Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:22])[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])=[C:12]([OH:21])[CH:11]=2)=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:35][CH2:36][CH2:37]Br>CN(C=O)C>[Br:35][CH2:36][CH2:37][O:21][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[CH:4]=1)=[O:22]
Reactant: CS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1OCCBr
Temperature: 50 °C
Reaction time: 18 h
Yield: 39 %

Procedure:
N-(4-Chloro-3-(pyridin-2-yl)phenyl)-3-hydroxy-4-(methylsulfonylmethyl)benzamide (1.00 g, 2.40 mmol) was dissolved in DMF (20 ml). Cesium carbonate (1.56 g, 4.8 mmol) and 1,2-dibromoethane (0.83 ml, 9.6 mmol) were added, and the reaction was stirred at 50° C. for 18 hours. The reaction was quenched with water, basified with 10% aqueous NaOH, and extracted with ethyl acetate twice. The ethyl extracts were washed with water once, brine once, dried with MgSO4, and evaporated to a crude oil which was purified by chromatography (25% hexanes in ethyl acetate) to yield 490 mg of 3-(2-bromoethoxy)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide as a yellow solid. 3-(2-Bromoethoxy)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide (100 mg, 0.19 mmol) was dissolved in DMF (2.0 ml), and potassium carbonate (32 mg, 0.23 mmol) and tert-butyl piperazine-1-carboxylate (38 mg, 0.21 mmol) were added. The reaction was stirred for 18 hours at room temperature, quenched in water, and extracted with ethyl acetate twice. The ethyl acetate extracts were washed with water once, brine once, dried with MgSO4, and evaporated to a crude oil. The oil was dissolved in dichloromethane (1 ml) and treated with trifluoroacetic acid (3 ml) for 1 hour. The reaction was evaporated to dryness, and the crude solid was purified on reverse phase HPLC to yield 63 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)-3-(2-(piperazin-1-yl)ethoxy)benzamide as a white solid. N-(4-Chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)-3-(2-(piperazin-1-yl)ethoxy)benzamide (30 mg, 0.047 mmol) was dissolved in dichloromethane (1.5 ml) and THF (1.0 ml). N-ethyl-N-isopropylpropan-2-amine (18 μl, 0.10 mmol) and methanesulfonyl chloride (4 μl, 0.051 mmol) were added, and the reaction stirred at room temperature for 72 hours. Additional N-ethyl-N-isopropylpropan-2-amine (9 μl, 0.051 mmol) and methanesulfonyl chloride (4 μl, 0.051 mmol) were added and the reaction stirred for 2 hours. After a further addition of methanesulfonyl chloride (4 μl, 0.051 mmol), the reaction was stirred for 2 hours and evaporated to a crude solid which was purified on reverse phase HPLC to yield 8 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-3-(2-(4-(methylsulfonyl)piperazin-1-yl)ethoxy)-4-(methylsulfonylmethyl)benzamide. MS (Q1) 607 (M)+.
Reaction SMILES: CO[C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([OH:15])[CH:6]=1)=[O:4].[CH2:16]([CH2:18][NH2:19])[OH:17]>C(Cl)(Cl)Cl>[OH:17][CH2:16][CH2:18][NH:19][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([OH:15])[CH:6]=1)=[O:4]
Reactant: NCCO
Reactant: COC(=O)c1cc(O)nc2ccccc12
Solvent: ClC(Cl)Cl
Product: O=C(NCCO)c1cc(O)nc2ccccc12

Procedure:
A solution of 4-methoxycarbonyl-2-hydroxyquinoline (40 mg) and ethanolamine (0.1 ml) in chloroform (5 ml) was stirred at 60° C. for 48 hours. After cooling the colourless product was isolated by filtration.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1)=[O:12]>C(N(CC)CC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]([C:13]2[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)=[O:12])[CH:7]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: CS(=O)(=O)c1ccc(C(=O)CBr)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(C(=O)Cn2cc(Cl)cnc2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.9 %

