Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].Br[C:21]1[CH:22]=[C:23]([C:29]2[S:33][C:32]([C:34]([O:36][CH3:37])=[O:35])=[C:31]([CH3:38])[C:30]=2[CH3:39])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28].C(O)C>C1(C)C=CC=CC=1>[CH3:28][O:27][C:26]1[C:25]([C:8]2[CH:9]=[CH:10][C:5]([S:2](=[O:4])(=[O:3])[NH2:1])=[CH:6][CH:7]=2)=[CH:24][C:23]([C:29]2[S:33][C:32]([C:34]([O:36][CH3:37])=[O:35])=[C:31]([CH3:38])[C:30]=2[CH3:39])=[CH:22][CH:21]=1
Reactant: NS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: COC(=O)c1sc(-c2ccc(OC)c(Br)c2)c(C)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1sc(-c2ccc(OC)c(-c3ccc(S(N)(=O)=O)cc3)c2)c(C)c1C
Temperature: 97.5 °C
Yield: 21.9 %

Procedure:
4-aminosulfonylbenzene boronic acid (0.54 g, 2.68 mmol) and potassium carbonate (0.67 g, 4.86 mmol) were added to the solution of methyl 5-(3-bromo-4-methoxyphenyl)-3,4-dimethylthiophene-2-carboxylate (step-4, 0.9 g, 2.43 mmol) in a mixture of toluene:ethanol (5:20 ml) in a tube at 25° C. Nitrogen gas was bubbled through reaction mixture for 15 minutes. Tetrakis(triphenylphosphine)(0) palladium (0.14 g, 0.12 mmol) was added to the reaction mixture under nitrogen atmosphere and tube was sealed. The reaction mixture was heated at 95-100° C. for 1 hr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to 25° C. and filtered through celite. The celite cake was washed with ethyl acetate (30 ml). The combined filtrate was concentrated under reduced pressure to obtain a crude product. The crude product so obtained was purified by column chromatography using 40% ethyl acetate in hexanes as an eluent to obtain the title compound 9e (0.23 g, 21.2%).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[C:4](=[O:17])[N:3]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.Cl[CH2:32][C:33]1[N:37]=[C:36]([CH3:38])[O:35][N:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:38][C:36]1[O:35][N:34]=[C:33]([CH2:32][N:7]2[C:6]3[CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[S:10][C:5]=3[C:4](=[O:17])[N:3]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:2]2=[O:1])[N:37]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(-c4ccccc4)sc3c2=O)CC1
Reactant: Cc1nc(CCl)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)no1

Procedure:
According to GP1 tert-butyl 4-(2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (200 mg; compound B50) is reacted with 3-(chloromethyl)-5-methyl-1,2,4-oxadiazole (62 mg; compound D2) in the presence of potassium carbonate (65 mg) in DMF (5 ml). Using WU1 the title compound is obtained as a solid.
Reaction SMILES: CS(O[CH2:6][CH:7]1[O:21][C:10]2=[C:11]3[C:16](=[C:17]([CH3:19])[CH:18]=[C:9]2[CH2:8]1)[NH:15][C:14](=[O:20])[CH2:13][CH2:12]3)(=O)=O.[NH2:22][CH2:23][C:24]1[S:25][CH:26]=[CH:27][CH:28]=1>>[CH3:19][C:17]1[CH:18]=[C:9]2[CH2:8][CH:7]([CH2:6][NH:22][CH2:23][C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)[O:21][C:10]2=[C:11]2[C:16]=1[NH:15][C:14](=[O:20])[CH2:13][CH2:12]2
Reactant: NCc1cccs1
Reactant: Cc1cc2c(c3c1NC(=O)CC3)OC(COS(C)(=O)=O)C2
Product: Cc1cc2c(c3c1NC(=O)CC3)OC(CNCc1cccs1)C2
Temperature: 150 °C
Reaction time: 1 h
Yield: 55.5 %

