Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[CH:3]=1.[Li]CCCC.[CH3:14][Si:15](Cl)([CH3:17])[CH3:16].O>CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Si:15]([CH3:17])([CH3:16])[CH3:14])[CH:3]=1
Reactant: Brc1cccc(Br)c1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: C[Si](C)(C)c1cccc(Br)c1
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
To a solution of 10 g (42.39 mmol) of 1,3-dibromobenzene in 80 mL of anhydrous Et2O, cooled to −78° C. and maintained under a nitrogen atmosphere, are added dropwise with stirring, over 30 minutes, 26.49 mL (42.39 mmol) of a solution of BuLi (1.5M/hexane). After stirring for a further 30 minutes at −78° C., 5.96 mL (46.63 mmol) of TMSCl are added dropwise to the reaction mixture. Stirring is maintained at this temperature for 90 minutes and the reaction mixture is then hydrolysed by adding 15 mL of water. The product is extracted with ethyl acetate (3×50 mL). The combined organic phases are washed with saturated aqueous NaCl solution (2×25 mL), dried over Na2SO4, filtered and evaporated under reduced pressure. The crude reaction product is purified by chromatography on a column of silica gel, eluting with heptane, to give 9.3 g of the expected 1-bromo-3-trimethylsilylbenzene, in the form of a colourless oil.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:17]=[CH:16][N:15]=[C:14]2[C:10]=1[NH:11][CH:12]=[N:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Br:24][CH2:25][CH2:26]Br>CN(C=O)C>[CH2:1]([NH:8][C:9]1[N:17]=[CH:16][N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[CH2:26][CH2:25][Br:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCBr
Reactant: c1ccc(CNc2ncnc3nc[nH]c23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: BrCCn1cnc2c(NCc3ccccc3)ncnc21
Yield: 82 %

Procedure:
6-Benzylaminopurine (1 g, 4.43 mmol), K2CO3 (2.45 g, 17.8 mmol) and 1,2-dibromoethane (1.15 mL, 13.3 mmol) was stirred for 16 h at room temperature under CaCl2 plug in DMF (30 mL). After removal of the DMF by vacuum evaporation, the resulting material was diluted with water (30 mL) and extracted into ethyl acetate (EtOAc) (3×15 mL). The organic fractions were combined, washed with water (2×10 mL), dried over Na2SO4, purified by carbofiltration and concentrated under vacuum. The pure product was purified by flash chromatography—chloroform:methanol (9:1) was used as an eluent. Yield: 82%.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]1[CH2:9][CH:8]([CH:10]=O)[CH2:7]1.[CH3:22][NH:23][C:24]1[CH2:28][S:27][C:26](=[O:29])[N:25]=1.CC(C)([O-])C.[K+].O>C(O)C>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]1[CH2:9][CH:8](/[CH:10]=[C:28]2/[C:24]([NH:23][CH3:22])=[N:25][C:26](=[O:29])[S:27]/2)[CH2:7]1
Reactant: O=CC1CN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)C1
Reactant: CNC1=NC(=O)SC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CNC1=NC(=O)S/C1=C\C1CN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)C1
Yield: 9.8 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]azetidine-3-carbaldehyde (90 mg) and 4-(methylamino)-1,3-thiazol-2(5H)-one (38 mg) in ethanol (3 mL) was added potassium tert-butoxide (32 mg) at room temperature, and the mixture was stirred with heating under reflux for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (12 mg).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][C:3]=1[C:14](=[O:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].I[CH2:24][CH2:25][OH:26]>C(#N)C>[F:1][C:2]1[C:7]([CH:8]2[CH2:9][CH2:10][N:11]([CH2:24][CH2:25][OH:26])[CH2:12][CH2:13]2)=[CH:6][CH:5]=[CH:4][C:3]=1[C:14](=[O:16])[CH3:15]
Reactant: CC(=O)c1cccc(C2CCNCC2)c1F
Reactant: OCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1cccc(C2CCN(CCO)CC2)c1F