Procedure:
A suspension of 5-chloropyrimidin-2-one (411 mg) and 2-bromo-4'-methylsulphonyl acetophenone (835 mg) in triethylamine (1 ml) and ethanol (20 ml) was stirred at ambient temperature for one hour. The resulting suspension was concentrated at reduced pressure then diluted with water (100 ml). The collected precipitate was crystallised from acetone, then from ethanol to give the title pyrimidinone (235 mg); m.p. 257°-258°; λmaxEtOH 242 nm (ε 23650), 286 nm (ε 1950), 334 nm (ε 1680), λinf 293 nm (ε 1850).
Reaction SMILES: [C:1]([C:3]1[CH:14]=[CH:13][C:6]([CH2:7][N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]=[O:24])=[CH:18][CH:17]=1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:7]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)[CH:23]([OH:24])[CH2:22][C:19]2[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=2)=[CH:13][CH:14]=1)#[N:2]
Reactant: N#Cc1ccc(Cn2ccnc2)cc1
Reactant: O=CCc1ccc(F)cc1
Product: N#Cc1ccc(C(C(O)Cc2ccc(F)cc2)n2ccnc2)cc1

Procedure:
1-[1-(4-cyanophenyl)-3-(4-fluorophenyl)-2-hydroxypropyl]-1H-imidazole is prepared according to the procedure of Example 1 using 1-(4-cyanobenzyl)-imidazole and 4-fluorophenylacetaldehyde as starting materials. The product is purified by flash chromatography.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=1)=[O:4].[I-:20].[Na+].CCCCCC>COCCOC>[OH:15][C:8]1[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:10][C:5]([C:3](=[O:4])[CH2:2][I:20])=[CH:6][C:7]=1[C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: [I-]
Reactant: CC(C)(C)c1cc(C(=O)CBr)cc(C(C)(C)C)c1O
Agent: [Na+]
Solvent: COCCOC
Solvent: CCCCCC
Product: CC(C)(C)c1cc(C(=O)CI)cc(C(C)(C)C)c1O
Reaction time: 16 h
Yield: 69.6 %

Procedure:
To a solution of 6.54 g (20 mmol) of 2-bromo-1-(4-hydroxy-3,5-di-tert-butylphenyl)-ethanone in 25 ml of 1,2-dimethoxyethane, a solution of 3.14 g (21 mmol) of sodium iodide in 25 ml of 1,2-dimethoxyethane is added dropwise at room temperature. After the addition, stirring is continued for 16 hours at room temperature. Then 10 ml of hexane is added and, after stirring for additional 15 minutes, the precipitated salts are removed by filtration. The obtained solution is evaporated and the resulting residue is purified by recrystallization from hexane to give 5.21 g (70%) of compound 202, m.p. 88-89° C.
Reaction SMILES: [CH3:1][CH:2]1[CH:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH2:4][N:3]1[C:17](Cl)=[O:18].[CH3:20][NH2:21]>O1CCCC1.O>[CH3:20][NH:21][C:17]([N:3]1[CH2:4][C@H:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[C@@H:2]1[CH3:1])=[O:18]
Reactant: CN
Reactant: CC1C(Oc2cccc(C(F)(F)F)c2)CN1C(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)N1C[C@H](Oc2cccc(C(F)(F)F)c2)[C@@H]1C
Reaction time: 6 h
Yield: 90.3 %

