Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5](=[O:32])[C@@H:6]([CH3:31])[NH:7][C:8](=[O:30])[C@H:9]([CH2:26][C:27](=[O:29])[OH:28])[NH:10][C:11](=[O:25])[C@@H:12]([CH3:24])[NH:13]C(OCC1C=CC=CC=1)=O)([CH3:3])[CH3:2].[H][H]>C(O)(=O)C.[Pd]>[CH:1]([O:4][C:5](=[O:32])[C@@H:6]([CH3:31])[NH:7][C:8](=[O:30])[C@H:9]([CH2:26][C:27](=[O:28])[OH:29])[NH:10][C:11](=[O:25])[C@@H:12]([CH3:24])[NH2:13])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)OC(=O)[C@@H](C)NC(=O)[C@H](CC(=O)O)NC(=O)[C@@H](C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)OC(=O)[C@@H](C)NC(=O)[C@H](CC(=O)O)NC(=O)[C@@H](C)N
Yield: 91.1 %

Procedure:
N-Benzyloxycarbonyl-D-alanyl-α-L-aspartyl-D-alanine isopropyl ester (2.5 g) was dissolved in 100 ml of 80% aqueous acetic acid, and the solution was subjected to catalytic reduction in a hydrogen gas stream at room temperature for four hours using palladium/carbon as catalyst. After filtering off the catalyst, the filtrate was concentrated to dryness under reduced pressure, affording 1.6 g of white powder. M.p.: 219°-221° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13]1[O:17][C:16]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[N:15][N:14]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[C:36]1[CH:37]=[N:38][CH:39]=[N:40][CH:41]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CO>[N:38]1[CH:37]=[C:36]([O:24][C:21]2[CH:22]=[CH:23][C:18]([C:16]3[O:17][C:13]([NH:12][C:3]4[CH:4]=[C:5]([C:8]([F:9])([F:10])[F:11])[CH:6]=[CH:7][C:2]=4[Cl:1])=[N:14][N:15]=3)=[CH:19][CH:20]=2)[CH:41]=[N:40][CH:39]=1
Reactant: Brc1cncnc1
Reactant: Oc1ccc(-c2nnc(Nc3cc(C(F)(F)F)ccc3Cl)o2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(Cl)c(Nc2nnc(-c3ccc(Oc4cncnc4)cc3)o2)c1
Temperature: 80 °C
Yield: 59.5 %

Procedure:
4-(5-{[2-chloro-5-(trifluoromethyl)phenyl]amino}-1,3,4-oxadiazol-2-yl)phenol (177.85 mg, 0.5 mmol) was dissolved in 3 mL of anhydrous DMF in a 2-5 mL microwave vial (Personal Chemistry). Solid potassium bis(trimethylsilyl)amide (200.0 mg, 1.0 mmol) was added and the reaction mixture was stirred with heating at 80° C. for 10 min, then 5-bromopyrimidine (95.4 mg, 0.6 mmol) was added, followed by anhydrous K2CO3 (69.1 mg, 0.5 mmol). Then the vial was capped and microwaved at 180° C. for 40 min. Then the reaction mixture was diluted with ca. 1 mL of MeOH, filtered through 0.22 um syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.01% TFA. Fractions, containing the product, were partitioned between ca. 50 mL of EtOAc and ca. 50 mL of saturated aqueous NaHCO3. EtOAc layer was washed with brine, dried over anhydrous Na2SO4 and filtered. Solvent was removed in vacuo to give the title product as a beige solid (129.1 mg). Yield 59.5%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:13])[CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][C:3]=1[OH:14].[OH-:15].[Na+].C(Cl)(Cl)Cl>CC(C)=O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:13])[CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][C:3]=1[O:14][C:6]([CH3:7])([CH3:5])[C:9]([OH:13])=[O:15]
Reactant: CCCC(=O)c1ccc(O)c(Cl)c1Cl
Reactant: [OH-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: CCCC(=O)c1ccc(OC(C)(C)C(=O)O)c(Cl)c1Cl
Reaction time: 3 h
Yield: 97.9 %

