Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](O)=O.C=O.[CH:6]1([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:27])=[C:16]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[C:17]=3[O:19][CH3:20])[C:12](=[O:28])[C:11]([C:29]([OH:31])=[O:30])=[CH:10]2)[CH2:8][CH2:7]1.O>C([O-])=O.[Na+]>[CH:6]1([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:27])=[C:16]([N:21]4[CH2:26][CH2:25][N:24]([CH3:1])[CH2:23][CH2:22]4)[C:17]=3[O:19][CH3:20])[C:12](=[O:28])[C:11]([C:29]([OH:31])=[O:30])=[CH:10]2)[CH2:7][CH2:8]1
Reactant: COc1c(N2CCNCC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: O=CO
Agent: C=O
Agent: O=C[O-]
Agent: [Na+]
Solvent: O
Product: COc1c(N2CCN(C)CC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reaction time: 2 h

Procedure:
In a mixture of sodium formate (22 mg), 87% formic acid (0.3 ml) and 37% formalin (25 μl) and 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid (60 mg) was stirred for 2 hours at 100° to 120° C. After cooling, water (1 ml) was added to the reaction mixture and then concentrated. To the residue was added water (0.5 ml), adjusted to pH 7 with 1N aqueous sodium hydroxide solution and the solution was allowed to stand in a refrigerator. The resulting precipitate was collected by filtration and washed with water to give the title compound (33 mg) as colorless needles, mp 229°-232° C. (decompd.).
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:31])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH2:29][CH3:30])[N:17]=2)[CH2:9]1.[OH:32][C:33]1([C:40]2[S:41][CH:42]=[CH:43][N:44]=2)[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1>>[CH2:29]([N:18]1[C:19]2[C:24](=[CH:23][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:21][CH:20]=2)[C:16]([NH:15][CH2:14][C:13]([NH:12][CH:10]2[CH2:9][N:8]([CH:36]3[CH2:35][CH2:34][C:33]([OH:32])([C:40]4[S:41][CH:42]=[CH:43][N:44]=4)[CH2:38][CH2:37]3)[CH2:11]2)=[O:31])=[N:17]1)[CH3:30]
Reactant: CCn1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Reactant: O=C1CCC(O)(c2nccs2)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCn1nc(NCC(=O)NC2CN(C3CCC(O)(c4nccs4)CC3)C2)c2cc(C(F)(F)F)ccc21

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(1-ethyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide TFA salt (as prepared in Example 67, Step A) and 4-hydroxy-4-thiazol-2-yl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:17]=[C:16]2[C:12]([N:13]=[C:14]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:22][CH2:21]3)[N:15]2[CH3:18])=[C:11]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:10]=1.[C:36](O)(=O)[CH2:37][CH3:38]>>[CH2:37]([C:38]1[N:8]([C:9]2[N:17]=[C:16]3[C:12]([N:13]=[C:14]([CH2:19][N:20]4[CH2:21][CH2:22][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:24][CH2:25]4)[N:15]3[CH3:18])=[C:11]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)[N:10]=2)[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1)[CH3:36]
Reactant: CCC(=O)O
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Nc3ccccc3N)nc21
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1

Procedure:
Following the procedures for 180, 2-(1-((2-(2-aminophenylamino)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol and propanoic acid were reacted to give 158. LCMS: M+H+=519.3. 1H-NMR (400 MHz, DMSO-d6): δ 8.02 (m, 1H), 7.63 (m, 1H), 7.26 (m, 2H), 4.24 (s, br, 4H), 4.02 (s, 1H), 3.82 (s, 3H), 3.77 (m, 4H), 3.73 (s, 2H), 3.28 (q, 2H), 2.90 (m, 2H), 2.00 (m, 2H), 1.66 (m, 2H), 1.34 (t, 3H), 1.22 (m, 3H), 1.02 (s, 6H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[C:4]([NH2:7])=[N:5][OH:6].[C:9]1([S:15][CH2:16][C:17](Cl)=O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1>[CH3:1][O:2][C:3]([C:4]1[N:7]=[C:17]([CH2:16][S:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][N:5]=1)=[O:8]
Reactant: COC(=O)C(N)=NO
Reactant: O=C(Cl)CSc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1noc(CSc2ccccc2)n1
Yield: 54.1 %

