Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:11][N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[C:9]#[N:10])=[CH:4][CH:3]=1.[OH-].[K+].N1C=CN=N1.BrCC(C#N)(C1C=CC=CC=1)CCC1C=CC=C([C:43]([F:46])([F:45])[F:44])C=1>CS(C)=O.C(OCC)(=O)C.O.C1(C)C=CC=CC=1>[C:5]1([C:8]([CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[C:23]([C:43]([F:46])([F:45])[F:44])[CH:24]=2)([CH2:11][N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[C:9]#[N:10])[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=1
Reactant: N#CC(CCc1ccccc1)(Cn1cncn1)c1ccc(F)cc1
Reactant: N#CC(CBr)(CCc1cccc(C(F)(F)F)c1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Agent: c1c[nH]nn1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: N#CC(CCc1cccc(C(F)(F)F)c1)(Cn1cncn1)c1ccccc1
Temperature: 100 °C
Yield: 76.7 %

Procedure:
A 250 ml 4 neck round bottom flask was charged with 4.05 gms of 87% KOH (0.062 mole, 1.25 eq.) and 4.8 gms (0.068 mole, 2.2 eq.) of triazole in 25 ml DMSO. The reaction was warmed to 90° C. until homogeneous and 25 ml of toluene was added and azeotroped for 4 hours. The toluene was distilled off at 165° C. and the reaction was cooled to 100° C. and 12.5 g of 1-bromo-2-cyano-2-phenyl-4-(3-trifluoromethylphenyl)butane (0.031 mole, 1.0 eq.) was added. The reaction was heated at 125° C. for 1 hour and then worked up with water and ethyl acetate, dried and concentrated. Purification by high pressure liquid chromatography (1:1) hexane:ethyl acetate gave 8.8 gms of a white solid having a melting point of 127°-128° C. (76.7% yield).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[NH:26][CH:25]=[C:24]4[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12].I[CH2:34][CH2:35][CH2:36][CH3:37]>CS(C)=O.C(OCC)(=O)C>[CH2:34]([N:26]1[C:27]2[C:23](=[CH:22][CH:21]=[CH:20][C:19]=2[C:16]2[N:15]=[C:14]([C:6]3[CH:7]=[CH:8][C:9]([O:10][CH:11]([CH3:12])[CH3:13])=[C:4]([Cl:3])[CH:5]=3)[O:18][N:17]=2)[C:24]([CH2:28][CH2:29][C:30]([O:32][CH2:5][CH2:4][CH2:9][CH3:8])=[O:31])=[CH:25]1)[CH2:35][CH2:36][CH3:37]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC(=O)O)c[nH]c34)no2)cc1Cl
Reactant: CCCCI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCOC(=O)CCc1cn(CCCC)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Potassium hydroxide (65 mg) was added to a solution of 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoic acid (E1) (100 mg) and 1-iodobutane (0.2 mL) in dimethyl sulfoxide (DMSO) (1 mL). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate. The organic solution was washed with water. The organic solution was dried over sodium sulfate. After concentration, the residue was purified via column chromatography to afford butyl 3-[1-butyl-7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoate (D123) (61 mg). δH (CDCl3, 400 MHz): 0.73 (3H, t), 0.92 (3H, t), 1.03 (2H, m), 1.34 (2H, m), 1.45 (8H, m), 1.59 (2H, m), 2.71 (2H, t), 3.12 (2H, t), 4.08 (2H, t), 4.16 (2H, t), 4.72 (1H, m), 6.94 (1H, s), 7.07 (1H, d), 7.19 (1H, t), 7.53 (1H, dd), 7.76 (1H, dd), 8.08 (1H, dd), 8.25 (1H, d); MS (ES): C30H36ClN3O4 requires 537; found 538.3 (M+H+).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]([CH3:6])[CH3:5].C(N(CC)CC)C.Cl.[F:15][C:16]([F:50])([F:49])[C:17]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[N:20]=[C:19]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([C:39]3[CH:40]=[C:41]([S:45](Cl)(=[O:47])=[O:46])[CH:42]=[CH:43][CH:44]=3)[CH:34]=2)[N:18]=1>C1COCC1>[CH2:3]([N:2]([CH3:1])[S:45]([C:41]1[CH:42]=[CH:43][CH:44]=[C:39]([C:35]2[CH:34]=[C:33]([C:19]3[N:18]=[C:17]([C:16]([F:15])([F:49])[F:50])[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:25][CH:24]=4)[N:20]=3)[CH:38]=[CH:37][N:36]=2)[CH:40]=1)(=[O:46])=[O:47])[CH:4]([CH3:6])[CH3:5]
Reactant: CNCC(C)C
Reactant: O=S(=O)(Cl)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)CN(C)S(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Temperature: 0 °C
Yield: 75.7 %