Procedure:
A solution of 4.02 g (0.01 mole) of crude (73%) 2-methyl-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarbonyl chloride cis isomer in 20 ml of tetrahydrofuran was treated while stirring with 1.6 g (0.02 mole) of 40% aqueous monomethylamine. After stirring for 6 hr, the reaction mixture was diluted with 100 ml of water and the oil which separated was extracted into methylene chloride (2×50 ml). The combined extracts were dried over magnesium sulfate and concentrated in vacuo (4.2 g). The oil solidified on standing and was recrystallized from isooctane with a trace of benzene to give 2.6 g (90.3%) of white crystalline product, m.p. 89°-91° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:22][C:23]2[N:28]=[CH:27][C:26]3[O:29][CH2:30][CH2:31][O:32][C:25]=3[CH:24]=2)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH:9]1[CH3:33])C1C=CC=CC=1>CO.C(O)(=O)C.[OH-].[Pd+2].[OH-]>[O:32]1[C:25]2[CH:24]=[C:23]([CH2:22][N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH:9]([CH3:33])[CH2:10]3)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[N:28]=[CH:27][C:26]=2[O:29][CH2:30][CH2:31]1
Reactant: CC1CC(N(Cc2cc3c(cn2)OCCO3)C(=O)OC(C)(C)C)CCN1Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CC1CC(N(Cc2cc3c(cn2)OCCO3)C(=O)OC(C)(C)C)CCN1
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
To a solution of 0.24 g of tert-butyl (1-benzyl-2-methylpiperidin-4-yl)(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)carbamate in 3 mL of methanol, 90 μL of acetic acid and 0.32 g of 20% palladium hydroxide were added. The reaction mixture was stirred for 4 hours 30 minutes under a hydrogen atmosphere. The insoluble substance was filtered off, and the solvent was distilled off under reduced pressure to obtain 0.16 g of tert-butyl (2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(2-methylpiperidin-4-yl)carbamate as a yellow foam.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([S:7]([OH:9])=[O:8])=[CH:3][CH:2]=1.[Li].[S:12]([CH2:16][CH2:17][NH:18][C:19](=[O:22])[CH2:20]Br)([OH:15])(=[O:14])=[O:13].O>C(O)C>[CH3:10][C:1]1[CH:6]=[CH:5][C:4]([S:7]([CH2:20][C:19]([NH:18][CH2:17][CH2:16][S:12]([OH:15])(=[O:14])=[O:13])=[O:22])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)O)cc1
Reactant: O=C(CBr)NCCS(=O)(=O)O
Agent: [Li]
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)CC(=O)NCCS(=O)(=O)O)cc1
Reaction time: 4 h
Yield: 89 %

Procedure:
To a 5-liter flask equipped with a mechanical stirrer and reflux condenser was added p-toluenesulfinic acid, lithium salt (308.57 g), N-(2-sulfoethyl)-2-bromoacetamide, lithium salt (527.39 g), water (180 ml), and ethyl alcohol (3380 ml). The resulting suspension was heated to reflux. After about an hour of reflux, nearly all of the reactants had dissolved. Reflux was continued another four hours, and the solution was filtered hot through a Celite pad to remove some haziness. The solution was cooled overnight to room temperature. The solid that formed was collected and washed with 1 liter of 95% ethyl alcohol/water. The white solid was air dried and then dried at high vacuum, providing 553.88 g (89% yield) of 2-(4-methylphenyl)sulfonyl-N-(2-sulfoethyl)acetamide, lithium salt (Intermediate 1). HPLC analysis showed no detectable impurities. Ion chromatography indicated 0.035 weight % bromide and 1.8 weight % lithium. The material exhibited an acceptable proton spectrum.
Reaction SMILES: [I:1]I.[F:3][C:4]1[CH:5]=[C:6]([OH:14])[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11]>C(Cl)(Cl)Cl.FC(F)(F)C([O-])=O.[Ag+]>[F:3][C:4]1[C:9]([C:10]([F:12])([F:13])[F:11])=[CH:8][C:7]([I:1])=[C:6]([OH:14])[CH:5]=1
Reactant: Oc1ccc(C(F)(F)F)c(F)c1
Reactant: II
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClC(Cl)Cl
Product: Oc1cc(F)c(C(F)(F)F)cc1I
Reaction time: 1 h
Yield: 55.7 %

Procedure:
A solution of iodine (0.874 g, 3.44 mmol) in chloroform (17.1 mL) was added in a drop-wise manner over 1.5 hours to a mixture of 3-fluoro-4-(trifluoromethyl)phenol (Preparation 7, 620 mg, 3.4 mmol) and silver trifluoroacetate (0.760 g, 3.44 mmol) in chloroform (3.4 mL). On completion of the addition, the reaction mixture was stirred for 1 hour. The reaction mixture was then filtered through diatomaceous earth, and the filtrate washed successively with 10% w/v aqueous sodium thiosulfate, half-saturated aqueous sodium bicarbonate, water and brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated onto diatomaceous earth. The residue was purified by automated silica gel flash chromatography (100% hexanes to 50% dichloromethane in hexanes gradient elution) and concentrated in vacuo to afford the title compound as a light yellow oil (579 mg).
Reaction SMILES: [NH2:1][C:2]1[C:33]([Cl:34])=[CH:32][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:35][CH3:36])[CH:3]=1.[CH:37](=O)[CH3:38].C([BH3-])#N.[Na+]>>[NH2:1][C:2]1[C:33]([Cl:34])=[CH:32][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:37][CH3:38])[CH2:22][C:23]3[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:35][CH3:36])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNCc2ccc([N+](=O)[O-])cc2)CC1
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN(CCCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)CC1)Cc1ccc([N+](=O)[O-])cc1