Procedure:
A mixture of 2,3-dichloro-4-butyrylphenol (15 g, 0.064 mole), acetone (140 ml) and sodium hydroxide (14.5 g, 0.36 mole) was stirred and heated to reflux. Chloroform (12 g, 0.1 mole) was added to the mixture dropwise over a period of 15 minutes. Refluxing was continued for 3 hours and the acetone was evaporated in vacuo. The residue was treated with ice water containing hydrochloric acid. The product was extracted with ether. The ether extract was washed with water, then with brine and finally dried over MgSO4. The ether was evaporated in vacuo and the residue chromatographed on a column containing silica gel (320 g) and eluted with methylene chloride/tetrahydrofuran/acetic acid 50/1/1. The appropriate fractions were combined and evaporated in vacuo to give 10 g of 2-(2,3-dichloro-4-butyrylphenoxy)-2-methylpropionic acid which was identified by NMR and the purity confirmed by thin layer chromatography.
Reaction SMILES: Br[C:2]1[O:6][C:5]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)CCC>>[N:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:2]1[O:6][C:5]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(Br)o1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(-c2ccccn2)o1

Procedure:
The title compound was prepared by a method analogous to that described in Example 14 from (R)-3′-(5-bromofuran-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 2-(tri-n-butylstannyl)pyridine. The title compound (356 mg) was obtained as an off-white solid, m/z 326 (MH+).
Reaction SMILES: [CH3:1][CH:2]([CH2:8][CH2:9][CH2:10][CH:11]([CH3:23])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][OH:7].N1C=CC=CC=1.[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>C(Cl)Cl>[CH3:1][CH:2]([CH2:8][CH2:9][CH2:10][CH:11]([CH3:23])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][O:7][S:36]([C:33]1[CH:34]=[CH:35][C:30]([CH3:40])=[CH:31][CH:32]=1)(=[O:38])=[O:37]
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCCC(C)CCCC(C)CCCC(C)CCCC(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
Under a nitrogen atmosphere, a solution of 30 g (0.09 mol) of 5,9,13,17-tetramethyl-1-octadecanol and 8.72 g (0.11 mol) of pyridine in 200 ml of dry methylene chloride was added dropwise to a solution of 19.3 g (0.10 mol) of p-toluenesulfonyl chloride in 100 ml of dry methylene chloride under ice cooling. After the dropwise addition, the mixture was agitated at room temperature overnight, the resulting reaction solution was successively washed with 200 ml of water, 200 ml of 2N hydrochloric acid, and 200 ml of a saturated sodium bicarbonate water, and it was dried over anhydrous magnesium sulfate. After the filtration, the resultant was concentrated under reduced pressure to obtain 42 g of (5,9,13,17-tetramethyloctadecyl)tosylate.
Reaction SMILES: [S:1]([C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[C:7](OC(C)C)=[O:8])([OH:4])(=[O:3])=[O:2].[CH2:17]([CH:19]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:20][OH:21])[CH3:18]>C(O)(C)C>[S:1]([C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[C:7]([O:21][CH2:20][CH:19]([CH2:17][CH3:18])[CH2:22][CH2:23][CH2:24][CH3:25])=[O:8])([OH:4])(=[O:3])=[O:2]
Reactant: CCCCC(CC)CO
Reactant: CC(C)OC(=O)c1ccccc1S(=O)(=O)O
Solvent: CC(C)O
Product: CCCCC(CC)COC(=O)c1ccccc1S(=O)(=O)O
Reaction time: 1 h

Procedure:
Into a one-liter, four-necked round bottom flask equipped with a thermometer, distillation head, and glass stirrer with TEFLON paddle were charged 82.5 grams of 2-propyl o-sulfobenzoate solution in isopropanol and 100 grams of 2-ethylhexanol. The solution was vacuum distilled to a pot temperature of 105° C. and subsequently the vacuum was turned off and the reaction mixture held at 105° C. for one hour. The resultant 2-ethylhexyl o-sulfobenzoate was a brown liquid with an acid value of 102.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C@@:16]1([CH2:26][C:27]#N)[CH2:25][C:20]2([CH2:24][CH2:23][CH2:22][CH2:21]2)[O:19][CH2:18][CH2:17]1.C[OH:30].O>C1(C)C=CC=CC=1>[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C@@:16]1([CH2:26][CH:27]=[O:30])[CH2:25][C:20]2([CH2:24][CH2:23][CH2:22][CH2:21]2)[O:19][CH2:18][CH2:17]1
Reactant: CO
Reactant: N#CC[C@@]1(c2ccccn2)CCOC2(CCCC2)C1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: O=CC[C@@]1(c2ccccn2)CCOC2(CCCC2)C1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 80 %

