Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[CH3:13][CH:14]([CH3:30])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:19]=1)=[O:16]>>[F:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:27]2[CH2:28][CH2:29][CH:24]([C:20]3[CH:19]=[C:18]([NH:17][C:15](=[O:16])[CH:14]([CH3:13])[CH3:30])[CH:23]=[CH:22][CH:21]=3)[CH2:25][CH2:26]2)=[CH:7][CH:8]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: Fc1ccc(OCCCCl)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCOc3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-(3-chloropropoxy)-4-fluorobenzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 399.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[C:6]([CH:16]=O)=[CH:5][CH:4]=1.[Li+].[Br-].[Si](Cl)(C)(C)C.C[SiH](C)O[SiH](C)C.[C-:32]#[N:33].[Na+]>C(#N)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[C:6]([CH2:16][C:32]#[N:33])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)c2c1oc1ccccc12
Reactant: [C-]#N
Agent: C[SiH](C)O[SiH](C)C
Agent: C[Si](C)(C)Cl
Agent: [Br-]
Solvent: ClCCl
Solvent: CC#N
Product: COc1ccc(CC#N)c2c1oc1ccccc12
Temperature: 0 °C

Procedure:
To a solution of 4-methoxy-dibenzofuran-1-carbaldehyde (13.5 g, 0.059 mol) in acetonitrile (200 ml) was added LiBr (9.8 g, 0.13 mol) and TMS chloride (11.5 ml, 0.089 mol) at room temperature under stirring. The reaction mass was cooled to 0° C., and at 0° C., 1,1,3,3-tetramethyl disiloxane (17 ml, 0.096 mol) was added drop wise. The reaction mass was allowed slowly to come to room temperature and was stirred for 4 hrs at room temperature. Once TLC confirmed the absence of starting material, the reaction mass was diluted with DCM (300 ml), and filtered through Hyflow. The filtrate was concentrated under vacuum and again dissolved in DCM and filtered. To the brown colored compound DMF (150 ml) was added and the reaction mass was stirred for 10 min, until it dissolved. To the solution NaCN (6.44 g, 0.131 mol) was added and the reaction mass was allowed to stir for 4 hrs at room temperature. The reaction mass was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried with sodium sulfate and concentrated under vacuum to get (4-methoxy-dibenzofuran-1-yl)-acetonitrile, Yield 12 g (85%) 1H-NMR (300 MHz, CDCl3) 7.9 (d, J=7.2, 1H); 7.67 (d, J=8.2, 1H); 7.55 (ddd, J=1.2, 7.3, 8.5, 1H); 7.43 (ddd, J=1, 7.8, 8.5, 1H), 7.29 (d, J=8.2, 1H), 6.98 (d, J=8.2, 1H); 4.15 (s, 2H), 4.0 (s, 3H)
Reaction SMILES: [Br:1][C:2]1[CH:33]=[C:32]([CH3:34])[C:5]([O:6][C:7]2[C:8]3[NH:31][CH:30]=[CH:29][C:9]=3[N:10]=[C:11]([N:13]([C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=3)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[N:12]=2)=[C:4]([CH3:35])[CH:3]=1.[Li+].[CH3:37][Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH3:35])[C:5]([O:6][C:7]2[C:8]3[N:31]([CH3:37])[CH:30]=[CH:29][C:9]=3[N:10]=[C:11]([N:13]([C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=3)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[N:12]=2)=[C:32]([CH3:34])[CH:33]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Cc1cc(Br)cc(C)c1Oc1nc(N(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)nc2cc[nH]c12
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(Br)cc(C)c1Oc1nc(N(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)nc2ccn(C)c12
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
To a cold mixture of tert-butyl 4-(4-bromo-2,6-dimethylphenoxy)-5H-pyrrolo[3,2-d]pyrimidin-2-yl(4-cyanophenyl)carbamate (0.81 g, 1.5 mmol) in THF (5 ml) at −78° C. was added a solution of LiHMDS (1 M, 2 ml, 2 mmol). The mixture was warmed to 0° C. over 2 hours and then was cooled to −78° C. Idomethane (0.37 ml, 6 mmol) was added and the mixture was warmed to room temperature over 2 hours and then stirred at this temperature for an additional 2 hours. The mixture was washed with brine, extracted with ethyl acetate (×3). The organic layers were combined dried over MgSO4 and concentrated to dryness. The crude material was purified by chromatography on silica to obtain the title compound (0.782 g, 1.42 mmol, 95%). 1H NMR (CDCl3, 400 MHz) δ 1.32 (s, 9H), 2.07 (s, 6H), 4.18 (s, 3H), 6.65 (d, J=3.8 Hz, 1H), 7.15 (d, J=8.8 Hz, 2H), 7.21 (s, 2H), 7.37 (d, J=3.8 Hz, 1H), 7.49 (d, J=8.8, 2H).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.C([O:11][C@@H:12]1[C@@H:17]([O:18]C(=O)C)[C@H:16]([O:22]C(=O)C)[C@@H:15]([CH2:26][O:27]C(=O)C)[O:14][C@H:13]1[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37]Br)[CH:32]=1)(=O)C.C[O-].[Na+]>CN(C)C=O.O1CCCC1.CO>[N:3]1([CH2:37][C:33]2[CH:32]=[C:31]([C@@H:13]3[O:14][C@H:15]([CH2:26][OH:27])[C@@H:16]([OH:22])[C@H:17]([OH:18])[C@H:12]3[OH:11])[CH:36]=[CH:35][CH:34]=2)[CH:7]=[CH:6][CH:5]=[CH:4]1
Reactant: c1cc[nH]c1
Reactant: CC(=O)OC[C@H]1O[C@@H](c2cccc(CBr)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CO
Product: OC[C@H]1O[C@@H](c2cccc(Cn3cccc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Yield: 35.3 %

