Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)C1C=C(C=CC=1)N.Cl[C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][N:14]=1.[CH3:20][C@@H:21]1[CH2:26][NH:25][CH2:24][CH2:23][NH:22]1>>[Cl:19][C:18]1[C:13]([N:25]2[CH2:24][CH2:23][NH:22][CH:21]([CH3:20])[CH2:26]2)=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: Clc1cccnc1Cl
Reactant: C[C@@H]1CNCCN1
Agent: C[Si](C)(C)c1cccc(N)c1
Product: CC1CN(c2ncccc2Cl)CCN1
Yield: 93.2 %

Procedure:
Compound A-02 can be synthesized according to method 1. Just R1, R2, and R3 of Scheme 1 are respectively —Cl, -Me and p-SiMe3. More specifically, compound 1 is 2,3-dichloro-pyridine (6 g), compound 2 is (R)-2-methylpiperazine, the synthesized compound 3 is 1-(3-chloro-2-pyridyl)-3-methyl-piperazine (38 g, yield about 93.2%).
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([NH:12][S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]([O:23]CC)=[O:22])[NH:6]2.CO.[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([NH:12][S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]([OH:23])=[O:22])[NH:6]2
Reactant: CCOC(=O)c1cc2c(C)c(C)cc(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(NS(=O)(=O)c2cccs2)c2[nH]c(C(=O)O)cc2c1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 93.9 %

Procedure:
To a mixed solution of ethyl 4,5-dimethyl-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (1.69 g) in tetrahydrofuran (30 mL)-methanol (20 mL) was added aqueous solution (10 mL) of 85% potassium hydroxide (0.90 g), and the mixture was stirred at room temperature for 15 hr. Aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with ethyl acetate-hexane to give the title compound (1.47 g, yield 94%) as colorless crystals. melting point>285° C. (decomposition).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH2:17][CH3:18])[CH2:5][CH2:6][O:7][C:8]1[C:9]([N+:14]([O-:16])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=1.C(N(CCN[C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])CCOC1C(F)=NC=CC=1)C>>[CH2:17]([N:4]([CH2:3][CH2:2][NH:1][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:5][CH2:6][O:7][C:8]1[C:9]([N+:14]([O-:16])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=1)[CH3:18]
Reactant: CCN(CCNC(=O)OC(C)(C)C)CCOc1cccnc1F
Reactant: CCN(CCN)CCOc1cccnc1[N+](=O)[O-]
Product: CCN(CCNC(=O)OC(C)(C)C)CCOc1cccnc1[N+](=O)[O-]
Yield: 64 %

Procedure:
This compound was prepared, starting from compound 59 (500 mg, 1.97 mmol), according to the procedure developed for compound 64. Reaction time at room temperature: 18 h to give compound 65 (444 mg, 1.25 mmol) as a yellow oil. Yield 64%; IR (CCl4) ν 1172, 1289, 1367, 1500, 1549, 1716, 2977 cm−1; 1H NMR (200 MHz, CDCl3) δ 1.00 (t, 3H, J=7.1 Hz), 1.36 (s, 9H), 2.60 (m, 4H), 2.89 (t, 2H, J=5.6 Hz), 3.13 (q, 2H, J=5.9 Hz), 4.13 (t, 2H, J=5.6 Hz), 7.51 (m, 2H), 8.05 (dd, 1H, J=2.4, 3.4 Hz); ESI-MS m/z 355.1 [M+H]+.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)(=O)[CH3:10].C(=O)(O)[O-].[Na+]>C(O)(=O)C>[C:1]1([NH:7][N:8]=[C:9]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)c1cccnc1
Reactant: NNc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=NNc1ccccc1)c1cccnc1

