Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[CH:18]=[C:17]([NH:19][CH:20]([CH3:22])[CH3:21])[C:14]([C:15]#[N:16])=[CH:13][N:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[S:23]=S.[NH4+]>CO>[S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[N:12]=[CH:13][C:14]([C:15](=[S:23])[NH2:16])=[C:17]([NH:19][CH:20]([CH3:22])[CH3:21])[CH:18]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: S=S
Reactant: CC(C)Nc1cc(Nc2ccc3ncsc3c2)ncc1C#N
Agent: [NH4+]
Solvent: CO
Product: CC(C)Nc1cc(Nc2ccc3ncsc3c2)ncc1C(N)=S
Temperature: 60 °C

Procedure:
To a stirred solution of 6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)nicotinonitrile (19) (30 mg, 0.09 mmol) in MeOH (2 mL), ammonium thiosulfide (5 mL) was added. The reaction mixture was heated at 60° C. in a pressure tube overnight. The reaction mixture was then evaporated to remove excess of solvent. The crude material was purified by column chromatography through silica gel and MeOH:CHCl3 as eluent to afford 6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridine-3-carbothioamide.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([O:10]C)=[O:9])[CH:5]=[C:4]([C:12]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:14][N:13]=2)[N:3]=1.[OH-].[Li+]>CO.O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[C:4]([C:12]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:14][N:13]=2)[N:3]=1
Reactant: COC(=O)c1cc(C2=NOC(c3ccccc3)C2)nc(C)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nc(C(=O)O)cc(C2=NOC(c3ccccc3)C2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.9 %

Procedure:
To a stirred solution of methyl 2-methyl-6-(5-phenyl-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxylate (0.15 g, 0.505 mmol, Preparation #19) in methanol (1.5 mL) and water (0.5 mL) mixture was added lithium hydroxide (0.036 g, 1.514 mmol, Sd Fine Chem). The reaction mixture was stirred for about 10 min at RT and the organic solvent was removed under reduced pressure. The aqueous layer was acidified with 10% citric acid solution. The solid was collected by filtration, washed with water and dried under vacuum to afford 2-methyl-6-(5-phenyl-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxylic acid 0.1 g, (70.0%) as a yellow solid. 1H NMR (400 MHz, DMSO) δ 14.0 (bs, 1H), 8.16 (s, 1H), 7.42 (m, 5H), 5.92 (m, 1H), 3:98 (m, 1H), 3.45 (m, 1H), 2.72 (s, 3H), MS m/z: 284.2 (m+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](O)([CH3:12])[CH3:11].CS(Cl)(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]([CH3:12])=[CH2:11]
Reactant: COc1ccc(C(C)(C)O)c(F)c1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)c1ccc(OC)cc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(2-fluoro-4-methoxyphenyl)propan-2-ol from Step A (3.89 g, 21.14 mmol) in methylene chloride (50 ml) at 0° C., MsCl (1.95 ml, 25.4 mmol) and triethylamine (6.52 ml, 46.5 mmol) were added. The solution was stirred at 0° C. and then room temperature for 2 h. The solution was diluted with methylene chloride (100 ml), washed with water, and dried over sodium sulfate. The title compound was obtained as an oil after flash column using EtOAc:hexane=1:9 as the elute. 1H NMR (CDCl3, 500 MHz) δ 7.25 (t, J=9.0 Hz, 1H), 6.68 (dd, J=8.5, 2.5 Hz, 1H), 6.63 (dd, J=13, 2.5 Hz, 1H), 5.20 (d, J=17.0 Hz, 2H), 3.82 (s, 3H), 2.18 (s, 3H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C@H:10]3[CH2:12][C@H:11]3NC)[C:4]=2[CH2:3][CH2:2]1.[CH2:15]([N:17](CC)CC)C.[C:22](Cl)(=[O:26])[CH2:23][CH2:24][CH3:25]>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C@H:10]3[CH2:12][C@H:11]3[CH2:15][NH:17][C:22](=[O:26])[CH2:23][CH2:24][CH3:25])[C:4]=2[CH2:3][CH2:2]1
Reactant: CN[C@@H]1C[C@@H]1c1cccc2c1CCO2
Reactant: CCCC(=O)Cl
Reactant: CCN(CC)CC
Product: CCCC(=O)NC[C@@H]1C[C@@H]1c1cccc2c1CCO2
Yield: 29.8 %