Procedure:
1.0 M DIBAL solution in toluene (3.0 ml, 3 mmol) was added drop-wise to a solution of 2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]acetonitrile (350 mg, 1.4 mmol) in 7 mL toluene at −78° C. The resulting mixture was stirred at −78° C. until completion (1.5 h). The reaction was then quenched with 5 eq of MeOH (0.28 mL) and 0.1 mL water, stir while warming, 175 mg NA2SO4 added, stir at room temp. 2 h to give 310 mg (80%) of 2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]acetaldehyde. LCMS m/z 250.6 (M+1) observed.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:13]=[C:12]([NH:14]C(=O)C(C)C)[N:11]=[C:10]3[C:6]=2[N:7]=[CH:8][N:9]3[C@@H:20]2[CH2:24][C@H:23]([CH2:25][OH:26])[CH:22]=[CH:21]2)[CH2:3][CH2:2]1.[OH-].[Na+].COC(C)(C)C.[OH:35][S:36]([OH:39])(=[O:38])=[O:37]>C(O)(C)C>[CH2:2]1[CH:1]([NH:4][C:5]2[C:6]3[N:7]=[CH:8][N:9]([C@H:20]4[CH:21]=[CH:22][C@@H:23]([CH2:25][OH:26])[CH2:24]4)[C:10]=3[N:11]=[C:12]([NH2:14])[N:13]=2)[CH2:3]1.[CH2:2]1[CH:1]([NH:4][C:5]2[C:6]3[N:7]=[CH:8][N:9]([C@H:20]4[CH:21]=[CH:22][C@@H:23]([CH2:25][OH:26])[CH2:24]4)[C:10]=3[N:11]=[C:12]([NH2:14])[N:13]=2)[CH2:3]1.[OH:38][S:36]([OH:39])(=[O:37])=[O:35]
Reactant: CC(C)C(=O)Nc1nc(NC2CC2)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: CC(C)O
Product: Nc1nc(NC2CC2)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Temperature: 22.5 °C
Yield: 96.9 %

Procedure:
N-{6-(cyclopropylamino)-9-[(1R,4S)-4-(hydroxymethyl)cyclopent-2-enyl]-9H-purin-2-yl}isobutyramide (6.56 g, 18.40 mmol) was slurried in a mixture of isopropanol (32.8 ml) and 10% solution of NaOH (36.1 ml, 92.0 mmol). The mixture was refluxed for 1 h. The resulting solution was cooled to 20-25° C. and tert-butyl methyl ether (32.8 ml) was added. The layers were separated and H2SO4 96% (0.61 ml, 11.03 mmol) was added dropwise to the organic layer. This mixture was cooled to 0-5° C. and the resulting slurry filtered off. The solid was dried under vacuum at 40° C. Abacavir hemisulfate (5.98 g, 97%) was obtained as a white powder.
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[C:13]2[NH:14][C:15]([C:17]3[C:18](=[O:33])[NH:19][CH:20]=[CH:21][C:22]=3[NH:23][CH2:24][C@@H:25]([OH:32])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:16][C:12]=2[CH:11]=[CH:10][CH:9]=1.Cl[C:35]([O:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)=[O:36]>C1COCC1>[CH3:45][O:44][C:41]1[CH:42]=[CH:43][C:38]([O:37][C:35](=[O:36])[NH:7][C:8]2[C:13]3[NH:14][C:15]([C:17]4[C:18](=[O:33])[NH:19][CH:20]=[CH:21][C:22]=4[NH:23][CH2:24][C@@H:25]([OH:32])[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[N:16][C:12]=3[CH:11]=[CH:10][CH:9]=2)=[CH:39][CH:40]=1
Reactant: Nc1cccc2nc(-c3c(NC[C@@H](O)c4ccccc4)cc[nH]c3=O)[nH]c12
Reactant: COc1ccc(OC(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(OC(=O)Nc2cccc3nc(-c4c(NC[C@@H](O)c5ccccc5)cc[nH]c4=O)[nH]c23)cc1
Temperature: 25 °C
Yield: 33 %

