Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]([CH2:20][CH3:21])[CH2:17][C:16]([CH3:23])([CH3:22])[C:15]2=[O:24])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+].[CH3:27]O>>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]([CH2:20][CH3:21])[CH2:17][C:16]([CH3:23])([CH3:22])[CH:15]2[O:24][CH3:27])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CO
Reactant: CCN1CC(C)(C)C(=O)c2cccc(CO[Si](C)(C)C(C)(C)C)c21
Agent: [BH4-]
Agent: [Na+]
Product: CCN1CC(C)(C)C(OC)c2cccc(CO[Si](C)(C)C(C)(C)C)c21
Reaction time: 0.5 h

Procedure:
To a solution of 8-(t-butyldimethylsilyloxymethyl)-4-oxo-3,3-dimethyl-1-ethyl-1,2,3,4-tetrahydroquinoline (1.60 g) in methanol (20 ml) was added sodium borohydride (0.30 g) and the mixture was stirred for 30 minutes. Methanol was distilled off and the resulting residue was extracted with dichloromethane. After drying the extract over anhydrous magnesium sulfate, the solvent was distilled off. The resulting crude 8-(t-butyldimethylsilyloxymethyl)-4-hydroxy-3,3-dimethyl-1-ethyl-1,2,3,4-tetrahydroquinoline was dissolved in dimethyl formamide (15 ml), followed by addition of sodium hydride (60%, 0.24 g), methyl iodide (0.85 g) was added thereto. The mixture was stirred overnight at room temperature. The reaction mixture was extracted with ethyl acetate-toluene and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography [eluent:n-hexane-ethyl acetate (20:1)] to give 8-(t-butyldimethylsilyloxymethyl)- 4-methoxy-3,3-dimethyl-1-ethyl-1,2,3,4-tetrahydroquinoline (1.40 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:11]([CH3:15])[C:12]([OH:14])=O)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[S:22]1[CH:26]=[N:25][N:24]=[C:23]1[NH2:27]>>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:11]([C:15]3[CH:8]=[CH:9][CH:4]=[CH:5][CH:6]=3)[C:12]([NH:27][C:23]3[S:22][CH:26]=[N:25][N:24]=3)=[O:14])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: Nc1nncs1
Reactant: CC(C(=O)O)C(c1ccccc1)c1ccc2[nH]ncc2c1
Product: O=C(Nc1nncs1)C(c1ccccc1)C(c1ccccc1)c1ccc2[nH]ncc2c1

Procedure:
Example 152 was prepared from 3-(1H-indazol-5-yl)-2-methyl-3-phenylpropanoic acid (10 and 30 mg, 0.03 and 0.88 mmol) and 1,3,4-thiadiazol-2-amine using General Coupling Method A to give 4 mg (% yield) and 6 mg of the respective diastereomers. MS found: (M+H)+=426. NMR(CDCl3) δ 8.8 (s, 1H); 7.97-8.01 (d, 1H); 7.60 (s, 1H) 7.0-7.59 (m, 12H); 4.85 (d, 1H); 4.56 (d, 1H).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]3[N:22]4[CH2:23][CH2:24][N:25]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:26][C:21]4=[N:20][C:14]=3[C:15]([NH2:19])=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.ClCCl.[Pd]>[NH2:19][C:15]1[C:14]2[N:20]=[C:21]3[CH2:26][N:25]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:24][CH2:23][N:22]3[C:13]=2[C:12]2[C:17](=[CH:18][C:9]([OH:8])=[CH:10][CH:11]=2)[N:16]=1
Reactant: CS(=O)(=O)N1CCn2c(nc3c(N)nc4cc(OCc5ccccc5)ccc4c32)C1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CS(=O)(=O)N1CCn2c(nc3c(N)nc4cc(O)ccc4c32)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 35.7 %