Procedure:
The title compound was prepared by the general procedure -described in Example 1 using (cis)-2-(2,3-dihydrobenzofuran-4-yl)cycloprop-1-yl methyl amine (0.79 mmol), triethylamine (2.37 mmol) and butyryl chloride (0.95 mmol). Purification by silica gel column chromatography (Hex:EtOAc, 2:1) provided 61 mg of the desired product (30%) as a white solid. HPLC purity=98%. m.p. 73-74°;
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:16][C:17](=[O:28])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([Cl:27])[CH:21]=1)C>>[Cl:27][C:22]1[CH:21]=[C:20]([CH2:19][CH2:18][C:17]([OH:28])=[O:16])[CH:25]=[CH:24][C:23]=1[O:26][CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: ClCc1cccnc1SC1CCC1
Reactant: CCOC(=O)CCc1ccc(O)c(Cl)c1
Product: O=C(O)CCc1ccc(OCc2cccnc2SC2CCC2)c(Cl)c1
Yield: 60.7 %

Procedure:
3-Chloromethyl-2-cyclobutylsulfanyl-pyridine (34 mg, 0.17 mmol) obtained in Step C of Preparation Example 23 and 3-(3-chloro-4-hydroxy-phenyl)-propionic acid ethyl ester (43 mg, 0.19 mmol) obtained in Step C of Preparation Example 42 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (39 mg, 73%).
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][C@H:2]1[C:5]([OH:7])=[O:6].Cl.Br[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1>[Cu](I)I.CC(N(C)C)=O>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([N:1]2[CH2:4][CH2:3][C@H:2]2[C:5]([OH:7])=[O:6])=[CH:11][CH:12]=1
Reactant: Clc1ccc(Br)cc1
Reactant: O=C(O)[C@@H]1CCN1
Agent: I[Cu]I
Agent: Cl
Solvent: CC(=O)N(C)C
Product: O=C(O)[C@@H]1CCN1c1ccc(Cl)cc1
Temperature: 110 °C

Procedure:
A sealed tube is charged with (S)-Azetidine-2-carboxylic acid; hydrochloride (2 g; 19.8 mmol), 4-bromochlorobenzene (3.8 g; 19.8 mmol) and copper iodide (I) (0.38 g; 1.99 mmol) is evacuated and back-filled with Argon 3 times. Dimethylacetamide (40 mL) is added and the tube is sealed and purged with Argon and evacuated 3 times. The sealed tube is heated in 110° C. oil bath for 72 hours. After this time, the reaction mixture is cooled to room temperature and partitioned between ethyl acetate and water. The organic layer is discarded. The aqueous layer is acidified to PH˜1 by adding 1N hydrochloric acid and then extracted with ethyl acetate twice. The organics are combined and washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography on silica gel using methanol/methylene chloride provides the title compound, m/z 212 [M+H+].
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([CH3:12])=[CH2:11])[CH:5]=1)([CH3:3])=[CH2:2].[ClH:13].[Cl-:14].[Na+].O>>[Cl:13][C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:1]([Cl:14])([CH3:3])[CH3:2])[CH:5]=1)([CH3:12])[CH3:11]
Reactant: [Cl-]
Reactant: C=C(C)c1cccc(C(=C)C)c1
Reactant: Cl
Agent: [Na+]
Solvent: O
Product: CC(C)(Cl)c1cccc(C(C)(C)Cl)c1
Yield: 99 %

