Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:8][O:9][C:10]([C:12]1([NH2:20])[CH2:17][CH2:16][N:15]([O:18][CH3:19])[CH2:14][CH2:13]1)=[O:11].[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=1[CH2:29][C:30](Cl)=[O:31]>C(#N)C>[CH3:8][O:9][C:10]([C:12]1([NH:20][C:30](=[O:31])[CH2:29][C:23]2[CH:24]=[C:25]([CH3:28])[CH:26]=[CH:27][C:22]=2[CH3:21])[CH2:17][CH2:16][N:15]([O:18][CH3:19])[CH2:14][CH2:13]1)=[O:11]
Reactant: Cc1ccc(C)c(CC(=O)Cl)c1
Reactant: COC(=O)C1(N)CCN(OC)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C1(NC(=O)Cc2cc(C)ccc2C)CCN(OC)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 71.6 %

Procedure:
To 5.4 g of potassium carbonate and 2 g of 4-amino-1-methoxy-piperidine-4-carboxylic acid methyl ester hydrochloride in 10 ml of acetonitrile was added 1.94 g of (2,5-dimethyl-phenyl)-acetyl chloride in 5 ml of acetonitrile at a temperature of 0-5° C. After stirring for 22 hours at room temperature, the reaction mixture was poured on ice water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and evaporated to yield 2.13 g of 4-[2-(2,5-dimethyl-phenyl)-acetylamino]-1-methoxy-piperidine-4-carboxylic acid methyl ester as a beige crystalline solid, mp: 91-93° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.[Mg].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16]>O1CCCC1>[CH2:16]([C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1)[CH2:15][CH2:14][CH2:13][CH:12]=[CH2:11]
Reactant: C=CCCCCBr
Reactant: Clc1ccc(Cl)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CCCCCc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 40 %

Procedure:
A solution containing 294 g (2 mol) of 1,4-dichlorobenzene in 500 ml of anhydrous tetrahydrofuran was added dropwise over a period of about 110 minutes under nitrogen at 80° C. to a stirred suspension containing 48.6 g (2.0 mol) of magnesium turnings. The mixture was subsequently heated for 2 hours at 80°-84° C., then decanted from the excess magnesium, and the resultant solution of the Grignard compound was added dropwise over a period of 30 minutes at 80° C. to a stirred solution containing 194 g (1.8 mol) of 6-bromo-1-hexene (Fluka GmbH, 7910 Neu-Ulm) in 200 ml of tetrahydrofuran. The mixture was then stirred for 4 hours at 80° C. and then poured onto ice. After acidification with hydrochloric acid, the mixture was extracted three times with a 1:1 mixture of diethyl ether/methyl tert-butyl ether, and the ether fractions were stirred thoroughly with activated charcoal and dried over sodium sulfate. The filtrate was evaporated, and the residue was fractionated. At a pressure of 13 hPa and a temperature of 116°-118° C., 156 g (corresponding to a yield of 40% of theory) of 4-(5-hexenyl)-1-chlorobenzene were obtained. 4-(8-Nonenyl)-1-chlorobenzene (b.p. 87° C. at 0.3 hPa), for example, can also be prepared in the same way.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>ClCCl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][O:12]2)=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: C1=COCCC1
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(COC2CCCCO2)cc1
Yield: 92.8 %