Procedure:
300 mg (2.54 mmol) of amino-hydroxyimino-acetic acid methyl ester and 428 mg (2.29 mmol, 0.9 eq) of phenylsulfanyl-acetyl chloride were stirred in 10 mL of THF at RT for 1 hour. The solvent was evaporated, the residue dissolved in dioxane, and the reaction mixture was heated at reflux over night in the presence of molecular sieves. Filtration, concentration under vacuum and column chromatography over silica gel with EtOAc/heptane 1:1 yielded 310 mg (49%) of 5-phenylsulfanylmethyl-[1,2,4]oxadiazole-3-carboxylic acid methyl ester as light yellow oil, MS: 268 (MNH4+).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15](=[N:23][OH:24])[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC(Cl)(Cl)[C:27]([N:29]=C=O)=[O:28].N.C(#N)C>O1CCCC1>[NH2:29][C:27]([O:24]/[N:23]=[C:15](/[C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:8]=1)\[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:28]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: COc1ccc(C(Cc2ccccc2)=NO)cc1OC1CCCC1
Agent: N
Solvent: C1CCOC1
Solvent: CC#N
Product: COc1ccc(/C(Cc2ccccc2)=N/OC(N)=O)cc1OC1CCCC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 27.1 %

Procedure:
To a magnetically-stirred solution of 1-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenyl ethanone oxime (4.51 mmol, 1.48 g) in dry tetrahydrofuran (45 mL) at 0° C. is added trichloroacetyl isocyanate (5.00 mmol, 0.943 mg; 0.596 mL) dropwise over 2 minutes and the resulting solution is allowed to stir as the temperature rises slowly from 0° C. to room temperature overnight. The reaction mixture is then cooled to 0° C. and saturated NH3 /acetonitrile solution (25 mL; prepared by bubbling gaseous ammonia through CH3CN at room temperature for 1 hour) is added dropwise to the reaction mixture. The solution is allowed to stir as it warms slowly from 0° C. to room temperature. After 1.5 hours, the tetrahydrofuran is removed in vacuo and the residue is partitioned between methylene chloride (200 mL) and water (200 mL). The aqueous phase is extracted with ethyl acetate (200 mL) and the combined organics are washed with water (200 mL), dried (Na2SO4), and concentrated in vacuo to afford a mixture of product and oxime (~1:1). The residue is purified via flash chromatography (SiO2 : 1) 2% ethyl acetate/methylene chloride, 2) 5% ethyl acetate/methylene chloride, 3) 7% ethyl acetate/methylene chloride) to give a white solid which is triturated with ether/hexane and dried in vacuo at 50° C. to afford analytically-pure title compound (1.22 mmol, 0.450 g; 27%).
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][CH2:6][CH3:7])[CH2:2]1.Cl.[C:9]1([CH3:16])[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=1>>[CH3:16][C:9]1[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][C:14]=1[CH:3]([CH2:4][CH2:5][CH2:6][CH3:7])[CH2:2][OH:1]
Reactant: CCCCC1CO1
Reactant: Cc1cccc(C)c1
Agent: Cl
Product: CCCCC(CO)c1ccc(C)cc1C
Temperature: 3 °C
Reaction time: 0.5 h

Procedure:
To a stirred, 0° C mixture of m-xylene 173g (1.63 mole) and anhydrous stannic chloride 78.0g (0.30 mole) which is constantly swept with nitrogen, is added dropwise, 1,2-epoxyhexane, 30.0 g (0.30 mole) in 50 g m-xylene. The exothermic temperature is maintained at 3° C by the rate of addition. After the addition is completed, the reaction which now contains 223 g (2.0 mole) m-xylene is stirred for 30 minutes at 0° C then poured into iced concentrated hydrochloric acid. The aqueous and organic layers are separated. After extracting the aqueous portion with ethyl ether, this organic layer is combined with the previous organic fraction. This combined organic material is washed successively with water, sodium bicarbonate and again water. The dried organic solvent mixture of ethyl ether and excess unreacted m-xylene is then removed on rotory evaporator. The concentrated residue is fractionally distilled in vacuo. The third fraction, 112° C/.5 mm, is shown to be the desired product by spectral and analytical data. The yield is 35.6g (57.6% theory).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[OH-].[K+].Br[CH2:13][CH2:14][Cl:15]>CCO>[Cl:15][CH2:14][CH2:13][N:4]1[C:3](=[O:8])[C:2]([CH3:9])([CH3:1])[NH:6][C:5]1=[O:7]
Reactant: CC1(C)NC(=O)NC1=O
Reactant: ClCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)NC(=O)N(CCCl)C1=O
Temperature: 25 °C