Procedure:
3-(Benzyloxy)-9-(methylsulfonyl)-8,9,10,11-tetrahydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinolin-6-amine, (3.34 g, 10.0 mmol) prepared as described in Example 368, was dissolved in a mixture of methanol (100 mL) and dichloromethane (100 mL) and transferred to a hydrogenation vessel charged with 10% palladium on carbon (5 g, 47 mmol). The vessel was placed under hydrogen pressure (50 psi, 3.45×105 Pa) and shaken for two days at ambient temperature. An analysis by LC/MS indicated the presence of starting material. The catalyst was removed by filtration through a layer of CELITE filter aid, and the filtrate was placed under hydrogen pressure (50 psi, 3.45×105 Pa) again for two days in the presence of 10% palladium on carbon (5 g, 47 mmol). The catalyst was removed by filtration through a layer of CELITE filter aid, and the filtrate was concentrated under reduced pressure. The residue (560 mg) was combined with material from another run to provide 1.19 g of 6-amino-9-(methylsulfonyl)-8,9,10,11-tetrahydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinolin-3-ol.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([O:14][C@H:15]1[C@H:20]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@@H:19]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@@:18]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[C:41]([CH2:46][C:47]3[CH:48]=[CH:49][C:50]4[O:54][CH2:53][CH2:52][C:51]=4[CH:55]=3)[CH:40]=2)([O:37][CH3:38])[O:17][C@@H:16]1[CH2:56][OH:57])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:7]([O:14][C@H:15]1[C@H:20]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@@H:19]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@@:18]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[C:41]([CH2:46][C:47]3[CH:48]=[CH:49][C:50]4[O:54][CH2:53][CH2:52][C:51]=4[CH:55]=3)[CH:40]=2)([O:37][CH3:38])[O:17][C@@H:16]1[CH:56]=[O:57])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc4c(c3)CCO4)c2)O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc4c(c3)CCO4)c2)O[C@H](C=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
Oxalyl chloride (0.76 mL, 8.91 mmol) was dissolved in 10 mL methylene chloride and cooled to −78° C., followed by dropwise addition of 10 mL of mixed solution (methylene chloride and dimethyl sulfoxide, v:v=10:0.85). The reaction mixture was stirred for 15 minutes. Then 25 mL solution of [(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-(2,3-dihydrobenzofuran-5-ylmethyl)phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol 5h (4.2 g, 5.94 mmol) in methylene chloride was dropwise added before the mixture was stirred for 40 minutes. The reaction mixture was warmed to room temperature and stirred for 2 hours after triethylamine (4.29 mL, 29.69 mmol) was dropwise added. Thereafter, the reaction mixture was partitioned after 35 mL 1 M hydrochloric acid were added, the organic extract was washed with saturated sodium chloride solution (35 mL×2), combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-(2,3-dihydrobenzofuran-5-ylmeth-yl)phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 51 (4.19 g, pale yellow grease), which was used directly in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C@:18]([OH:25])([CH2:23][OH:24])[C:19]([F:22])([F:21])[F:20])=[O:15].N1C=CC=CC=1.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>ClCCl>[CH3:42][C:32]1[CH:37]=[CH:36][C:35]([S:38]([O:24][CH2:23][C@:18]([CH2:17][NH:16][C:14]([C:3]2[CH:4]=[N:5][N:6]([C:7]3[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=3)[C:2]=2[NH2:1])=[O:15])([OH:25])[C:19]([F:22])([F:21])[F:20])(=[O:40])=[O:39])=[CH:34][CH:33]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1c(C(=O)NC[C@](O)(CO)C(F)(F)F)cnn1-c1ccc(F)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@](O)(CNC(=O)c2cnn(-c3ccc(F)cc3)c2N)C(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
(S)-5-Amino-1-(4-fluorophenyl)-N-[3,3,3-trifluoro-2-hydroxy-2-(hydroxymethyl)propyl]-1H-pyrazole-4-carboxamide (90 mg) was dissolved in dry dichloromethane (3 ml) and dry pyridine (3 ml) and cooled in an ice bath under nitrogen. p-Toluenesulphonyl chloride (62 mg) was added and the reaction was stirred at ice bath temperature for 1 hour and then at room temperature for 24 hours. p-Toluenesulphonyl chloride (25 mg) was added and the reaction was stirred at room temperature, under nitrogen over the weekend. p-Toluenesulphonyl chloride (25 mg) was added and the reaction was stirred at room temperature under nitrogen for 2 hours and heated at 50° C. for 2 hours and left stirring at room temperature overnight. The solvent was evaporated and the residue was partitioned between dichloromethane and water. The organic layer was washed with 1M hydrochloric acid, water, sodium bicarbonate and brine, dried using a hydrophobic frit and evaporated to give a beige foam (94 mg). This was dissolved in dichloromethane and applied to a 10 g SPE cartridge and purified on the Flashmaster eluting with a 0-50% ethyl acetate in cyclohexane over a 20 minute gradient. The appropriate fraction was evaporated to give the title compound as a colourless oil (83 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][CH:9]([S:11]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[C:28]3[C:23](=[C:24]([C:40]([NH2:42])=[O:41])[CH:25]=[C:26]([C:29]4[CH:33]=[C:32]([CH2:34][N:35]([CH3:39])[CH2:36][CH2:37]C)[S:31][CH:30]=4)[CH:27]=3)[NH:22][CH:21]=2)[CH2:16][CH2:15]1)(=[O:13])=[O:12])[CH3:10].CNCCC>>[CH2:36]([N:35]([CH2:34][C:32]1[S:31][CH:30]=[C:29]([C:26]2[CH:27]=[C:28]3[C:23](=[C:24]([C:40]([NH2:42])=[O:41])[CH:25]=2)[NH:22][CH:21]=[C:20]3[CH:17]2[CH2:18][CH2:19][N:14]([S:11]([CH:9]([CH3:8])[CH3:10])(=[O:12])=[O:13])[CH2:15][CH2:16]2)[CH:33]=1)[CH3:39])[CH3:37]
Reactant: CCCN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)C(C)C)CC4)c3c2)cs1
Agent: CCCNC
Solvent: O=C(O)C(F)(F)F
Product: CCN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)C(C)C)CC4)c3c2)cs1
Yield: 15.9 %

