Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([O:13][C@H:14]2[CH2:19][CH2:18][C@@H:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:15]2)[CH:4]=1.[CH3:28][Si](C)(C)[N-][Si](C)(C)C.[Li+].CI>C1COCC1>[CH3:1][S:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([O:13][C@H:14]2[CH2:19][CH2:18][C@@H:17]([N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH3:28])[CH2:16][CH2:15]2)[CH:4]=1
Reactant: COC(=O)c1ccc(SC)cc1O[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)CC1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)c1ccc(SC)cc1O[C@H]1CC[C@@H](N(C)C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 7 h
Yield: 41.8 %

Procedure:
To a mixture of methyl 4-methylthio-2-[cis-4-(t-butoxy-carbonylamino)cyclohexyloxy]benzoate (3.0 g, 7.59 mmol) in THF (15 mL) at −20° C. was added 1 M lithium hexamethyl-disilazide (LiHMDS)/hexane (8.0 ml, 7.97 mmol, 1.05 eq), and the mixture was warmed to 0° C. for 10 min. To the reaction mixture was added methyl iodide (0.5 mL, 7.97 mmol, 1.05 equivalent), the mixture was warmed to room temperature and stirred for 7 h, and the reaction was quenched with satd citric acid. The mixture was diluted with CH2Cl2 and partitioned. The organic layer was dried (Na2SO4) and concentrated. This material was combined with the crude product from a small scaled reaction (500 mg, 1.27 mmol), chromatographed (400 g, SiO2, hexanes to 20% EtOAc/hexanes) and triturated with Et2O to give the title compound as a white solid (1.3 g, 36%).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[C:7]([CH3:12])=[CH:6][C:5]=1[O:13][CH2:14][CH3:15].[C:17]([O:24]C([O-])=O)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=O>C(#N)C.CN(C1C=CC=CN=1)C>[C:10]([C:8]1[C:7]([CH3:12])=[CH:6][C:5]([O:13][CH2:14][CH3:15])=[C:4]([CH:9]=1)[C:3]([N:2]([CH3:1])[C:17](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:16])#[N:11]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: CCOc1cc(C)c(C#N)cc1C(=O)NC
Agent: CN(C)c1ccccn1
Solvent: CC#N
Product: CCOc1cc(C)c(C#N)cc1C(=O)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.4 %

Procedure:
After suspending N1,4-dimethyl-5-cyano-2-ethoxybenzamide (92 g) in acetonitrile (11), tert-butyl dicarbonate (110 g) and dimethylaminopyridine (2.6 g) were added and the mixture was stirred at room temperature overnight. The reaction mixture was heated to 90° C. and stirred for 3 hours. tert-Butyl dicarbonate (110 g) was further added and the mixture was stirred at 50° C. overnight. After cooling to room temperature, the precipitated crystals were filtered off (24.3 g). The filtrate was concentrated and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (81.1 g) as a white solid.
Reaction SMILES: C([O:8][C:9]1[C:18]([O:19]CC2C=CC=CC=2)=[CH:17][C:16]([C:27]([F:30])([F:29])[F:28])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[C:18]([OH:19])=[CH:17][C:16]([C:27]([F:28])([F:29])[F:30])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cc(C(F)(F)F)cc(OCc2ccccc2)c1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(C(F)(F)F)cc(O)c1O
Reaction time: 16 h

Procedure:
To a solution of methyl 2,3-bis-benzyloxy-5-trifluoromethyl-benzoate (280 mg, 0.67 mmol) in 10 mL MeOH, Pd/C (10%, 30 mg) was added and the mixture was stirred 16 h under a H2 atmosphere. The reaction mixture was then filtered through Celite and evaporated in vacuo to yield the title compound as a greyish solid.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9]([Cl:15])=[N:10][C:11](I)=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[F:28][C:29]1[C:34](B(O)O)=[CH:33][CH:32]=[CH:31][N:30]=1>>[C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9]([Cl:15])=[N:10][C:11]([C:34]2[C:29]([F:28])=[N:30][CH:31]=[CH:32][CH:33]=2)=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(I)nc1Cl
Reactant: OB(O)c1cccnc1F
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(-c2cccnc2F)nc1Cl

Procedure:
By carrying out the operation analogously to example 1, starting from 2-chloro-6-iodo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation X, and 2-fluoro-3-pyridineboronic acid, the desired product is obtained in the form of a white powder (yield=27%).
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1)([O-])=O.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=1[CH2:21][CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:4]2[CH:5]=[C:6]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:8][CH:9]=2)=[CH:16][C:15]=1[CH2:21][CH3:22]
Reactant: CCc1cc(O)ccc1Cl
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCc1cc(Oc2cccc([N+](=O)[O-])c2)ccc1Cl
Temperature: 100 °C
Yield: 78.5 %