Procedure:
A 40 l V4A steel stirred reactor was initially charged with 18.0 kg (114 mol) of 1,3-diisopropenylbenzene. 10.1 kg (277 mol) of hydrogen chloride were passed in within 8 h at an internal temperature of 5-10° C. (brine cooling) and an internal pressure of 1.1 bar. The remaining HCl was removed by stripping with nitrogen. 26 kg (99%) of 1,3-bis(α-chloroisopropyl)benzene were obtained as a colorless liquid; chlorine content 30.1%; 1H-NMR (CD2Cl2, 360 MHZ): 2.00 (s, 12 H, methyl), 7.29–7.52 (m, 3 H, aromat. H), 7.82-7.83 (m, 1 H, aromat. H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[S:5][C:6]=1[CH:7]([OH:9])[CH3:8]>C(Cl)(Cl)Cl.O=[Mn]=O>[CH3:1][C:2]1[N:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[S:5][C:6]=1[C:7](=[O:9])[CH3:8]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(C)O
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: CC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Yield: 100.7 %

Procedure:
A mixture of 1-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl-]-ethanol (1.0 g, 3.48 mmol) and MnO2 (0.45 g, 5.22 mmol) in chloroform (30 mL) is heated to reflux, after 24 hrs, additional MnO2 (300 mg) is added and refluxed for another 9 hrs, the reaction mixture is filtered through celite. Concentration of filtrate gave the title compound (1.0 g).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19](=[S:21])[NH2:20])[C:3]=1[S:22]([CH3:24])=[O:23].[CH2:25]1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].CI>O1CCCC1.C(=O)=O>[CH3:25][S:21][C:19]([C:4]1[C:3]([S:22]([CH3:24])=[O:23])=[C:2]([NH2:1])[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:8]=2[Cl:18])[N:5]=1)=[NH:20]
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: CS(=O)c1c(C(N)=S)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Agent: CC(C)(C)[O-]
Agent: O=C=O
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CSC(=N)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(C)=O
Reaction time: 0.28 h
Yield: 99.2 %