Procedure:
A solution of 19.7 of phenylhydrazine (21.63 g) and 22 ml of 3-acetylpyridine (24.23 g) in glacial acetic acid (100 ml) is stirred and refluxed for 4.5 hours. The solution is cooled in an ice-water bath and neutralized with a saturated sodium bicarbonate solution (180 ml). The precipitate is collected, washed and dried to give 3-acetylpyridine phenylhydrazone.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]([O:13][CH2:14][CH3:15])=[O:12].[CH3:16][C:17]([CH3:51])([O:19][C:20]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][CH:31]2[CH2:36][CH2:35][N:34]([C:37]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:38])[CH2:33][CH2:32]2)=[C:26]([C:47]([O:49][CH3:50])=[O:48])[CH:25]=1)=[O:21])[CH3:18]>C(Cl)Cl>[CH3:18][C:17]([CH3:51])([O:19][C:20]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:31]2[CH2:36][CH2:35][N:34]([C:37]([O:39][CH2:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)=[O:38])[CH2:33][CH2:32]2)=[C:26]([C:47]([O:49][CH3:50])=[O:48])[CH:25]=1)=[O:21])[CH3:16]
Reactant: CCOC(=O)Cl
Reactant: COC(=O)c1cc(CNC(=O)OC(C)(C)C)ccc1NC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N(c1ccc(CNC(=O)OC(C)(C)C)cc1C(=O)OC)C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 96 h
Yield: 47.8 %

Procedure:
2.08 g of DIEA and then 1.745 g of ethyl chloroformate are added to a solution of 1.6 g of benzyl 4-{[4-({[(1,1-dimethylethoxy)carbonyl]amino}methyl)-2-(methoxycarbonyl)phenyl]amino}piperidine-1-carboxylate obtained in stage 5.2 in 11 ml of DCM. The mixture is stirred at AT for 4 days. It is evaporated under reduced pressure. The residue is taken up in 10 ml of pyridine (10 ml) and 0.7 g of ethyl chloroformate is added. The mixture is stirred at AT for 4 h 00. It is evaporated under reduced pressure. The residue is chromatographed on silica gel, elution being carried out with an AcOEt/heptane mixture, (10/90, v/v) as far as (30/70, v/v), to give 0.875 g of the expected product.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][NH:19][CH2:20][CH:21]([O:24][CH3:25])[O:22][CH3:23])[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3][CH2:2]1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1>C(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]([CH2:20][CH:21]([O:22][CH3:23])[O:24][CH3:25])[C:34]([NH:33][C:30]4[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=4)=[O:35])[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: COC(CNCCN1CCN(c2cccc3c2OCCO3)CC1)OC
Solvent: ClCCl
Product: COC(CN(CCN1CCN(c2cccc3c2OCCO3)CC1)C(=O)Nc1ccc(F)cc1)OC