Procedure:
A solution of 5.9 g (38.7 mmol) of 4-nitrobenzyl alcohol, 17.6 ml(193.5 mmol) of 3,4-dihydro-2H-pyran and 500 mg (2.6 mmol) of p-toluene sulfonic acid monohydrate in 200 ml of dichloromethane was stirred at room temperature for 4 hours. The reaction mixture was evaporated and the residue purified by flash chromatography on silica gel, using 1:4 ethyl acetate/hexane as eluent. Product containing fractions were combined and evaporated to give 8.52 g (93%) of 2-(4-nitrobenzyloxy)-tetrahydropyran as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)([CH3:5])[C:3]#N.[H-].C([Al+]CC(C)C)C(C)C.S(=O)(=O)(O)[OH:27]>C1(C)C=CC=CC=1>[CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)([CH3:5])[CH:3]=[O:27]
Reactant: CC(C)(C#N)c1ccc(C(F)(F)F)cc1
Reactant: O=S(=O)(O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC(C)(C=O)c1ccc(C(F)(F)F)cc1
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 119.8 grams (0.56 mole) of 2-methyl-2-(4-trifluoromethylphenyl)propanenitrile in 100 mL of toluene was cooled to -50° C., and 487 mL (0.73 mole) of diisobutylaluminium hydride (1.5M in toluene) was added dropwise during a 45 minute period while keeping the reaction mixture temperature between -45° and -50° C. Upon completion of addition, the reaction mixture was stirred at -50° C. for 30 minutes. The reaction mixture was then warmed to about 0° C., where it stirred for an additional 30 minutes. After this time, the reaction mixture was carefully poured into 1000 mL of ice-cold aqueous 1.5M sulfuric acid. The resultant mixture was stirred for about three hours, then it was allowed to stand for about 18 hours. The aqueous layer was separated and extracted with 200 mL of diethyl ether. The organic layer and the diethyl ether extract were combined and dried with magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure, yielding 102.3 grams of 2-methyl-2-(4-trifluoromethylphenyl)propanaldehyde. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[C:10]=2[CH3:18])=[N:5]1.[S:20]1[CH:24]=[C:23]([C:25](O)=[O:26])[N:22]=[CH:21]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:17][C:11]1[C:10]([CH3:18])=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:25]([C:23]3[N:22]=[CH:21][S:20][CH:24]=3)=[O:26])[CH3:19])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: O=C(O)c1cscn1
Reactant: Cc1c(-c2ccn(C[C@H](C)N)n2)ccc(C#N)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-c2ccn(C[C@H](C)NC(=O)c3cscn3)n2)ccc(C#N)c1Cl
Yield: 313.3 %

Procedure:
The title compound was prepared from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile (0.2 g, 0.728 mmol), 1,3-thiazole-4-carboxylic acid (0.113 g, 0.874 mmol), HOBt (0.118 g, 0.874 mmol), DIPEA (0.152 ml, 0.874 mmol) and EDCI (0.167 g, 0.874 mmol) using DCM as solvent using the method of Example 34(d) affording 0.88 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.16 (d, 3H), 2.51 (s, 3H), 4.37 (m, 2H), 6.61 (d, 1H), 7.67 (d, 1H), 7.83-7.85 (m, 2H), 8.27 (d, 1H), 8.56 (d, 1H), 9.20 (d, 1H).
Reaction SMILES: [I-].[CH3:2][S+](C)C.[H-].[Na+].[CH3:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1>CS(C)=O.O>[C:9]1([CH3:8])[CH:16]=[CH:15][C:12]([CH:13]2[CH2:2][O:14]2)=[CH:11][CH:10]=1
Reactant: C[S+](C)C
Reactant: Cc1ccc(C=O)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(C2CO2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Trimethylsulfonium iodide (1-1.2 equiv.) in DMSO is added sodium hydride 60% dispersion in oil (1-1.8 equiv.) portionwise over 5 min. and stirred for 1 h at RT. A solution of 4-methylbenzaldehyde (1 equiv.) in DMSO is added to the reaction mixture dropwise over 20 min. and stirred at RT for 4 h. The reaction is monitored by TLC and the reaction mixture poured in water and extracted with EtOAc. The combined organic extract is washed with water, followed by brine, and dried over anhydrous sodium sulfate and evaporated to dryness to afford 2-p-tolyloxirane as crude product.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][N:48]([CH3:55])[CH:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([N:52]4[CH2:53][CH2:54][CH:49]([N:48]([CH3:55])[CH3:47])[CH2:50][CH2:51]4)=[O:42])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: CN(C)C1CCNCC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N2CCC(N(C)C)CC2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 4-dimethylamino-piperidine (Oakwood) to give the title compound. LC-MS (ES+) 775 [(M+H)+].
Reaction SMILES: O.[H-].[Na+].[Cl:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[CH2:12][C:13]#[N:14].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24]Br)=[CH:18][CH:17]=1>CS(C)=O>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH:12]([C:6]2[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:5]=2[Cl:4])[C:13]#[N:14])=[CH:18][CH:17]=1
Reactant: N#CCc1ccc(Cl)cc1Cl
Reactant: BrCCOc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CC(CCOc1ccc(Br)cc1)c1ccc(Cl)cc1Cl
Reaction time: 0.5 h