Procedure:
The title compound was prepared according to the general procedure of 3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-5-(5-{[methyl(propyl)amino]methyl}-3-thienyl)-1H-indole-7-carboxamide trifluoroacetate, substituting ethyl(methyl)amine (59 mg, 1.0 mmol) for methyl(propyl)amine to afford 8.0 mg of the title compound (15.9%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][CH:3]=1.[CH:10]([NH2:13])([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:13][CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(C)N
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)NCc1ccc(Br)cc1
Yield: 76.7 %

Procedure:
A solution of 1-bromo-4-(bromomethyl)benzene (2.0 g, 8.0 mmol), isopropylamine (950 mg, 16 mmol) and potassium carbonate (2.2 g, 16 mmol) in acetonitrile (40 mL) was stirred at room temperature for 18 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica, 0-100% methylene chloride/methanol) to afford the desired product (1.4 g, 78%) as a brown solid: ESI MS m/z 228 [C10H14BrN+H]+.
Reaction SMILES: N[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:5]=[N:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].N([O-])=O.[Na+].C(Cl)(Cl)[Cl:23].S(=O)=O>Cl.O>[Cl:23][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:5]=[N:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: ClC(Cl)Cl
Reactant: CCOC(=O)c1ncn(-c2ccccn2)c1N
Agent: Cl
Agent: O=N[O-]
Agent: O=S=O
Solvent: O
Product: CCOC(=O)c1ncn(-c2ccccn2)c1Cl
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 550.2 %