Procedure:
5,5-Dimethylhydantoin (5 g, 39 mmol, 1 eq.) was added to a solution of potassium hydroxide (2.18 g, 39 mmol, 1 eq.) in EtOH (100 mL). 1-bromo-2-chloroethane (11.2 g, 78 mmol, 2 eq.) was added in one portion. The resulting mixture was refluxed overnight. Reaction was cooled to room temperature and concentrated in vacuo. Crude residue was re-suspended in ethyl acetate (150 mL), and washed with H2O (100 mL), saturated aqueous sodium bicarbonate (100 mL) then brine (100 mL). Organic layer was dried (Na2SO4) and concentrated in vacuo to yield the crude product, which was directly used in the next step. Yield: 5.4 g (73%). LCMS—[M+H] m/z 191.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:25][CH2:24][CH2:23][CH2:22][C:21]([C:26]([NH:28][C:29]4[CH:34]=[CH:33][C:32]([S:35]([CH2:37][C:38]5[N:42]([CH2:43][CH2:44][CH3:45])[CH:41]=[N:40][CH:39]=5)=[O:36])=[CH:31][CH:30]=4)=[O:27])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH:47]1([CH:50]=O)[CH2:49][CH2:48]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:50][CH:47]4[CH2:49][CH2:48]4)[CH2:24][CH2:23][CH2:22][C:21]([C:26]([NH:28][C:29]4[CH:30]=[CH:31][C:32]([S:35]([CH2:37][C:38]5[N:42]([CH2:43][CH2:44][CH3:45])[CH:41]=[N:40][CH:39]=5)=[O:36])=[CH:33][CH:34]=4)=[O:27])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cncn4CCC)cc2)CCCN3)cc1
Reactant: O=CC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cncn4CCC)cc2)CCCN3CC2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.3 %

Procedure:
To a solution of (−)-8-(4-(2-butoxyethoxy)phenyl)-N-(4-(((1-propylimidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydro-1-benzazocine-5-carboxamide (120 mg) in 1,2-dichloroethane (10 ml), cyclopropanecarboxaldehyde (65.6 mg) and sodium triacetoxyborohydride (119 mg) were added. The mixture was stirred at room temperature for overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated NaHCO3, brine, and dried over MgSO4. The volatile materials were removed in vacuo and the residue was purified by column chromatography (basic silicagel, ethyl acetate) to give (−)-8-(4-(2-butoxyethoxy)phenyl)-1-(cyclopropylmethyl)-N-(4-(((1-propylimidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydro-1-benzazocine-5-carboxamide (55 mg) (compound 57) as a yellow amorphous.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=O)=[CH:2]1.[S:12]1[CH2:18][C:16](=[O:17])[NH:15][C:13]1=[S:14].C([O-])(=O)C.[Na+].O>C(O)(=O)C>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:18]2[S:12][C:13](=[S:14])[NH:15][C:16]2=[O:17])=[CH:2]1
Reactant: O=C1CSC(=S)N1
Reactant: O=Cc1c[nH]c2ncccc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1NC(=S)SC1=Cc1c[nH]c2ncccc12
Temperature: 25 °C
Yield: 102.4 %

Procedure:
The suspension of 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (example 1b, 1.2 g, 8.22 mmol), rhodanine (1.09 g, 8.22 mmol) and sodium acetate (2.69 g, 32.8 mmol) in acetic acid (12 mL) was stirred under reflux for 12 h. After cooling to room temperature, water (150 mL) was added. The solid was collected by filtration, washed with water and dried to obtain 5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethylene)-2-thioxo-thiazolidin-4-one (2.2 g, 100%) as a brawn solid. LC-MS m/e 262 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5](O)=[N:6][CH:7]=1.P(Cl)(Cl)([Cl:12])=O>>[Cl:12][C:5]1[C:4]([OH:9])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cc(Cl)cnc1O
Product: Oc1cc(Cl)cnc1Cl
Temperature: 180 °C

Procedure:
A mixture of 5-chloro-2,3-dihydroxypyridine (1.0g.) and phosphoryl chloride (10ml.) was heated overnight at 180°C. in a sealed tube. The phosphoryl chloride was distilled off, and the residue was chromatographed, to give 2,5-dichloro-3-hydroxypyridine, m.p. 160°-161°C. (ethyl acetate - petrol).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:17][CH2:18][CH2:19]Br>CN(C=O)C>[Br:17][CH2:18][CH2:19][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: BrCCBr
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCCBr)cc1
Reaction time: 8 h
Yield: 84.8 %