Procedure:
EX-8A) To a solution of 1,3-dinitrobenzene (16.8 g, 0.1 mol) and 4-chloro-3-ethylphenol (15.6 g, 0.1 mol) in 200 mL of dimethylsulfoxide was added cesium carbonate (65 g, 0.2 mol). The reaction mixture was heated at 100° C. under nitrogen overnight then cooled to room temperature. The reaction mixture was filtered through celite then rinsed with diethyl ether and a small amount of water. The filtrate was extracted several times with diethyl ether. The organic layers were combined, washed with water and brine, dried over MgSO4, and concentrated in vacuo to give 21.8 g (78%) of the desired 3-(4-chloro-3-ethylphenoxy)-1-nitrobenzene product as a dark orange oil, which was greater than 90% pure by reverse phase HPLC analysis. HRMS calcd. for C14H12ClNO3: 295.0849 [M+NH4]+, found 295.0862.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[CH2:7][CH2:6]2)=O.Cl.[OH:18][NH2:19].C([O-])(=O)C.[Na+]>C(O)C.O>[OH:18][N:19]=[CH:1][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[CH2:7][CH2:6]2
Reactant: NO
Reactant: CCC(=O)NC1CCc2cc(C=O)ccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCC(=O)NC1CCc2cc(C=NO)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
1.18 g of N-(5-formylindan-1-yl)propionic acid amide were suspended in 20 ml of ethanol and 10 ml of water. 0.57 g of hydroxyamine hydrochloride and 0.67 g of sodium acetate were added to this suspension followed by stirring overnight at room temperature. The reaction liquid was concentrated under reduced pressure followed by pouring into ice water and extracting with ethyl acetate. After washing the organic layer with saturated aqueous sodium bicarbonate and saturated brine, the organic layer was dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 1.25 g of the target compound. Yield: 100%
Reaction SMILES: [CH:1]1([C:5]2[CH:6]=[N:7][CH:8]=[CH:9][C:10]=2[O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[CH2:4][CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:22]>ClCCl>[CH:1]1([C:5]2[CH:6]=[N+:7]([O-:22])[CH:8]=[CH:9][C:10]=2[O:11][CH2:12][C:13]([F:16])([F:14])[F:15])[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: FC(F)(F)COc1ccncc1C1CCC1
Solvent: ClCCl
Product: [O-][n+]1ccc(OCC(F)(F)F)c(C2CCC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.3 %

Procedure:
To a solution of 3-cyclobutyl-4-(2,2,2-trifluoroethoxy)pyridine (Example 108c, 3.81 g, 16.5 mmol) in dichloromethane (100 ml) was added 3-chloroperoxybenzoic acid (5.54 g, 24.7 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was transferred into a separatory funnel and extracted with an 2.0M aqueous solution of sodium carbonate. The organic phase was collected and the aqueous phase was back-extracted with dichloromethane. The organic phases were combined, dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a dichloromethane/methanol gradient to yield the title compound (3.52 gr, 82%) as a white solid. MS (ESI, m/z): 248.5 (M+H+).
Reaction SMILES: [Cl:1][CH:2]([CH3:6])[C:3](O)=[O:4].[F:7][C:8]([F:21])([F:20])[O:9][C:10]1[CH:11]=[C:12]([NH:16][CH2:17][CH2:18][NH2:19])[CH:13]=[CH:14][CH:15]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[Cl:1][CH:2]([CH3:6])[C:3]([NH:19][CH2:18][CH2:17][NH:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([O:9][C:8]([F:7])([F:20])[F:21])[CH:11]=1)=[O:4]
Reactant: CC(Cl)C(=O)O
Reactant: NCCNc1cccc(OC(F)(F)F)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(Cl)C(=O)NCCNc1cccc(OC(F)(F)F)c1
Yield: 92.2 %

