Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[F:9])#[CH:2].I[CH3:11].[N-:12]=[N+:13]=[N-:14].[Na+]>C(#N)C.O.[Cu]I>[F:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]1[N:12]=[N:13][N:14]([CH3:11])[CH:2]=1
Reactant: C#Cc1ccccc1F
Reactant: CI
Reactant: [N-]=[N+]=[N-]
Agent: [Cu]I
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cn1cc(-c2ccccc2F)nn1
Yield: 24.2 %

Procedure:
Solution A was composed of 1-ethynyl-2-fluorobenzene (4.2 g, 35 mmol) and iodomethane (5.96 g, 42 mmol) in acetonitrile (94 mL) and Solution B was composed of sodium azide (2.73 g, 42 mmol) and copper(I) iodide (1.33 g, 6.99 mmol) in water (100 mL). The reaction was ran in Uniqsis FlowSyn apparatus at 150° C. at 100 psi with flow rate of 1.0 mL/min and residence time of 1.5 min for each solution A and B. The reaction flow eluent was collected in an aqueous ammonium hydroxide solution (25%) and the mixture extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 10 to 60% ethyl acetate in heptane) afforded the title compound (1.5 g, 24%) as a light yellow solid. MS: m/e=178.3 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:6](#N)[CH2:7][C:8]#[N:9].Cl.C(OCC)(=[O:14])C>CCOCC.O>[NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH2:7][C:8]#[N:9])=[O:14]
Reactant: N#CCC#N
Reactant: c1cc[nH]c1
Reactant: CCOC(C)=O
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: N#CCC(=O)c1ccc[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into an ice-chilled solution of 30 g of pyrrole and 30 g of malononitrile in 800 ml of dry ether is passed by HCl for 20 minutes. After standing several hours the suspension is filtered to give 65 g of orange-brown, water-soluble solid. The solution of 50 g of this intermediate (the enamine nitrile hydrochloride) in 600 ml of water is covered with 400 ml of ethyl acetate and stirred for 21/2 hours at room temperature. The organic layer is separated, dried (MgSO4) and evaporated to give crystals, m.p. 77°-9°; additional product is obtained by warming the aqueous layer on steam cone for 1/2 hour and extracting with ethyl acetate. Recrystallization from water gives 2-pyrroloylacetonitrile, m.p. 79°-81°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:12]([OH:14])=O.[CH3:15][N:16]([CH3:34])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:12]([N:24]([CH2:23][C:20]1[CH:19]=[CH:18][C:17]([N:16]([CH3:34])[CH3:15])=[CH:22][CH:21]=1)[C:25]1[CH:26]=[CH:27][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:29][CH:30]=1)=[O:14]
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Reactant: O=C(O)C1CCOc2ccc(Cl)cc21
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCOc3ccc(Cl)cc32)cc1
Yield: 25.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 6-chlorochroman-4-carboxylic acid (0.66 g) and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.83 g) as starting materials, 6-chloro-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)chroman-4-carboxamide (0.36 g) was obtained.
Reaction SMILES: P(OC)(OC)OC.C(N(CC)CC)C.[CH2:15]1[CH2:43][O:42][C:17]([C@@H:19]2[C@:36]3([CH3:37])[C@H:22]([C@H:23]4[C@H:33]([C:34](=[O:38])[CH2:35]3)[C@:31]3([CH3:32])[C@H:26]([CH2:27][C:28](=[O:41])[C:29](=[CH:39]O)[CH2:30]3)[CH2:25][CH2:24]4)[CH2:21][CH2:20]2)([CH3:18])[O:16]1>C(O)(C)C.O.Cl.Cl.Cl[Ir](Cl)(Cl)Cl>[CH2:43]1[CH2:15][O:16][C:17]([C@@H:19]2[C@:36]3([CH3:37])[C@H:22]([C@H:23]4[C@H:33]([C:34](=[O:38])[CH2:35]3)[C@:31]3([CH3:32])[C@H:26]([CH2:27][C:28](=[O:41])[C@H:29]([CH3:39])[CH2:30]3)[CH2:25][CH2:24]4)[CH2:21][CH2:20]2)([CH3:18])[O:42]1
Reactant: CC1([C@H]2CC[C@H]3[C@@H]4CC[C@H]5CC(=O)C(=CO)C[C@]5(C)[C@H]4C(=O)C[C@]23C)OCCO1
Agent: Cl[Ir](Cl)(Cl)Cl
Agent: COP(OC)OC
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: C[C@@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C5(C)OCCO5)[C@@]4(C)CC(=O)[C@@H]32)CC1=O
Yield: 6.7 %