Procedure:
A solution of 1-(1,4-benzodioxan-5-yl)-4-(2-(2,2-dimethoxy-1-ethylamino)-1-ethyl)piperazine (2.3 g) and 4-fluorophenyl isocyanate (0.9 g) in methylene chloride (100 ml) was refluxed for 2 h. Removal of solvent in vacuo gave an oil which was purified on a silica gel column (eluent: ethyl acetate/methanol=3:1). The product, 1-(1,4-benzodioxan5-yl)-4-(2-(N-(2,2-dimethoxy 1-ethyl)-N-(4-fluorophenylaminocarbonyl)-amino)-1-ethyl)piperazine, was obtained as a solid (2.5 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[N:17]=2)=[O:15])[C:10]([CH3:25])([CH3:24])[CH2:9]1)=O)(C)(C)C.[C:26]([OH:32])([C:28]([F:31])([F:30])[F:29])=[O:27]>C(Cl)Cl>[F:29][C:28]([F:31])([F:30])[C:26]([OH:32])=[O:27].[CH3:24][C:10]1([CH3:25])[CH2:9][NH:8][CH2:13][CH2:12][N:11]1[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[N:17]=1)=[O:15]
Reactant: COc1cccc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(C(=O)N2CCNCC2(C)C)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 780 mg (2.23 mmol) 4-(6-methoxy-pyridine-2-carbonyl)-3,3-dimethyl-piperazine-1-carboxylic acid tert-butyl ester and 2.00 mL (25.9 mmol) TFA in 10 mL DCM was stirred at RT for 12 h. The solvent was evaporated and the residue triturated with diethyl ether. The precipitate was filtered off, washed with diethyl ether and dried.
Reaction SMILES: C[O:2][C:3](=[O:34])[C@H:4]([CH2:30][CH2:31][S:32][CH3:33])[NH:5][C:6](=[O:29])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:20]=2Cl)=[CH:9][C:8]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28].[H-].[Na+:36]>CN(C=O)C.C(O)CC>[Na+:36].[CH2:3]([O:2][C:20]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[CH:14]=[CH:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]([NH:5][C@H:4]([C:3]([O-:2])=[O:34])[CH2:30][CH2:31][S:32][CH3:33])=[O:29])=[C:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH:9]=1)[CH2:4][CH3:30]
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(C=Cc2cnccc2Cl)cc1-c1ccccc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCO
Product: CCCOc1ccncc1C=Cc1ccc(C(=O)N[C@@H](CCSC)C(=O)[O-])c(-c2ccccc2C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-[4-(2-(4-chloropyridin-3-yl)ethenyl)-2-(2-methylphenyl)benzoyl]methionine methyl ester, prepared as in Example 1040, (28 mg, 0.06 mmol) was dissolved in DMF (1 mL) with n-propanol (0.1 mL) and treated with NaH (60% in mineral oil, 6.8 mg, 0.17 mmol). After stirring 18 hours at ambient temperature, the reaction was evaporated and lyophilized from water to provide 29 mg of the title compound. MS m/e 505 (M+H)+. 1H NMR (d6-DMSO, 300 MHz) δ 1.03 (m, 3H), 1.24 (m, 2H), 1.6 (m, 3H), 2.0 (m, 7H), 3.71 (m, 2H), 6.94 (m, 1H), 7.3 (m, 9H), 7.74 (m, 1H), 8.33 (m, 1H), 8.52 (m, 1H), 8.67 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:13])=[CH:4][C:5]2[CH:9]=[C:8]([CH3:10])[S:7][C:6]=2[C:11]=1[Cl:12].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].CC(=O)CC.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][O:13][C:3]1[C:2]([Cl:1])=[C:11]([Cl:12])[C:6]2[S:7][C:8]([CH3:10])=[CH:9][C:5]=2[CH:4]=1)[CH3:20]
Reactant: CCOC(=O)CBr
Reactant: Cc1cc2cc(O)c(Cl)c(Cl)c2s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCC(C)=O
Product: CCOC(=O)COc1cc2cc(C)sc2c(Cl)c1Cl
Yield: 93.9 %

Procedure:
A mixture of 2.1 g of 6,7-dichloro-5-hydroxy 2-methylbenzo[b]thiophene, 1.88 g of ethyl bromoacetate, 20 ml of 2-butanone, 2 ml of dimethylformamide and 4.0 g of sodium bicarbonate is refluxed for 16 hours. The cooled mixture is diluted with ice, extracted 3 times with ether and the ether solution is washed, dried and concentrated. The crude oil after removal of solvent is purified by passing it through an alumina column. Elution with ether gives 2.7 g of ethyl[(6,7-dichloro-2-methylbenzo[b]thien-5-yl)oxy]acetate as off-white crystals, mp 91°-92°. An analytical sample is recrystallized twice from hexane and dried at 80°.
Reaction SMILES: C[O:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[Se](=O)=O.[O:15]1CCOC[CH2:16]1>O.C(OCC)(=O)C>[OH2:2].[CH3:16][O:15][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:4]([CH:3]=[O:2])=[O:5]
Reactant: COCC(=O)c1ccccc1
Reactant: C1COCCO1
Agent: O=[Se]=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccccc1C(=O)C=O