Procedure:
4-Amino-5-chloro-2-methoxy-N-((1-(5-(4-nitrobenzylamino)pentyl)-piperidin-4-yl)methyl)benzamide (1.5 g) as starting compound, acetaldehyde (0.21 ml) and sodium cyanoborohydride (0.24 g) were reacted and treated in the same manner as in Example 136 to give 0.6 g of 4-amino-5-chloro-N-((1-(5-(N-ethyl-N-(4-nitrobenzyl)amino)pentyl)-piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [I:1][C:2]1[CH:8]=[C:7](Cl)[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[I:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][S:18]([CH3:17])(=[O:20])=[O:19]
Reactant: Nc1ccc(Cl)cc1I
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccccc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 111.1 %

Procedure:
To the mixture of the 2-iodo-4-chloroaniline (5.0 g, 20 mmol) and triethylamine (8.3 mL, 60 mmol) in methylene chloride (200 mL), the solution of methanesulfonyl chloride (3.4 mL, 44 mmol) was added slowly. The solution then was stirred at room temperature for 2 h. After being washed by HCl solution (0.5 N, 2×100 mL), NaOH solution (0.5 N, 2×100 mL), brine (100 mL), the organic layer was dried over Na2SO4 and concentrated providing the title compound (6.6 g).
Reaction SMILES: [NH2:1][C:2]1[NH:3][CH:4]=[C:5]([S:7]([OH:10])(=[O:9])=[O:8])[N:6]=1.[Cl:11][C:12]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:13]=1[CH:14]=[C:15]([C:19](=O)[CH3:20])[C:16]([NH2:18])=[O:17]>CCO.O>[C:16]([C:15]1[CH:14]([C:13]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:12]=2[Cl:11])[N:3]2[CH:4]=[C:5]([S:7]([OH:10])(=[O:9])=[O:8])[N:6]=[C:2]2[NH:1][C:19]=1[CH3:20])(=[O:17])[NH2:18]
Reactant: Nc1nc(S(=O)(=O)O)c[nH]1
Reactant: CC(=O)C(=Cc1ccc(Cl)cc1Cl)C(N)=O
Solvent: O
Solvent: CCO
Product: CC1=C(C(N)=O)C(c2ccc(Cl)cc2Cl)n2cc(S(=O)(=O)O)nc2N1
Temperature: 80 °C

Procedure:
A suspension of 2-amino-1H-imidazole-4-sulfonic acid (82 mg, 0.5 mmol) and 2-(2,4-dichlorobenzylidene)-3-oxobutanamide (125 mg, 0.5 mmol) in 3:1 EtOH/H2O (2 mL) was heated to 80° C. for 14 h. After removal of solvent, the residue was dissolved in 1N NaOH and extracted with EtOAc (5 mL×2). The aqueous solution was then acidified with conc. HCl to pH=1. The precipitation which had formed was collected and further washed with H2O. After drying in vacuo, 6-carbamoyl-5-(2,4-dichlorophenyl)-7-methyl-5,8-dihydroimidazo[1,2-a]pyrimidine-2-sulfonic acid was obtained a yellow solid (97 mg, 48%).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17]([CH2:22][N:23]2[CH2:26][CH:25]([C:27]([OH:29])=[O:28])[CH2:24]2)[CH:16]=[C:15]3[CH:30]2[CH2:32][CH2:31]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:33]([C@H]1CC[C@H](OC2C=C3C(=CC=2)N=C(CN2CCC(C(O)=O)C2)C=C3C)CC1)(C)(C)C>>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17]([CH2:22][N:23]2[CH2:33][CH2:26][CH:25]([C:27]([OH:29])=[O:28])[CH2:24]2)[CH:16]=[C:15]3[CH:30]2[CH2:32][CH2:31]2)[CH2:9][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(CN2CCC(C(=O)O)C2)nc2ccc(O[C@H]3CC[C@H](C(C)(C)C)CC3)cc12
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3nc(CN4CC(C(=O)O)C4)cc(C4CC4)c3c2)CC1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3nc(CN4CCC(C(=O)O)C4)cc(C4CC4)c3c2)CC1