Procedure:
Sodium hydride (42 mg) was added to a solution of pyrrole (64 mg) in dimethylformamide (10 ml) under cooling with ice, and the mixture was stirred for half an hour at room temperature. After the mixture was cooled to −30° C., a solution of (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-[3-(bromomethyl)phenyl]-D-glucitol (80 mg) in tetrahydrofuran (2 ml) was added dropwise thereto, and the resultant was stirred for one hour at room temperature. Methanol (10 ml) and sodium methoxide (44 mg) was added thereto, and the resultant was stirred for one hour at the same temperature. After the completion of the reaction, the reaction mixture was concentrated to give the residue. The resulting residue was purified by a reversed-phase column chromatography (water-methanol) to obtain (1S)-1,5-anhydro-1-[3-(1H-pyrrole-1-ylmethyl)-phenyl]-D-glucitol (18 mg).
Reaction SMILES: ClC1[C:3](F)=[CH:4][C:5](F)=[C:6]([CH:14]=1)[C:7](NS(C)(=O)=O)=[O:8].[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24].C12(CO)CC3CC(CC(C3)C1)C2.C1(CO)CCCC1>>[Cl:17][C:18]1[C:19]([O:8][CH2:7][CH:6]2[CH2:5][CH2:4][CH2:3][CH2:14]2)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24]
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC12CC3CC(CC(C3)C1)C2
Agent: OCC1CCCC1
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(OCC2CCCC2)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide and adamantan-1-ylmethanol with cyclopentylmethanol, the title compound was obtained as a colorless solid (0.12 g, 32%): 1H NMR (300 MHz, DMSO-d6) δ 11.77 (s, 1H), 7.73 (d, J=7.4 Hz, 1H), 7.24 (d, J=12.4 Hz, 1H), 4.03 (d, J=6.8 Hz, 2H), 2.87 (s, 6H), 2.39-2.29 (m, 1H), 1.82-1.72 (m, 2H), 1.65-1.51 (m, 4H), 1.38-1.30 (m, 2H); MS (ES−) m/z 377.1, 379.1 (M−1).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:25][N:24]=[C:23]([C:26]3[N:27]=[CH:28][C:29]([C:32](OCC)=[O:33])=[N:30][CH:31]=3)[N:22]=2)=[CH:17][CH:16]=1)[CH:12]([CH3:14])[CH3:13]>C1(C)C=CC=CC=1>[CH2:11]([C:15]1[CH:16]=[CH:17][C:18]([C:21]2[O:25][N:24]=[C:23]([C:26]3[N:27]=[CH:28][C:29]([CH2:32][OH:33])=[N:30][CH:31]=3)[N:22]=2)=[CH:19][CH:20]=1)[CH:12]([CH3:14])[CH3:13]
Reactant: CCOC(=O)c1cnc(-c2noc(-c3ccc(CC(C)C)cc3)n2)cn1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC(C)Cc1ccc(-c2nc(-c3cnc(CO)cn3)no2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 111.1 %

