Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[F:6][C:7]([F:43])([F:42])[C:8]1[CH:9]=[C:10]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH2:11][N:12]1[C:16](Cl)=[C:15]([C:18]([C:20]2[O:24][C:23]([CH:25]3[CH2:27][CH2:26]3)=[N:22][C:21]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])=[O:19])[N:14]=[N:13]1.CCOC(C)=O>CS(C)=O>[F:41][C:38]([F:39])([F:40])[C:36]1[CH:35]=[C:10]([CH:9]=[C:8]([C:7]([F:6])([F:43])[F:42])[CH:37]=1)[CH2:11][N:12]1[C:16]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[C:15]([C:18]([C:20]2[O:24][C:23]([CH:25]3[CH2:26][CH2:27]3)=[N:22][C:21]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])=[O:19])[N:14]=[N:13]1
Reactant: c1c[nH]cn1
Reactant: O=C(c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1Cl)c1oc(C2CC2)nc1-c1ccccc1Cl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C(c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-n1ccnc1)c1oc(C2CC2)nc1-c1ccccc1Cl
Temperature: 80 °C
Yield: 88.3 %

Procedure:
Add imidazole (0.37 g, 5.44 mmol) to a solution of [1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazol-4-yl]-[4-(2-chloro-phenyl)-2-cyclopropyl-oxazol-5-yl]-methanone (0.16 g, 0.28 mmol) in DMSO (1.0 mL) and heat to 80° C. for 18 h. Dilute reaction mixture with EtOAc and wash with water and brine, then dry, filter, and concentrate. Purify by flash chromatography using a linear gradient of 30% to 70% EtOAc in hexane to give the title compound (0.15 g, 76%). MS (ES) 607.1 (M+H). 1H NMR (400 MHz, CHCl3) δ 7.88 (s, 1H), 7.61 (s, 1H) 7.51 (m, 3H), 7.21–7.33 (m, 4H), 6.92 (s, 1H), 5.43 (s, 2H), 2.20 (m, 1H), 1.17–1.31 (m, 4H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.[NH2:52][C:53]1[CH:58]=[C:57]([C:59]2[S:60][CH:61]=[CH:62][CH:63]=2)[CH:56]=[CH:55][C:54]=1[NH:64][C:65](=[O:71])[O:66][C:67]([CH3:70])([CH3:69])[CH3:68]>CN(C=O)C.CN(C)C1C=CN=CC=1>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[N:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([NH:52][C:53]3[CH:58]=[C:57]([C:59]4[S:60][CH:61]=[CH:62][CH:63]=4)[CH:56]=[CH:55][C:54]=3[NH:64][C:65](=[O:71])[O:66][C:67]([CH3:69])([CH3:68])[CH3:70])=[O:17])=[CH:9][CH:8]=2)[CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Reactant: O=C(O)/C=C/c1ccc(N2CCOCC2)nc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)/C=C/c1ccc(N2CCOCC2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a solution of 164 (0.275 g, 1.17 mmol) in DMF (10 mL) was added triethylamine (0.168 mL, 1.21 mmol) and BOP reagent (0.563 g, 1.27 mmol) and the mixture was stirred at room temperature for 30 min. Then amine 4 (0.309 g, 1.06 mmol) and excess triethylamine (0.443 mL, 3.18 mmol) were added and the reaction mixture was allowed to stir for 18 h at room temperature. Then 4-(dimethylamino)pyridine (catalytic amount) was added and the reaction mixture was heated to 50-60° C. for 24 h. The solution was concentrated, diluted with AcOEt, washed with saturated NaHCO3, H2O, brine, dried over MgSO4, filtered and concentrated. The resulting yellow solid was triturated from ethyl ether to give compound 165 (0.435 g, 81% yield).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][CH:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([F:19])([F:18])[F:17])[C:6](OC)=[O:7].O.[NH2:21][NH2:22]>C(O)C>[NH2:21][N:22]1[CH2:3][CH:2]([OH:1])[CH2:4][CH:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[C:6]1=[O:7]
Reactant: COC(=O)C(CC1CO1)c1ccccc1C(F)(F)F
Reactant: NN
Solvent: O
Solvent: CCO
Product: NN1CC(O)CC(c2ccccc2C(F)(F)F)C1=O