Procedure:
3 g of 2-methoxyacetophenone are dissolved in 15 ml of dioxane, and a solution of 3.3 g of selenium dioxide in 1.5 ml of water is added thereto. The solution is refluxed for 15 hours. After the reaction, insoluble materials are removed by filtration, and the filtrate is concentrated. The oily residue thus obtained is dissolved in ethyl acetate. The ethyl acetate solution is washed with water and then with an aqueous sodium bicarbonate solution and water. Then, said solution is dried and evaporated to remove solvent. 3.1 g of 2-methoxyphenylglyoxal hydrate are obtained as a crude oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:36]=2[Cl:42])=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.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>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:29]=[CH:30][C:31]([S:34][C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:36]=3[Cl:42])=[CH:32][CH:33]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1
Reactant: Clc1ccc(Sc2ccc(Br)cc2)c(Cl)c1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(Sc3ccc(Cl)cc3Cl)cc2)c1C
Yield: 28.8 %

Procedure:
A stirred solution of [6-fluoro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.55 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.032 g, 0.028 mmol), impure 1-(4-bromo-phenylsulfanyl)-2,4-dichlorobenzene (0.2 g, 0.61 mmol) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {4-[4-(2,4-dichloro-phenylsulfanyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.077 g, 29%) as a solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH2:11]([O:13][C:14]([C:16]1[C:17]([CH3:24])=[C:18]([CH:22]=O)[NH:19][C:20]=1[CH3:21])=[O:15])[CH3:12]>N1CCCCC1.C(O)C>[CH3:21][C:20]1[NH:19][C:18]([CH:22]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])=[C:17]([CH3:24])[C:16]=1[C:14]([O:13][CH2:11][CH3:12])=[O:15]
Reactant: O=C1Cc2ccccc2N1
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1C
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3ccccc32)c1C
Temperature: 90 °C
Reaction time: 3 h
Yield: 78.3 %

Procedure:
A reaction mixture of 134.0 mg of oxindole, 234.3 mg of the 4-ethoxycarbonyl-3,5-dimethylpyrrole-2-carboxaldehyde, and 3 drops of piperidine in 3 mL of ethanol was stirred at 90° C. for 3 h. After cooling, the precipitate was filtered, washed with cold ethanol, and dried to yield 244.6 mg (79%) of the title compound as a yellow solid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].N[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.N([O-])=O.[Na+]>O.Cl.C(Cl)(Cl)Cl>[N:1]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1cccnc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: [N-]=[N+]=Nc1cccnc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 97.9 %

Procedure:
Sodium azide (1.5 g) dissolved in 5 ml of water was dropped into a solution of 2.0 g of 3-aminopyridine in 15 ml of 10% hydrochloric acid under cooling with ice. After the reaction solution was stirred for 20 minutes under cooling with ice, 1.8 g of sodium nitrite dissolved in 5 ml of water was dropped in the reaction solution. After temperature of the reaction solution was raised up to room temperature, it was stirred for 1 hour. The reaction solution was diluted with chloroform, washed with water and then with a saturated saline solution and dried over sodium sulfate. The solvent was evaporated in vacuo to give 2.5 g of the title crude compound as a brown oily substance.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:6][CH2:5][C:4]([C:7]([OH:9])=[O:8])=[CH:3]1.[C:11]([OH:19])(=[S:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1CCCCC1>[C:11]([S:18][C@@H:3]1[C:2]([CH3:10])([CH3:1])[CH2:6][CH2:5][C@H:4]1[C:7]([OH:9])=[O:8])(=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OC(=S)c1ccccc1
Reactant: CC1(C)C=C(C(=O)O)CC1
Solvent: C1CCCCC1
Product: CC1(C)CC[C@@H](C(=O)O)[C@@H]1SC(=O)c1ccccc1
Temperature: 120 °C
Yield: 51.6 %