Procedure:
11.0 g of 5-amino-4-ethoxycarbonyl-1-(2-pyridyl)imidazole was dissolved in 60 ml of conc. hydrochloric acid and the resulting solution was cooled to -5° C. Subsequently, 3.9 g of sodium nitrite was dissolved in 10 ml of water and the resulting solution was added dropwise to the previously prepared solution while maintaining the temperature at -5° C. or lower. After completion of the dropwise addition, the resulting mixture was stirred at the same temperature for 0.5 hour. The thus obtained solution was added dropwise at around 5° C. to 150 ml of a solution of chloroform containing 1.0 g of cuprous chloride and 12 g of sulfur dioxide. After the resulting mixture was stirred at room temperature for 1 hour, was added thereto 300 ml of water and the organic layer was separated. The aqueous layer was extracted with chloroform and the organic layers were combined, washed with water and dried. The solvent was then removed by distillation to give 11.6 g of 5-chloro-4-ethoxycarbonyl-1-(2-pyridyl)imidazole as an oil.
Reaction SMILES: Br[C:2]1[C:3](=[O:31])[N:4]([CH3:30])[C:5](=[O:29])[C:6]=1[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[NH:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2>CO.[OH-].[OH-].[Pd+2]>[NH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[C:20]1[CH2:19][CH2:18][CH2:17][CH2:16][C:8]1[NH:9][C:10]2[C:15]([C:7]=1[CH:6]1[CH2:2][C:3](=[O:31])[N:4]([CH3:30])[C:5]1=[O:29])=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: CN1C(=O)C(Br)=C(c2c(CCCCc3cc4ccccc4[nH]3)[nH]c3ccccc23)C1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CN1C(=O)CC(c2c(CCCCc3cc4ccccc4[nH]3)[nH]c3ccccc23)C1=O

Procedure:
A solution of 240 mg (0.50 mmol) of 3-bromo-4-(2-(4-(1H-2-indolyl)butyl)-1H-3-indolyl)-1-methyl-2,5-dihydro-1H-pyrrole-2,5-dione and 140 mg (0.25 mmol) of Pd(OH)2/C (20%) in 30 ml of MeOH is stirred under an H2 atmosphere at room temperature for 24 h. For work-up, the mixture is filtered, the filtrate is concentrated and the residue is purified by column chromatography (SiO2:CH2Cl2/EA 95:5). On concentrating the pure fraction, the product is crystallized by addition of PE. Yield: 48.0 mg (24%), beige powder
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([N:17]2[CH2:22][CH2:21][CH:20]([CH2:23]O)[CH2:19][CH2:18]2)=[O:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:44]N1C(=O)CCC1=O>C1C=CC=CC=1>[Br:44][CH2:23][CH:20]1[CH2:21][CH2:22][N:17]([C:15]([O:14][C:11]2[CH:12]=[CH:13][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:9][CH:10]=2)=[O:16])[CH2:18][CH2:19]1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(Oc1ccc(Oc2ccccc2)cc1)N1CCC(CO)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: O=C(Oc1ccc(Oc2ccccc2)cc1)N1CCC(CBr)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 210.1 %

Procedure:
The hydroxymethyl derivative produced in Example 30 (5.0 g, 15 mmol) and triphenylphosphine (4.0 g, 15 mmol) were dissolved in 100 ml of benzene and the resulting solution put under a nitrogen atmosphere. N-Bromosuccinimide (2.7 g, 15 mmol) was added in portions to the above solution and the reaction stirred at room temperature overnight. The solvent was removed under reduced pressure to give 12.3 g of a brown oil. Purification of this oil by chromatography on 600 g of silica gel (230-400 mesh) using ethyl acetate-hexane as the eluent gave 4.52 g of a white solid. Recrystallization of this solid from diisopropyl ether gave the title compound as a white crystalline solid (4.12 g, 68%), mp 76°-78° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.Cl.Cl.[NH2:22][CH:23]1[CH2:30][CH:29]2[N:31]([CH3:32])[CH:25]([CH2:26][CH2:27][CH2:28]2)[CH2:24]1>>[CH3:32][N:31]1[CH:25]2[CH2:26][CH2:27][CH2:28][CH:29]1[CH2:30][CH:23]([NH:22][C:17]([C:16]1[C:10]3[O:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[N:12][C:11]=3[CH:13]=[CH:14][CH:15]=1)=[O:19])[CH2:24]2
Reactant: O=C(O)c1cccc2nc(-c3ccc(Cl)cc3)oc12
Reactant: CN1C2CCCC1CC(N)C2
Agent: Cl
Product: CN1C2CCCC1CC(NC(=O)c1cccc3nc(-c4ccc(Cl)cc4)oc13)C2
Yield: 43 %