Procedure:
Methyl 3-oxiranyl-2-(2-trifluoromethylphenyl)propionate (2.61 g) was dissolved in ethanol (20 mL). Hydrazine monohydrate (2.3 mL) was added at room temperature, and the mixture was reacted for 24 hours. Concentration under reduced pressure gave an oil which was partitioned with methylene chloride and water. The aqueous layer was extracted with methylene chloride four times. After drying over magnesium sulfate, concentration under reduced pressure gave the title compound (1.8 g) as a pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:13]([O:15][CH3:16])=[O:14])=[N:6][NH:7][C:8]=1[C:9]([O:11][CH3:12])=[O:10])([O-:3])=[O:2].[CH2:17]([O:19][CH2:20][CH2:21]Br)[CH3:18].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:17]([O:19][CH2:20][CH2:21][N:7]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([C:13]([O:15][CH3:16])=[O:14])=[N:6]1)[CH3:18]
Reactant: COC(=O)c1n[nH]c(C(=O)OC)c1[N+](=O)[O-]
Reactant: CCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOCCn1nc(C(=O)OC)c([N+](=O)[O-])c1C(=O)OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Dimethyl 4-nitro-1H-pyrazole-3,5-dicarboxylate (2.0 g, 8.83 mmol, WO00/24745, page 48, preparation 2) was added to a solution of 2-ethoxyethyl bromide (1.18 mL, 10.45 mmol) and potassium carbonate (1.32 g, 9.56 mmol) in N,N-dimethylformamide (35 mL) and the reaction mixture stirred for 48 hours at room temperature. The reaction mixture was concentrated in vacuo and the residue partitioned between ethyl acetate (200 mL) and water (100 mL). The organic layer was separated, dried over magnesium sulphate and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with pentane:ethyl acetate 100:0 to 70:30 to yield the title product, 1.63 g.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].Br[C:16]1[S:17][CH:18]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[N:20]=1>>[CH3:24][O:23][C:21]([C:19]1[N:20]=[C:16]([C:2]#[C:1][C:3]2[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:5][O:6][C:7]=2[CH3:8])[S:17][CH:18]=1)=[O:22]
Reactant: COC(=O)c1csc(Br)n1
Reactant: C#Cc1c(-c2ccccc2)noc1C
Product: COC(=O)c1csc(C#Cc2c(-c3ccccc3)noc2C)n1
Yield: 70 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using methyl 2-bromothiazole-4-carboxylate instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 113 mg, 70%) which was obtained as a light yellow solid. MS: m/e=325.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1B(O)O.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:13]1[CH:12]=[CH:11][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(N)C(=O)OC(C)(C)C
Reactant: OB(O)c1ccc2ccccc2c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CN(Nc1ccc2ccccc2c1)C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 45.1 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 1.50 g, 10.26 mmol), 2-naphthaleneboronic acid (Lancaster; 1.90 g, 11.05 mmol), copper(II) acetate (1.90 g, 10.46 mmol) and triethylamine (3.6 mL, 25.8 mmol) in 1,2-dichloroethane (40 mL) was heated in an oil bath at 50° C. for 45 min. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 120 g column, eluting with 15-20% ethyl acetate/hexanes, to give N-methyl-N′-naphthalen-2-yl-hydrazinecarboxylic acid tert-butyl ester (1.26 g, 45%) as an orange oil that partially solidified. The Boc region of the 1H NMR spectrum integrated high, but the material was used directly in subsequent steps without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2]>O>[C:4]1([C@@H:1]([OH:3])[CH3:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Solvent: O
Product: C[C@H](O)c1ccccc1
Reaction time: 24 h

Procedure:
Washed cicer arietinum L (bengal grams) 50 g. were taken into a conical flask and allowed to soak in deionised water (400 ml) for a period of 24 hr. Acetophenone (0.500 g; 0.004 moles) I(a) was added to the soaked cicer arietinum L (bengal grams) in the above water, covered and allowed to shake for 24 hr at room temperature (28° C). Then the green grams were filtered off and washed with deionised water (3×100 ml). The combined filtrate was extracted with chloroform (3×500 ml). The chloroform layer was dried and the crude product obtained (80 mg.). Pure 1-phenyl-(1S)-ethan-1-ol II(a) was obtained after column chromatography with silica gel using chloroform as eluent.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH3:27])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl>CO>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH3:27])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Yield: 81.5 %