Procedure:
A solution of chloroiridic acid (30 mg.) and trimethyl phosphite (4.5 ml.) in aqueous 90% isopropanol (60 ml.) was heated under reflux for 17 hr. The solution was then neutralised with triethylamine and 20,20-ethylenedioxy 2-hydroxymethylene-5α-pregnane-3,11-dione (2 g.) was added. The mixture was heated under reflux for 40 hr. then cooled and partitioned between water and methylene chloride. The organic layer was dried (MgSO4) and evaporated in vacuo. The residue (1.94 g.) was subjected to preparative t.l.c. giving two fractions. The less polar fraction (0.18 g.) was crystallised from methanol to give 20,20-ethylenedioxy-2α-methyl-5α-pregnane-3,11-dione (0.13 g.), m.p. 179°-180°, [α]D + 77.5°.
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]([CH2:15][O:16][C@H:17]([CH3:30])[CH2:18][O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6].[Cl:31][C:32]1[C:33]([N:40]2[C:44]3=[N:45][CH:46]=[N:47][C:48](Cl)=[C:43]3[CH:42]=[N:41]2)=[C:34]([CH:37]=[CH:38][CH:39]=1)[C:35]#[N:36].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O.CCOC(C)=O>[Cl:31][C:32]1[CH:39]=[CH:38][CH:37]=[C:34]([C:35]#[N:36])[C:33]=1[N:40]1[C:44]2=[N:45][CH:46]=[N:47][C:48]([O:3][C@@H:4]([CH2:15][O:16][C@H:17]([CH3:30])[CH2:18][O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:21]([CH3:23])[CH3:22])[CH:24]([CH3:26])[CH3:25])[C:5]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=3)=[O:6])=[C:43]2[CH:42]=[N:41]1
Reactant: N#Cc1cccc(Cl)c1-n1ncc2c(Cl)ncnc21
Reactant: Cc1ccc(NC(=O)[C@@H](O)CO[C@H](C)CO[Si](C(C)C)(C(C)C)C(C)C)nc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)[C@H](CO[C@H](C)CO[Si](C(C)C)(C(C)C)C(C)C)Oc2ncnc3c2cnn3-c2c(Cl)cccc2C#N)nc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 68.9 %

Procedure:
Sodium hydride (64.3 mg, 1.61 mmol) was added to (S)-2-hydroxy-N-(5-methylpyridin-2-yl)-3-((R)-1-(triisopropylsilyloxy)propan-2-yloxy)propanamide (Intermediate AU4) (300 mg, 0.73 mmol) in anhydrous THF (10 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 3-chloro-2-(4-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)benzonitrile (Intermediate AH6) (212 mg, 0.73 mmol) added. The reaction mixture was allowed to warm to ambient temperature and stirred for 2 hours. The reaction mixture was neutralised with 1M citric acid and then diluted with water (50 mL) and EtOAc (100 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (2×100 mL). The combined organics were washed with saturated brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 20 to 40% EtOAc in isohexane to afford the product (334 mg, 68.8%). 1H NMR (400 MHz, DMSO) δ 0.98-0.86 (21H, m), 1.09 (3H, d), 2.24 (3H, s), 3.58-3.47 (1H, m), 3.64 (1H, m), 3.81-3.71 (1H, m), 4.10 (2H, m), 5.92 (1H, s), 7.58 (1H, d), 7.89 (2H, t), 8.18 (3H, m), 8.59 (1H, s), 8.72 (1H, s), 10.88 (1H, s). m/z (ES+) (M+H)+=664; HPLC tR=3.99 min.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1.[N:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C(Cl)Cl.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:12]1[CH:17]=[CH:16][C:15]([C:2]2[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1ccc(Br)s1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1ccc(-c2ccncc2)s1
Temperature: 100 °C
Yield: 65.7 %