Procedure:
1-(4-hydroxyphenyl)ethanone (8.2 g, 60.2 mmol), potassium carbonate (15.2 g, 110.1 mmol), and KI (1.0 g, 6.0 mmol) in 100 DMF was stirred for 5 min, then 1,2-dibromoethane (60 ml, 696.2 mmol)was added. The mixture was stirred overnight, evaporated, diluted with EtAc/Hexane (1:1), washed with 0.1 M HCl/NaCl (conc), dried over MgSO4, filtered, evaporated and purified by SiO2 chrmatography eluted with EtAc/Hexane (1:3 to 2:3) to afford 12.41 g (85.2%) of the title compound. 1H NMR (CDCl3) 7.87 (ddd, 2H, J=2.8, 4.9, 9.7 Hz), 6.88 (ddd, 2H, J=2.8, 4.9, 9.6 Hz), 4.29 (t, 2H, J=6.2 Hz), 3.59 (t, 2H, J=6.2 Hz); 13C NMR 196.88, 162.11, 131.15, 130.54, 113.80, 68.06, 29.50, 26.62; MS m/z+ 264.80 (M+Na), 266.80 (M+2+Na).
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][N:6]=[CH:5][CH:4]=1.[CH2:8]([NH2:10])[CH3:9]>C1COCC1>[CH2:8]([NH:10][CH2:2][C:3]1[S:7][N:6]=[CH:5][CH:4]=1)[CH3:9]
Reactant: CCN
Reactant: ClCc1ccns1
Solvent: C1CCOC1
Product: CCNCc1ccns1

Procedure:
prepared by reaction of 5-chloromethyl-isothiazole with 2M ethylamine in THF.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[N:14]2[N:15]=[C:16](Cl)[CH:17]=[CH:18][C:13]2=[N:12][CH:11]=1.Cl.[NH:21]1[CH2:25][CH2:24][C@H:23]([CH2:26][OH:27])[CH2:22]1.C(=O)([O-])O.[Na+]>C(O)CCC>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[N:14]2[N:15]=[C:16]([N:21]3[CH2:25][CH2:24][C@H:23]([CH2:26][OH:27])[CH2:22]3)[CH:17]=[CH:18][C:13]2=[N:12][CH:11]=1
Reactant: Clc1ccc2ncc(-c3cc4ccccc4o3)n2n1
Reactant: OC[C@H]1CCNC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: OC[C@H]1CCN(c2ccc3ncc(-c4cc5ccccc5o4)n3n2)C1

Procedure:
150 mg (0.56 mmol) 3-(1-benzofur-2-yl)-6-chloroimidazo[1,2-b]pyridazine, 183.7 mg (1.34 mmol) (3S)-pyrrolidin-3-ylmethanol hydrochloride (1:1) and 186.9 mg (2.23 mmol) sodium hydrogencarbonate in 4.0 mL butan-1-ol were stirred 72 h at 150° C. The solvent was removed. The residue was purified by HPLC to yield 65 mg (35%).
Reaction SMILES: [C:1]([C:3]1[NH:7][C:6]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=2[Cl:19])=[N:5][C:4]=1C(O)=O)#[N:2].O>C(O)COCCO>[C:1]([C:3]1[NH:7][C:6]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([C:15]([F:16])([F:18])[F:17])=[CH:10][C:9]=2[Cl:19])=[N:5][CH:4]=1)#[N:2]
Reactant: N#Cc1[nH]c(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C(=O)O
Solvent: OCCOCCO
Solvent: O
Product: N#Cc1cnc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)[nH]1
Temperature: 170 °C
Yield: 35.1 %