Procedure:
A mixture of 3,3-dimethyl-1-cyclopentene-1-carboxylic acid (2 g) and thio-benzoic acid (2.37 g) is heated to 120° C. for 14 hours under Argon stream. The reaction mixture is cooled, taken up with a small amount of cyclohexane and filtered yielding 2.05 g of trans 2-benzoylthio-3,3-dimethylcyclopentyl carboxylic acid. M.p. 131° C. (from hexane)
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][OH:8])[CH2:2][CH2:3][CH3:4].[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14](O)=[O:15].CCCCCCCC(O[Sn](OC(CCCCCCC)=O)(CCCC)CCCC)=O>C1(C)C(C)=CC=CC=1>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:14]([C:10]1[O:9][CH:13]=[CH:12][CH:11]=1)=[O:15])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)c1ccco1
Reactant: CCCCOCCO
Agent: CCCCCCCC(=O)O[Sn](CCCC)(CCCC)OC(=O)CCCCCCC
Solvent: Cc1ccccc1C
Product: CCCCOCCOC(=O)c1ccco1

Procedure:
2-Butoxyethanol (butyl cellosolve) 121 g (1.02 m), furoic acid 95 g (0.85 m) and 1 g dibutyltin dioctoate were heated with a xylene azeotrope to acid number 3. Xylene removed by distillation to a pot temperature of 200° and reaction product distilled. 2-Butoxyethylfuroate collected in fraction 2, 111°-104°. Yield 162 g, 86%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[C:27]([Cl:29])[CH:28]=1)[O:5][CH:6]([CH2:24][CH3:25])[C:7]([NH:9][C:10]([CH3:23])([CH3:22])[C:11]#[C:12][CH2:13]O[Si](C(C)(C)C)(C)C)=[O:8].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CCCCCC.[C:54](OCC)(=[O:56])C>O1CCCC1>[Cl:29][C:27]1[CH:26]=[C:4]([CH:3]=[C:2]([Cl:1])[CH:28]=1)[O:5][CH:6]([CH2:24][CH3:25])[C:7]([NH:9][C:10]([CH3:22])([CH3:23])[C:11]#[C:12][CH2:13][CH2:54][OH:56])=[O:8]
Reactant: CCOC(C)=O
Reactant: CCC(Oc1cc(Cl)cc(Cl)c1)C(=O)NC(C)(C)C#CCO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(Oc1cc(Cl)cc(Cl)c1)C(=O)NC(C)(C)C#CCCO
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2-(3,5-Dichlorophenoxy)-N-(1-tert-butyldimethylsilyloxy-4-methylpent-2-yn-4-yl)butyramide (prepared as described in Example 1; 3.35 g) in tetrahydrofuran (60 ml) was stirred at 3-5° C. and a solution of tetra n-butylammonium fluoride (14.6 ml of 1M solution in tetrahydrofuran) was added dropwise over 5 minutes. On completion of the addition, the mixture was stirred for 0.5 hour at 0° C., 2 hours at ambient temperature and stored for 18 hours. The solvent was evaporated under reduced pressure and the residue partitioned between ethyl acetate and aqueous ammonium chloride. The organic phase was separated, washed with aqueous ammonium chloride, brine, dried over magnesium sulphate and evaporated under reduced pressure to give a colourless solid that was fractionated by chromatography (silica; hexane/ethyl acetate, 2:1 by volume) to give the required product as a colourless solid (2.01 g) mp 104-106° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[NH:12][CH3:13].[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1)([O-:23])=[O:22]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:30]([C:27]1[CH:26]=[CH:25][C:24]([N+:21]([O-:23])=[O:22])=[CH:29][CH:28]=1)(=[O:31])=[O:32])[C:6](=[O:11])[C:5]2([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[NH:12][CH3:13]
Reactant: CNC1(c2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: CNC1(c2ccccc2Cl)C(=O)N(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)c2ccc(Cl)cc21
Yield: 68.9 %