Procedure:
To a stirred and cooled (water-bath) suspension of 7 parts of a sodium hydride dispersion 78% and 75 parts of dimethylsulfoxide is added dropwise, during a 30 minutes-period, a solution of 37 parts of 2,4-dichlorobenzeneacetonitrile in 100 parts of dimethylsulfoxide. The whole is stirred for 30 minutes while cooling in a water-bath. Then there is added dropwise, during a 30 minutes-period, a solution of 56 parts of 1-bromo-4-(2-bromoethoxy)benzene in 125 parts of dimethylsulfoxide and stirring is continued for another 30 minutes. The reaction mixture is poured onto water and the product is extracted twice with 2,2'-oxybispropane. The combined extracts are washed twice with water, dried, filtered and evaporated. The residue is triturated in petroleumether. The product is filtered off and crystallized from ethanol, yielding 38 parts of α-[2-(4-bromophenoxy)ethyl]-2,4-dichlorobenzeneacetonitrile; mp. 73.9° C.
Reaction SMILES: F[C:2]1C=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([N:14]3[CH2:19][CH2:18][N:17]([S:20]([CH2:23][C@H:24]([CH:29]([CH3:31])[CH3:30])[C:25]([NH:27][OH:28])=[O:26])(=[O:22])=[O:21])[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.CC(C)[C@@H](CS([N:42]1CCN(C2N=CC(C3C=NC=CC=3)=CN=2)CC1)(=O)=O)C(O)=O>>[N:42]1[CH:2]=[CH:3][CH:4]=[C:5]([C:8]2[CH:13]=[N:12][C:11]([N:14]3[CH2:15][CH2:16][N:17]([S:20]([CH2:23][C@H:24]([CH:29]([CH3:30])[CH3:31])[C:25]([NH:27][OH:28])=[O:26])(=[O:22])=[O:21])[CH2:18][CH2:19]3)=[N:10][CH:9]=2)[CH:6]=1
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3cccnc3)cn2)CC1)C(=O)O
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)NO
Product: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3cccnc3)cn2)CC1)C(=O)NO
Yield: 88 %

Procedure:
Prepared according to the method for the preparation of 2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-N-hydroxy-3-methylbutyramide, from 3-methyl-2-(R)-[4-(5-pyridin-3-ylpyrimidin-2-yl)piperazine-1-sulfonylmethyl]-butyric acid (0.137 g), to provide the title compound as a white solid (0.126 g, 88%).
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[CH:9]=[C:8]([O:10][Si](C)(C)C)[CH:7]=[CH:6][N:5]=1.[CH3:17][CH:18]([CH3:22])[C:19](Cl)=[O:20]>C(Cl)Cl>[OH:10][C:8]1[CH:7]=[CH:6][N:5]=[C:4]([O:3][C:19](=[O:20])[CH:18]([CH3:22])[CH3:17])[CH:9]=1
Reactant: CC(C)C(=O)Cl
Reactant: C[Si](C)(C)Oc1ccnc(O[Si](C)(C)C)c1
Solvent: ClCCl
Product: CC(C)C(=O)Oc1cc(O)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.2 %

Procedure:
To 2.0 g of 2,4-bis(trimethylsilyloxy)-pyridine in 20 ml of methylene chloride was added 1.01 g of 2-methylpropionyl chloride and the mixture was stirred at room temperature for one hour. Following thereafter the general procedure of Example 27, 230 mg of the title compound was obtained in a yield of 16.1%.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[P:18]([O:23]C)([O:21][CH3:22])[O:19][CH3:20]>>[CH2:1]([P:18](=[O:23])([O:21][CH3:22])[O:19][CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: COP(OC)OC
Product: CCCCCCCCCCCCCCCCP(=O)(OC)OC
Temperature: 116 °C
Reaction time: 24 h

