoyl)-6-methyltetrahydropyran-2,4-dione (2.2 g), mp 135°-136.5° C., as a light cream crystalline solid.
Reaction SMILES: [C:1]1([C:6]([CH2:8][C:9]#[N:10])=O)[S:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:12][OH:13].C([O-])(=O)C.[Na+]>C(Cl)Cl.CO>[S:5]1[CH:4]=[CH:3][CH:2]=[C:1]1[C:6]1[CH:8]=[C:9]([NH2:10])[O:13][N:12]=1
Reactant: NO
Reactant: N#CCC(=O)c1cccs1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Nc1cc(-c2cccs2)no1
Temperature: 40 °C

Procedure:
A mixture of 2-thenoylacetonitrile (1 g, 6.6 mmol), hydroxylamine hydrochloride (1.38 g, 19.8 mmol) and sodium acetate (2.17 g, 26.5 mmol) in DCM (20 ml) and MeOH (20 ml) was heated at 40° C. overnight, cooled to rt and concentrated. The residue was partitioned between EtOAc and water, the organic layer was washed with water, brine, dried over magnesium sulfate and concentrated to give a brown solid 1-4. 1H NMR (400 MHz, CDCl3) δ 7.38 (m, 2H), 7.08 (m, 1H), 5.40 (s, 1H), 4.49 (bs, 21-1); ESI+ MS [M+H]+ C7H7N2OS=167.1.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13](C=O)[CH:12]=1>C(O)(=O)C.C(O)C>[C:1]([NH:9][N:10]=[C:15]1[CH:14]=[CH:13][CH:12]=[N:11][CH2:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: NNC(=O)c1cccnc1
Reactant: O=Cc1cccnc1
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(NN=C1C=CC=NC1)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Five drops of glacial acetic acid are added at room temperature to a solution of 41.1 g of nicotinic acid hydrazide and 32.1 g of pyridine-3-carbaldehyde in 300 ml of ethanol. The reaction mixture, which exotherms slightly, is stirred for ca. 2 hours at room temperature. The precipitated product is isolated by filtration, washed with ca. 100 ml of ethanol and dried, affording the title compound of formula ##STR8## with a melting point of 213°-216° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:10][OH:11])[CH:6]=[CH:7][C:8]=1[CH3:9]>[O-2].[Mn+2].ClCCl>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([CH:4]=1)[CH:10]=[O:11]
Reactant: COc1cc(CO)ccc1C
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClCCl
Product: COc1cc(C=O)ccc1C
Reaction time: 8 h

Procedure:
At ambient temperature, 36.35 g (238.8 mmol) of (3-methoxy-4-methylphenyl)-methanol and 207.6 g (2.4 moles/10 eq.) of manganese oxide are mixed into 730 mL of dichloromethane. Stirring is carried out at ambient temperature overnight, followed by filtration over Celite and rinsing with dichloromethane. After concentration of the combined filtrates, the desired product is obtained.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][N:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[CH:13]=2)O1.Br[C:22]1[N:27]=[C:26]([S:28]([NH2:31])(=[O:30])=[O:29])[CH:25]=[CH:24][CH:23]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([N:12]2[CH:13]=[C:9]([C:22]3[N:27]=[C:26]([S:28]([NH2:31])(=[O:30])=[O:29])[CH:25]=[CH:24][CH:23]=3)[CH:10]=[N:11]2)[CH:15]=1
Reactant: CC1(C)OB(c2cnn(-c3cccnc3)c2)OC1(C)C
Reactant: NS(=O)(=O)c1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: NS(=O)(=O)c1cccc(-c2cnn(-c3cccnc3)c2)n1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
Under argon, 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]pyridine (0.2 g, 0.74 mmol, prepared by the methods described in WO 2011/045224), 6-bromopyridin-2-sulphonamide (0.175 g, 0.74 mmol) and tetrakis(triphenylphosphine)palladium (0.025 g, 0.022 mmol) were added to a mixture, degassed by means of argon, of sodium carbonate solution in water (2.9 ml, 2 M/L) and acetonitrile (4 ml). The reaction mixture was stirred at 70° C. for 18 h. After cooling, the reaction mixture was poured onto water and the precipitated crystals were filtered off with suction. They were subsequently stirred with diethyl ether and filtered off with suction. This gave 0.23 g (97% of theory) of 6-[1-(pyridin-3-yl)-1H-pyrazol-4-yl]pyridine-2-sulphonamide.
Reaction SMILES: [CH2:1]([O:5][C@H:6]1[N:9]([C:10](=[O:27])[C:11]([O:13][CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:8](=[O:28])[C@@H:7]1[NH:29][C:30](=[O:38])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:2]([CH3:4])=[O:3].C(O)(=O)C>C(Cl)Cl.[Zn]>[CH2:1]([O:5][C@H:6]1[N:9]([CH:10]([OH:27])[C:11]([O:13][CH:14]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:8](=[O:28])[C@@H:7]1[NH:29][C:30](=[O:38])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:2]([CH3:4])=[O:3]
Reactant: CC(=O)CO[C@@H]1[C@@H](NC(=O)Cc2ccccc2)C(=O)N1C(=O)C(=O)OC(c1ccccc1)c1ccccc1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)CO[C@@H]1[C@@H](NC(=O)Cc2ccccc2)C(=O)N1C(O)C(=O)OC(c1ccccc1)c1ccccc1