Procedure:
Preparation according to Example 1: 1-(2-fluoro-3-piperidin-4-ylphenyl)ethanone (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and 2-iodoethanol (0.01 g). MS m/z (rel. intensity, 70 eV) 265 (M+, 1), 235 (16), 234 (bp), 133 (5), 109 (5).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:7]([C:10]1[CH:11]=[C:12]([CH:21]=[CH:22][C:23]=1Cl)[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14])([O-:9])=[O:8].Cl.N1CCCCC1>>[N+:7]([C:10]1[CH:11]=[C:12]([CH:21]=[CH:22][C:23]=1[N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14])([O-:9])=[O:8]
Reactant: O=C(c1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: C1CCNCC1
Agent: Cl
Product: O=C(c1ccccc1)c1ccc(N2CCCCC2)c([N+](=O)[O-])c1
Reaction time: 0.07 h

Procedure:
15 ml. of piperidine are added at once to 13 g. of 3-nitro-4-chloro-benzophenone under stirring. Due to the highly exothermic reaction the mixture warms to 98° to 100° C within 4 to 5 minutes, thereafter piperidine hydrochloride starts to separate from the homogeneous reaction mixture. The mixture is stirred for 10 minutes at 98° to 100° C, thereafter cooled, the product is triturated with 30 ml. of n-hexane, and filtered. The crystalline substance is washed on the filter with 2×30 ml. of n-hexane, suctioned well, and suspended several times in distilled water to remove piperidine hydrochloride. The obtained product is dried until constant weight. 15.5 g. of crystalline 3-nitro-4-piperidino-benzophenone are obtained; m.p.: 77° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][OH:11].[CH:12]1([CH2:18][C:19](O)=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.C(Cl)(Cl)Cl>[CH:12]1([CH2:18][C:19]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][CH2:9][CH2:10][OH:11])=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C(O)CC1CCCCC1
Reactant: Nc1ccccc1CCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C(CC1CCCCC1)Nc1ccccc1CCCO
Temperature: 25 °C
Reaction time: 113 h
Yield: 51.9 %

Procedure:
To a solution of 3-(2-aminophenyl)propan-1-ol (180 mg) and cyclohexylacetic acid (203 mg) in dichioromethane (12mL) were added 1-hydroxybenzotriazole (193 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (274 mg) under ice cooling. The solution was stirred at room temperature for 113 hours. Chloroform was then added to the solution and it was washed in turn with water and saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, hexane: ethyl acetate=1:1) to give the title compound (170 mg).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[NH:12]1[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[CH:14]=[CH:13]1>ClCCl>[NH+:12]1([O-:9])[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[CH:14]=[CH:13]1
Reactant: c1cnc2[nH]ccc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][NH+]1C=Cc2cccnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A solution of 3-chloroperbenzoic acid (224.3 g) in dichloromethane (1500 mL) was cooled to 0° C. To this a solution of 1H-pyrrolo[2,3-b]pyridine (59.1 g) in dichloromethane (500 mL) was added dropwise over 30 minutes. The reaction mixture was stirred at room temperature for 1 hour. The solution was concentrated, diluted with methanol (1500 mL) and treated with 10% potassium carbonate in water (300 mL). The slurry was filtered and the filtrate was evaporated to dryness. The residue was chromatographed on neutral alumina with 20% methanol in dichloromethane to give the title compound as a tan solid (47.0 g). MS: 135 (MH+). 1HNMR (CDCl3): δ 13.1 (s, 1H), 8.2 (d, 1H), 7.65 (d, 1H), 7.4 (d, 1H), 7.0 (m, 1H), 6.55 (d, 1H).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:16])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[N:6][CH:7]=1.[CH2:17]([Sn](CCCC)(CCCC)C=C)[CH2:18]CC.[Cl-].[Li+]>C1(C)C=CC=CC=1.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>[O:16]=[C:9]([NH:8][C:5]1[CH:4]=[N:3][C:2]([CH:17]=[CH2:18])=[CH:7][N:6]=1)[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)CCC(=O)Nc1cnc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=Cc1cnc(NC(=O)CCC(=O)OC)cn1
Temperature: 150 °C
Yield: 51 %