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 11 from 7.03 g of 5-chloro-3-(2-chlorophenyl)-1,3-dihydro-3-(methylamino)indol-2-one and 5.73 g of 4-nitrobenzenesulfonyl chloride. Chromatography on silica using DCM as the eluent gives 7.76 g of the expected product after crystallization from iso ether. M.p.=220°-221° C.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.[CH3:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C:22]1=[O:27]>CCOCC>[CH3:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C:22]1([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[OH:27]
Reactant: COC1CCCCC1=O
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: COC1CCCCC1(O)c1cccnc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of 2.5M n-butyllithium in hexane (13.2 ml, 33 mmol) at -78° C. was added diethyl ether (15 ml) followed by a solution of 3-bromopyridine (4.7 g, 30 mmol) in ether (90 ml) over a period of 10 minutes. After 1 hour at -78° C. a solution of (±)-2-methoxycyclohexanone (3.84 g, 30 mmol) in ether (20 ml) was added dropwise during 10 minutes. After 2 hours at -78° C. and 30 minutes at 0° C. the reaction mixture was warmed to 20° C. and then poured onto ice (150 g). The mixture was extracted with ether (2×50 ml) and then the combined organic extracts were extracted with 1N hydrochloric acid (50 ml). This aqueous extract was washed with ether (20 ml) and then treated with 2M sodium hydroxide solution (25 ml) and extracted with ether (3×100 ml). The organic extracts were combined, washed with brine then dried over anhydrous sodium sulphate. Concentration in vacuo afforded (±)-2-methoxy-1-(pyrid-3-yl)cyclohexanol (5.0 g, 24 mmol) as a 4:1 mixture of cis and trans isomers;
Reaction SMILES: [C:1](=[NH:23])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=2)=[CH:8][CH:7]=1)[NH2:2].FC(F)(F)C([O-])=O.[CH:31]([CH:33]([CH2:38][C:39]1[CH:40]=[N:41][C:42]([O:45][CH3:46])=[N:43][CH:44]=1)[C:34](OC)=O)=[O:32].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[CH3:46][O:45][C:42]1[N:41]=[CH:40][C:39]([CH2:38][C:33]2[C:31](=[O:32])[N:23]=[C:1]([O:3][CH2:4][CH2:5][C:6]3[CH:7]=[CH:8][C:9]([O:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=4)=[CH:10][CH:11]=3)[NH:2][CH:34]=2)=[CH:44][N:43]=1
Reactant: COC(=O)C(C=O)Cc1cnc(OC)nc1
Reactant: N=C(N)OCCc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: O=C([O-])C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ncc(Cc2c[nH]c(OCCc3ccc(Oc4ccc(C(F)(F)F)cn4)cc3)nc2=O)cn1
Temperature: 80 °C

Procedure:
To the solution of 4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenethyl carbamimidate, Trifluoroacetate (600 mg, 1.369 mmol) and methyl 2-formyl-3-(2-methoxypyrimidin-5-yl)propanoate (246 mg, 1.095 mmol) in 1,4-dioxane (6 mL) was added K2CO3 (757 mg, 5.48 mmol). The mixture was heated with a microwave reactor at 80° C. for 0.5 h. Purification via MDAP then afforded the title compound (2 mg, 0.293 yield). LCMS: rt=3.09 min, [M+H+]=500
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[NH:4][C:5](=O)[CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH3:11].C(N(CC)CC)C.C(Cl)(Cl)=O.[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[N:4]=[C:5]([N:29]1[CH:33]=[CH:32][N:31]=[CH:30]1)[CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH3:11]
Reactant: c1c[nH]cn1
Reactant: CCCOCCC(=O)Nc1ccc(Cl)cc1Cl
Agent: O=C(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCOCCC(=Nc1ccc(Cl)cc1Cl)n1ccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.5 %

Procedure:
6.9 g of 2',4'-dichloro-3-(propoxy)propionanilide and 8 g of triethylamine were dissolved in 30 ml of chloroform and 3.7 g of phosgene were introduced thereto at 0° to 10° C. under cooling with ice. After raising the temperature of the solution to room temperature, the solution was stirred for 2 hours, and then, 2 g of imidazole were added thereto. The mixture was heated under reflux for 2 hours. After completion of the reaction, the resulting reaction solution was cooled to room temperature, washed with water and dried over anhydrous magnesium sulfate. Removal of chloroform from the solution by distillation gave 7.7 g of the desired compound. (nD29 1.5688)