Procedure:
To a solution of diphenylmethyl α-[4(R)-acetonyloxy-3(R)-phenylacetamido-2-oxo-azetidin-1-yl]glyoxalate (2.312 g) in a mixture of methylene chloride (10 ml) and glacial acetic acid (10 ml) is added activated zinc powder (2.50 g) with stirring, and the mixture is stirred for 3 hours at room temperature. The reaction mixture is filtered through a layer of Celite which is washed with methylene chloride. The filtrate is washed with water, dried over sodium sulfate, and evaporated under reduced pressure to give the product as a mixture of epimers at position α.
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][C:4]1[N:8]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH:7]=[N:6][CH:5]=1.[CH3:17][N:18](C)C=[O:20].CN.N>ClC(Cl)Cl.CO>[OH2:20].[ClH:2].[ClH:1].[CH3:17][NH:18][CH2:3][C:4]1[N:8]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH:7]=[N:6][CH:5]=1
Reactant: CC(c1ccccc1)n1cncc1CCl
Reactant: CN(C)C=O
Agent: CN
Agent: Cl
Agent: N
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CNCc1cncn1C(C)c1ccccc1
Product: O
Yield: 44.5 %

Procedure:
Through a stirred mixture of 3 parts of 5-(chloromethyl)-1-(1-phenylethyl)-1H-imidazole monohydrochloride and 45 parts of N,N-dimethylformamide were bubbled 3 equivalents of gaseous methanamine at room temperature during a 1 hour-period: exothermic reaction, the temperature rose to 50° C. The reaction mixture was taken up in trichloromethane and methanol, previously saturated with ammonia, was added. The formed precipitate was filtered off and the filtrate was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in 2-propanol. The salt was filtered off, washed with 2-propanol, dried and crystallized from 2-propanol, yielding 1.6 parts (44.5%) of (±)-N-methyl-1-(1-phenylethyl)-1H-imidazole-5-methanamine dihydrochloride monohydrate; mp. 109° C. (compound 8.38).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([CH3:21])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:28][C:29]1[CH:34]=[N:33][C:32]([CH:35]=[CH2:36])=[CH:31][N:30]=1.N1C=CC=CC=1>C(Cl)Cl.CN(C)C=O>[CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([CH3:21])[CH:12]=2)[C:8]([NH:28][C:29]2[CH:34]=[N:33][C:32]([CH:35]=[CH2:36])=[CH:31][N:30]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1cc([C@@H](CC2CCCC2)C(=O)O)ccc1S(C)(=O)=O
Reactant: C=Cc1cnc(N)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=Cc1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(C)c2)cn1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 62.1 %

Procedure:
A solution of 3-cyclopentyl-2(R)-(4-methanesulfonyl-3-methyl-pheny)-propionic acid (prepared as in Example 57, 465 mg, 1.5 mmol) in methylene chloride (20 mL) was treated with oxalyl chloride (0.3 mL, 3.4 mmol) and N,N-dimethylformamide (1–2 drops). The solution was stirred at 0° C. for 5 min and then at 25° C. for 15 min. The reaction mixture was concentrated in vacuo. The residue was dissolved in methylene chloride (20 mL), cooled to 0° C., and then treated with a solution of 2-amino-5-vinylpyrazine (prepared as in Example 54, 182 mg, 1.5 mmol) and pyridine (0.37 mL, 4.6 mmol) in methylene chloride (5 mL). The mixture was stirred at 0° C. then stirred at 25° C. overnight. The solution was diluted with methylene chloride (25 mL). The organic layer was washed with a 1N aqueous sodium hydroxide solution (25 mL) and a 1N aqueous hydrochloric acid solution (25 mL). Each aqueous phase was back-extracted with a small volume of methylene chloride. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 1/3 to 1/1 ethyl acetate/hexanes) afforded 3-cyclopentyl-2(R)-(4-methanesulfonyl-3-methyl-phenyl)-N-(5-vinyl-pyrazin-2-yl)-propionamide (385 mg, 63%) as a white foam: (ES)+-HRMS m/e calcd for C22H27N3O3S (M+H)+ 414.1846, found 414.1849.
Reaction SMILES: [OH-].[Li+].C([O:11][CH:12]([CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:38][CH:37]=1)[CH:13]([C:27]([O:29]C(C)(C)C)=[O:28])[CH2:14][CH2:15][NH:16][C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[O:18])(=O)C1C=CC=CC=1.Cl>O1CCCC1.CO.O.O>[C:39]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:38]=[CH:37][C:36]([CH2:35][CH2:34][CH:12]([OH:11])[CH:13]([CH2:14][CH2:15][NH:16][C:17]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)=[O:18])[C:27]([OH:29])=[O:28])=[CH:41][CH:40]=1
Reactant: CC(C)(C)OC(=O)C(CCNC(=O)Nc1ccc(F)cc1)C(CCc1ccc(-c2ccccc2)cc1)OC(=O)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCCC(C(=O)O)C(O)CCc1ccc(-c2ccccc2)cc1)Nc1ccc(F)cc1
Yield: 41.7 %

Procedure:
Aqueous solution of lithium hydroxide (22 mg in 1 ml) was added to the solution of the compound (130 mg) obtained from Step 1 above, in tetrahydrofuran:methanol:water (3:1:1, 5 ml) and the reaction mixture was stirred at 40° C. overnight. The reaction mixture was concentrated and the residue thus obtained was taken in distilled water, acidified with dilute hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with distilled water and brine solution and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure to furnish the title compound (40 mg)