Procedure:
Diisobutylaluminum hydride (1.5 M solution in toluene, 2.12 mL) was added dropwise to a cold (−78° C.) solution of ethyl 5-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]pyrazine-2-carboxylate (0.51 g, 1.45 mmol) in toluene (10 mL) and stirred for 0.5 hours at −78° C. The reaction mixture was warmed to 0° C., quenched with 1N HCl (10 mL) and extracted with EtOAc (3×10 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to provide the title compound (0.50 g) as a crude orange oil.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](Cl)=[N:14][OH:15])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:17]([C:19]1[C:20]([NH2:26])=[N:21][C:22]([NH2:25])=[CH:23][CH:24]=1)#[CH:18].C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[CH:18]=[C:17]([C:19]3[C:20]([NH2:26])=[N:21][C:22]([NH2:25])=[CH:23][CH:24]=3)[O:15][N:14]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(CC(Cl)=NO)cc1
Reactant: C#Cc1ccc(N)nc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCOc1ccc(Cc2cc(-c3ccc(N)nc3N)on2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 115.7 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (4-butoxy-phenyl)-acetohydroximoyl chloride (150 mg, 0.621 mmol) described in Manufacturing Example 67-1-4 and 3-ethynyl-pyridin-2,6-diamine (52.8 mg, 0.396 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (216 μL, 1.55 mmol). This mixture was stirred for 4 hours at room temperature. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate: heptane=1:1˜ethyl acetate) to obtain the title compound (155 mg, 74%).
Reaction SMILES: B(F)(F)F.C[O+](C)C.[CH2:9]([O:16][C:17]1[CH:22]=[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]([Br:31])=[CH:19][C:18]=1[C:32]1ON=[C:34]([CH3:37])[C:33]=1[C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl.[NH2:47][OH:48].C(=O)([O-])[O-].[K+].[K+]>ClCCl.CO>[CH2:9]([O:16][C:17]1[CH:22]=[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]([Br:31])=[CH:19][C:18]=1[C:32]1[C:33]([C:38]2[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=2)=[C:34]([CH3:37])[O:48][N:47]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NO
Reactant: COc1ccc(-c2c(C)noc2-c2cc(Br)c(OCc3ccccc3)cc2OCc2ccccc2)cc1
Agent: C[O+](C)C
Agent: Cl
Agent: FB(F)F
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(-c2c(-c3cc(Br)c(OCc4ccccc4)cc3OCc3ccccc3)noc2C)cc1
Reaction time: 3 h
Yield: 35.9 %

Procedure:
Trimethyloxonium boron trifluoride (Aldrich; 70 mg, 0.47 mmol) was added to a stirred solution of 5-(2,4-Bis-benzyloxy-5-bromo-phenyl)-4-(4-methoxy-phenyl)-3-methyl-isoxazole (Example 3, Step 1) (120 mg, 0.22 mmol) in dichloromethane (3 ml) and stirring was continued for 3 h. The resulting mixture was concentrated in vacuo to leave a white semisolid, which was mixed with hydroxylamine hydrochloride (70 mg, 1.0 mmol), potassium carbonate (120 mg, 0.87 mmol) and methanol (2 ml), and heated at reflux for 18 h. The reaction mixture was partitioned between water (20 ml) and ethyl acetate (2×10 ml) and the combined organic phases were dried over anhydrous magnesium sulphate and evaporated in vacuo to leave an colourless oil. The crude product was purified by column chromatography, silica (10 g), eluting with hexane, followed by diethyl ether/hexane (1:1), to give 3-(2,4-Bis-benzyloxy-5-bromo-phenyl)-4-(4-methoxy-phenyl)-5-methyl-isoxazole as a white solid (44 mg, 37%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][CH:9]=[C:8]([C:11]#[N:12])[C:5]2=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:9]=[C:8]([C:11]#[N:12])[C:5]2=[N:6][CH:7]=1
Reactant: N#Cc1c[nH]c2cc(Br)cnc12
Reactant: BrCC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cn(CC2CCOCC2)c2cc(Br)cnc12
Temperature: 100 °C