Procedure:
Synthesized as per 1-[6-(trans-4-tert-Butyl-cyclohexyloxy)-4-cyclopropyl-quinolin-2-ylmethyl]-azetidine-3-carboxylic acid using the appropriate intermediate available from the synthesis of 1-[6-(trans-4-tert-Butyl-cyclohexyloxy)-4-methyl-quinolin-2-ylmethyl]-pyrrolidine-3-carboxylic acid). ESI-MS(M+H+): 451.3; 1H NMR (400 MHz, METHANOL-d4) Shift 7.99 (d, J=9.29 Hz, 1H), 7.70 (d, J=2.51 Hz, 1H), 7.42 (dd, J=2.64, 9.16 Hz, 1H), 7.13 (s, 1H), 4.60-4.72 (m, 2H), 4.35-4.49 (m, 1H), 3.81 (dd, J=6.53, 12.05 Hz, 1H), 3.72 (dd, J=8.66, 11.92 Hz, 1H), 3.50-3.66 (m, 2H), 3.37-3.49 (m, 1H), 2.42-2.55 (m, 2H), 2.38 (td, J=6.96, 13.68 Hz, 1H), 2.29 (d, J=10.29 Hz, 2H), 1.85-1.98 (m, 2H), 1.36-1.52 (m, 2H), 1.18-1.34 (m, 4H), 1.03-1.18 (m, 1H), 0.91 (s, 9H), 0.79-0.89 (m, 2H).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[C:10]([C:17]([F:20])([F:19])[F:18])[CH:9]=1)(=[O:3])[CH3:2].[H][H]>[C].[Pd].C(OCC)(=O)C>[C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([C:17]([F:18])([F:19])[F:20])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCOc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)OCCOc1ccc(N)c(C(F)(F)F)c1
Yield: 121.1 %

Procedure:
In the ethyl acetate (30 mL) solution of 4-nitro-3-trifluoromethyl-phenoxyethyl acetate (3.24 g (theoretical amount: 2.83 g, 9.66 mmol) which had been obtained in 1), 10% palladium carbon (0.3 g) was added and hydrogen was added. After the catalyst had been separated by filtration, the solvent was removed by distillation under reduced pressure and crude 4-amino-3-trifluoromethyl-phenoxyethyl acetate (BB03, 3.08 g (theoretical amount: 2.54 g)−100%) was obtained as oily matter.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH3:18])=[O:5])[CH3:2].[Br:19]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[N:8][C:7]=1[CH2:18][Br:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(-c2ccc(Cl)cc2)nc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1sc(-c2ccc(Cl)cc2)nc1CBr
Temperature: 25 °C
Yield: 100.9 %

Procedure:
A mixture of 2-(4-chloro-phenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester (2.50 g, 8.88 mmol), N-bromosuccinimide (2.13 g, 12.0 mmol) and benzoyl peroxide (150 mg, 0.62 mmol) in carbon tetrachloride (50 mL) was refluxed for 24 h before it was cooled to room temperature and partitioned between dichloromethane and water. The organic layer was washed with saturated aqueous sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a yellow solid (3.23 g, product is 69% pure by 1H NMR, impurities are starting material and dibromonated compound): 1H NMR (CDCl3, 200 MHz): δ=7.90 (d, 2H), 7.44 (d, 2H), 4.96 (s, 3H), 4.38 (q, J=7.0 Hz, 2H), 1.44 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH:1]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[C:19]1[C:23]([NH2:24])=[CH:22][NH:21][N:20]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CS(C)=O>[NH:12]1[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:10]=[C:11]1[C:19]1[C:23]([NH:24][C:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:9])=[CH:22][NH:21][N:20]=1
Reactant: Nc1c[nH]nc1-c1nc2ccccc2[nH]1
Reactant: O=C(O)C1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CS(C)=O
Product: O=C(Nc1c[nH]nc1-c1nc2ccccc2[nH]1)C1CCCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 32.3 %