Procedure:
To a stirred solution of 1.00 gram (0.0024 mole) of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carbothioamide, (Compound 4, prepared as described in applicants' copending U.S. patent application Ser. No. 08/418,680, entitled "PESTICIDAL 1-ARYLPYRAZOLE-3-THIOCARBOXAMIDES" [Attorney Docket No. 022650-284 (PH95008)], filed concurrently herewith, incorporated by reference herein in its entirety and relied upon) and a few crystals of 18-crown-6 in 30 milliliters of dry tetrahydrofuran, was added 0.27 gram (0.00244 mole) of potassium tertiary-butoxide, and the mixture was strirred for a few minutes. A 0.16 milliliter (0.00264 mole) portion of methyl iodide was then injected into the reaction mixture, followed by stirring for a two-hour period. An additional 0.08 milliliter (0.0013 mole) portion of methyl iodide and 0.09 gram of potassium tertiary-butoxide were added and stirring was continued for a period of 17 minutes. The mixture was neutralized by passing in gaseous CO2 for about 10 minutes and volatiles were then removed under reduced pressure. The residue was taken up in dichloromethane and filtered, and the filtrate was evaporated to give the product as a crude residue. This was chromatographed on silica, eluting with 2:1 ethyl acetate/hexane, followed by a second chromatography employing 4:1 chloroform/acetone as the solvent, resulting in 0.67 gram (0.00155 mole) of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboximidothioic acid methyl ester (99.2% purity) having a melting point of 206.5° C. This compound is referred to hereinafter as Compound 2.
Reaction SMILES: ClC(N(C)C)=C(C)C.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1[C:17]1[S:18][CH:19]=[C:20]([C:22]([OH:24])=O)[N:21]=1.[NH2:25][C:26]1[C:27]([N:44]2[CH2:49][CH2:48][CH2:47][C@H:46]([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[CH2:45]2)=[C:28]2[CH:34]=[CH:33][N:32]([S:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)(=[O:37])=[O:36])[C:29]2=[N:30][CH:31]=1.N1C=CC=CC=1>C(Cl)Cl>[F:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([F:9])[C:11]=1[C:17]1[S:18][CH:19]=[C:20]([C:22]([NH:25][C:26]2[C:27]([N:44]3[CH2:49][CH2:48][CH2:47][C@H:46]([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:55])([CH3:54])[CH3:56])[CH2:45]3)=[C:28]3[CH:34]=[CH:33][N:32]([S:35]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)(=[O:37])=[O:36])[C:29]3=[N:30][CH:31]=2)=[O:24])[N:21]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Reactant: O=C(O)c1csc(-c2c(F)cccc2F)n1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(NC(=O)c3csc(-c4c(F)cccc4F)n3)cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
A solution of 1-chloro-N,N,2-trimethylpropenylamine (114.1 mg, 0.8539 mmol) in DCM (1.0 mL) was added slowly to a suspension of 2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (Example 2, Step 2, 74.2 mg, 0.308 mmol) in DCM (1.0 mL). The mixture was stirred at room temperature for 2 h. A solution of tert-butyl {(3S)-1-[5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]piperidin-3-yl}carbamate (125.1 mg, 0.2653 mmol) in DCM (2.0 mL) was added, followed by pyridine (217.3 mg, 2.747 mmol), and the mixture was then stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to give the sub-title compound as a dark oil (175.3 mg, 95%). LCMS calc. for C33H33F2N6O5S2 (M+H)+: m/z=695.2. found 695.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.ClC(Cl)(O[C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.[CH3:36][CH:37]([NH2:41])[CH:38]([CH3:40])[CH3:39]>C(Cl)(Cl)Cl.C(N(CC)CC)C.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:28]([NH:41][CH:37]([CH3:36])[CH:38]([CH3:40])[CH3:39])=[O:34])=[C:18]([F:23])[CH:17]=1
Reactant: CC(C)C(C)N
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC(C)C(C)C)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (100 mg) was dissolved in chloroform (5 ml) and triethylamine (1 ml), and a solution of triphosgene (47 mg) in dichloromethane was then added to the solution. The mixture was stirred at room temperature for 30 min. Next, 1,2-dimethylpropylamine (55 μl) was added to the reaction solution, and the mixture was stirred at room temperature for 10 min. The solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/acetone (2/1) to give 89 mg (yield 65%) of the title compound.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]#[N:11].C[O-].[Na+].[C:15]([O:19]C)(=O)[CH:16]=[CH2:17].Cl.[CH2:22]1COC[CH2:23]1>>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([C:10]#[N:11])[CH2:17][CH2:16][C:15](=[O:19])[CH2:23][CH2:22]1
Reactant: CSc1ccccc1CC#N
Reactant: C=CC(=O)OC
Reactant: C1CCOC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: CSc1ccccc1C1(C#N)CCC(=O)CC1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
3.05 g of (2-methylsulfanylphenyl)acetonitrile were added dropwise to a mixture of 3.3 ml of 30% strength sodium methylate solution in MOH and 10 ml of dry THF and stirred for 1 h at 20° C. 1.69 ml of methyl acrylate were then added at 20° C. and the reaction mixture was heated for 4 h under reflux. After cooling, the reaction mixture was poured onto cold 2 N hydrochloric acid and extracted three times with 100 ml each of DCM. The combined organic phases were washed with 100 ml of water and 100 ml of sodium chloride solution, dried with magnesium sulfate and concentrated in vacuo. The residue (4.7 g) was dissolved in 10 ml of dimethyl sulfoxide, 1.5 g of sodium chloride were added and the mixture was heated for 5 h at 180° C. After cooling, 150 ml of EA were added and the mixture was washed three times with 100 ml each of water. The organic phase was dried with magnesium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC (acetonitrile/water). 1.2 g of the title compound were obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.F[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
To a solution of 1-methylpiperazine (0.605 m, 5.45 mmol) in DMF (6.25 ml) was added 4-fluoronitrobenzene (0.750 m, 7.07 mmol) and potassium carbonate (1.13 g, 8.18 mmol) and the reaction mixture stirred at 90° C. overnight. The reaction was then cooled to room temperature, diluted with DCM and washed with water. The organic phase was dried over MgSO4 and the solvent removed in vacuo. The residue was purified by silica gel silica chromatography using a 0-10% MeOH in DCM gradient to afford 1-methyl-4-(4-nitrophenyl)piperazine (1.03 g, 4.66 mmol, 85%) as a yellow solid. 1H NMR (DMSO) δ 2.37 (3H, s), 2.58 (4H, t), 3.45 (4H, t), 6.82 (2H, d), 8.12 (2H, d). LCMS (1) Rt: 1.63 min; m/z (ES+) 222.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH:19]1[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]1)[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]
Reactant: CCOC(=O)CC(NC(=O)OCc1ccccc1)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CC(NC(=O)OCc1ccccc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 4-(1-(benzyloxycarbonylamino)-3-ethoxy-3-oxopropyl)piperidine-1-carboxylate (660 mg, 1.52 mmol) in CH2Cl2 (5 mL), TFA (5 mL) was added. The mixture was stirred at room temperature for 3 h. It was concentrated in vacuo. The residue was purified by HPLC to give ethyl 3-(benzyloxycarbonylamino)-3-(piperidin-4-yl)propanoate as TFA salt. The salt was dissolved in EtOAc (50 mL), which was washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give ethyl 3-(benzyloxycarbonylamino)-3-(piperidin-4-yl)propanoate as free base (102 mg).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([Te:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=O)=[CH:13][CH:12]=1>C(Cl)(Cl)Cl>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([Te:17][C:14]2[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)=[CH:24][CH:23]=1.[C:5]1(=[O:6])[CH:7]=[CH:8][C:1](=[O:2])[CH:3]=[CH:4]1
Reactant: COc1ccc([Te](=O)c2ccc(OC)cc2)cc1
Reactant: Oc1ccc(O)cc1
Solvent: ClC(Cl)Cl
Product: COc1ccc([Te]c2ccc(OC)cc2)cc1
Product: O=C1C=CC(=O)C=C1
Yield: 65 %
Yield: 4 %