Procedure:
Methyl 4-[(5-bromopyrazin-2-yl)amino]-4-oxo-butanoate (A2, 1.00 g, 3.47 mmol) was dissolved in toluene in a microwave vial and tributyl vinyl tin (1.22 g, 3.82 mmol), lithium chloride (0.178 g, 4.17 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.405 g, 0.347 mmol) were added. Argon was bubbling through the mixture for ca. 5 min and the vial was heated under microwave irradiation for 5 min at 150° C. The mixture was diluted with ethyl acetate, washed with water and brine, dried and evaporated. The product was purified by flash chromatography (AcOEt/cyclohexane: 1/99→99/1) to give methyl 4-oxo-4-[(5-vinylpyrazin-2-yl)amino]butanoate A32 (0.42 g, 1.8 mmol, 51% Yield). 1H NMR (400 MHz, CDCl3) 9.42 (1H, s), 9.15 (1H, s), 8.22 (1H, s), 6.72 (1H, m), 6.21 (1H, d), 5.48 (1H, s), 3.72 (3H, s), 2.78 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[C:5]([CH2:7][C:8]#[N:9])=O.O.[NH2:15][NH2:16]>C(O)C>[NH2:9][C:8]1[CH:7]=[C:5]([C:4]2[CH:10]=[CH:11][C:12]([Cl:13])=[C:2]([Cl:1])[CH:3]=2)[NH:16][N:15]=1
Reactant: NN
Reactant: N#CCC(=O)c1ccc(Cl)c(Cl)c1
Solvent: CCO
Solvent: O
Product: Nc1cc(-c2ccc(Cl)c(Cl)c2)[nH]n1

Procedure:
3,4-Dichlorobenzoylacetonitrile (3.0 g) was dissolved in ethanol (15 ml) to which was subsequently added hydrazine monohydrate (0.67 ml) while cooling with ice. The mixture was heatedunder reflux for 5 hours and allowed to cool. Then, the solvent was distilled away under a reduced pressure. The resulting residue was recrystallized from ethyl acetate-hexane to obtain the title compound (1.72 g) as colorless crystals (melting point: 169-170° C.).
Reaction SMILES: [CH3:1][N:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([C:10]3[CH:11]=[N:12][N:13]([CH3:15])[CH:14]=3)[N:8]=[CH:9][C:4]=2[C:3]1=[O:18].[Br:19]Br.O>CC(O)=O>[Br:19][C:16]1[C:5]2[N:6]=[C:7]([C:10]3[CH:11]=[N:12][N:13]([CH3:15])[CH:14]=3)[N:8]=[CH:9][C:4]=2[C:3](=[O:18])[N:2]([CH3:1])[CH:17]=1
Reactant: BrBr
Reactant: Cn1cc(-c2ncc3c(=O)n(C)ccc3n2)cn1
Solvent: O
Solvent: CC(=O)O
Product: Cn1cc(-c2ncc3c(=O)n(C)cc(Br)c3n2)cn1
Yield: 68.5 %

Procedure:
The title compound from step 3 (220 mg, 0.912 mmol) and Br2 (146 mg, 0.912 mmol) in HOAc (15 mL) were stirred at room temperature for 2 h. Water (150 mL) was added, and the resulting solid was collected and triturated with DCM: PE=10:1 (10 mL) to give the title compound (200 mg, yield: 69.0%). 1H NMR (CDCl3, 400 MHz) δ 9.54 (s, 1H), 8.33 (s, 1H), 8.27 (s, 1H), 7.77 (s, 1H), 4.01 (s, 3H), 3.62 (s, 3H).
Reaction SMILES: CS(O[C@@H:6]1[C@@H:11]([CH3:12])[CH2:10][C@@H:9]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:8][C@H:7]1[NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])(=O)=O.[C:35]([O-:38])(=[S:37])[CH3:36].[K+]>CN(C=O)C>[C:35](=[O:38])([S:37][C@H:6]1[C@@H:11]([CH3:12])[CH2:10][C@@H:9]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[NH:19][C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:8][C@H:7]1[NH:27][C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH3:36]
Reactant: CC([O-])=S
Reactant: C[C@H]1C[C@@H](c2ccncc2NC(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1OS(C)(=O)=O
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)S[C@H]1[C@@H](C)C[C@@H](c2ccncc2NC(=O)OC(C)(C)C)C[C@H]1NC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 6 h
Yield: 87 %