Procedure:
To mixture of 6-bromo-1H-pyrrolo[3,2-b]pyridine-3-carbonitrile (500 mg, 2.252 mmol) in N,N-dimethylformamide (4.5 mL) was added sodium hydride (60% dispersion in mineral oil) (59.4 mg, 2.477 mmol) followed by 4-(bromomethyl)tetrahydro-2H-pyran (444 mg, 2.477 mmol). The mixture was heated at 100° C. for 2 hours. The reaction was diluted with 50 mL of ethyl acetate and the organic mixture was washed with a solution of aqueous sodium bicarbonate (1×50 mL), water (1×50 mL), and brine (1×30 mL), dried over magnesium sulfate, filtered, concentrated, and purified by silica gel flash chromatography (Isco®, Redi-Sep® column) eluting with a gradient of 30-100% ethyl acetate/hexane to afford the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]#[N:8])=[CH:5][C:4]([CH3:9])=[N:3]1>[Pd].C(O)C>[CH3:1][N:2]1[C:6]([CH2:7][NH2:8])=[CH:5][C:4]([CH3:9])=[N:3]1
Reactant: Cc1cc(C#N)n(C)n1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(CN)n(C)n1
Reaction time: 17 h
Yield: 90 %

Procedure:
A suspension of 2,5-Dimethyl-2H-pyrazole-3-carbonitrile (654 mg, 5.4 mmol) and 10% palladium on carbon (200 mg) in ethanol (15 mL) was shaken in a Parr hydrogenation apparatus under 45 psi H2 for 17 hr. The mixture was filtered through celite and the filtrate was concentrated under reduced pressure to give 608 mg of an oil which was used without any further purification. 1H NMR (CDCl3) δ 5.91 (1H, s), 3.81, 3.73 (2H,2s), 3.75 (3H, s), 2.21 (3H, s).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[CH3:11][N:12]1[C:20]2[C:15](=[CH:16][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:18][CH:19]=2)[C:14]([CH3:30])=[N:13]1>>[CH3:11][N:12]1[C:20]2[C:15](=[CH:16][C:17]([C:2]3[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=3)=[CH:18][CH:19]=2)[C:14]([CH3:30])=[N:13]1
Reactant: Cc1nn(C)c2ccc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: Nc1c(F)cc(Br)cc1F
Product: Cc1nn(C)c2ccc(-c3cc(F)c(N)c(F)c3)cc12
Yield: 39.6 %

Procedure:
Potassium acetate (0.344 g, 3.51 mmol) and bis(pinacolato)diboron (351 mg, 1.4 mmol) were added to a solution of 5-bromo-1,3-dimethyl-1H-indazole (240 mg, 1.06 mmol) in dioxane (10 ml) and mixture was degassed with nitrogen for 30 min. tetrakis(triphenylphosphine) palladium(0) was added and degassed for further 30 min. Reaction mixture was refluxed for 2 h. After completion of the reaction, work-up (AcOEt/H2O) followed by column afforded 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (85 mg) as a white solid. The title compound (26 mg) was prepared from 4-bromo-2,6-difluoroaniline (50 mg, 0.24 mmol) and 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (85 mg, 0.31 mmol) as a white solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.93 (s, 1H), 7.66 (dd, J 1.5, 8.8, 1H), 7.55 (d, J 8.8, 1H), 7.33 (dd, J 2, 8.2, 2H), 5.22 (s, 2H), 3.94 (s, 3H), 2.49 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:4][C@@H:5]1[O:8][C:7](=[O:9])[CH2:6]1.[OH-:19].[Na+]>C1COCC1.O>[OH:8][C@@H:5]([CH2:4][CH:3]([O:2][CH3:1])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:6][C:7]([OH:19])=[O:9]
Reactant: [OH-]
Reactant: CCCCCCCCCC(C[C@H]1CC(=O)O1)OC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCC(C[C@H](O)CC(=O)O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 7 (187 mg, 0.729 mmol, 1.0 equiv) in THF (2.5 mL) was added a solution of NaOH (32.) mg, 0.802 mmol, 1.1 equiv) in water (1 L). The reaction mixture was stirred at rt for 2 h, transferred to a separatory funnel, diluted with water (5 mL) and extracted with ether. The aqueous layer was acidified with 2 N HCl (3 mL) and extracted with ether (2×15 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo to afford (3S)-1 (187 mg, 93%) as a colorless oil that was used without further purification: ATR/IR 2920, 2851, 1709, 1412, 1189, 1079, 738 cm−1; 1H NMR (CDCl3) 4.85-4.7 (m, 1H), 3.55-3.45 (m, 1H), 3.39, 3.38 (2s, 3H), 2.56-2.52 (m, 2H), 1.80-1.35 (m, 3H), 1.35-1.25 (m, 14H), 0.90 (t, 3H, J=6.9 Hz); 13C NMR (CDCl3) 176.5, 175.8, 81.5, 78.7, 68.0, 65.3, 56.7, 55.9, 41.5, 39.6, 39.0, 32.8, 32.6, 31.8, 29.7, 29.5, 29.2, 25.1, 24.4, 22.6, 14.1; MS (EI) m/z 274 (M+, 0.5), 256 (0.5), 171, 25, 129 (100), 97 (15).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:11][O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:9]=1[NH2:10])=[O:4].CO[CH:32]([N:35]([CH3:37])[CH3:36])OC>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:11][O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:8][C:9]=1[N:10]=[CH:32][N:35]([CH3:37])[CH3:36])=[O:4]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)c1sc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1N
Product: COC(=O)c1sc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1N=CN(C)C