Procedure:
A mixture of n-hexadecyl bromide (4.89 g, 16 mmol) and freshly distilled trimethyl phosphite (2.48 g, 20 mmol) is stirred at 116° C. for 24 hours. The excess trimethyl phosphite is then removed by distillation in vacuo and the residue is stored over phosphorus pentoxide in vacuo for 24 hours. The corresponding dimethyl n-hexadecylphosphonate is isolated from the residue by extracting twice with 10 ml of methanol each time. The two methanol extracts are combined and concentrated in vacuo. The oily colorless residue thus obtained, which still contains n-hexadecyl bromide in addition to the methyl n-hexadecylphosphonate, is further reacted with trimethylsilyl chloride (1.02 g, 9.4 mmol) and sodium iodide (1.4 g, 9.4 mmol) in 4.7 ml of anhydrous acetonitrile. The reaction is carried out with stirring at room temperature and lasts 15 minutes.
Reaction SMILES: [CH3:1][C@H:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([O:22][CH3:23])[N:13]2C2CCCCO2)=[C:9]([NH2:24])[N:8]=1)[CH2:3][CH2:4][CH3:5].[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>CO>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[CH3:1][C@H:2]([O:6][C:7]1[NH:8][C:9]([NH2:24])=[C:10]2[C:14]([N:15]=1)=[N:13][C:12]([O:22][CH3:23])=[N:11]2)[CH2:3][CH2:4][CH3:5]
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCC[C@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Temperature: 20 °C
Reaction time: 72 h
Yield: 81.1 %

Procedure:
2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (6 g, 17.89 mmol) was dissolved in methanol (50 ml). Trifluoroacetic acid (20.67 ml, 268 mmol) was added dropwise, and the mixture stirred at 20° C. for 72 hours under an atmosphere of nitrogen. The solvent was removed in vacuo, and the resulting solid was washed with ethyl acetate and filtered. The filtrate was stripped and the residue washed with ethyl acetate. The combined solid residues were dried in the vacuum oven for 2 hours to give the title compound as an off-white solid (5.3 g).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1
Reactant: Clc1ncnc2[nH]cnc12
Reactant: C1=COCCC1
Product: Clc1ncnc2c1ncn2C1CCCCO1

Procedure:
In one embodiment, PG2 is 2-tetrahydropyranyl. In some embodiments, X is selected from fluoro, chloro, bromo, and iodo. In one embodiment, X is chloro. In certain embodiments, the step comprises combining 6-chloro-9H-purine with 3,4-dihydro-2H-pyran to afford 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=2)[NH:4][CH:3]=1.[H-].[Na+].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.Cl>CN(C=O)C.O>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=2)[N:4]([S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=2)(=[O:24])=[O:23])[CH:3]=1
Reactant: O=C(O)c1ccc2[nH]cc(I)c2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(C(=O)O)ccc32)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100.6 %

Procedure:
A solution of 3-iodo-1H-indole-5-carboxylic acid (3.70 g, 12.89 mmol) in DMF (9.5 mL) at 0° C. was treated with NaH (60% in mineral oil) (1.289 g, 32.2 mmol). After 15 min at 0° C., p-toluenesulfonyl chloride (2.95 g, 15.47 mmol) was added in 1 g portions at 0° C. every 15 min and the reaction was warmed slowly in the ice bath to 10° C. After 2 h, the mixture was dumped into H2O and the mixture was acidified with 5 M HCl. The precipitate was collected by filtration, washed with water and dried to afford crude 3-iodo-1-tosyl-1H-indole-5-carboxylic acid (5.72 g) as a tan solid. MS (ESI, pos. ion) m/z: 442 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.20 (1H, s), 8.03-8.09 (1H, m), 7.93-8.02 (3H, m), 7.91 (1H, s), 7.42 (2H, d, J=8.0 Hz), 2.33 (3H, s)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][Cl:15]>>[Cl:15][CH2:14][CH2:13][CH2:12][CH2:11][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cccc(O)c1
Reactant: ClCCCCBr
Product: COc1cccc(OCCCCCl)c1

Procedure:
Prepared by Procedure U and Scheme AK using 3-methoxyphenol and 1-bromo-4-chlorobutane.
Reaction SMILES: [OH:1][CH:2]([CH3:28])[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:13][N:12]=2)=[CH:7][CH:6]=1.[C:29](Cl)(=[O:33])[CH2:30][CH2:31][CH3:32]>N1C=CC=CC=1.C1(C)C=CC=CC=1>[C:29]([O:1][CH:2]([CH3:28])[CH:3]=[CH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:13][N:12]=2)=[CH:9][CH:10]=1)(=[O:33])[CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCCOc1cnc(-c2ccc(C=CC(C)O)cc2)nc1
Reactant: CCCC(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCCCOc1cnc(-c2ccc(C=CC(C)OC(=O)CCC)cc2)nc1
Reaction time: 4 h
Yield: 88.7 %