Procedure:
A mixture of 2-methanesulfonyloxymethyl-5-methyl-2,3,6,7,8,9-hexahydrofuro-[2,3-f]quinoline-7-one (1350 g) and 2-aminomethylthiophene (7.06 g) was stirred in a hot bath (150° C.) for 1 hour in the stream of argon. The solvent was distilled off under reduced pressure, and the residue was dissolved in chloroform The obtained solution was washed with sodium bicarbonate water and water, then dried. When crystallized from ethanol, 0.790 g of a free base of the title compound was obtained in pale yellow prisms (mp.: 151°-153° C., yield: 55.5%).
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[C:18]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:16])=[CH:10][C:8]=2[CH:9]=1)=[O:4].[Li+].[OH-]>C1COCC1.CO.O>[F:32][C:29]([F:30])([F:31])[C:26]1[CH:25]=[CH:24][C:23]([C:18]2[C:17]([C:15]([NH:14][C:11]3[CH:12]=[CH:13][C:7]4[O:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][C:8]=4[CH:10]=3)=[O:16])=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:28][CH:27]=1
Reactant: COC(=O)c1cc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2o1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
The product from step (c) (8.1 g) was dissolved in THF (100 mL) and methanol (100 mL). Under stirring conditions was added LiOH (2 g) in water (100 mL). The reaction mixture was stirred at room temperature for 30 minutes. The reaction solution was then concentrated in vacuo, acidified by adding 1N HCl solution. The product was extracted with ether (2×300 mL), and combined organic layers were washed with brine (2×50 mL) and then dried over MgSO4. The organic layer was then concentrated in vacuo to give the crude product which was purified by recrystallization from ether/hexane to give 7.1 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[CH:24]([NH:27][CH2:28][CH2:29][CH2:30][NH2:31])([CH3:26])[CH3:25].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][NH:31][CH2:30][CH2:29][CH2:28][NH:27][CH:24]([CH3:26])[CH3:25])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:11][CH:10]([CH2:16][CH:14]([CH2:13]3)[CH2:15]1)[CH2:9]2)=[O:5]
Reactant: O=Cc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Reactant: CC(C)NCCCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)NCCCNCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 4.7 %

Procedure:
A mixture of 2-chloro-5-formyl-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.244 g, Example 25b), N-isopropyl-1,3-propanediamine (0.211 g), p-toluenesulfonic acid (0.005 g) and toluene (30 ml) were refluxed together under Dean-Stark conditions for 3 h. The mixture was cooled and concentrated under reduced pressure to an oil. This was dissolved in ethanol (30 ml) and cooled to 0° C. under a nitrogen atmosphere. Solid sodium borohydride (0.040 g) was added portionwise and the mixture stirred at room temperature for 30 min, then concentrated under reduced pressure and the residue purified by column chromatography over silica (eluting with 9:1:0.1 dichloromethane/methanol/35% aqueous ammonia) to give the title compound (0.015 g) and a by-product (see Example 27).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:12]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:5]=[N:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1cncc(Br)c1
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1cncc(-c2ccc(OC)cc2)c1
Temperature: 85 °C
Reaction time: 18 h

Procedure:
22.26 g (96.78 mmol) of ethyl 5-bromonicotinate, 25.00 g (164.5 mmol) of 4-methoxyphenylboronic acid, 0.56 g (0.48 mmol) of tetrakis(triphenylphosphine)palladium(0) and 20.51 g (193.6 mmol) of sodium carbonate were dissolved in a mixture of 180 ml of 1,2-dimethoxyethane, 50 ml of water and 400 ml of dimethylformamide and stirred at 85° C. for 18 h. For work-up, some of the dimethylformamide was removed under reduced pressure, and the reaction mixture was diluted with water and extracted with dichloromethane. The organic phase was dried over sodium sulphate and the crude product was purified by flash chromatography (dichloromethane/acetonitrile 100:2<100:5). Yield: 20.18 g (72% of theory)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].[O:19]([CH2:26][CH2:27][CH2:28][CH2:29]Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CS(C)=O>[O:19]([CH2:26][CH2:27][CH2:28][CH2:29][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCCCCOc1ccccc1
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1ccc(-c2ccc(OCCCCOc3ccccc3)cc2)cc1
Reaction time: 8 h
Yield: 99 %