Procedure:
The solution of 7-{2-(2-formamido-4-thiazolyl)-2-methoxyiminoacetamido}-3-cephem-4-carboxylic acid (syn isomer 10.8 g.), conc. hydrochloric acid (11 g.) and methanol (350 ml.) was stirred at room temperature for 4 hours. After concentrating the resultant solution under reduced pressure, ethyl acetate was added to the residue. The solution was adjusted to pH 8.0 with a saturated aqueous solution of sodium bicarbonate and the aqueous layer was separated and washed with diethyl ether. After nitrogen gas was bubbled in the aqueous solution, the aqueous solution was adjusted to pH 4.0 with 10% hydrochloric acid. The precipitates were collected by filtration and washed with water to give 7-{2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido}-3-cephem-4-carboxylic acid (syn isomer, 8.2 g.), m.p. >290° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.O[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:1][CH:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)[CH:16]=1
Reactant: Oc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccnc2)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
To a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (500 mg, 2.67 mmol) in anhydrous THF (13 mL) under nitrogen were added 3-hydroxypyridine (508 mg, 5.34 mmol) and triphenylphosphine (1.40 g, 5.34 mmol). The reaction mixture was cooled to 0° C. and DEAD (775 μL, 4.27 mmol) was added dropwise. The solution was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure then diluted with dichloromethane and filtered. The filtrate was washed three times with NaOH 0.2N, dried over Na2SO4 then concentrated. The residue was purified on column chromatography (eluent: pentane/acetone 9/1 to 7/3) to give the title compound (606 mg, 86%) as a wax.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[CH3:12][NH:13][CH2:14][CH2:15][OH:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:13]([CH3:12])[CH2:14][CH2:15][OH:16])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: CNCCO
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(CCO)c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 111.8 %

Procedure:
5-bromo-2-fluoronitrobenzene (5.0 g, 22.7 mmol), 2-(methylamino)ethanol (4.26 g, 56.8 mmol) and K2CO3 (9.4 g, 68.1 mmol) in DMF (20 mL) was heated to 60° C. for 1.5 hours, cooled to rt, diluted with water and extracted with EtOAc. The organic phases were washed with water, brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to provide 6.98 g (100%) of the desired product 2-((4-bromo-2-nitrophenyl)(methyl)amino)ethanol (25B): 1H NMR (300 MHz, CDCl3) δ 7.87 (1H, d), 7.51 (1H, dd), 7.10 (1H, d), 3.77 (2H, t), 3.39 (2H, t), 2.83 (3H, s).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:10]([OH:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH:10]([O:22][CH2:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: COc1ccc(C2CCN(Cc3ccccc3)CC2O)cc1
Product: COc1ccc(C2CCN(Cc3ccccc3)CC2OCc2ccc3ccccc3c2)cc1

Procedure:
In an analogous manner to that described in Example 12(b), by alkylating (3RS,4RS)-1-benzyl-4-(4-methoxy-phenyl)-piperidin-3-ol [Example 44 (c)] with 2-bromomethylnaphthalene there was obtained (3RS,4RS)-1-benzyl-4-(4-methoxy-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine as a beige coloured solid; MS: 437 (M)+. Subsequent reaction with 2,2,2-trichloroethyl chloroformate gave 2,2,2-trichloro-ethyl (3RS,4RS)-4-(4-methoxy-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a yellowish oil; MS: 539, 541 (M+NH4)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:4]2([CH2:9][CH2:8][C:7]([CH3:10])=[CH:6][CH2:5]2)[O:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:23]([OH:25])[CH3:24]>>[CH2:23]([O:25][C:2]([C:4]1([OH:3])[CH2:9][CH2:8][C:7]([CH3:10])=[CH:6][CH2:5]1)([CH3:11])[CH3:1])[CH3:24]
Reactant: CCO
Reactant: CC1=CCC2(CC1)OC2(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC(C)(C)C1(O)CC=C(C)CC1

Procedure:
By procedures similar to those described in Embodiments 57 and 58, 2,2,6-trimethyl-1-oxaspiro(2.5)oct-5-ene was treated with ethanol in the presence of p-toluenesulfonic acid to obtain 1-(1-ethoxy-1-methylethyl)-4-methyl-3-cyclohexen-1-ol. This alcohol was treated with vanadium(IV) bis(2,4-pentanedionate)oxide and tert-butyl hydroperoxide followed by p-toluenesulfonic acid to obtain (±)-2-exo-hydroxy-4-(1-ethoxy-1-methylethyl)-1-methyl-7-oxabicyclo[2.2.1]heptane. This intermediate was treated with benzyl chloride to yield the desired product, b.p. 120°-125° C. (0.2 mm).
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]2[N:10]=[C:9]([CH3:11])[C:8]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[C:7]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])[N:6]2[CH:29]=1)#[N:2].[N-:30]=[N+:31]=[N-:32].[Na+].[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[C:7]1[N:6]2[CH:29]=[C:3]([C:1]3[NH:32][N:31]=[N:30][N:2]=3)[N:4]=[C:5]2[N:10]=[C:9]([CH3:11])[C:8]=1[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: Cc1nc2nc(C#N)cn2c(-c2ccc(Cl)cc2Cl)c1CNC(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nc2nc(-c3nnn[nH]3)cn2c(-c2ccc(Cl)cc2Cl)c1CNC(=O)OC(C)(C)C
Temperature: 100 °C
Yield: 70.1 %