Procedure:
Pyridine (2.0 ml) was added to a solution of 3-(7-amino-1H-benzoimidazol-2-yl)-4-((S)-2-hydroxy-2-phenyl-ethylamino)-1H-pyridin-2-one (0.060 g, 0.166 mmol) (Prepared according to the general method for the intermediates of formula II and III above) and 4-methoxyphenyl chloroformate (0.062 g, 0.32 mmol) in THF (2 ml) and the reaction stirred at room temperature. After 20 hours the reaction was concentrated and the crude mixture was purified by column chromatography (1-2% methanol, dichloromethane) to give the desired product (0.028 g; 33%).
Reaction SMILES: [CH2:1]([O:3][C@H:4]([CH3:54])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][N:17](S(C3C=CC(C)=CC=3)(=O)=O)[C@H:16]([CH2:47][C:48]([CH3:53])([CH3:52])[C:49]([OH:51])=O)[CH2:15]2)=[CH:10][CH:9]=1)[CH3:2].[CH3:55][NH2:56]>>[CH2:1]([O:3][C@H:4]([CH3:54])[CH2:5][O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][NH:17][C@H:16]([CH2:47][C:48]([CH3:53])([CH3:52])[C:49]([NH:56][CH3:55])=[O:51])[CH2:15]2)=[CH:12][CH:13]=1)[CH3:2]
Reactant: CN
Reactant: CCO[C@H](C)COCc1ccc([C@H]2C[C@@H](CC(C)(C)C(=O)O)N(S(=O)(=O)c3ccc(C)cc3)C[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Product: CCO[C@H](C)COCc1ccc([C@H]2C[C@@H](CC(C)(C)C(=O)NC)NC[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1

Procedure:
According to general procedure D, 1.0 mmol of 3-[(2S,4R,5R)-4-[4((R)-2-ethoxy-propoxymethyl) -phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-2,2-dimethyl-propionic acid are reacted with methylamine (8M in EtOH) to afford the title compound as a yellow oil. Rf=0.28 (EtOAc/heptane 8:1); Rt=5.29 (gradient I).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7])#[N:2].[N+:11]([CH3:14])([O-:13])=[O:12].C(NCC)C>C1COCC1>[OH:7][CH:6]([C:5]1[CH:4]=[C:3]([CH:10]=[CH:9][CH:8]=1)[C:1]#[N:2])[CH2:14][N+:11]([O-:13])=[O:12]
Reactant: N#Cc1cccc(C=O)c1
Reactant: C[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CCNCC
Product: N#Cc1cccc(C(O)C[N+](=O)[O-])c1

Procedure:
3-Cyanobenzaldehyde (3.0 g, 22.9 mmol), nitromethane (4.2 g, 68.7 mmol) and diethylamine (167 mg, 2.29 mmol) were stirred for 48 h in THF at 55° C. in the presence of 4 Å molecular sieves. The resulting reaction mixture was filtered through celite and the resulting solution was concentrated in vacuo, then partitioned between EtOAc (20 mL) and H2O (100 mL). The EtOAc layer was washed with H2O (2×75 mL) and brine (1×50 mL), then dried (MgSO4), filtered, and concentrated in vacuo. The resulting residue was filtered through silica gel, eluting with hexanes:EtOAc (2:1) to obtain 3-(1-hydroxy-2-nitroethyl)benzonitrile as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1B1OC(C)(C)C(C)(C)O1)[O:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]([CH3:13])[CH:7]=1.C([O-])(O)=O.[Na+].Br[C:32]1[CH:37]=[CH:36][N:35]([CH2:38][CH2:39][CH2:40][CH3:41])[C:34](=[O:42])[C:33]=1[C:43]#[N:44]>O1CCOCC1.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>[CH2:38]([N:35]1[CH:36]=[CH:37][C:32]([C:16]2[CH:15]=[CH:14][C:4]([O:5][C:6]3[CH:7]=[C:8]([CH3:13])[N:9]=[C:10]([CH3:12])[CH:11]=3)=[CH:3][C:2]=2[F:1])=[C:33]([C:43]#[N:44])[C:34]1=[O:42])[CH2:39][CH2:40][CH3:41]
Reactant: Cc1cc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)c(F)c2)cc(C)n1
Reactant: CCCCn1ccc(Br)c(C#N)c1=O
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: C1COCCO1
Product: CCCCn1ccc(-c2ccc(Oc3cc(C)nc(C)c3)cc2F)c(C#N)c1=O