Procedure:
Hydroquinone (55 mg, 0.50 mmol) and bis-(p-methoxyphenyl)-telluroxide (196 mg, 0.55 mmol) were stirred in chloroform (2 ml) at room temperature under argon for 16 h. Separation of the reaction components by p.l.c. (benzene-ethyl acetate 9:1) gave bis-(p-methoxyphenyl)-telluride (8 mg, 4%) and p-benzoquinone (35 mg, 65%) as yellow needles m.p. 114°-115° (lit., 115.7°).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[NH:38]1[CH2:43][CH2:42][CH:41]([OH:44])[CH2:40][CH2:39]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:38]3[CH2:43][CH2:42][CH:41]([OH:44])[CH2:40][CH2:39]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Reactant: OC1CCNCC1
Product: O=C(Nc1ccc(Oc2ccnc(N3CCC(O)CC3)n2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and piperidin-4-ol according to conditions described in general procedure C. Mp: 106-108° C.; 1H NMR (400 MHz, CDCl3) δ 1.37-1.46 (m, 2 H), 1.81-1.85 (m, 2 H), 3.13-3.20 (m, 2H), 3.24 (t, J=4.4 Hz, 4 H), 3.83-3.92 (m, 5 H), 4.20 (d, J=12.4 Hz, 1 H), 5.98 (d, J=5.6 Hz, 1 H), 6.76 (d, J=11.6 Hz, 1 H), 7.07 (d, J=8.0 Hz, 1 H), 7.30 (d, J=8.0 Hz, 1 H), 7.49-7.58 (m, 3 H), 7.88-7.93 (m, 2 H), 7.99 (d, J=8.4 Hz, 1 H), 8.16 (d, J=5.2 Hz, 1 H), 8.21 (s, 1 H).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:6]([NH2:7])=[C:5]([F:13])[CH:4]=1.[C:14](Cl)(Cl)=[O:15]>C1(C)C=CC=CC=1>[Cl:2][C:3]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:6]([N:7]=[C:14]=[O:15])=[C:5]([F:13])[CH:4]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1cc([N+](=O)[O-])c(Cl)cc1F
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C=Nc1cc([N+](=O)[O-])c(Cl)cc1F
Temperature: 85 °C
Yield: 37.7 %