Procedure:
To a solution of (+/−)-(1R,2R,4R,6S)-2-(tert-butoxycarbonylamino)-4-(3-(tert-butoxycarbonylamino)pyridin-4-yl)-6-methylcyclohexyl methanesulfonate (1.0 equiv.) in DMF (0.25 M) was added potassium thioacetate (6.0 equiv.). The mixture was stirred for 6 hours in a 60° C. bath under Ar. Upon cooling and the residue was partitioned between EtOAc and H2O. The organic layer was washed with H2O (3x), Na2CO3(sat), NaCl(sat), dried over MgSO4, filtered, concentrated and purified by ISCO SiO2 chromatography to yield (+/−)S-((1S,2R,4R,6S)-2-((tert-butoxycarbonyl)amino)-4-(3-((tert-butoxycarbonyl)amino)pyridin-4-yl)-6-methylcyclohexyl) ethanethioate in 87% yield. LC/MS (m/z)=480.3 (MH+), Rt=0.82 min.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:17])[C@@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[NH2:6].[Br:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.Cl>N1C=CC=CC=1>[CH3:2][O:3][C:4](=[O:17])[C@H:5]([NH:6][S:25]([C:22]1[CH:23]=[CH:24][C:19]([Br:18])=[CH:20][CH:21]=1)(=[O:27])=[O:26])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: COC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)[C@@H](Cc1c[nH]c2ccccc12)NS(=O)(=O)c1ccc(Br)cc1
Reaction time: 8 h

Procedure:
To 1 g (3.9 mmol) of D-tryptophan methyl ester hydrochloride in 12 mL of pyridine at ambient temperature is added 1 g (3.9 mmol) of 4-bromobenzene sulfonyl chloride. The yellow mixture is allowed to stir overnight. It is then poured into aqueous 10% HCl and extracted with several portions of ethyl acetate. The combined organic phases are washed with aqueous 10% HCl, water, and brine, and dried over sodium sulfate. The solution is decolorized with activated charcoal, and concentrated to 1.1 g (65%) of a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[NH:5][C:6]1[C:11]([C:12]#[N:13])=[CH:10][N:9]=[C:8]2[C:14]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[C:15]=3[S:16][C:7]=12.CO>[Fe].O>[NH2:21][C:17]1[C:15]2[S:16][C:7]3[C:8](=[N:9][CH:10]=[C:11]([C:12]#[N:13])[C:6]=3[NH:5][C:4]3[CH:24]=[CH:25][CH:26]=[C:2]([Br:1])[CH:3]=3)[C:14]=2[CH:20]=[CH:19][CH:18]=1
Reactant: N#Cc1cnc2c(sc3c([N+](=O)[O-])cccc32)c1Nc1cccc(Br)c1
Agent: [Fe]
Solvent: CO
Solvent: O
Product: N#Cc1cnc2c(sc3c(N)cccc32)c1Nc1cccc(Br)c1
Reaction time: 12 h

Procedure:
A mixture of 4-(3-bromoanilino)-6-nitro[1]benzothieno[3,2-b]pyridine-3-carbonitrile (0.213 g, 0.5 mmol), iron powder (0.168 g, 3.0 mmol) ammonium chloride (0.325 g, 6.0 mmol), methanol (90 mL) and water (90 mL) is heated at reflux temperature with vigorous stirring under nitrogen for 12 hours. The final mixture is concentrated, and the residue is extracted with ethyl acetate (5×20 mL). The extract is dried over sodium sulfate, evaporated, and re-dissolved in a small volume of chloroform/methanol/DMSO. Purification by silica gel chromatography, eluting with 20:1 chloroform/methanol, yields 6-amino-4-(3-bromoanilino)[1]benzothieno[3,2-b]pyridine-3-carbonitrile as a brown solid, m. p. 256-258° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([Cl:12])=[C:8]([CH:11]=1)[CH:9]=O)([O-:3])=[O:2].Cl.[NH2:14][CH2:15][CH2:16][SH:17].C([BH3-])#N.[Na+].C(O)(=O)C>CO>[ClH:12].[Cl:12][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][C:8]=1[CH2:9][NH:14][CH2:15][CH2:16][SH:17]
Reactant: NCCS
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=[N+]([O-])c1ccc(Cl)c(CNCCS)c1
Reaction time: 24 h
Yield: 78.8 %