Procedure:
A mixture of cyclohexanecarboxylic acid (36 mg, 0.28 mmol), 3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (50 mg, 0.25 mmol), EDC (58 mg, 0.30 mmol) and HOBt (41 mg, 0.30 mmol) in DMSO (2 ml) was stirred at ambient temperature for 24 h. The reaction mixture was partitioned between EtOAc (40 ml) and water (40 ml) and the organic portion dried (MgSO4), filtered and reduced in vacuo. The residue was purified by flash column chromatography [SiO2, EtOAc-petrol (1:4, 1:3, 1:2, 1:1)] affording cyclohexanecarboxylic acid [3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-amide as an off-white solid (25 mg, 32%). (LC/MS: Rt 3.59, [M+H]+ 310.16).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]([F:16])([F:15])[CH:8]([CH2:12][CH2:13][OH:14])[CH2:9][CH2:10][OH:11].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][S:2]([O:11][CH2:10][CH2:9][CH:8]([C:7]([F:15])([F:16])[F:6])[CH2:12][CH2:13][O:14][S:2]([CH3:1])(=[O:4])=[O:3])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCCC(CCO)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCC(CCOS(C)(=O)=O)C(F)(F)F
Temperature: 0 °C

Procedure:
With stirring at 0° C., 63 ml of methylsulfonyl chloride in 40 ml of toluene are added dropwise to a solution of 69.3 g of 3-trifluoromethyl-1,5-pentanediol and 140 ml of triethylamine in 150 ml of toluene. After 12 hours' stirring at room temperature, the solid portions are filtered off and the toluene solution is concentrated in vacuo to give in almost quantitative yield 1,5-bismethanesulfonyloxy-3-trifluoromethylpentane; m.p. 40°-45° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=[O:14].CO.[CH2:18](Cl)Cl.C[Si](C=[N+]=[N-])(C)C>CCOCC>[CH3:18][O:14][C:13](=[O:15])[CH2:12][C:3]1[CH:4]=[C:5]([O:10][CH3:11])[C:6]([C:8]#[N:9])=[CH:7][C:2]=1[Cl:1]
Reactant: COc1cc(CC(=O)O)c(Cl)cc1C#N
Reactant: ClCCl
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)Cc1cc(OC)c(C#N)cc1Cl

Procedure:
(2-Chloro-4-cyano-5-methoxyphenyl)acetic acid (545 mg, 2.4 mmol) was taken up in 1:1 MeOH:DCM (50 mL) and excess 2M trimethylsilyldiazomethane in ether was added until the yellow color persisted, the excess was quenched with acetic acid and the solution was concentrated in vacuo. Flash chromatography (10-50% ethyl acetate/hexanes) gave the title ester as a white solid. 1H-NMR (500 MHz, CDCl3) δ ppm 3.703 (s, 3H), 3.767 (s, 2H), 3.897 (s, 3H), 6.896 (s, 1H), 7.526 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]([CH2:12][OH:13])[CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:24][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O:13][CH2:12][CH:9]2[CH2:8][C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:11]=3[O:10]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: COc1cccc2c1OC(CO)C2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc2c1OC(COS(=O)(=O)c1ccc(C)cc1)C2
Temperature: 50 °C
Reaction time: 12 h
Yield: 68 %

Procedure:
To a solution of (±)-tert-butyl[(7-methoxy-2,3-dihydro-1-benzofuran-2-yl)methoxy]dimethylsilane (34.12 g; 0.116 mol) in tetrahydrofuran (700 mL) cooled to 0° C. was added via an addition funnel tetrabutylammonium fluoride (140 mL, 1.0 M solution in tetrahydrofuran) and the reaction mixture was allowed to stir at room temperature for 6 h. The reaction was diluted with water (500 mL) and extracted with ethyl acetate (2×300 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (400 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give (±)-(7-methoxy-2,3-dihydro-1-benzofuran-2-yl)methanol, a crude oil. The alcohol was dissolved in dichloromethane (700 mL) and p-toluenesulfonyl chloride (33.14 g, 0.174 mol) was added followed by triethylamine (21.11 g, 0.209 mol) and then 4-(dimethylamino)pyridine (2.12 g, 0.017 mol). The reaction mixture was allowed to stir at 50° C. for 12 h. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, ethyl acetate:hexanes 3:7) provided 26.45 g (68%) of (±)-(7-methoxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white crystalline solid. Rf=0.38 (silica, ethyl acetate:hexanes 3:7); mp 98-103° C.; Anal. calcd. for C17H18O5S: C, 61.06; H, 5.43. Found: C, 60.80; H, 5.37.