Procedure:
A solution of 4-(4′-hydroxyphenyl)benzoic acid (4 g) and 1N sodium hydroxide (41 ml) in dimethyl sulfoxide (40 ml) was heated for 30 minutes at 85° C., then treated with 4-phenoxybutyl bromide (6.42 g) and heating continued for 8 hours. After cooling, the reaction was poured into water and adjusted to pH 2 and the resulting precipitate was collected, washed with water, and dried to give 4-[4′-(4-phenoxybutyloxy) phenyl]benzoic acid (6.7 g).
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.[OH:25][CH2:26][CH:27]([NH:30][S:31]([C:34]1[S:35][C:36](Br)=[CH:37][CH:38]=1)(=[O:33])=[O:32])[CH2:28][OH:29]>>[OH:25][CH2:26][CH:27]([NH:30][S:31]([C:34]1[S:35][C:36]([C:13]#[C:12][C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:24])=[CH:4][C:5]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=4)=[N:6][C:7]=23)=[CH:37][CH:38]=1)(=[O:33])=[O:32])[CH2:28][OH:29]
Reactant: O=S(=O)(NC(CO)CO)c1ccc(Br)s1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: O=S(=O)(NC(CO)CO)c1ccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 7-difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (169 mg, 0.5 mmol) and 5-bromo-thiophene-2-sulfonic acid (2-hydroxy-1-hydroxymethyl-ethyl)-amide (example B.54) (158 mg, 0.5 mmol) according to general procedure II. Obtained as a light brown solid (53 mg, 18%). MS (ISN) 571.0 [(M−H)−]; mp 152° C.
Reaction SMILES: CS(Cl)(=O)=O.[S:6]([O:10][C:11]1[CH:26]=[C:25]2[C:14]([CH2:15][C:16]3[CH:20]=[CH:19][N:18]([CH2:21][CH:22](O)[CH3:23])[C:17]=32)=[CH:13][CH:12]=1)([CH3:9])(=[O:8])=[O:7].C(N(CC)CC)C.[N-:34]=[N+:35]=[N-:36].[Na+]>ClCCl.CN(C)C=O.O>[N:34]([CH:22]([CH3:23])[CH2:21][N:18]1[CH:19]=[CH:20][C:16]2[CH2:15][C:14]3[C:25]([C:17]1=2)=[CH:26][C:11]([O:10][S:6]([CH3:9])(=[O:8])=[O:7])=[CH:12][CH:13]=3)=[N+:35]=[N-:36]
Reactant: CC(O)Cn1ccc2c1-c1cc(OS(C)(=O)=O)ccc1C2
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Cn1ccc2c1-c1cc(OS(C)(=O)=O)ccc1C2)N=[N+]=[N-]
Yield: 87.3 %

Procedure:
0.37 ml of methanesulfonyl chloride was added dropwise while stirring to a solution, cooled to 0°, of 0.72 g of (RS)-1-(7-mesyloxy-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol and 1.33 ml of triethylamine in 30 ml of dichloromethane and the mixture was stirred at this temperature for an additional 1.5 hours. The reaction mixture was subsequently diluted with 100 ml of dichloromethane, washed twice with 70 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 70 ml of dichloromethane. The combined organic phases were washed with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The green oil obtained was dissolved in 30 ml of anhydrous dimethylformamide, treated with 0.62 g of sodium azide and the reaction mixture was heated to 60° for 16 hours while stirring. After cooling, the solution was poured into 70 ml of water and extracted twice with 100 ml of ethyl acetate each time. The combined organic phases were washed once with 70 ml of water and once with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (ethyl acetate/hexane 1:4). 0.68 g (86%) of (RS)-1-(2-azido-propyl)-7-mesyloxy-1,4-dihydro-indeno[1,2-b]pyrrole was obtained as a light yellowish solid which was used directly in the next reaction.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15]2[N:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]([F:30])[F:29])=[CH:23][CH:22]=3)=[CH:17][N:16]=2)[CH:9]=1)(=O)=O.[NH:31]1[CH2:36][CH2:35][CH:34]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:33][CH2:32]1>CN(C=O)C>[F:30][CH:28]([F:29])[O:27][C:24]1[CH:25]=[CH:26][C:21]([C:18]2[CH:19]=[N:20][C:15]([NH:14][C:10]3[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=3)[CH2:7][CH2:6][N:31]3[CH2:36][CH2:35][CH:34]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:33][CH2:32]3)=[N:16][CH:17]=2)=[CH:22][CH:23]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: CS(=O)(=O)OCCc1cccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)c1
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(CCc2cccc(Nc3ncc(-c4ccc(OC(F)F)cc4)cn3)c2)CC1
Temperature: 95 °C

Procedure:
3-(5-(4-(Difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenethyl methanesulfonate 42b (0.7 mmol) and ethyl piperidine-4-carboxylate (1.7 mmol) are dissolved in DMF (6 mL) and heated to 95° C. for 6 h then cooled to rt. The reaction mixture is partitioned with EtOAc and water. The organic layer is washed with water, brine, dried over magnesium sulfate, filtered and reduced to dryness. The crude material is purified by column chromatography on silica with hexane:EtOAc=1:1 to 100% EtOAc as eluant to yield ethyl 1-(3-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenethyl)piperidine-4-carboxylate 43 as clear crystalline solid. MS (m/z) (M+1)+: 497.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[CH:13]=[C:12]([CH3:14])[C:11]([C:15](=[O:17])[CH3:16])=[C:10]([CH3:18])[CH:9]=2)=[CH:5][CH:4]=1.[Br-:21].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[Br:21][CH2:16][C:15]([C:11]1[C:12]([CH3:14])=[CH:13][C:8]([O:7][C:6]2[CH:19]=[CH:20][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:9][C:10]=1[CH3:18])=[O:17]
Reactant: [Br-]
Reactant: COc1ccc(Oc2cc(C)c(C(C)=O)c(C)c2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: COc1ccc(Oc2cc(C)c(C(=O)CBr)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 106.6 %