Procedure:
T a slurry of 5-nitro-2-chloro-benzaldehyde (1.5 g, 0.0078 mol), 2-aminoethanethiol hydrochloride (2.73 g, 0.023 mol), sodium cyanoborohydride (0.49 g, 0.0078 mol) in anhydrous methanol (30 mL) was added acetic acid (5 mL) and stirred 24 hrs. The mixture was evaporated and the residue triturated with isopropanol giving 2-(2-chloro-5-nitro-benzylamino)-ethanethiol hydrochloride (0.87 g, 45%) as a white solid. MP: 228-231° C.; 1H-NMR (DMSO-d6) δ 9.76-82 (br, 2H), 8.75 (s, 1H), 8.28-31 (d, 1H), 7.85-90 (d, 1H), 4.40 (s, 2H), 3.15-25 (m, 2H), 2.80-90 (m, 2H); LC/MS (ESI+): 247 (M+H).
Reaction SMILES: [F:1][C:2]1[C:3]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[C:14]([NH:15][C:16]([N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[O:17])=[CH:13][N:12](C4CCCCO4)[N:11]=3)[NH:7][C:6]=2[CH:30]=1>ClCCl.FC(F)(F)C(O)=O>[F:1][C:2]1[C:3]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[C:14]([NH:15][C:16]([N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[O:17])=[CH:13][NH:12][N:11]=3)[NH:7][C:6]=2[CH:30]=1
Reactant: O=C(Nc1cn(C2CCCCO2)nc1-c1nc2cc(OCCCCN3CCCCC3)c(F)cc2[nH]1)N1CCCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1c[nH]nc1-c1nc2cc(OCCCCN3CCCCC3)c(F)cc2[nH]1)N1CCCCC1
Yield: 77.7 %

Procedure:
A solution of 130 mg of piperidine-1-carboxylic acid [3-[6-fluoro-5-(4-piperidin-1-ylbutoxy)-1H-benzimidazol-2-yl]-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]amide in 2 mL of dichloromethane and 500 μL of trifluoroacetic acid are stirred for 72 hours at ambient temperature. After evaporation of the solvent under vacuum in a rotary evaporator, the reaction crude is purified by flash chromatography on an Analogix RS-12 cartridge with an eluent of 100% dichloromethane to 90/10 dichloromethane/methanol. 86 mg of N-{3-[6-fluoro-5-(4-piperidin-1-ylbutoxy)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}piperidine-1-carboxamide in the form of a trifluoroacetate salt are obtained in the form of a yellow solid. 1H NMR (300 MHz, DMSO-d6, δ in ppm): for this batch, we observe a 60%-40% resolution of tautomers with: from 1.20 to 1.94 (broad m, 16H); from 2.70 to 3.43 (m partially masked, 6H); 3.50 (m, 4H); 4.11 (m, 2H); 7.11 (d, J=7.5 Hz, 0.6H); 7.27 (d, J=11.0 Hz, 0.4H); 7.37 (d, J=7.5 Hz, 0.4H); 7.51 (d, J=11.0 Hz, 0.6H); 8.01 (broad s, 1H); 8.94 (broad m, 1H); 9.83 (s, 0.4H); 9.87 (s, 0.6H); 12.95 (s, 0.4H); 13.0 (s, 0.6H); 13.05 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[C:17]([C:19]3[C:20](=[O:42])[N:21]([CH2:40][CH3:41])[C:22]4[C:27]([CH:28]=3)=[CH:26][N:25]=[C:24]([N:29](CC3C=CC(OC)=CC=3)[CH3:30])[CH:23]=4)[C:16]([CH3:43])=[CH:15][C:14]=2[F:44])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.C1(OC)C=CC=CC=1>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[C:17]([C:19]3[C:20](=[O:42])[N:21]([CH2:40][CH3:41])[C:22]4[C:27]([CH:28]=3)=[CH:26][N:25]=[C:24]([NH:29][CH3:30])[CH:23]=4)[C:16]([CH3:43])=[CH:15][C:14]=2[F:44])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCn1c(=O)c(-c2cc(NC(=O)Nc3cc(F)cc(Cl)c3)c(F)cc2C)cc2cnc(N(C)Cc3ccc(OC)cc3)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3cc(F)cc(Cl)c3)c(F)cc2C)cc2cnc(NC)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.2 %