Procedure:
To a cooled (ice-water bath) and stirred mixture of N-methylisobutylamine (0.26 g, 3.0 mmol), triethylamine (0.29 ml, 2.1 mmol) and THF (4 ml) was added drop wise a solution of 3-{4-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonyl chloride hydrochloride (example I.1) (0.58 g, 1.0 mmol) in THF (6 ml). The mixture was allowed to stir at room temperature for 16 h. Purification of the reaction mixture by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (dichloromethane/MeOH/hexane) yielded the title compound as a white solid (0.45 g, 80%). MS (ISP) 594.7 [(M+H)+]; mp 144° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17](Cl)=[O:18])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][NH:21][CH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH:29]=[C:28]([OH:33])[CH:27]=[CH:26]2.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[OH:33][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([CH2:22][N:21]([CH3:20])[C:17]([C:10]1[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:9]=1)=[O:18])[CH:32]=[CH:31]2
Reactant: O=C(Cl)c1cn(Cc2ccccc2)c2ccccc12
Reactant: CNCc1ccc2cc(O)ccc2c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(Cc1ccc2cc(O)ccc2c1)C(=O)c1cn(Cc2ccccc2)c2ccccc12
Reaction time: 8 h
Yield: 100 %

Procedure:
1-Benzyl-1H-indole-3-carbonyl chloride, prepared in the previous step, in 50 mL of anhydrous THF was added dropwise under nitrogen over 2 h to a mixture of 6-methylaminomethyl-naphthalen-2-ol (2.5 g, 13.37 mmol), prepared in step 1 of Example 32, and triethylamine (1.86 mL, 13.37 mmol) in 300 mL of anhydrous THF at room temperature. The reaction stirred for 17.5 h (overnight). A trace amount of solid was removed by filtration and the filtrate was concentrated under reduced pressure to give a brown oil. The oil was diluted with ethyl acetate, extracted two times with 1N HCl, dried (MgSO4) and the solvent removed under reduced pressure to give 1-benzyl-1H-indole-3-carboxylic acid (6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide (5.83 g, 100%) as a brown foam, MS m/z: 421 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9](O)=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19].S(Cl)(Cl)=O.[CH:26]1[CH:27]=[CH:28][N:29]2[CH2:35][C:34]3[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=3[NH:32][CH2:31][C:30]=12.C(N(CC)C(C)C)(C)C>CN(C)C=O.C1(C)C=CC=CC=1>[CH:26]1[CH:27]=[CH:28][N:29]2[CH2:35][C:34]3[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=3[N:32]([C:9]([C:7]3[CH:6]=[CH:5][C:4]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[C:18]([F:21])([F:20])[F:19])=[C:3]([O:2][CH3:1])[CH:8]=3)=[O:10])[CH2:31][C:30]=12
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: COc1cc(C(=O)O)ccc1-c1ccccc1C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Temperature: 70 °C
Reaction time: 1 h
Yield: 50.3 %

Procedure:
The 2-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-carboxylic acid of Step C (1.6 g, 5.40 mmol) was added to a flask containing toluene (30 mL), thionyl chloride (1.4 mL) and one drop of N,N-dimethylformamide. The solution was stirred at 70° C. for 1 hour and then concentrated in vacuo. The residue was diluted with dichloromethane (40 mL) and to this solution was added 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.94 g, 5.16 mmol). After the solution became homogeneous, N,N-diisopropylethyl amine (1.07 mL, 6.19 mmol) was added in one portion at 0° C. After 30 minutes the solution was concentrated, and the residue partitioned between water and ethyl acetate. The ethyl acetate was dried and concentrated to give a crude oil, which was chromatographed on silica gel eluting with 30% ethyl acetate in hexane to yield 1.2 g of product. The solid was recrystallized from ethyl acetate/hexane to provide the desired title product (0.87 g) as colorless crystals, m.p. 146–148° C.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([C:11]#[C:12][Si](C)(C)C)=[CH:9][C:8]([CH2:17][OH:18])=[CH:7][C:6]=1OC)(=O)C.[C:21]([OH:24])(=[O:23])[CH3:22].[F-].C([NH+](CCCC)CCCC)CCC.[NH4+].[Cl-]>C1COCC1>[C:21]([O:24][C:6]1[C:5]([O:4][CH3:1])=[C:10]([C:11]#[CH:12])[CH:9]=[C:8]([CH2:17][OH:18])[CH:7]=1)(=[O:23])[CH3:22]
Reactant: COc1cc(CO)cc(C#C[Si](C)(C)C)c1OC(C)=O
Reactant: CC(=O)O
Agent: CCCC[NH+](CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1cc(CO)cc(OC(C)=O)c1OC
Reaction time: 0.67 h
Yield: 90.8 %