Procedure:
3-Amino-5-(tert-butyldiphenylsilanyloxymethyl)thiophene-2-carboxylic acid methyl ester and dimethoxymethyldimethylamine were reacted by method B. The product with the molecular weight of 480.71 (C26H32N2O3SSi) was obtained in this way; MS (ESI): 481 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([C:31]1[S:35][C:34]([NH2:36])=[N:33][N:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH2:24]([C:31]1[S:35][C:34]([NH:36][C:19]([C:18]2[CH:17]=[CH:16][C:15]([CH:12]3[CH2:13][CH2:14][CH:9]([CH2:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][CH2:11]3)=[CH:23][CH:22]=2)=[O:21])=[N:33][N:32]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Nc1nnc(Cc2ccccc2)s1
Reactant: CC(C)(C)OC(=O)CC1CCC(c2ccc(C(=O)O)cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC1CCC(c2ccc(C(=O)Nc3nnc(Cc4ccccc4)s3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 34 %

Procedure:
0.45 g of 4-(4-tert-butoxycarbonylmethylcyclohexyl)benzoic acid (1.41 mmol, 1 eq.) is placed in a mixture of 5 mL of dimethylformamide at room temperature. 0.539 g of 5-benzyl-1,3,4-thiadiazol-2-amine (2.82 mmol, 2 eq.), 0.791 g of bromotris-pyrrolidinophosphonium hexafluorophosphonate (1.70 mmol, 1.2 eq.) and 0.49 mL of diisopropylethylamine (2.83 mmol, 2 eq.) are successively added. The reaction mixture is stirred for 16 hours at room temperature, diluted in ethyl acetate and washed three times with water. The organic phase is concentrated. The residue is taken up and washed with ethanol, filtered and dried. 0.236 g of tert-butyl {4-[4-(5-benzyl[1.3.4]thiadiazol-2-ylcarbamoyl)phenyl]cyclohexyl}acetate is obtained.
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1[Cl:3].CN(C)C=O.[Cl:15][C:16]1[C:17]([CH3:38])=[C:18]([C:27]2[CH:28]=[CH:29][C:30]([C:33]([N:35]([CH3:37])[CH3:36])=[O:34])=[N:31][CH:32]=2)[C:19]([O:25][CH3:26])=[C:20]([CH:22](O)[CH3:23])[CH:21]=1.O>ClCCl>[Cl:15][C:16]1[C:17]([CH3:38])=[C:18]([C:27]2[CH:28]=[CH:29][C:30]([C:33]([N:35]([CH3:37])[CH3:36])=[O:34])=[N:31][CH:32]=2)[C:19]([O:25][CH3:26])=[C:20]([CH:22]([Cl:3])[CH3:23])[CH:21]=1
Reactant: COc1c(C(C)O)cc(Cl)c(C)c1-c1ccc(C(=O)N(C)C)nc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(C(C)Cl)cc(Cl)c(C)c1-c1ccc(C(=O)N(C)C)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.7 %