Procedure:
A solution of 2-chloropropionic acid (103 mg, 0.95 mmol) in CH2Cl2 (10 mL) was added dropwise at −30° C. to a solution of N1-(3-trifluoromethoxy-phenyl)-ethane-1,2-diamine (210 mg, 0.95 mmol) and N,N′-dicyclohexylcarbodiimide (226 mg, 1.10 mmol) in CH2Cl2 (20 mL), then after 1 h insoluble material was removed by filtration and the filtrate evaporated. Chromatography (SiO2; heptane/EtOAc 3:2) afforded the title compound (272 mg, 92%). Colorless oil, MS: 309.3 (M−H)−.
Reaction SMILES: [P:1]([O-:10])([O:6][CH:7]([CH3:9])[CH3:8])[O:2][CH:3]([CH3:5])[CH3:4].C(N(CC)CC)C.[CH2:18]=[O:19]>>[OH:19][CH2:18][P:1](=[O:10])([O:6][CH:7]([CH3:9])[CH3:8])[O:2][CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)OP([O-])OC(C)C
Reactant: C=O
Solvent: CCN(CC)CC
Product: CC(C)OP(=O)(CO)OC(C)C
Reaction time: 0.17 h
Yield: 89.6 %

Procedure:
A mixture of 33.2 g (0.20 mol) of diisopropyl phosphite, 2.8 mL (0.02 mol) of triethylamine, and 6.0 g (0.20 mol) of paraformaldehyde, was immersed in a 100° C. oil bath and then heated between 100°-120° C. for 45 minutes under nitrogen. An exotherm occurred within 10 minutes and all of the paraformaldehyde dissolved rapidly. The triethylamine was removed at reduced pressure, and the residue was bulb-to-bulb distilled in four portions to provide a total of 35.17 g (91%) of title compound as a colorless oil.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:29]=2[NH:28][CH:27]=[C:26]3[S:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:17][CH2:16]1)=O)(C)(C)C.[OH-].[NH4+]>ClCCl.O>[C:31]1([S:30][C:26]2[C:25]3[C:29](=[C:21]([N:18]4[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]4)[CH:22]=[CH:23][CH:24]=3)[NH:28][CH:27]=2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c(Sc4ccccc4)c[nH]c23)CC1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: c1ccc(Sc2c[nH]c3c(N4CCNCC4)cccc23)cc1

Procedure:
Trifluoroacetic acid (5 mL) was added to a solution of 4-(3-phenylsulfanyl-1H-indol-7-yl)piperazine-1-carboxylic acid tert-butyl ester (700 mg, 1.7 mmol), prepared as described in Example 1 Step 1, in 4 mL of dichloromethane. After 15 min the solution was diluted with water, basified with ammonium hydroxide, and extracted with dichloromethane. The dichloromethane was washed with brine and evaporated to afford 3-phenylsulfanyl-7-piperazin-1-yl-1H-indole (701) as a solid. The hydrochloride salt crystallized from ethanol-HCl to afford 500 mg of white solid, m.p. 300° C. Similarly replacing 4-(3-phenylsulfanyl-1H-indol-7-yl)piperazine-1-carboxylic acid tert-butyl ester with the appropriate sulfanyl derivatives, prepared as described in other examples herein, the following compounds were prepared:
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[CH2:27][CH2:28][OH:29]>C(Cl)Cl>[Cl:23][C:24]1[CH:25]=[C:26]([CH2:27][CH:28]=[O:29])[CH:30]=[CH:31][CH:32]=1
Reactant: OCCc1cccc(Cl)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=CCc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.9 %

Procedure:
Dess-Martin periodinane (1.02 g, 2.4 mmol) was diluted in anhydrous CH2Cl2 (25 mL) under argon, and when solution was affected, 3-chlorophenethyl alcohol (33, 0.313 g, 2.00 mmol) was added dropwise. The mixture was stirred for 2 h and 15 min at room temperature, and was then quenched by addition of 20 mL sat. aq. Na2S2O3. After stirring at room temperature for 15 min, the layers were separated, and the aqueous layer was extracted with CH2Cl2 (2×50 mL). The organic layer was washed with H2O and sat. aq. NaCl (50 mL each) and was dried over anhydrous sodium sulfate and concentrated. The resulting semisolid residue was triturated with 10% EtOAc in hexanes, and the solid was filtered out and discarded. The filtrate was concentrated, and the oily residue was purified by flash column chromatography (SiO2), eluting with a gradient of hexanes to 10% EtOAc in hexanes to afford the title compound as a clear yellow volatile oil (0.241 g, 78%). 1H-NMR (500 MHz; CDCl3): δ 9.75 (t, J=2.1 Hz, 1 H), 7.31-7.23 (m, 3 H), 7.11-7.09 (m, 1 H), 3.69 (d, J=2.1 Hz, 2 H).
Reaction SMILES: C[O:2][C:3](=[O:34])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]2[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:33])=[O:25])=[CH:19][CH:18]=1)[NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])=[S:7].[OH-].[Na+]>C(O)C>[Cl:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:8]=1[C:6](=[S:7])[NH:5][C@H:4]([C:3]([OH:34])=[O:2])[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([NH:23][C:24]([C:26]2[C:27]([Cl:33])=[CH:28][CH:29]=[CH:30][C:31]=2[Cl:32])=[O:25])=[CH:21][CH:22]=1
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=S)c1c(C)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(Cl)c1C(=S)N[C@@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)C(=O)O
Temperature: 52.5 °C
Reaction time: 3.5 h
Yield: 96.1 %