Procedure:
N-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-chlorophenyl)benzoxazole-7-carboxamide was prepared from 2-(4-chlorophenyl)benzoxazole-7-carboxylic acid and 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride using the method outlined in Step C of Example 14. This compound was obtained in 43% yield as an off-white solid: mp 193-196° C.; 1H NMR (500 MHz, DMSO-d6) δ 8.14 (d, J=8.4 Hz, 2H), 8.06 (d, J=7.7 Hz, 1H), 7.88 (d, J=7.7 Hz, 1H), 7.55 (d, J=8.4 Hz, 2H), 7.46 (t, J=7.8 Hz, 1H); 6.88 (d, J=6.6 Hz, 1H), 4.62 (m, 1H), 3.19 (d, J=10.0 Hz, 2H), 2.84-2.60 (m, 2H), 2.56 (s, 3H), 2.08 (m, 3H), 1.60 (m, 1H), 1.50 (t, J=11.4 Hz, 2H), 1.30-1.15 (m, 2H); MS (ESI) m/z 410 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C@:6]2([CH:10]=[CH:9][C@@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:7]2)[CH2:5][CH2:4][O:3]1.CO.[BH4-].[Na+]>O.CCOC(C)=O>[OH:3][CH2:4][CH2:5][C@@:6]1([CH2:2][OH:1])[CH2:7][C@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:15])[CH3:16])[CH:9]=[CH:10]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C=C[C@@]2(CCOC2=O)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1C=C[C@@](CO)(CCO)C1
Temperature: 2 °C
Reaction time: 2.5 h

Procedure:
To a 5-L three-neck round bottom flask equipped with a mechanical stirrer, Claisen adapter with temperature probe and nitrogen inlet, and N2 outlet was purged with nitrogen for 2 h before use. The product of Step A (255.9 g, 1.01 mol, 1 eq) and MeOH (2 L) were added and the solution was chilled to 2° C. in an ice bath. NaBH4 (75 g, 1.98 mol, 2 eq) was added in ˜5 equal portions; the temperature exothermed to 17° C. before coming back to 6° C., when the next portion was added. The addition took ˜2.5 h and the reaction was judged complete by HPLC after the last addition. The reaction was quenched at 7° C. by addition of aqueous NH4Cl (saturated, 1 L), wherein the temperature rose to about 10° C. The white hazy mixture was concentrated on a rotary evaporate to about 1 L (45° C. bath) when a white solid with some liquid resulted. The mixture was diluted with water and EtOAc (1 L each), transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with EtOAc (3×250 mL). The combined organics were washed with brine (125 mL), dried over MgSO4, filtered through Celite and evaporated at a bath temperature of 55° C. and provided the product of Step B as a thick oil. 1H NMR (CHLOROFORM-d) δ: 5.74 (s, 2H), 4.65-4.95 (m, 2H), 3.70 (t, J=5.7 Hz, 2H), 3.40-3.57 (m, 2H), 2.76 (br. s., 1H), 2.28 (br. s., 1H), 2.19 (dd, J=13.4, 8.8 Hz, 1H), 1.70 (t, J=5.7 Hz, 2H), 1.55 (dd, J=13.8, 4.0 Hz, 1H), 1.44 (s, 9H). Calculated for C13H23NO4: 280.2 (M+23). found: 280.2.
Reaction SMILES: [F:1][C:2]1([C:18]([OH:20])=O)[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:4][CH2:3]1.[F:21][C:22]([F:34])([F:33])[CH:23]([CH3:32])[O:24][C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1>>[F:21][C:22]([F:33])([F:34])[CH:23]([CH3:32])[O:24][C:25]1[CH:26]=[CH:27][C:28]([NH:31][C:18]([C:2]2([F:1])[CH2:3][CH2:4][N:5]([S:8]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)(=[O:10])=[O:9])[CH2:6][CH2:7]2)=[O:20])=[CH:29][CH:30]=1
Reactant: CC(Oc1ccc(N)cc1)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)N2CCC(F)(C(=O)O)CC2)cc1
Product: Cc1ccc(S(=O)(=O)N2CCC(F)(C(=O)Nc3ccc(OC(C)C(F)(F)F)cc3)CC2)cc1
Yield: 10.3 %

