Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[O:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.CCO>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([C:18]([F:20])([F:21])[F:19])=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[O:22][C:23]2[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Oc2c(-c3ccc(O)cc3)c(C(F)(F)F)cc3ccccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1ccc(Oc2c(-c3ccc(O)cc3)c(C(F)(F)F)cc3ccccc23)cc1
Yield: 75.4 %

Procedure:
Methyl ester (189) (63 mg, 0.15 mmol) was saponified with 1 N NaOH in THF and EtOH to give 48 mg (79%) of the title compound (190) as a white solid. mp 244-245° C. 1H NMR (400 MHz, CH3OH-d4): δ 6.60 (d, J=8.8 Hz, 2H), 6.64 (d, J=8.6 Hz, 2H), 6.96 (d, J=8.4 Hz, 2H), 7.60-7.72 (m, 2H), 7.79 (d, J=9.0 Hz, 2H), 7.88 (d, J=8.1 Hz, 1H), 8.15 (d, J=7.9 Hz, 1H), 8.34 (s, 1H). LCMS (ESI): m/z 447 (M+Na)+, m/z 423 (M−H)−. Anal. Calc for C24H15F3O4.0.25H2O: C, 67.21; H, 3.64. Found: C, 67.05; H, 3.47.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[C:4]1[CH:9]=[C:8]([C:10]2[O:11][C:12]([N+:15]([O-])=O)=[CH:13][CH:14]=2)[N:7]=[CH:6][N:5]=1)[CH3:2].[Al].[C:21](OC(=O)C)(=[O:23])[CH3:22].[ClH:28]>C(OCC)(=O)C.O.C(OCC)C>[ClH:28].[CH2:1]([N:3]([CH2:18][CH3:19])[C:4]1[CH:9]=[C:8]([C:10]2[O:11][C:12]([NH:15][C:21](=[O:23])[CH3:22])=[CH:13][CH:14]=2)[N:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCN(CC)c1cc(-c2ccc([N+](=O)[O-])o2)ncn1
Agent: Cl
Agent: [Al]
Solvent: O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCN(CC)c1cc(-c2ccc(NC(C)=O)o2)ncn1

Procedure:
To a mixture of 2.62 g. (0.01 mole) of 4-diethylamino-6-(5-nitro-2-furyl)pyrimidine and aluminum amalgam, prepared from 4.0 g. of aluminum turnings, in 60 ml. of diethyl ether is added 4 ml. of water. Acetic anhydride (2.0 g.; 0.02 mole) is added dropwise during the ensuing reaction which is maintained by heating the reaction vessel in a warm water bath. The ether is filtered and the filtrate dried over sodium sulfate. Removal of the solvent under reduced pressure provides the crude product. The residue is dissolved in ethyl acetate and treated with gaseous hydrogen chloride until a precipitate no longer forms. The resulting hydrochloride salt is further purified by several recrystallizations form methanol/hexane.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH2:16]([O:8][CH2:4][CH2:5][CH2:6][CH2:7][CH3:2])[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCBr
Agent: O=C([O-])[O-]
Agent: Oc1cccc(Br)c1
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCOCCCCC
Temperature: 60 °C

Procedure:
To a solution of 5.0 gm of 3-Bromophenol in 60 mls of dimethylformamide is added 6.0 gm of potassium carbonate followed by 4.3 ml of 1-bromopentane. This mixture is heated to 60° C. for 6 hours and then cooled to room temperature and filtered. The filtrate is diluted with ether and washed with water and brine. After drying over magnesium sulfate and concentrating, the crude oil obtained is chromatographed over silica gel, and eluted with 3:2 hexane:ether to yield 3-bromo-phenol, n-pentyl ether as a clear oil.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[OH-].[Na+].[CH3:10][N:11]([CH3:16])[C:12](=[NH:15])[CH2:13]Cl>C(O)C>[CH3:10][N:11]([CH3:16])[C:12]([CH2:13][S:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1)=[NH:15]
Reactant: CN(C)C(=N)CCl
Reactant: Sc1nnc(S)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)C(=N)CSc1nnc(S)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.3 %