Procedure:
Cyanuric chloride (85 mg, 0.46 mmol) was added to N,N-dimethylformamide (0.036 mL, 0.46 mmol) at room temperature. After the formation of a white solid (10 minutes), methylene chloride (2 mL) was added, followed by 5-[3-chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]-N,N-dimethylpyridine-2-carboxamide (115 mg, 0.330 mmol, from Example 11, step 3). After the addition, the mixture was stirred at room temperature overnight. Water was added, and then diluted with dichloromethane. The organic phase was washed with sat. NaHCO3 solution, water and brine, then dried over MgSO4, concentrated. The residue was purified on silica gel (eluting with 0 to 80% EtOAc in hexanes) to give the desired product (76 mg, 63%). LCMS calculated for C18H21Cl2N2O2 (M+H)+: m/z=367.1; Found: 367.0.
Reaction SMILES: [C:1]1([C@@H:7]([NH2:19])[CH2:8][O:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:20][C:21]1[C:29]2[C:24](=[CH:25][C:26]([C:30](O)=[O:31])=[CH:27][CH:28]=2)[NH:23][CH:22]=1>>[Cl:20][C:21]1[C:29]2[C:24](=[CH:25][C:26]([C:30]([NH:19][C@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][O:9][CH2:10][CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)=[O:31])=[CH:27][CH:28]=2)[NH:23][CH:22]=1
Reactant: O=C(O)c1ccc2c(Cl)c[nH]c2c1
Reactant: N[C@@H](COCCCN1CCCCC1)c1ccccc1
Product: O=C(N[C@@H](COCCCN1CCCCC1)c1ccccc1)c1ccc2c(Cl)c[nH]c2c1

Procedure:
Using coupling method A, (R)-1-phenyl-2-[3-(piperidin-1-yl)propoxy]ethylamine (218 mg, 0.83 mmol) and 3-chloro-indole-6-carboxylic acid (179 mg, 0.91 mmol) afforded, after purification (SiO2: 50% EtOAc in hexane), 115 mg (32%) of the title compound.
Reaction SMILES: OC1CCN(CC2C=CC=CC=2)CC1.C([N:22]1[CH2:27][CH2:26][CH:25]([O:28][C:29](=[O:43])[NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:24][CH2:23]1)C1C=CC=CC=1.Cl.C([O-])=O.[NH4+]>C(O)C>[NH:22]1[CH2:23][CH2:24][CH:25]([O:28][C:29](=[O:43])[NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:26][CH2:27]1
Reactant: O=C(Nc1ccccc1-c1ccccc1)OC1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: O=C[O-]
Agent: OC1CCN(Cc2ccccc2)CC1
Solvent: CCO
Product: O=C(Nc1ccccc1-c1ccccc1)OC1CCNCC1
Temperature: 50 °C
Yield: 100 %

Procedure:
Biphenyl-2-isocyanate (97.5 g, 521 mmol) and 4-hydroxy-1-benzylpiperidine (105 g, 549 mmol) (both commercially available from Aldrich, Milwaukee, Wis.) were heated together at 70° C. for 12 h, during which time the formation of biphenyl-2-ylcarbamic acid 1-benzylpiperidin-4-yl ester was monitored by LCMS. The reaction mixture was then cooled to 50° C. and ethanol (1 L) was added, and then 6M hydrochloric acid (191 mL) was added slowly. The reaction mixture was then cooled to ambient temperature and ammonium formate (98.5 g, 1.56 mol) was added and nitrogen gas was bubbled through the solution vigorously for 20 min. Palladium (10 wt. % (dry basis) on activated carbon) (20 g) was then added. The reaction mixture was heated at 40° C. for 12 h and then filtered through a pad of Celite. The solvent was then removed under reduced pressure and 1M hydrochloric acid (40 mL) was added to the crude residue. Sodium hydroxide (10N) was then added to adjust the pH to 12. The aqueous layer was extracted with ethyl acetate (2×150 mL) and dried (magnesium sulfate), and then the solvent was removed under reduced pressure to give biphenyl-2-ylcarbamic acid piperidin-4-yl ester (155 g, 100%). HPLC (10-70) Rt=2.52; MS m/z: [M+H+] calc'd for C18H20N2O2 297.15; found 297.3.