Procedure:
A mixture of ethyl 5-bromothiophene-2-carboxylate (1.560 g, 6.65 mmol), pyridine-4-boronic acid (0.98 g, 7.98 mmol), tetrakis(triphenylphosphine)palladium(0) (768 mg, 0.665 mmol) and cesium carbonate (6.50 g, 19.9 mmol) in 1,4-dioxane (20 mL) and water (3.35 mL) was stirred and heated at 100° C. under an atmosphere of nitrogen overnight. The reaction was a clear light orange with a small amount of a second liquid phase on the bottom of the flask. An aliquot was taken, quenched into water, and extracted with ethyl acetate. A TLC on silica gel (1:1 DCM:hexane) indicated that all of the starting material had been consumed. A major new product with Rf ˜0.4 was seen. The reaction was cooled to room temperature then was quenched into stirring water and extracted with ethyl acetate. The ethyl acetate extracts were washed with saline, dried over sodium sulfate, filtered, and evaporated to leave crude product as an off-white solid. The crude product was dissolved in minimal DCM then was purified by column chromatography on silica gel (gradient 100% DCM to 50% ethyl acetate) to afford product 1.02 g (66% yield) as white solid. LC/MS (FA) ES+ 234. 1H NMR (400 MHz, DMSO) δ 8.68-8.60 (m, 2H), 7.91-7.83 (m, 2H), 7.78-7.71 (m, 2H), 4.37-4.27 (d, J=7.1 Hz, 2H), 1.35-1.27 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:9]=2)[C:4](=O)[CH2:3]1.[CH3:17][C:18]1([C:24](=[O:28])[CH2:25][C:26]#[N:27])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH3:1][C:2]1([CH3:16])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:9]=2)[C:4](=[C:25]([C:24]([C:18]2([CH3:17])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:28])[C:26]#[N:27])[CH2:3]1
Reactant: CC1(C(=O)CC#N)CCCCC1
Reactant: CC(C)(C)c1ccc2c(c1)C(C)(C)CC2=O
Product: CC1(C(=O)C(C#N)=C2CC(C)(C)c3cc(C(C)(C)C)ccc32)CCCCC1

Procedure:
3,3-Dimethyl-5-tert-butyl-1-indanone are reacted with 3-(1′-methylcyclohexyl)-3-oxo-propiononitrile analogously to Example 1.
Reaction SMILES: [NH3:1].[CH2:2]([NH:9][C:10](=[O:25])[CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[O:18][C:17]([CH3:23])([CH3:22])[CH:16]3[O:24][CH:15]3[C:14]=2[CH:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O>C(O)C>[NH2:1][CH:15]1[C:14]2[C:19](=[CH:20][CH:21]=[C:12]([CH2:11][C:10]([NH:9][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[O:25])[CH:13]=2)[O:18][C:17]([CH3:23])([CH3:22])[CH:16]1[OH:24]
Reactant: N
Reactant: CC1(C)Oc2ccc(CC(=O)NCc3ccccc3)cc2C2OC21
Solvent: O
Solvent: CCO
Product: CC1(C)Oc2ccc(CC(=O)NCc3ccccc3)cc2C(N)C1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
250 ml of a 25%-strength aqueous ammonia solution was added to a solution of 35 g of the N-benzyl-2-(2,2-dimethyl-1a,7b-dihydro-2H-oxireno[c]chromen-6-yl)acetamide obtained above in 250 ml ethanol, and the mixture was stirred for 18 hours at room temperature. The reaction mixture was poured into 500 ml water and extracted with 250 ml dichloromethane. The organic phase was separated, dried over sodium sulfate and largely evaporated under reduced pressure. 200 ml diethyl ether was added to the remaining residue. The crystals produced after a while were removed by suction and dried on a rotary evaporator at 60° C. and 20 bar. 11 g 2-(4-amino-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-N-benzylacetamide was obtained as grey solid, which was used without further purification or characterization for the subsequent reaction.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][NH2:13].C1([CH:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:21](O)=[O:22])C=CC=CC=1.[CH3:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>>[C:42]1([CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:20][C:21]([NH-:1])=[O:22])[CH:41]=[CH:40][CH:45]=[CH:44][CH:43]=1.[C:42]1([CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:20][C:21]([NH-:1])=[O:22])[CH:41]=[CH:40][CH:45]=[CH:44][CH:43]=1.[C:42]1([CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:20][C:21]([NH-:1])=[O:22])[CH:41]=[CH:40][CH:45]=[CH:44][CH:43]=1.[NH2:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2][NH2:1]
Reactant: CCCCCC
Reactant: CCCCCCCCCCCCCCCCC(C(=O)O)c1ccccc1
Agent: NCCNCCNCCNCCN
Product: [NH-]C(=O)CCCCCCCCCCCCCCCCCc1ccccc1
Temperature: 175 °C
Reaction time: 2 h