Procedure:
A solution of 5-cyano-2-(2,6-dichloro-4-trifluoromethylphenyl)imidazole-4-carboxylic acid (7.09 g, 0.02 mol) in diethyleneglycol (70 ml) was stirred and heated at 170° C. in an atmosphere of nitrogen for 36 hours. The reaction mixture was cooled to room temperature and water (150 ml) was added. The reaction mixture was extracted with ethyl acetate (2×100 ml), washed with water (50 ml), dried over anhydrous sodium sulphate and evaporated to dryness. The solid residue was purified by chromatography on silica gel eluting with a mixture of ethyl acetate and petroleum ether (b.p. 60°-80° C.)(1:1) and recrystallised from a mixture of ethyl acetate and petroleum ether (b.p. 60°-80° C.) to give 5-cyano-2-(2,6-dichloro-4-trifluoromethylphenyl)imidazole (2.15 g) as a white solid m.p. 210°-212° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([CH3:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:4][CH:3]=1.C([Sn]([C:29]1[S:30][CH:31]=[CH:32][CH:33]=1)(CCCC)CCCC)CCC.O>CN(C=O)C>[CH3:15][CH:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)=[CH:3][CH:4]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCC(C)Oc1ccc(Br)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCC(C)Oc1ccc(-c2cccs2)cc1
Temperature: 100 °C
Reaction time: 68 h
Yield: 44.4 %

Procedure:
Tetrakistriphenylphosphinpalladium(0), (20.45 g, 17.70 mmol) is suspended in anhydrous DMF (400 mL) in a 2000 mL 3-necked flask with magnetic stirrer and condenser under an argon atmosphere. To this, 1-bromo-4-(1-methyl-hexyloxy)-benzene (240.00 g, 884.96 mmol) and tri-n-butylstannylthiophene (330.24 g, 884.96 mmol) are added. The resulting solution is stirred at 100° C. for 68 hours. After cooling to room temperature the mixture is poured into water (2000 mL) and divided into two portions of the same volume. Extraction with n-hexane (3×300 mL) results in two layers and an emulsion between those two layers. The organic layers are separated, combined, washed with diluted sodium chloride solution (2×400 mL) and dried (MgSO4). After removal of solvent by rotary evaporation most of the byproducts are removed by distillation (p=10−3 millibar, maximum temperature Tmax=130° C.). The residue is subjected to filtration using a layer of SiO2 (30×10 cm) and n-hexane as eluent. After removal of solvent, a yellowish oil (107.88 g, about 44%) with sufficient purity for synthetic purposes is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(O[CH:22]=[C:23]1[C:34]2[C:26](=[CH:27][CH:28]=[C:29]3[C:33]=2[S:32][CH:31]=[N:30]3)[NH:25][C:24]1=[O:35])C>>[OH:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][N:11]([CH3:12])[S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][CH:22]=[C:23]2[C:34]3[C:26](=[CH:27][CH:28]=[C:29]4[C:33]=3[S:32][CH:31]=[N:30]4)[NH:25][C:24]2=[O:35])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: CCOC=C1C(=O)Nc2ccc3ncsc3c21
Reactant: CN(CCOCCO)S(=O)(=O)c1ccc(N)cc1
Product: CN(CCOCCO)S(=O)(=O)c1ccc(NC=C2C(=O)Nc3ccc4ncsc4c32)cc1