Procedure:
To a suspension of N-[(2-chloro-6-methylphenyl)thioxomethyl]-4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester (2.89 mmol, 1.55 g) in ethanol (8 mL) was added aqueous 1.ON sodium hydroxide (5 mL) at room temperature. The mixture was heated to 50-55° C. and the resulting clear solution was stirred for 3-4 h. TLC analysis of the mixture indicated the absence of starting material. The mixture was concentrated to remove ethanol, then was diluted with 15 mL of water and extracted with 25 mL of diethyl ether to remove any neutral impurities. The aqueous layer was acidified with 1N HCl and the precipitated colorless solid was extracted into ethyl acetate (2×30 mL). The combined extracts were washed with brine, dried (MgSO4) and concentrated in vacuo to afford 1.45 g (96%) of N-[(2-chloro-6-methylphenyl)thioxomethyl]-4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine as an amorphous colorless solid. HRMS: Obs. mass, 521.0241. Calcd. mass, 521.0260 (M+H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16](=[O:18])[CH3:17].B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16](=[O:18])[CH3:17]
Reactant: COc1ccccc1Nc1ccccc1C(C)=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(=O)c1ccccc1Nc1ccccc1O

Procedure:
[I; R, R' and R"=H, OH at 2-position, Alk=CH3 ] is obtainable by reacting 1-[2-(2-methoxyphenylamino)phenyl]ethanone with boron tribromide. A preferred procedure comprises adding boron tribromide in an inert solvent such as methylene dichloride dropwise to a solution of the methoxy compound in an inert solvent, e.g. methylene dichloride cooled to a low temperature (-40° to -80° C.) and then stirring the mixture for several hours.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]2[CH:14]=1)([CH3:3])[CH3:2].Cl[S:16]([O:19][Si](C)(C)C)(=[O:18])=[O:17]>ClC(Cl)C>[C:12]([C:10]1[CH:9]=[CH:8][N:7]2[C:14]([S:16]([OH:19])(=[O:18])=[O:17])=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[C:6]2[CH:11]=1)#[N:13]
Reactant: CC(C)c1cn2ccc(C#N)cc2n1
Reactant: C[Si](C)(C)OS(=O)(=O)Cl
Solvent: CC(Cl)Cl
Product: CC(C)c1nc2cc(C#N)ccn2c1S(=O)(=O)O
Temperature: 100 °C
Yield: 94.6 %

Procedure:
The 2-isopropylimidazo[1,2-a]pyridine-7-carbonitrile (2.00 g, 10.8 mmol) obtained in step 1 of Example 7 was dissolved in dichloroethane (22 mL). Under ice-cooled condition, trimethylsilyl chlorosulfonate (4.08 g, 21.6 mmol) was added, and the mixture was stirred at 100° C. for hours. The solvent was evaporated under reduced pressure, and the residue was slurried in heptane. The resulting crystals were collected by filteration to give 7-cyano-2-isopropylimidazo[1,2-a]pyridine-3-sulfonic acid (2.71 g, yield 95%).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Br[CH2:9][C:10]1[S:11][C:12]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:13]=2[N:14]=1>O1CCCC1>[NH:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH2:9][C:10]1[S:11][C:12]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:13]=2[N:14]=1
Reactant: BrCc1nc2c(ccc3ccccc32)s1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc2c(c1)ccc1sc(Cc3ncc[nH]3)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
0.06 g of sodium hydride (60%) was added to a solution of 0.10 g of imidazole in tetrahydrofuran (30 ml). After 30 minutes of stirring at room temperature, a solution of 2-bromomethylnaphtho[1,2-d]thiazole in tetrahydrofuran (10 ml) was added to the solution. After stirring at room temperature for 1 hour and evaporation of the solvent, the residue was partitioned between 1N hydrochloric acid and ethyl acetate. The organic layer was extracted with 1N hydrochloric acid. The combined aqueous layer was neutralized with sodium bicarbonate and then extracted with chloroform. After drying over anhydrous magnesium sulfate, the solvent was evaporated to obtain 0.27 g (100%) of 2-(1-imidazolylmethyl)naphtho[1,2-d]thiazole. This free base was dissolved in methanol and mixed with 0.10 g of fumaric acid to effect crystallization to give 0.32 g of fumarate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH:22]=[CH:21][C:20]3[C:15](=[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[Cl:30])[C:17]([F:23])=[CH:18][CH:19]=3)[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>C(O)C.C(OCC)(=O)C.[Pt](=O)=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[Cl:30])[C:17]([F:23])=[CH:18][CH:19]=3)[O:14]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C=Cc3ccc(F)c(-c4ccccc4Cl)c3O2)cc1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3ccc(F)c(-c4ccccc4Cl)c3O2)cc1
Yield: 99.8 %