Procedure:
Into a 300 ml reaction flask equipped with a thermometer, an agitator and an addition funnel, 6 g (0.03 mole) tetraethylenepentamine was added and heated to 70°-75° C. with agitation. From the addition funnel, 32.4 g (0.09 mole) phenylstearic acid was added over 10 minutes. To insure complete addition of phenylstearic acid, 15-20 ml hexane was added to the addition funnel and thence into the reaction mixture after hexane was allowed to evaporate away, the contents of the flask was placed under reduced pressure and heated to 175° C. with agitation. Heating was continued at 175° C. for 2 hours allowing the condensation water to distill off. The product, tetraethylenepentamine tris(phenylstearoylamide) was viscous, amber colored liquid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[N:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:15][CH:14]=1.C([O-])(=O)C.[Na+].[CH:29]([NH2:31])=O.C(OC(=O)C)(=O)C>[Cu]I.C(OCCCC)(=O)C>[C:29]([C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[N:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:15][CH:14]=1)#[N:31]
Reactant: NC=O
Reactant: CCN(CC)c1ccc(N=Nc2ccc([N+](=O)[O-])cc2Br)cc1
Agent: [Cu]I
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CCCCOC(C)=O
Product: CCN(CC)c1ccc(N=Nc2ccc([N+](=O)[O-])cc2C#N)cc1
Temperature: 110 °C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
2-Bromo-4-nitro-4'-(N,N-diethylamino)azobenzene (1.9 parts), copper (I) iodide (0.95 parts), anhydrous sodium acetate (1.2 parts), formamide (1.8 parts), acetic anhydride (2.0 parts) and n-butyl acetate (44 parts) are mixed together and heated, with stirring, to 110° C. during 15 minutes. The temperatures is maintained at 110° C. for 31/2 hours when reaction is adjudged complete by thin layer chromatography. The solvent is removed at 80° C. under reduced pressure and the residue is slurried in water (250 parts), collected and dried. 2-Cyano-4-nitro-4'-(N,N-diethylamino)azobenzene is obtained in 75% yield and requires no purification.
Reaction SMILES: [C:1]([O:6][C@@H:7]([C:9]1[N:14]=[C:13](Cl)[CH:12]=[CH:11][N:10]=1)[CH3:8])(=[O:5])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[N:23]1([C:29]2[O:30][C:31]3[C:36]([N:37]=2)=[CH:35][CH:34]=[CH:33][N:32]=3)[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(O)(C)C>[C:1]([O:6][C@@H:7]([C:9]1[N:14]=[C:13]([N:26]2[CH2:25][CH2:24][N:23]([C:29]3[O:30][C:31]4[C:36]([N:37]=3)=[CH:35][CH:34]=[CH:33][N:32]=4)[CH2:28][CH2:27]2)[CH:12]=[CH:11][N:10]=1)[CH3:8])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)O[C@H](C)c1nccc(Cl)n1
Reactant: c1cnc2oc(N3CCNCC3)nc2c1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CCCC(=O)O[C@H](C)c1nccc(N2CCN(c3nc4cccnc4o3)CC2)n1
Temperature: 25 °C
Yield: 94 %