Procedure:
Compound 4 (10 g, 34 mmol) was dissolved in THF (100 mL), then acetic acid (4.0 mL, 70 mmol) and tributylammoniumfloride (1.0 M in THF) (51 mL, 51 mmol) were added at room temperature. After stirring for 40 min at the same temperature, a saturated aqueous solution of NH4Cl (50 mL) was added, followed by extraction with ethyl acetate (3×60 mL), and the combined extracts was dried (Na2SO4). The solvent was removed under a vacuum, and the residue was purified by flash chromatography (dichloromethane) to give 5 (Rf=0.5, ethyl acetate/hexane 1:1) as a yellowish liquid (6.8 g, 90%). 1H NMR (500 MHz, CDCl3): δ 7.11 (s, 1H), 7.05 (s, 1H), 4.68 (s, 2H), 3.87 (s, 3H), 3.23 (s, 1 H), 2.38(s, 3H). 13C NMR (500 MHz, CDCl3): δ 168.85, 151.75, 140.85, 139.92, 122.99, 117.37, 111.86, 82.08, 78.54, 64.66, 56.31, 20.75.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[O:6][C:7]([C:10]3[CH:11]=[C:12]4[C:16](=[CH:17][CH:18]=3)[N:15]([S:19]([C:22]3[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:14]=[C:13]4B3OC(C)(C)C(C)(C)O3)=[N:8][N:9]=2)[CH2:3][CH2:2]1.Cl[C:39]1[CH:44]=[N:43][CH:42]=[C:41]([CH:45]2[CH2:47][CH2:46]2)[N:40]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:1]1([NH:4][C:5]2[O:6][C:7]([C:10]3[CH:11]=[C:12]4[C:16](=[CH:17][CH:18]=3)[N:15]([S:19]([C:22]3[CH:23]=[CH:24][C:25]([CH3:26])=[CH:27][CH:28]=3)(=[O:20])=[O:21])[CH:14]=[C:13]4[C:39]3[CH:44]=[N:43][CH:42]=[C:41]([CH:45]4[CH2:47][CH2:46]4)[N:40]=3)=[N:8][N:9]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(-c4nnc(NC5CC5)o4)ccc32)cc1
Reactant: Clc1cncc(C2CC2)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(C4CC4)n3)c3cc(-c4nnc(NC5CC5)o4)ccc32)cc1
Temperature: 130 °C
Yield: 19.5 %

Procedure:
To a 20 mL microwave vial was added N-cyclopropyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (200 mg, 0.456 mmol), 2-chloro-6-cyclopropylpyrazine (CombiPhos Catalysts Inc., 78 mg, 0.502 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (13.05 mg, 0.027 mmol), Pd2(dba)3 (12.5 mg, 0.014 mmol), and potassium phosphate (291 mg, 1.369 mmol) followed by purging with argon. The solids were treated with dioxane (4.0 mL) and water (0.4 mL) and heated in the microwave at 130° C. for 20 min. The mixture was treated with H2O and extracted with EtOAc, dried over MgSO4, filtered and concentrated. Purification (0-100% EtOAc in Hex) afforded N-cyclopropyl-5-(3-(6-cyclopropylpyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (45.6 mg, 19%) as a pale yellow solid. MS (ESI, pos. ion) m/z: 513.1 (M+1).
Reaction SMILES: [CH3:1][CH:2]([SH:4])[CH3:3].Cl[C:6]1[C:7]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:8]=2[S:9][C:10]=1[C:11]([NH2:13])=[O:12].C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>CN(C=O)C.C(OCC)(=O)C>[CH3:19][O:18][C:16]1[CH:15]=[CH:14][C:8]2[S:9][C:10]([C:11]([NH2:13])=[O:12])=[C:6]([S:4][CH:2]([CH3:3])[CH3:1])[C:7]=2[CH:17]=1
Reactant: COc1ccc2sc(C(N)=O)c(Cl)c2c1
Reactant: CC(C)S
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2sc(C(N)=O)c(SC(C)C)c2c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 80 %