Procedure:
To a solution of 1-(4-(4-methoxyphenoxy)-2,6-dimethylphenyl)ethanone (3.80 g, 14.1 mmol) in acetonitrile (28.1 mL) was added tetrabutylammoniumtribromide (TBABr3, 7.46 g, 15.5 mmol). The reaction was stirred at room temperature overnight. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 2-bromo-1-(4-(4-methoxyphenoxy)-2,6-dimethylphenyl)ethanone (5.25 g), which was used directly for the next step without further purification.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([F:22])=[N:20][CH:21]=1>CN(C)C=O>[F:22][C:19]1[N:20]=[CH:21][C:16]([CH2:15][N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)=[CH:17][CH:18]=1
Reactant: Fc1ccc(CBr)cn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(F)nc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
tert-Butyl piperazine-1-carboxylate (Aldrich, St. Louis, Mo., 17.77 g, 95 mmol) was added to a stirred solution of 5-(bromomethyl)-2-fluoropyridine (15.11 g, 80 mmol) in N,N-dimethylformamide (120 mL) at 0° C. and the suspension was stirred at room temperature overnight. The resulting thick reaction mixture was quenched with cold water (50 mL), the resulting suspension was stirred for 30 min, and the resulting solid was collected and washed with additional cold water (50 mL). The off-white precipitate was dried under vacuum to give the title compound tert-butyl 4-((6-fluoropyridin-3-yl)methyl)piperazine-1-carboxylate (19.7494 g, 66.9 mmol, 84% yield) as a white solid. LCMS (API-ES) m/z 296 (M+H)+; 1H NMR (400 MHz, d6-DMSO) δ 8.13 (s, 1H) 7.90 (td, J=8.02, 1.37 Hz, 1H) 7.15 (dd, J=8.31, 2.05 Hz, 1H) 3.51 (s, 2H) 3.30 (br. s., 4H) 2.10-2.40 (m, 4H) 1.39 (s, 9H).
Reaction SMILES: C([O:3][C:4](=[O:33])[C:5]([CH3:32])([O:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][CH2:15][CH2:16][CH2:17][C:18]#[C:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=2)=[CH:10][C:9]=1[CH3:31])[CH3:6])C.[Li+].[OH-]>C1COCC1.CCO.CCOCC>[CH3:32][C:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][CH2:15][CH2:16][CH2:17][C:18]#[C:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:24][CH:25]=2)=[CH:10][C:9]=1[CH3:31])([CH3:6])[C:4]([OH:33])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(SCCCC#Cc2ccc(OC(F)(F)F)cc2)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOCC
Product: Cc1cc(SCCCC#Cc2ccc(OC(F)(F)F)cc2)ccc1OC(C)(C)C(=O)O
Reaction time: 22 h