Procedure:
To a solution of 3.3 g (31 mmol) of 2-(2-aminoethoxy)ethanol in 30 mL of MeOH was added 7.0 g (30 mmol) of N-acetylsulfanilyl chloride, followed by 3.3 g (33 mmol) of TEA. The reaction mixture was stirred for 30 min at rt and then acidified with 5 mL (60 mmol) of concentrated HCl and stirred at reflux for 75 min. After cooling, the mixture was diluted with 40 mL of water and made basic with solid NaHCO3. MeOH was removed on a rotary evaporator, and the residual aqueous solution was extracted with four 50-mL portions of EtOAc. The combined extracts were dried over Na2CO3, and the solvent was removed on a rotary evaporator to give 4-amino-N-(2-(2-hydroxyethoxy)ethyl)-benzenesulfonamide as a viscous oil (7.5 g, 96%): 1H NMR (DMSO-d6): δ 2.77 (q, J=6.0 Hz, 2H), 3.30 (t, J=4.9 Hz, 2H), 3.31 (t, J=6.5 Hz, 2H), 3.41 (q, J=5.2 Hz, 2H), 4.54 (t, J=5.5 Hz, 1H), 5.89 (s, 2H), 6.57 (d, J=8.7 Hz, 2H), 7.10 (t, J=7.37 (d, J=8.6 Hz, 2H); ESI-MS m/s 259 (M−H)−. To a solution of 0.63 g (2.4 mmol) of 4-amino-N-(2-(2-hydroxyethoxy)ethyl)-benzenesulfonamide in 10 mL of THF was added 0.10 g (2.5 mmol) of 60% sodium hydride. The mixture was stirred for 1 h at rt, 1 mL of DMSO and ˜0.2 mL (˜3 mmol) of methyl iodide were added to the resulting suspension. The reaction mixture was stirred 2 h at rt and then poured into 15 mL of half saturated NaCl solution and extracted with 30 mL of EtOAc. The organic solution was dried with MgSO4 and concentrated on a rotary evaporator. The residue was chromatographed on silica gel with EtOAc to give 4-amino-N-(2-(2-hydroxyethoxy)ethyl)-N-methyl-benzenesulfonamide as an oil (0.43 g, 65%): 1H NMR (DMSO-d6): δ 2.59 (s, 3H), 2.96 (t, J=5.9 Hz, 2H), 3.36 (t, J=5.2 Hz, 2H), 3.43 (t, J=5.2 Hz, 2H), 3.47 (t, J=5.9 Hz, 2H), 4.55 (t, J=5.4 Hz, 1H), 5.99 (s, 2H), 6.59 (d, J=8.7 Hz, 2H), 7.34 (d, 8.8 Hz, 2H); APCI-MS m/z 297 (M+Na)+. The title compound was prepared from 4-amino-N-(2-(2-hydroxyethoxy)ethyl)-N-methyl-benzenesulfonamide and 8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one according to Procedure J: mp 165° C.; 1H NMR (DMSO-d6): δ 2.71 (s, 3H), 3.11 (t, J=5.6 Hz, 2H), 3.37 (t, J=5.0 Hz, 2H), 3.44 (dt, J=5.1, 5.0 Hz, 2H), 3.52 (t, J=5.6 Hz, 2H), 4.56 (br t, J=5.2 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 7.61 (d, J=8.7 Hz, 2H), 7.75 (d, J=8.7 Hz, 2H), 7.81 (d, J=8.5 Hz, 1H), 8.06 (d, J=12.0 Hz, 1H), 9.25 (s, 1H), 10.91 (s, 1H), 11.16 (d, J=12.0 Hz, 1H); APCI-MS m/z 474 M−. Anal. Calcd for C21H22N4O5S2.H2O: C, 51.21; H, 4.91; N, 11.37. Found: C, 51.18; H, 4.88; N, 11.33.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([N:14]2[C:18]([CH2:19][CH3:20])=[C:17]([CH2:21][N:22]3[C@@H:31]([CH2:32][O:33][CH2:34][CH3:35])[CH2:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:23]3)[C:16]([CH2:36][CH3:37])=[N:15]2)=[C:9]([CH3:38])[CH:8]=1.O>O1CCCC1>[CH3:13][C:11]1[CH:12]=[CH:7][CH:8]=[C:9]([CH3:38])[C:10]=1[N:14]1[C:18]([CH2:19][CH3:20])=[C:17]([CH2:21][N:22]2[C@@H:31]([CH2:32][O:33][CH2:34][CH3:35])[CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23]2)[C:16]([CH2:36][CH3:37])=[N:15]1
Reactant: CCOC[C@H]1Cc2ccccc2CN1Cc1c(CC)nn(-c2c(C)cc(Br)cc2C)c1CC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCOC[C@H]1Cc2ccccc2CN1Cc1c(CC)nn(-c2c(C)cccc2C)c1CC
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 60.6 %

Procedure:
To a solution of n-butyl lithium (2.5 M hexane solution; 0.028 ml, 0.071 mmol) chilled to -78° C., a solution of (R)-2-[1-(4-bromo-2,6-dimethylphenyl)-3,5-diethyl-1H-pyrazol-4-ylmethyl]-3-ethoxymethyl-1,2,3,4-tetrahydro-isoquinoline (33 mg, 0.065 mmol) in anhydrous tetrahydrofuran (0.1 ml) was added dropwise. After stirring at -78° C. for 10 minutes, water (0.1 ml) was added. The resulting mixture was warmed to room temperature and stirred for 20 minutes. The reaction was quenched by addition of aqueous ammonium chloride (1 ml), and then extracted with ethyl acetate/water (5 ml of each). The separated organic extract was washed with an equal volume solution of aqueous ammonium chloride, dried over anhydrous sodium sulfate and concentrated in vacuo to afford a yellow oil (17 mg). Flash chromatography (silica gel, 40 micron mesh; elution with ethyl acetate/hexane=1:5 in volume) afforded the title compound (2 mg) as a yellow oil.