Procedure:
2-Propanethiol (1.1 mL, 12.4 mmol) is added to a suspension of 3-chloro-5-methoxybenzo[b]thiophene-2-carboxamide (3.00 g, 12.4 mmol) in 24 mL of DMF. Diazabicycloundecene (DBU) (1.8 mL, 12.4 mmol) is added and the mixture is warmed to 80° C. After 6 hours, additional amounts of 2-propanethiol (110 μL) and of DBU (180 μL) are added. Heating is continued for 1 hour. The reaction mixture is allowed to cool and then is diluted with ethyl acetate and washed with 1N NaOH, 1N HCl, water, and brine. The organic layer is dried over MgSO4. Filtration followed by concentration in vacuo and recrystallization from ethyl acetate:hexane gives 5-methoxy-3-[(1-methylethyl)thio]benzo[b]thiophene-2-carboxamide in 80% yield. An analytical sample is obtained by a second recrystallization from ethyl acetate:hexane; mp=143°-143.5° C.
Reaction SMILES: O[CH:2]([C:14]1[CH:19]=[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:17]([O:24]COCC[Si](C)(C)C)=[C:16]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH:15]=1)[C:3]#[C:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1.ClCCl.FC(F)(F)C(O)=O>O>[C:33]([C:16]1[C:17](=[O:24])[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:19][C:14](=[CH:2][C:3]#[C:4][C:5]2[CH:6]=[CH:7][C:8]([C:9]([OH:11])=[O:10])=[CH:12][CH:13]=2)[CH:15]=1)([CH3:34])([CH3:35])[CH3:36]
Reactant: CC(C)(C)c1cc(C(O)C#Cc2ccc(C(=O)O)cc2)cc(C(C)(C)C)c1OCOCC[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)(C)C1=CC(=CC#Cc2ccc(C(=O)O)cc2)C=C(C(C)(C)C)C1=O

Procedure:
2.2 g (4.7 mmol) of 4-{3-Hydroxy-3-[3,5-di-tert-butyl-4-(2-trimethylsilylethoxymethoxy)phenyl]-1-propynyl}benzoic acid and 75 ml of dichloromethane are introduced into a three-necked flask. 360 μl (4.7 mmol) of trifluoroacetic acid are added at -78° C. and the mixture is allowed to return to room temperature. The reaction medium is poured into water and extracted with ethyl ether, and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. The residue obtained is triturated from heptane, filtered and then dried. 1.6 g (90%) of 4-[3-(3,5-di-tert-butyl-4-oxo-2,5cyclohexadien-1-ylidene)-1-propynyl]benzoic acid are collected, with a melting point of 216-8° C.
Reaction SMILES: O.O.[Sn](Cl)Cl.C([O-])(O)=O.[Na+].[CH3:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:15][C:14]=1[N+:25]([O-])=O.O>CCOC(C)=O.OS([O-])(=O)=O.[K+]>[CH3:11][NH:12][C:13]1[C:14]([NH2:25])=[CH:15][C:16]([CH2:19][N:20]2[CH2:21][CH2:22][CH2:23][CH2:24]2)=[CH:17][CH:18]=1
Reactant: CNc1ccc(CN2CCCC2)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Solvent: CCOC(C)=O
Solvent: O
Product: CNc1ccc(CN2CCCC2)cc1N

Procedure:
4.85 g (21.5 mmol) tin(II)chloride dihydrate and 4.45 g (53.0 mmol) NaHCO3 are added to a solution of 1.00 g (4.25 mmol) methyl-(2-nitro-4-pyrrolidin-1-ylmethyl-phenyl)-amine in 60 mL EtOAc at RT. The reaction is refluxed for 2 h and then diluted with 100 mL 1 M KHSO4 solution and some water. The mixture is filtered. The aqueous phase is combined with K2CO3 and extracted twice with 80 mL EtOAc. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:15][O:16][CH:17]([O:21][CH3:22])N(C)C>>[CH3:15][O:16][CH:17]([O:21][CH3:22])[N:12]1[CH2:13][CH2:14][CH:9]([CH2:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:10][CH2:11]1
Reactant: COC(OC)N(C)C
Reactant: c1cn(CCCC2CCNCC2)cn1
Product: COC(OC)N1CCC(CCCn2ccnc2)CC1
Temperature: 100 °C