Procedure:
Treatment of ((2R)-8-(2-chlorophenyl)-7-fluoro-2H-chromen-2-yl)methyl 4-methylbenzenesulfonate (0.7 g, 1.57 mmol) in ethanol (40 mL) and ethyl acetate (10 mL) with platinum (IV) oxide (84% Pt, 0.21 g) according to the procedure described for Example 69, Step 8 provided 0.7 g (100%) of ((2R)-8-(2-chlorophenyl)-7-fluorochroman-2-yl)methyl 4-methylbenzenesulfonate as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].C=O.Cl.[C:15](O)(=O)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9]([CH2:15][O:7][C:6]2=[O:8])=[CH:10][CH:11]=1
Reactant: CC(=O)O
Reactant: COc1cccc(C(=O)O)c1
Agent: C=O
Agent: Cl
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)C(=O)OC2
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of 20 g (131 mmol) of 3-methoxybenzoic acid, 13 ml (160 mmol) of 37% strength formalin soln., 16 ml (162 mmol) of 37% strength HCl and 150 ml of 100% strength acetic acid is heated to 90° C., while stirring. After a clear solution has formed, the stirrer is switched off and the mixture is left at this temperature for 14 hours. The acetic acid is stripped off at 80° C. in vacuo, the residue is taken up in 150 ml of toluene and the mixture is concentrated to 80 ml. The 80° C. hot solution is washed with 40 ml portions of 20% strength Na2SO4 solution until the pH of the aqueous solution is alkaline, and is then washed with 40 ml of H2O. After addition of 6 ml of morpholine, the organic phase is stirred at 80° C. for 2 h and then washed with 50 ml portions of 10% strength H2SO4 until the aqueous phase is acidic, and twice with 50 ml of H2O each time. For crystallization of the product, the mixture is concentrated to 50 ml, a seed crystal is added if necessary, and the mixture is stirred until it has cooled to room temperature. The product is obtained by filtering off in the form of white crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=3[CH3:20])=[C:10]([C:21]([O:23]CC)=[O:22])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[K+].CCO>>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=3[CH3:20])=[C:10]([C:21]([OH:23])=[O:22])[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cc(-c2ccnc(N)n2)[nH]c1-c1cc(Cl)ccc1C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(Cl)cc1-c1[nH]c(-c2ccnc(N)n2)cc1C(=O)O
Temperature: 5 °C
Yield: 99.9 %

Procedure:
Ethyl 5-(2-aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-1H-pyrrole-3-carboxylate (1.0 g, 2.80 mmol) was treated with a 1.5 M solution of potassium hydroxide in 95% EtOH (32.4 mL, 20 eq) under reflux for 20 h. After cooling, the residue was concentrated, dissolved in water and washed with DCM. To the aqueous phase cooled to 5° C., a solution of 2 N HCl was added, under agitation. The resultant precipitate was collected by filtration to give the title compound (0.92 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31]([CH:33]3[CH2:35][CH2:34]3)=[O:32])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([NH:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:31]([CH:33]5[CH2:35][CH2:34]5)=[O:32])[CH:25]=4)[CH2:20][CH2:19]3)=[O:13])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Reactant: NCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1
Product: O=C(Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4)CC3)CC2)c1)C1CC1

Procedure:
Example 118 was prepared from 1-(4-chlorophenyl)cyclopropanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopropanecarboxamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.12–7.88 (br, 1H), 7.48–7.14 (m, 7H), 6.85 (d, 1H, J=7.2 Hz), 5.83–5.66 (br, 1H), 3.29–3.09 (m, 4H), 2.66–2.53 (m, 2H), 2.53–2.40 (m, 1H), 2.37–2.17 (m, 2H), 1.95–1.53 (m, 7H), 1.14–0.91 (m, 6H), 0.89–0.71 (m, 2H); ESMS m/e: 480.2 (M+H)+; Anal. Calc. (HCl salt) C28H35Cl2N3O2.0.38CHCl3: C, 60.64; H, 6.34; N, 7.47. Found: C, 60.38; H, 6.57; N, 7.80.