Procedure:
To a solution of (R)-1-(4-chloro-pyrimidin-2-yl)-ethyl butyrate (prepared according to the method of Preparation Seven, 6.8 g, 29.9 mmol) and triethylamine (12.5 mL, 89.6 mmol) in isopropanol (100 mL) was added 2-(1-piperazinyl)oxazolo[5,4-b]pyridine (prepared according to the method of Example 9, Step A, 6.1 g, 29.9 mmol). This mixture was stirred at reflux overnight, cooled to room temperature, and evaporated. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with chloroform (3×). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (1.5→2% methanol/chloroform) to give 11.1 g (94%) of the title compound of Example 9, Step B as a yellow oil which solidified upon standing. 1H NMR (CDCl3, 250 MHz) δ 8.28 (d, 1H), 7.97 (dd, 1H), 7.60 (dd, 1H), 7.25 (dd, 1H), 6.44 (d, 1H), 5.70 (q, 1H), 3.85 (app s, 8H), 2.42 (t, 2H), 1.78 -1.61 (c, 2H), 1.60 (d, 3H), 0.98 (t, 3H); MS (APCI) 397 (MH+).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:14])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[CH:3]=1.C(C1N=C(C2C=C(O[CH:39]3[CH2:57][CH:56]4[N:41]([C:42](=[O:62])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH:49]=[CH:50][CH:51]5[C:53]([C:59]([OH:61])=[O:60])([NH:54][C:55]4=[O:58])[CH2:52]5)[CH2:40]3)C3C(=CC(OC)=CC=3)N=2)SC=1)(C)C>>[S:16]1[CH:17]=[CH:18][N:19]=[C:15]1[C:4]1[CH:3]=[C:2]([O:1][CH:39]2[CH2:57][CH:56]3[N:41]([C:42](=[O:62])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH:49]=[CH:50][CH:51]4[C:53]([C:59]([OH:61])=[O:60])([NH:54][C:55]3=[O:58])[CH2:52]4)[CH2:40]2)[C:11]2[C:6](=[C:7]([CH3:14])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1
Reactant: COc1ccc2c(O)cc(-c3nccs3)nc2c1C
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nccs3)nc2c1C

Procedure:
The title compound was prepared from quinoline 24 and intermediate 7 following the procedure (Step F-H) reported for 18-[2-[4-(isopropyl)thiazol-2-yl]-7-methoxyquinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid 10: m/z=605 (M+H)+.
Reaction SMILES: CS[C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[S:5][N:4]=1.Cl[C:16]1C=C(C=CC=1)C(OO)=O.[S:26]([O-:29])([O-])=[O:27].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:16][S:26]([C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[S:5][N:4]=1)(=[O:29])=[O:27]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])[O-]
Reactant: CSc1nsc(-c2cccc(F)c2)n1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1nsc(-c2cccc(F)c2)n1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
In 8 ml of chloroform, 360 mg of 3-methylthio-5-(3-fluorophenyl)-1,2,4-thiadiazole was dissolved, to the resulting solution was added 982 mg of 3-chloroperoxybenzoic acid (65%<) with ice-cooling, and the mixture was stirred at room temperature for 7 hours. The reaction mixture was poured into an aqueous sodium sulfite solution, and the layers were separated. The organic layer was washed with an aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated to obtain 520 mg of 3-methylsulfonyl-5-(3-fluorophenyl)-1,2,4-thiadiazole.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)[CH:5]=[CH:6]C=1.[NH2:19]C1C=CN=CC=1.N1C=CC=CC=1C=O>>[N:19]1[CH:6]=[CH:5][C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)=[CH:3][CH:2]=1
Reactant: Clc1cccc(-n2nnc(-c3ccccn3)n2)c1
Reactant: Nc1ccncc1
Agent: O=Cc1ccccn1
Product: c1ccc(-c2nnn(-c3ccncc3)n2)nc1