Procedure:
A mixture of 4-[3-(1H-imidazol-1-yl)propyl]-piperidine (1.5 g, 0.0078M) and dimethylformamide dimethylacetal (10 ml) was heated at 100° C. for 16 hrs. The excess of dimethylformamide dimethylacetal was removed to give 4-[3-(1H-imidazol-1-yl)propyl]-1-piperidinecarboxaldehyde dimethylacetal. To the mixture of 6-aminopenicillanic acid (1.16 g, 0.0053M) and diisopropylethylamine (1.03 ml) in dry CHCl3 (9 ml) was added the above piperidinecarboxaldehyde in CHCl3 (5 ml) at 0° C. and stirred at that temperature for 1 hr, then at room temperature for 3 hrs. After the reaction, the solvent was removed and the residue dissolved in water (40 ml). The aqueous solution, washed with diethyl ether, was adjusted to pH 3 with dilute aqueous HCl and purified on Sephadex LH 20 column to give [2S-(2alpha,5alpha,6beta)]-6-[[4-[3-(1 H-imidazol-1-yl)propyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid 1.2 mole hydrochloride monohydrate (0.87 g, 39% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[CH2:5][NH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:13]([C:17]#[N:18])=[CH:12][CH:11]=[CH:10][C:9]=2[N:8]=1.Cl.[NH2:24][OH:25].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[OH:25][NH:24][C:17]([C:13]1[C:14]2[CH:15]=[CH:16][C:7]([NH:6][CH2:5][C:4]3[CH:19]=[CH:20][CH:21]=[CH:22][C:3]=3[O:2][CH3:1])=[N:8][C:9]=2[CH:10]=[CH:11][CH:12]=1)=[NH:18]
Reactant: NO
Reactant: COc1ccccc1CNc1ccc2c(C#N)cccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccccc1CNc1ccc2c(C(=N)NO)cccc2n1
Yield: 90 %

Procedure:
A stirred suspension of 2-(2-methoxy-benzylamino)-quinoline-5-carbonitrile (example 136, step B) (289 mg, 1.0 mmol), hydroxylamine hydrochloride (257 mg, 3.7 mmol) and sodium carbonate (212 mg, 2.0 mmol) in ethanol (4 ml) and water (4 ml) was heated under reflux conditions for 17 h, water (5 ml) was added, the precipitate was collected by filtration, washed with water and heptane and dried to yield the crude product as solid which was further purified by crystallization (diethyl ether/ methanol) to yield N-hydroxy-2-(2-methoxy-benzylamino)-quinoline-5-carboxamidine as off-white solid (290 mg, 90%). MS (ISP): m/e=323.2 (M+H+); m.p. 161° C.
Reaction SMILES: CO[C:3]([C:5]1([NH:14][C:15](=[O:26])[CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH3:25])[CH2:10][CH2:9][N:8]([N:11]([CH3:13])[CH3:12])[CH2:7][CH2:6]1)=[O:4].CC(C)([O-])C.[K+].O.Cl>CN(C)C=O>[CH3:13][N:11]([CH3:12])[N:8]1[CH2:7][CH2:6][C:5]2([NH:14][C:15](=[O:26])[CH:16]([C:17]3[C:18]([CH3:25])=[CH:19][C:20]([CH3:24])=[CH:21][C:22]=3[CH3:23])[C:3]2=[O:4])[CH2:10][CH2:9]1
Reactant: COC(=O)C1(NC(=O)Cc2c(C)cc(C)cc2C)CCN(N(C)C)CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)c(C2C(=O)NC3(CCN(N(C)C)CC3)C2=O)c(C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.7 %