Procedure:
1.0 g of (-)-2-(4-(3-hydroxy-1-butenyl)phenyl)-5-decyloxypyrimidine was dissolved in 20 ml of pyridine, added with 0.5 g of butyryl chloride and stirred at 25°-30° C. for 4 hours. The reaction mixture was diluted with 100 ml of toluene and washed with 4N hydrochloric acid, water, a 5% sodium bicarbonate solution and water successively in that order. The toluene layer was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using toluene/ethyl acetate as eluent to obtain 1.05 g of (+)-2-(4-(3-butyryloxy-1-butenyl)phenyl)-5-decyloxy-pyrimidine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:10]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH3:9].CC1(C)C(C)(C)OB([C:31]2[CH:36]=[CH:35][C:34]([S:37]([N:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)(=[O:39])=[O:38])=[CH:33][CH:32]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>[Pd].C1COCC1>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:10]([CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[C:31]2[CH:36]=[CH:35][C:34]([S:37]([N:40]3[CH2:41][CH2:42][CH2:43][CH2:44]3)(=[O:39])=[O:38])=[CH:33][CH:32]=2)[CH3:9])[C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:12]=1
Reactant: CC1(C)OB(c2ccc(S(=O)(=O)N3CCCC3)cc2)OC1(C)C
Reactant: CC(c1ccccc1Br)N(c1cccnc1)c1cccnc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CC(c1ccccc1-c1ccc(S(=O)(=O)N2CCCC2)cc1)N(c1cccnc1)c1cccnc1
Temperature: 160 °C

Procedure:
In 0.5-2 mL microwave vial with stirbar was placed crude product N-(1-(2-bromophenyl)ethyl)-N-(pyridin-3-yl)pyridin-3-amine (3-2) (0.030 g, 0.08 mmol), 1-[4-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonyl]pyrrolidine (0.040 g, 0.12 mmol), Pd (dppf) Cl2 dichloromethane adduct (0.013 g, 0.0 16 mmol), Cs2CO3 (1 M aq. solution, 0.5 mL, 0.5 mmol) and THF (0.5 mL). The vial was sealed and heated in microwave to 160° C. for 10 min. The organic phase was filtered through packed celite, concentrated and dried. Reverse phase chromatography yielded a TFA salt Analytical LCMS: single peak (214 nm), 2.426 min. 1H NMR (300 MH, CDCl3): δ 9.00 (s, 1 H), 8.65 (s, 1 H), 8.35 (d, J=5.1 Hz, 1 H), 8.17-8.25 (m, 2 H), 7.75-7.82 (m, 4 H), 7.56-7.7.67 (m, 4 H), 7.45-7.47 (m, 2 H), 7.28-7.31 (m, 1 H), 6.20 (q, J=6-6 Hz, 1 H), 3.19-3.24 (m, 4 H), 2.07 (d, J=6.6 Hz, 3 H), 1.76-1.80 (m, 4 H). m/e (m+1): 485.1.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[C:10]([O:14][C:15]([NH:17][CH:18]1[CH2:22][CH2:21][NH:20][CH2:19]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>CN(C=O)C>[C:10]([O:14][C:15]([NH:17][CH:18]1[CH2:22][CH2:21][N:20]([CH2:6][C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:19]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: ClCc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(Cc2ccc(Cl)cc2)C1
Temperature: 70 °C
Reaction time: 15 h
Yield: 80.2 %