Procedure:
Following the procedure described in EXAMPLE 1 for the synthesis of 2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]pyridine, 4-aminopyridine (56.5 mg, 0.6 mmol) and 2-pyridinecarboxaldehyde (64.2 mg, 0.6 mmol) were employed to obtain 2-[2-(4-pyridyl)-2H-tetrazol-5-yl]pyridine as an orange solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][C:14]([CH3:19])([CH3:18])[CH2:13]2)=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[C:25]([N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][C:33]1=O)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].[Cl-].[NH4+].C1C[O:44]CC1>C(OCC)(=O)C>[CH3:18][C:14]1([CH3:19])[CH2:15][CH2:16][CH2:17][N:12]([CH2:11][CH2:10][CH2:9][O:8][C:5]2[CH:6]=[CH:7][C:2]([C:35]3([OH:44])[CH2:36][CH2:37][N:32]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:33][CH2:34]3)=[CH:3][CH:4]=2)[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Reactant: C1CCOC1
Reactant: CC1(C)CCCN(CCCOc2ccc(I)cc2)C1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: CC1(C)CCCN(CCCOc2ccc(C3(O)CCN(C(=O)OC(C)(C)C)CC3)cc2)C1
Temperature: 2.5 °C
Reaction time: 2.5 h

Procedure:
A solution of 1-{3-[(4-iodophenyl)oxy]propyl}-3,3-dimethylpiperidine (25 g) in THF (125 ml) is stirred for about 15 min, then cooled to 0-5° C. Isopropyl magnesium chloride solution (70.5 ml, 1.9M) is added at 0-5° C. over about 40 min, then the mixture is stirred at 0-5° C. for 2-3 h. The mixture is then cooled to −78 to −80° C. and a precooled solution (−20 to −30° C.) of N-Boc-piperidinone (16 g) in THF (125 ml) is added over about 1-2 h and the reaction mixture is stirred for about 1.5 h at −78 to −80° C. The reaction mixture is allowed to warm to 25-30° C., then stirred for 23-24 h. Saturated ammonium chloride solution (375 ml) is added at 25-30° C., followed by ethyl acetate (500 ml) and the mixture stirred for about 50 min. The aqueous layer is extracted with ethyl acetate (250 ml). The combined organic layers are washed with water (375 ml), dried over sodium sulfate and concentrated under reduced pressure to give the crude title compound (30.3 g).
Reaction SMILES: [Cu:1]=O.N1C=CC=CC=1.[CH3:9][C:10]([OH:12])=[O:11]>>[CH3:9][C:10]([O-:12])=[O:11].[CH3:9][C:10]([O-:12])=[O:11].[Cu+2:1]
Reactant: O=[Cu]
Reactant: CC(=O)O
Solvent: c1ccncc1
Product: CC(=O)[O-]
Product: [Cu+2]
Temperature: 650 °C

Procedure:
A 0.4M solution of Cu(OAc)2 (0.5 g) in pyridine/HOAc (~4:1) was prepared at a temperature of approximately 120° C., generating a homogenous precursor solution. Thin films were deposited and heat treated on a 300° C. hot plate and then heated to 650° C. to form the copper oxide thin film.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:28][CH2:27][C:10]2[C:11]3[C:12](Cl)([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:13]([F:19])([F:18])[CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H][H]>CCO.[Pd]>[CH2:1]([O:3][C:4]([N:6]1[CH2:28][CH2:27][C:10]2[C:11]3[CH:12]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:13]([F:19])([F:18])[CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2ccc3c(c2CC1)C(Cl)(c1ccccc1)C(F)(F)C3
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)N1CCc2ccc3c(c2CC1)C(c1ccccc1)C(F)(F)C3
Yield: 78.6 %

Procedure:
Into a 500 ml Parr bottle, the product from step (d) (5.9 g, 14.56 mmol) dissolved in EtOH (150 ml) was added. To the solution, 5% Pd—C (3 g) was added. The reaction mixture was shaken over hydrogen (50 psi) for 16 hours. The reaction mixture was filtered through celite and the volatiles were evaporated in vacuo to give the crude product. Purification by silica-gel chromatography (gradient elution: 0 to 20% EtOAc in hexanes) gave the sub-title compound as a colorless oil (4.25 g). 1H NMR (300 MHz, CHCl3) δ 7.28-7.26 (m, 3H); 7.10 (s, 2H); 7.01-6.98 (m, 2H); 4.64 (d, J=20.1 Hz, 1H); 4.11-4.01 (m, 2H); 3.66-3.60 (m, 1H); 3.54-3.31 (m, 4H); 3.13-3.06 (m, 1H); 2.89-2.85 (m, 2H); 2.67-2.47 (m, 2H); 1.26-1.22 (m, 3H); MS: ESI (positive): 372 (M+1).