Procedure:
300 mg 1-Dimethylamino-4-[2-(2,4,6-trimethyl-phenyl)-acetylamino]-piperidine-4-carboxylic acid methyl ester (from Step 3) is dissolved in 5 ml N,N-dimethylformamide, and 466 mg potassium t-butoxide is added. The mixture is stirred at room temperature for 18 hours. Then water is added, and the pH adjusted to 5.2 by the addition of aqueous hydrochloric acid. The mixture is extracted with ethyl acetate, the organic layer washed with brine, dried over sodium sulfate, and the solvent evaporated. The residue is purified by chromatography on silica gel, with toluene/ethanol/dioxane/triethylamine/water (20:8:4:4:1) as a solvent. Thus, 196 mg 8-Dimethylamino-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]decane-2,4-dione is obtained as a solid, mp 237-241° C. 1H-NMR (d4-methanol): 6.94 ppm (s, 2H), 3.09 ppm (m, 2H), 2.79 ppm (m, 2H), 2.53 ppm (s, 6H), 2.28 ppm (m, 5H), 2.16 ppm (s, 6H), 1.64 ppm (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH:15]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.O1CCCC1>CO.[Pd].[H][H]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc([N+](=O)[O-])c2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(N)c2)CC1
Yield: 99.7 %

Procedure:
To a solution of 2.54 g of tert-butyl 1,2,3,6-tetrahydro-4-(3-nitrophenyl)pyridine-1-carboxylate (which was prepared by the method as described in Synthesis, 1991, 993-995) in 20 ml of methanol, 250 mg of 10% palladium-on-carbon catalyst was added, and stirred for an hour in hydrogen atmosphere at ambient temperature and pressure. After addition of 20 ml of tetrahydrofuran to the reaction liquid, the liquid was filtered with Celite. Distilling the solvent off under reduced pressure, 2.30 g of the title compound was obtained.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([C:16]3[N:20]([C:21]4[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=4)[NH2:24])[N:19]=[C:18]([C:28]([F:31])([F:30])[F:29])[CH:17]=3)=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].C[Si]([N:36]=[C:37]=[O:38])(C)C.C(N(CC)CC)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl.C1COCC1>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([C:16]3[N:20]([C:21]4[CH:22]=[C:23]([NH:24][C:37]([NH2:36])=[O:38])[CH:25]=[CH:26][CH:27]=4)[N:19]=[C:18]([C:28]([F:31])([F:29])[F:30])[CH:17]=3)=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(C(F)(F)F)nn3-c3cccc(N)c3)s2)c1
Reactant: C[Si](C)(C)N=C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(C(F)(F)F)nn3-c3cccc(NC(N)=O)c3)s2)c1
Reaction time: 8 h
Yield: 49 %

Procedure:
To a solution of the 3-(5-(5-(3-(methylsulfonyl)phenyl)-thiophen-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)aniline in anhydrous DCM (1.0 mL) and THF (3.0 mL) was added trimethylsilyl isocyanate (112 mg, 0.85 mmol) and triethyl amine (29 mg, 0.28 mmol). The reaction mixture was stirred under nitrogen atmosphere for overnight. A 1.0 M solution of tetra-butylammonium fluoride (1.42 mL, 1.42 mmol) in THF was added and the mixture was stirred at room temperature for overnight. The solvent was evaporated in vacuo and the resulting residue was purified by HPLC, providing the urea product (70 mg, 49%). 1H-NMR (Acetone-d6): δ 8.56 (s, 1H), 8.13 (m, 1H), 7.98 (m, 1H), 7.91 (m, 1H), 7.69 (m, 1H), 7.60 (m, 1H), 7.49 (m, 1H), 7.20 (m, 1H), 7.17 (m, 1H), 6.44 (br, 2H), 3.18 (s, 3H). MS (ES): 507 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.[C-:12]#[N:13].[Na+].O>CN(C=O)C>[N+:9]([C:5]1[CH:4]=[C:3]([CH2:2][C:12]#[N:13])[CH:8]=[CH:7][CH:6]=1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1cccc([N+](=O)[O-])c1
Yield: 43.9 %

Procedure:
A solution of 1-(bromomethyl)-3-nitrobenzene (30 g, 0.139 mol) and NaCN (10.21 g, 0.208 mol) in DMF (150 mL) was stirred at 50° C. for 5 hrs. The mixture was poured into water and extracted with ethyl acetate. The combined organic layer were dried, concentrated and purified by silica-gel column chromatography (PE:EA 20:1˜6:1) to give compound 2-(3-nitrophenyl)acetonitrile (9.9 g, yield 44%).