Procedure:
To a solution of intermediate 18 (1.078 mmol) in 1,4-dioxane (6 ml) and a saturated solution of NaHCO3 (5 ml) was added intermediate 6 (0.25 g, 0.979 mmol). The resulting solution was degassed using a stream of nitrogen and to this was added Pd(PPh3)4 (0.113 mg, 0.098 mmol). The reaction was then microwaved in a sealed tube at 150° C. for 10 minutes. The resulting cooled reaction mixture was filtered through a pad of diatomaceous earth and the pad of diatomaceous earth was washed with EtOAc. The combined filtrates were washed with water and the organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The crude reaction mixture was then purified by column chromatography (silica gel; DCM to DCM/MeOH up to 2% as eluent). The desired fractions were collected and evaporated in vacuo to yield compound 6 that was precipitated from diethylether (0.220 g, 57%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([CH:18]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=1.C([O:23][B:24](OC(C)C)[O:25]C(C)C)(C)C.C1COCC1.[Li]CCCC>C1(C)C=CC=CC=1>[CH3:19][C:5]1[CH:4]=[CH:3][C:2]([B:24]([OH:25])[OH:23])=[CH:18][C:6]=1[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1ccc(Br)cc1Oc1ccc(C(F)(F)F)cn1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc(B(O)O)cc1Oc1ccc(C(F)(F)F)cn1
Temperature: -40 °C
Reaction time: 1 h
Yield: 126.8 %

Procedure:
2-(5-Bromo-2-methylphenoxy)-5-(trifluoromethyl)pyridine (1 g, 0.003 mol) and triisopropylborate (0.8 mL, 0.003 mol) were dissolved in toluene (20 mL) and THF (5 mL) and cooled to −78° C. under a N2 atmosphere. n-BuLi (2.69 mL, 0.003 mol) was added while maintaining the reaction at −70° C. and then the reaction was stirred for 1 h at −40° C. Gradually the temperature was increased to −20-0° C. and then the reaction was quenched with 2N HCl. The reaction mixture was warmed to RT, concentrated and extracted with EtOAc. The organic extract was dried over Na2SO4 and concentrated under reduced pressure to give the title compound (1.13 g). m/z (296.4, 298.3, M− H−).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([S:14][CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH3:24])[C@@H:9]1[O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])([CH3:4])([CH3:3])[CH3:2].[CH2:34](I)[CH3:35]>>[C:1]([O:5][C:6](=[O:33])[N:7]([C@@H:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([S:14][CH2:15][C:16]2[C:17]([CH3:24])=[CH:18][C:19]([CH3:23])=[CH:20][C:21]=2[CH3:22])[C@@H:9]1[O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:27])[CH3:28])[CH2:34][CH3:35])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCI
Reactant: Cc1cc(C)c(CS[C@@H]2CCC[C@@H](NC(=O)OC(C)(C)C)[C@H]2O[Si](C)(C)C(C)(C)C)c(C)c1
Product: CCN(C(=O)OC(C)(C)C)[C@@H]1CCC[C@@H](SCc2c(C)cc(C)cc2C)[C@@H]1O[Si](C)(C)C(C)(C)C

Procedure:
A solution of [(1R, 2R, 3R)-2-(tert-butyl-dimethyl-silanyloxy)-3-(2,4,6-trimethyl-benzylsulfanyl)-cyclohexyl]-carbamic acid tert-butyl ester+(1S, 2S, 3S)diastereomer (3.0 g, 6.08 mmol) was treated with ethyl iodide according to the method of Example 7 Step A. After work up and chromatography of the reaction mixture (silica, cyclohexane/ethyl acetate=3/1) [(1R, 2R, 3R)-2-(tert-butyl-dimethyl-silanyloxy)-3-(2,4,6-trimethyl-benzylsulfanyl)-cyclohexyl]-ethyl-carbamic acid tert-butyl ester+(1S, 2S, 3S)diastereomer (1.20 g, 38%) was obtained.
Reaction SMILES: C([O:8][C:9](=O)[CH:10]([N:14]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[N:15]1)[C:11](=O)[CH3:12])C1C=CC=CC=1.[NH2:24][NH2:25].[Cl-].[NH4+]>CCO>[CH3:12][C:11]1[C:10]([N:14]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[N:15]2)=[C:9]([OH:8])[NH:24][N:25]=1
Reactant: CC(=O)C(C(=O)OCc1ccccc1)n1ccc(C(F)(F)F)n1
Reactant: NN
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1n[nH]c(O)c1-n1ccc(C(F)(F)F)n1