Procedure:
To a stirred solution of tert-butyl (2-cyano-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidin-6-yl)methylcarbamate (intermediate for Example 152, 27 mg, 0.06 mmol) in DMF (2 mL) was added NaN3 (6 mg, 0.09 mmol) and NH4Cl (5 mg, 0.09 mmol). After heating to 100° C. for 24 h, the reaction was diluted with EtOAc. The organic layer was washed with satd aq NH4Cl and brine prior to drying over MgSO4. Filtration, concentration under reduced pressure and purification by silica gel chromatography afforded crude tert-butyl (5-(2,4-dichlorophenyl)-7-methyl-2-(1H-tetrazol-5-yl)imidazo[1,2-a]pyrimidin-6-yl)methylcarbamate (20 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH:5]([C:18](OCC)=[O:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH3:14])=[CH:9][C:8]=1[N+:15]([O-])=O)[CH3:2].[H][H]>[Pd].O1CCOCC1>[CH3:14][NH:13][C:10]1[CH:9]=[C:8]2[C:7]([CH2:6][CH:5]([C:4]([O:3][CH2:1][CH3:2])=[O:23])[C:18](=[O:19])[NH:15]2)=[CH:12][CH:11]=1
Reactant: CCOC(=O)C(Cc1ccc(NC)cc1[N+](=O)[O-])C(=O)OCC
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: CCOC(=O)C1Cc2ccc(NC)cc2NC1=O
Yield: 25.1 %

Procedure:
A mixture of 2.6 g of the diester (4), of 10% Pd on charcoal and 75 mL of dioxane were shaken under 50 psi of hydrogen for 17 hours at 50° C. The catalyst was removed by filtering through Celite and the solvent was removed. The residue was chromatographed on 200 g of silica gel eluting with 3:17 (v/v) acetone: CH2Cl2. Fractions 75-120 (17 mL/fraction) were combined and concentrated to yield 0.5 g of a white powder. Recrystallization from MeOH-H2O produced an analytical sample, m.p. 171°-172° C.
Reaction SMILES: [CH3:1][S:2]([C:4]1[S:8][C:7]([N:9]=[C:10]=[O:11])=[N:6][N:5]=1)=[O:3].[CH3:12][NH:13][CH2:14][CH:15]=[O:16]>C1C=CC=CC=1>[CH3:12][N:13]([CH2:14][CH:15]=[O:16])[C:10]([NH:9][C:7]1[S:8][C:4]([S:2]([CH3:1])=[O:3])=[N:5][N:6]=1)=[O:11]
Reactant: CS(=O)c1nnc(N=C=O)s1
Reactant: CNCC=O
Solvent: c1ccccc1
Product: CN(CC=O)C(=O)Nc1nnc(S(C)=O)s1