Procedure:
0.105 g (0.22 mmol) of the above prepared 2-methyl-2-{2-methyl-4-[5-(4-trifluoromethoxy-phenyl)-pent-4-ynylsulfanyl]-phenoxy}-propionic acid ethyl ester was dissolved in 4 ml of THF/EtOH (1:1), treated at 0° C. with 0.66 ml (0.66 mmol) of 1N LiOH, and kept at ambient temperature for 22 h. The reaction mixture was taken up in ether and washed with aqueous 10% KHSO4 solution and aqueous 10% NaCl solution. The water phases were extracted with ether (two times). The organic phase was dried (Na2SO4) and evaporated. The crude product was precipitated in pentane (RT to 4° C.) and decanted to give 28 mg of the title compound as colorless oil.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:16]2[CH:21]=[CH:20][C:19](B3OC(C)(C)C(C)(C)O3)=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Si:31]([O:38][C:39]1[CH:40]=[CH:41][C:42](I)=[C:43]2[C:48]=1[N:47]=[CH:46][CH:45]=[CH:44]2)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].C1(C)C=CC=CC=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>O.CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1>[Si:31]([O:38][C:39]1[CH:40]=[CH:41][C:42]([C:19]2[CH:18]=[CH:17][C:16]([C:8]3[N:7]([C:11]4[CH:10]=[CH:15][CH:14]=[CH:13][CH:12]=4)[C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=4[N:9]=3)=[CH:21][CH:20]=2)=[C:43]2[C:48]=1[N:47]=[CH:46][CH:45]=[CH:44]2)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: CC1(C)OB(c2ccc(-c3nc4ccccc4n3-c3ccccc3)cc2)OC1(C)C
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(I)c2cccnc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2ccc(-c3nc4ccccc4n3-c3ccccc3)cc2)c2cccnc12
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1-phenyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-1H-benzimidazole (8.9 g, 22.4 mmol), 8-(tert-butyldimethylsilyl-oxy)-5-iodoquinoline (7.2 g, 18.69 mmol), toluene (110 ml) and dioxane (110 ml) is degassed by passing through of N2 for 30 min. Pd(OAc)2 (9 mg, 0.04 mmol) and tris-o-tolylphosphine (75.6 mg, 0.25 mmol) is then added, and the mixture is heated at 80° C. for 8 h. After cooling to room temperature, the mixture is diluted with water (100 ml) and extracted with ethyl acetate (3×50 ml). The combined organic phases are dried over sodium sulfate, and the solvent is removed under reduced pressure. The crude product is purified by flash chromatography on silica and crystallisation (7.9 g, 80%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([O:18][CH:19]3[CH2:36][CH:35]4[CH:21]([C:22](=[O:42])[N:23]([CH3:41])[CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH:29][CH:30]5[C:32]([C:38](O)=[O:39])([NH:33][C:34]4=[O:37])[CH2:31]5)[CH2:20]3)[C:15]3[C:10](=[C:11]([CH3:45])[C:12]([O:43][CH3:44])=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:58]1([S:61]([NH2:64])(=[O:63])=[O:62])[CH2:60][CH2:59]1.C1CCN2C(=NCCC2)CC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.[Cl-].[Na+].O.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([O:18][CH:19]3[CH2:36][CH:35]4[CH:21]([C:22](=[O:42])[N:23]([CH3:41])[CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH:29][CH:30]5[C:32]([C:38]([NH:64][S:61]([CH:58]6[CH2:60][CH2:59]6)(=[O:63])=[O:62])=[O:39])([NH:33][C:34]4=[O:37])[CH2:31]5)[CH2:20]3)[C:15]3[C:10](=[C:11]([CH3:45])[C:12]([O:43][CH3:44])=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)nc(-c3cccc(F)c3)nc2c1C
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)C4C3)nc(-c3cccc(F)c3)nc2c1C
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A mixture of the acid 159 (200 mg, 0.324 mmol) and CDI (105 mg, 0.649 mmol) in dry THF (12 mL) was heated at reflux for 2 h under N2. The reaction mixture was cooled 50° C. and a pre-mixed solution of cyclopropyl sulfonamide (118 mg, 0.973 mmol) and DBU (138 μL, 0.908 mmol) in 2 ml of dry THF was added to the reaction mixture. The reaction was stirred at 50° C. for 18 h. The solution was pored in a separatory funnel and acidified with approx. 20 mL citric acid 10% (aq). Additional brine (20 mL) and EtOAc (40 mL) was added. The mixture was extracted with EtOAc and washed with brine, thereafter dried with Na2SO4, filtered and the solvent was removed by rotary evaporation. The crude product was purified by HPLC on an Ace-5 C8 column (100×21.2 mm) with a gradient going from 35 to 60% acetonitrile (0.1% TFA) in H2O (0.1% TFA) over 8 minutes. The title compound was obtained as a white solid (144 mg, 62%), LRMS (M+H) 720.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.Cl.[N:9]1([CH:15](N2CCCCC2)[CH2:16]Cl)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[OH-].[K+]>CO>[NH2:1][C:2]1[S:3][C:4]([S:7][CH2:16][CH2:15][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[N:5][N:6]=1
Reactant: Nc1nnc(S)s1
Reactant: ClCC(N1CCCCC1)N1CCCCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Nc1nnc(SCCN2CCCCC2)s1
Yield: 111.2 %

Procedure:
2-Amino-5-mercapto-1,3,4-thiadiazole (4.0 g), dipiperidinoethylchloridehydrochloride (6.0 g), and potassium hydroxide (3.4 g) were stirred in methanol (100 ml) overnight at room temperature. The reaction mixture was concentrated under a vacuum. The residue, with water added thereto, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride, and then concentrated under a vacuum. The resulting solid was recrystallized from n-hexane/ethanol, thereby yielding 6.1 g of the aimed compound.