Procedure:
4-Chlorobenzyl chloride (4.15 g, 25.8 mmol) and 2Pr2NEt (6.67 g, 51.6 mmol) were added to a solution of 3-{(tert-butoxycarbonyl)amino}pyrrolidine (4.81 g, 25.8 mmol) in DMF (50 mL). The reaction mixture was stirred at 70° C. for 15 h and the solvent was removed under reduced pressure. Recrystallization (CH3CN, 50 mL) provided the desired material, 3-(tert-butoxycarbonyl)amino-1-(4-chlorobenzyl)pyrrolidine as a pale yellow solid (6.43 g, 80.2%): 1H NMR (CDCl3, 300 MHz) δ 1.37 (s, 9 H), 1.5-1.7 (br, 1 H), 2.1-2.4 (m, 2 H), 2.5-2.7 (m, 2 H), 2.83 (br, 1 H), 3.57 (s, 2 H), 4.1-4.3 (br, 1 H), 4.9-5.1 (br, 1 H), 7.15-7.35 (br, 4 H); The purity was determined by RPLC/MS (98%); ESI/MS m/e 311.0 (M++H, C16H24ClN2O2).
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][C:9]([C:16]#[CH:17])=[CH:10][CH:11]=3)[C:6]([CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH3:37])([CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])[C:5]=2[CH:4]=1)#[CH:2].I[C:39]1[S:43][C:42]([CH:44]=[O:45])=[CH:41][CH:40]=1>C1(C)C=CC=CC=1.CCN(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:37][O:36][CH2:35][CH2:34][O:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28][C:6]1([CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])[C:7]2[CH:8]=[C:9]([C:16]#[C:17][C:39]3[S:43][C:42]([CH:44]=[O:45])=[CH:41][CH:40]=3)[CH:10]=[CH:11][C:12]=2[C:13]2[C:5]1=[CH:4][C:3]([C:1]#[C:2][C:39]1[S:43][C:42]([CH:44]=[O:45])=[CH:41][CH:40]=1)=[CH:15][CH:14]=2
Reactant: C#Cc1ccc2c(c1)C(CCOCCOCCOC)(CCOCCOCCOC)c1cc(C#C)ccc1-2
Reactant: O=Cc1ccc(I)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COCCOCCOCCC1(CCOCCOCCOC)c2cc(C#Cc3ccc(C=O)s3)ccc2-c2ccc(C#Cc3ccc(C=O)s3)cc21
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 81.3 %

Procedure:
Air was removed from a solution of 2,7-diethynyl-9,9-bis[2-[2-(2-methoxyethoxy)ethoxy]ethyl]-9H-fluorene (0.120 g, 0.237 mmol) in 8.2 mL of toluene and 1.8 mL of Et3N by blowing argon for 20 min. Then Pd(PPh3)2Cl2 (10 mg, 6 mol %) and CuI (2.7 mg, 6 mol %), and 5-iodothiophene-2-carboxaldehyde (0.135 g, 0.568 mmol) were added, and deaeration was continued for 15 min. Thereafter the mixture was stirred at 40° C. for 17 h. After completion of the reaction, reaction mixture was filtered and evaporated to dryness. The crude product was purified by column chromatography on silica gel (CH2Cl2/AcOEt 60:40 then AcOEt) to yield 0.140 g (81%) of 5,5′-[9,9-bis[2-[2-(2-methoxyethoxy)ethoxy]ethyl]-9H-fluorene-2,7-diyldi-2,1-ethynediyl]bis-2-thiophenecarboxaldehyde, mp 84° C.; 1H NMR (CDCl3) δ 2.43 (t, 4H, J=7.5 Hz), 2.79 (t, 4H, J=7.2 Hz), 3.21 (m, 4H), 3.33 (s, 6H), 3.39 (m, 4H), 3.54-3.46 (m, 8H), 7.37 (d, 2H, J=3.9 Hz), 7.57 (dd, 2H, J=1.5 Hz, J=7.1 Hz), 7.62 (d, 2H, J=1.2 Hz), 7.71 (d, 2H, J=7.1 Hz), 7.72 (d, 2H, J=3.9 Hz), 9.90 (s, 2H); 13C NMR (CDCl3) δ 39.6, 51.6, 59.0, 66.8, 70.1, 70.4, 70.5, 71.8, 83.0, 98.5, 120.5, 121.2, 126.6, 131.3, 132.6, 132.8, 136.2, 140.7, 143.9, 149.7, 182.5. HRMS (ESI) calcd for C41H42O8NaS2 [(M+Na)+] m/z 749.2219. found 749.2226. Anal. Calcd for C41H42O8S2 (726.90): C, 67.75; H, 5.82; S, 8.82. Found: C, 67.86; H, 5.82; S, 8.63.