Procedure:
A mixture of 5-methylsulfinyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-methylaminoacetaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-methyl-3-(5-methylsulfinyl-1,3,4-thiadiazol-2-yl)ureido]-acetaldehyde.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.[Cl:47][C:48]1[CH:65]=[CH:64][C:51]2[NH:52][C:53]([C@@H:55]([NH2:63])[CH2:56][C:57]3[CH:62]=[CH:61][N:60]=[CH:59][CH:58]=3)=[N:54][C:50]=2[CH:49]=1>CN(C)C=O>[Cl:47][C:48]1[CH:65]=[CH:64][C:51]2[NH:52][C:53]([C@@H:55]([NH:63][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[CH2:56][C:57]3[CH:58]=[CH:59][N:60]=[CH:61][CH:62]=3)=[N:54][C:50]=2[CH:49]=1
Reactant: N[C@@H](Cc1ccncc1)c1nc2cc(Cl)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N[C@@H](Cc2ccncc2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 0.150 g (0.579 mmol) of 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, 0.186 g (0.579 mmol) of TBTU, and 0.20 mL (1.78 mmol) of N-methylmorpholine in 2 mL of N,N-dimethylformamide is stirred for 10 minutes at ambient temperature and then combined with a solution of 0.158 g (0.579 mmol) of (S)-1-(5-chloro-1H-benzimidazol-2-yl)-2-pyridin-4-ylethylamine. The reaction mixture is stirred for one day at ambient temperature, then poured onto ice water and extracted three times with ethyl acetate. The combined organic phases are dried with sodium sulfate and concentrated. The residue is chromatographed on silica gel, eluting with dichloromethane/methanol (95:10). Yield: 61.5 mg (22% of theory); Rf value: 0.44 (silica gel; dichloromethane/methanol=9:1); C27H26ClN5O2 (487.99); mass spectrum: (M−H)−=486/488 (chlorine isotope).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH3:11])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].C[N+]1([O-])CC[O:19]CC1>C(#N)C>[CH2:10]([O:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]=[O:19])=[C:4]([N+:12]([O-:14])=[O:13])[CH:5]=1)[CH3:11]
Reactant: CCOc1ccc(CBr)c([N+](=O)[O-])c1
Reactant: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: CCOc1ccc(C=O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
A mixture of 1-(bromomethyl)-4-ethoxy-2-nitrobenzene (11.3 g), 4-methylmorpholine N-oxide (10.1 g), molecular sieves 4A (11 g) and acetonitrile (220 ml) was stirred under an argon atmosphere at room temperature for 1 hr. The reaction mixture was filtered through celite, and the solvent of the filtrate was evaporated under reduced pressure. The residue was diluted with ethyl acetate, and the mixture was washed twice with water. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a yellow solid (5.65 g).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.[F:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[C:33]1([S:47]([C:50]2[CH:55]=[CH:54][C:53]([CH:56]=O)=[CH:52][CH:51]=2)(=[O:49])=[O:48])[CH2:38][CH2:37][CH:36]([NH:39][S:40]([C:43]([F:46])([F:45])[F:44])(=[O:42])=[O:41])[CH2:35][CH2:34]1.C(#[N:60])C>O>[C:56]([C:53]1[CH:54]=[CH:55][C:50]([S:47]([C:33]2([C:27]3[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:26]=3[F:25])[CH2:38][CH2:37][CH:36]([NH:39][S:40]([C:43]([F:46])([F:45])[F:44])(=[O:42])=[O:41])[CH2:35][CH2:34]2)(=[O:49])=[O:48])=[CH:51][CH:52]=1)#[N:60]
Reactant: CC#N
Reactant: O=Cc1ccc(S(=O)(=O)C2(c3cc(F)ccc3F)CCC(NS(=O)(=O)C(F)(F)F)CC2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: N#Cc1ccc(S(=O)(=O)C2(c3cc(F)ccc3F)CCC(NS(=O)(=O)C(F)(F)F)CC2)cc1
Reaction time: 1.5 h
Yield: 71 %

Procedure:
Triphenyl phosphine (0.32 g, 1.2 mmol), followed by carbon tetrachloride (0.06 ml, 0.60 mmol), were added to a solution of the product from Example 80 (0.16 g, 0.30 mmol) in acetonitrile (1.5 ml). The mixture was stirred for 1.5 hours, additional carbon tetrachloride (0.18 ml, 0.18 mmol) was added, and the mixture was stirred for 0.5 hours, diluted with water (10 ml) and extracted with diethyl ether (2×10 ml). The combined organic phases were washed with brine (sat. 20 ml), dried (magnesium sulfate) and evaporated in vacuo. The crude product was chromatographed on silica, eluting with 20% ethyl acetate/isohexane to give the nitrile (0.11 g, 71%). 1H NMR (CDCl3, 360 MHz): 1.63-1.69 (2H, m), 2.04-2.09 (2H, m), 2.48 (2H, bt, J=13.0), 2.59-2.64 (2H, m), 3.81 (1H, m), 5.66 (1H, d, J=7.3), 6.79-6.86 (1H, m), 7.07-7.13 (2H, m), 7.52 (2H, d, J=8.5), 7.70 (2H, d, J=8.5)
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22](Cl)(=[O:24])=[O:23].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:12]=[CH:11][C:10]([NH:13][S:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=2)(=[O:24])=[O:23])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: Nc1ccc(C(F)(F)F)c2cccnc12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1ccc(C(F)(F)F)c2cccnc12)c1ccccn1
Yield: 31.7 %

Procedure:
In a similar fashion using route 14 general procedure 27, 5-trifluoromethyl-quinolin-8-ylamine (Intermediate 45) (125 mg, 0.58 mmol), pyridine-2-sulfonyl chloride (Intermediate 18) (125 mg, 0.70 mmol), pyridine (0.09 ml, 1.17 mmol), DMAP (cat.) and DCM (5 ml) gave the title compound (65 mg, 31%) after purification by column chromatography with n-hexane/DCM (50:50) as the eluent.