Procedure:
This material was made in analogy to example 1 from 4-fluoro-1-(toluene-4-sulfonyl)-piperidine-4-carboxylic acid (0.15 g), (rac)-4-(2,2,2-trifluoro-1-methyl-ethoxy)-phenylamine (0.102 g) to give the desired (rac)-4-fluoro-1-(toluene-4-sulfonyl)-piperidine-4-carboxylic acid [4-(2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-amide (0.025 g) as an off-white solid. MS (ESI): 489.25 (MH+).
Reaction SMILES: N1C=CC=CC=1C(O)=O.[NH2:10][C:11]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[CH:15][CH:14]=[CH:13][N:12]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].I[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[CH:34]=1>[Cu]I.CS(C)=O>[CH3:39][C:35]1[CH:34]=[C:33]([CH:38]=[CH:37][CH:36]=1)[O:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]2[C:11]([NH2:10])=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:18][CH:19]=1
Reactant: Cc1cccc(I)c1
Reactant: Nc1ncccc1-c1ccc(O)cc1
Agent: [Cu]I
Agent: O=C(O)c1ccccn1
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Product: Cc1cccc(Oc2ccc(-c3cccnc3N)cc2)c1
Temperature: 130 °C
Reaction time: 5 h
Yield: 68.9 %

Procedure:
Copper(I) iodide (102 mg) was added to a mixture of picolinic acid (66.1 mg), 4-(2-aminopyridin-3-yl)phenol (500 mg), tripotassium phosphate (1710 mg), 1-iodo-3-methylbenzene (703 mg) and DMSO (8 ml). The mixture was stirred at 130° C. under nitrogen for 5 hr. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc). Water was added and the extracted organic layer was washed with brine. Silica-gel was added to the organic layer and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH-silica gel, eluted with EtOAc in hexane) to give the title compound (511.5 mg) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[OH:12].Br[CH:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[CH:4][C:3]=1[O:12][CH:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1ccc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccc(C(F)(F)F)cc1Cl

Procedure:
10.00 g (50.87 mmol) of 2-chloro-4-trifluoromethyl-phenol, 7.11 mL (55.00 mmol) of ethyl 2-bromopropionate and 7.60 g (55 mmol) of potassium carbonate in 100 mL DMF was stirred for 16 hours at 50° C. and then filtered. The filtrate was evaporated down i. vac., combined with water and exhaustively extracted with EtOAc. The combined org. extracts were washed with 10% aqueous sodium carbonate solution and water, dried over sodium sulphate and evaporated down i. vac.
Reaction SMILES: [CH2:1]([CH:8]([NH:32][C:33]([C:35]1[CH:44]=[N:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:36]=1)=[O:34])[CH:9]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:10][CH:11]([C:18](=O)[NH:19][CH2:20][CH2:21][OH:22])[CH2:12][CH2:13][C:14]([F:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC(Cl)(Cl)C(Cl)(Cl)Cl.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([CH:8]([NH:32][C:33]([C:35]1[CH:44]=[N:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:36]=1)=[O:34])[CH:9]([O:24][Si:25]([C:28]([CH3:29])([CH3:31])[CH3:30])([CH3:26])[CH3:27])[CH2:10][CH:11]([C:18]1[O:22][CH2:21][CH2:20][N:19]=1)[CH2:12][CH2:13][C:14]([F:17])([CH3:16])[CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(F)CCC(CC(O[Si](C)(C)C(C)(C)C)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)C(=O)NCCO
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(F)CCC(CC(O[Si](C)(C)C(C)(C)C)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)C1=NCCO1
Reaction time: 2 h
Yield: 74.7 %

Procedure:
To a solution of quinoxaline-2-carboxylic acid [1-benzyl-2-(tert-butyl-dimethyl-silanyloxy)-7-fluoro-4-(2-hydroxy-ethylcarbamoyl)-7-methyl-octyl]-amide (100 mg, 0.160 mmol) in methylene chloride (1.5 mL) was added triphenylphosphine (63 mg, 0.240 mmol), hexachloroethane (57 mg, 0.240 mmol), and triethylamine (0.045 mL, 0.320 mmol). The reaction was stirred for 2 hours than chromatographed directly on silica gel to give the title compound (72.5 mg, 75%).