Procedure:
A solution of 1-(3-chloro-5-fluorophenyl)-3-(5-(1-ethyl-7-((4-methoxybenzyl)(methyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)urea (0.105 g, 0.170 mmol) in TFA (3 mL) was treated with anisole (0.093 ml, 0.849 mmol) and stirred at RT for 4 h. The mixture was concentrated to dryness and purified via reverse-phase chromatography (MeCN/H2O with 0.1% TFA). The combined fractions were neutralized with satd. NaHCO3, extracted with EtOAc (2×) and the combined organics were washed with water, then brine, dried over Na2SO4 and concentrated to dryness to afford 1-(3-chloro-5-fluorophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)urea (62 mg, 73% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.54 (s, 1H), 8.69 (s, 1H), 8.40 (s, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.66 (s, 1H), 7.35 (s, 1H), 7.27 (dt, J=11.3, 2.1 Hz, 1H), 7.14 (d, J=12.1 Hz, 1H), 7.00-6.95 (m, 2H), 6.24 (s, 1H), 4.14 (q, J=7.1 Hz, 2H), 2.85 (d, J=4.9 Hz, 3H), 2.07 (s, 3H), 1.21 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 498.2 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[N:3]=[CH:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[C:26]=1[S:33](Cl)(=[O:35])=[O:34]>C1COCC1>[S:1]1[CH:5]=[C:4]([N:6]([S:33]([C:26]2[C:27]([F:32])=[CH:28][C:29]([F:31])=[CH:30][C:25]=2[F:24])(=[O:35])=[O:34])[C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[N:3]=[CH:2]1
Reactant: O=S(=O)(Cl)c1c(F)cc(F)cc1F
Reactant: CC(C)(C)OC(=O)Nc1cscn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1c(F)cc(F)cc1F
Yield: 77.7 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 86a by using tert-butyl 1,3-thiazol-4-ylcarbamate (Synthesis, 2010, 3152-3162; 1.00 g, 4.99 mmol), lithium bis(trimethylsilyl)amide (1.0 M solution in THF; 5.99 mL, 5.99 mmol), 2,4,6-trifluorobenzenesulfonyl chloride (1.38 g, 5.99 mmol) and THF (15 mL), to yield the title compound (1.53 g, 78%) as a pale yellow solid.
Reaction SMILES: [CH:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[O:9]=[CH:10][C:11]([Cl:14])([Cl:13])[Cl:12].[Cl-].[Cl-].[Cl-].[Al+3]>>[Cl:12][C:11]([Cl:14])([Cl:13])[CH:10]1[CH:6]2[CH2:7][CH2:8][CH:1]([CH2:2][CH2:3][CH2:4][CH2:5]2)[O:9]1
Reactant: C1=CCCCCCC1
Reactant: O=CC(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: ClC(Cl)(Cl)C1OC2CCCCC1CC2
Temperature: 0 °C
Reaction time: 4 h

Procedure:
44.10 g (0.4 mole) of cyclooctene and 58.95 g (0.4 mole) of chloral in 60 ml of petroleum ether were initially taken in a 2-necked flask equipped with a magnetic stirrer, an internal thermometer and a drying tube. The mixture was cooled to ≤0° C. by means of a cold bath. 5.5 g (0.04 mole) of aluminum trichloride were added a little at a time in the course of 15 minutes, the temperature being kept at 0° C. Stirring was continued for a further 4 hours at this temperature, after which the mixture was left to stand for 15 hours at room temperature. For hydrolysis, the mixture was cooled to 0° C., and an equal volume of ice water was slowly added. The dark brown petroleum ether phase was separated off, filtered to remove the insoluble polymers and washed three times with saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulfate and evaporated down in a rotary evaporator. The crude product was purified by fractional distillation under reduced pressure (105°-118° C.; 0.5 mm Hg). 78 g (0.3 mole; 75% by weight) of a mixture of two compounds in a ratio of 1:1 were obtained. The two compounds were separated by liquid chromatography over a silica gel column (diameter 5 cm, length 20 cm) using a 1:1 cyclohexane/methylene chloride mixture as the mobile phase. In addition to 3-(1'-hydroxy-2',2',2'-trichloroethyl)-1-cyclooctene, a compound of the probable structure 8-trichloromethyl-7-oxabicyclo[4.2.2]decane, of the formula ##STR37## was isolated.