Procedure:
Dry HCl gas is passed into a solution of 66.7 g (0.35 mol) of 4-chloro-2-fluoro-5-nitroaniline in 1180 ml of toluene at 0° to 5° C. until the solution is saturated. 34.7 g (0.35 ml) of phosgene are subsequently metered in, and the mixture is heated slowly at 85° C. After a further 17.3 g (0.175 mol) of phosgene have been added and the mixture has been heated at 85° C. (1 h), the batch is flushed with nitrogen until free from phosgene and cooled. Removal of the precipitate by filtration and concentration gives 28.6 g (37.7% of theory) of 4-chloro-2-fluoro-5-nitrophenyl isocyanate of melting point 43°-46° C.; boiling point 125° C. at 0.3 torr (bulb-tube distillation).
Reaction SMILES: [C:1]([C:6]1[C:10]([O:11][C:12]([F:17])([F:16])[CH:13]([Cl:15])[F:14])=[CH:9][N:8]([C:18]2[C:23]([Cl:24])=[CH:22][C:21]([C:25]([F:28])([F:27])[F:26])=[CH:20][C:19]=2[Cl:29])[N:7]=1)([O:3]CC)=[O:2].[OH-].[Na+].CO.Cl>O>[C:1]([C:6]1[C:10]([O:11][C:12]([F:16])([F:17])[CH:13]([Cl:15])[F:14])=[CH:9][N:8]([C:18]2[C:23]([Cl:24])=[CH:22][C:21]([C:25]([F:26])([F:28])[F:27])=[CH:20][C:19]=2[Cl:29])[N:7]=1)([OH:3])=[O:2]
Reactant: CCOC(=O)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1OC(F)(F)C(F)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1OC(F)(F)C(F)Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 78.2 %

Procedure:
A mixture of (RS)-3-carboethoxy-4-(2-chloro-1,1,2-trifluoroethoxy)-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole 5 (0.95 g), aqueous sodium hydroxide solution (2M; 20 ml) and methanol (20 ml) was stirred at room temperature for 20 hours. The solution was acidified with hydrochloric acid (2M), diluted with water (50 ml) and extracted with ether (2×30 ml). The combined extracts were dried over magnesium sulfate and evaporated to give (RS)-3-carboxy-4-(2-chloro-1,1,2-trifluoroethoxy)-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (0.7 g) as a yellow solid, m.p. 149°-159° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>CC(O)=O.CCCCCC>[C:13]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1)(=[O:15])[CH3:14]
Reactant: O=C(O)c1ccc2[nH]ncc2c1
Reactant: CC(=O)OC(C)=O
Solvent: CCCCCC
Solvent: CC(=O)O
Product: CC(=O)n1ncc2cc(C(=O)O)ccc21
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 78.5 %

Procedure:
To a solution of 1H-indazole-5-carboxylic acid (8.6 g, 53.04 mmol) in AcOH (200 ml) was added acetic anhydride (16.2 g), and the reaction was stirred for 2.5 h at 80° C. The resulting solution was diluted with n-hexane (400 ml). The solids were collected by filtration and washed with hexane (5×100 ml) to afford 1-acetyl-1H-indazole-5-carboxylic acid as an orange solid (8.5 g, 78%).