Procedure:
3-Oxo-2-(3-trifluoromethyl-pyrazol-1-yl)-butyric acid benzyl ester (800 mg, 2.452 mmol), EtOH (12.30 ml) and hydrazine (0.231 ml, 7.36 mmol) are stirred at 50° C. for hour. The volatiles are removed in vacuo yielding a wet solid which is added to ammonium chloride (sat. aq. 100 ml) and the product is extracted into EtOAc (2×100 ml). The combined organic extracts are washed with brine, dried over Na2SO4, and concentrated in vacuo to give a pale yellow solid. The crude product is purified by ISCO combiflash chromatography, eluting with 0 to 100% (EtOAc/Iso-hexane) on a 24 g SiO2-column to afford the title compound as an orange oil; MS: m/z 233.09 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:4]=1[CH2:5][N:6]1[C:14](=[O:15])[NH:13][C:12]2[C:7]1=[N:8][C:9]([C:16]1[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[N:17]=1)=[N:10][CH:11]=2.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:46][CH:47]1[CH2:49][CH2:48]1.O>CN(C=O)C>[CH:47]1([CH2:46][N:13]2[C:12]3[C:7](=[N:8][C:9]([C:16]4[C:24]5[C:19](=[N:20][CH:21]=[CH:22][CH:23]=5)[N:18]([CH2:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[F:32])[N:17]=4)=[N:10][CH:11]=3)[N:6]([CH2:5][C:4]3[CH:33]=[CH:34][C:35]([O:37][CH3:38])=[CH:36][C:3]=3[O:2][CH3:1])[C:14]2=[O:15])[CH2:49][CH2:48]1
Reactant: BrCC1CC1
Reactant: COc1ccc(Cn2c(=O)[nH]c3cnc(-c4nn(Cc5ccccc5F)c5ncccc45)nc32)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)n(CC3CC3)c3cnc(-c4nn(Cc5ccccc5F)c5ncccc45)nc32)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
500 mg (0.980 mmol) of the compound from example 82A were dissolved in 10 ml of DMF, 414 mg (1.270 mmol) of cesium carbonate and 150 mg (1.08 mmol) of 2-bromomethylcyclopropane were added and the mixture was stirred at RT for 18 h. Water was added and the mixture was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator. The residue was dried under high vacuum. 482 mg (72% of theory, purity 82%) of the title compound were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[O:20]1[C:25]2[CH:26]=[CH:27][C:28]([C:30](O)=[O:31])=[CH:29][C:24]=2[O:23][CH2:22][CH2:21]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:30]([C:28]1[CH:27]=[CH:26][C:25]2[O:20][CH2:21][CH2:22][O:23][C:24]=2[CH:29]=1)=[O:31]
Reactant: O=C(O)c1ccc2c(c1)OCCO2
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccc2c(c1)OCCO2

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid. MS: 422.4 (M+H).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:12]3[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:11]=3[N:10]=[C:9]2[C:19]2[C:20]([OH:25])=[N:21][CH:22]=[CH:23][CH:24]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:32][O:33][C:34](=[O:45])[CH2:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43]Br)=[CH:39][CH:38]=1>CC(C)=O>[CH3:32][O:33][C:34](=[O:45])[CH2:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][O:25][C:20]2[C:19]([C:9]3[N:8]([CH2:7][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[C:12]4[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:11]=4[N:10]=3)=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:39][CH:38]=1
Reactant: Oc1ncccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCC1
Reactant: COC(=O)COc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(COc2ncccc2-c2nc3cc(F)c(F)cc3n2CC2CCCCC2)cc1
Yield: 50 %

Procedure:
To a stirred solution of 3-(1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazol-2-yl)-pyridin-2-ol (58 mg, 0.17 mmol) in acetone (10 ml) was added cesium carbonate (0.085 g, 0.26 mmol) followed by (4-bromomethyl-phenoxy)-acetic acid methyl ester (49 mg, 0.19 mmol; CAS Reg. No. 104508-23-8) and the reaction mixture was refluxed for 2 h. The reaction mixture was filtered, and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography using silica gel (50-60% ethyl acetate/n-hexane) to yield the desired compound as a brown solid (50%). MS (Turbo Spray): m/z=522.5 (M+H).