Procedure:
In 30 ml of ethanol was suspended 2.25 g of 2,5-dimercapto-1,3,4-thiadiazole, and 30 ml of 1N-sodium hydroxide solution was added to the suspension. The mixture was stirred at room temperature for 30 minutes. To the mixture was added 2.36 g of N,N-dimethylchloroacetamidine. The mixture was stirred at room temperature for an hour and concentrated under reduced pressure. The precipitating crystals were collected by filtration and washed with cold water and then a (1:1) mixture of methanol and ethyl ether to obtain 1.87 g of 2-(N,N-dimethylamidinomethylthio)-5-mercapto-1,3,4-thiadiazole as colorless crystals (mp 95°-97° C.).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4]([OH:14])=[CH:3][CH:2]=1.[H-].[Na+].[CH:17]1([CH2:20]Br)[CH2:19][CH2:18]1>CN(C=O)C>[CH:17]1([CH2:20][O:14][C:4]2[C:5]3[O:6][C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=4[C:9]=3[CH:1]=[CH:2][CH:3]=2)[CH2:19][CH2:18]1
Reactant: BrCC1CC1
Reactant: Oc1cccc2c1oc1ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc2c(c1)oc1c(OCC3CC3)cccc12
Yield: 89.7 %

Procedure:
A solution of Dibenzo[b,d]furan-4-ol (1 g, 5.43 mmol) in DMF (5 ml) was added to a stirred and cooled (0° C.) suspension of 60% sodium hydride (326 mg, 8.12 mmol) in DMF (20 ml). The mixture was stirred at 0° C. for 5 min and cyclopropylmethyl bromide (1.31 g, 10.85 mmol) in DMF (5 ml) was added dropwise over a period of 10 min. The cooling bath was removed and the mixture was stirred for 1 h at room temperature. The reaction mixture was diluted with ice-cold water (100 ml) and extracted with EtOAc (3×50 ml). The combined organic extracts were washed with water (2×100 ml), brine (100 ml) and dried (Na2SO4), to give 1.16 g (90%) of the product as viscous liquid
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C@@H:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.CN(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:40](I)[CH3:41]>O>[CH2:40]([O:12][C:11](=[O:13])[C@H:10]([CH3:14])[CH2:9][C@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:6][CH:5]=1)[CH3:41].[C:1]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:9][C@@H:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:5][CH:6]=1
Reactant: CCI
Agent: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 g of (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (3-a, R1=BOC, R2=R3=H) is added to dimethylformamide (80 ml). Cesium carbonate (69 g) is then added. Ethyl iodide (13.6 g) is then added and the mixture is stirred overnight at room temperature. Water (200 ml) is added to the mixture and the mixture is then extracted with isopropyl acetate (2×200 ml). The combined organic phases are washed with brine, dried (MgSO4) and concentrated in vacuo to give (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid ethyl ester (3-a, R1=BOC, R2=H, R3=Et) (56 g). 1H NMR (DMSO): 1.12 (3H), 1.19 (3H), 1.36 (9H), 1.53 (1H), 1.84 (1H), 2.55 (1H), 2.75 (2H), 3.74 (1H), 4.05 (2H), 6.04 (1H), 7.23 (2H), 7.30 (1H), 7.41 (2H), 7.50 (2H), 7.57 (2H). m/z (ES+): 412 ([MH]+, 100%), 356 (63), 312 (73).
Reaction SMILES: C([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1Br)(C)(C)C.[C:18]1([C:24]#[CH:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>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.C(#N)C>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:17])=[C:10]([C:25]#[C:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]=1
Reactant: C#Cc1ccccc1
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(O)COc1ccc(Cl)cc1C#Cc1ccccc1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A solution of tert-butyl(2-bromo-4-chlorophenoxy)acetate (350 mg; 1.09 mmol) and phenylacetylene (Aldrich; 122 mg; 1.20 mmol) in degassed, anhydrous ACN (2.80 mL) was treated with dichlorobis(triphenylphosphine)palladium(II) (38 mg; 0.05 mmol), copper(I) iodide (10 mg; 0.05 mmol) and triethylamine (0.45 mL; 3.26 mmol). The reaction mixture was heated at 50° C. under stirring for 16 hours. The solvent was evaporated, the residue dissolved in DCM (4 mL) and TFA (1 mL) was added. After stirring for 45 minutes, the solvents were removed under vacuum and the crude product purified by preparative HPLC. The title compound was obtained as a brown solid.
Reaction SMILES: C([N:8]([CH2:31][C@H:32]([OH:53])[CH2:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([O:41]CC2C=CC=CC=2)=[C:37]([S:49]([CH3:52])(=[O:51])=[O:50])[CH:36]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:30]=[CH:29][C:18]([C:19]([NH:21][NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)C1C=CC=CC=1>C(O)C.O1CCCC1.[Pd]>[OH:53][C@H:32]([CH2:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[C:37]([S:49]([CH3:52])(=[O:51])=[O:50])[CH:36]=1)[CH2:31][NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:30]=[CH:29][C:18]([C:19]([NH:21][NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1
Reactant: CS(=O)(=O)c1cc(OC[C@@H](O)CN(Cc2ccccc2)[C@H]2CC[C@H](c3ccc(C(=O)NNc4ccccc4)cc3)CC2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CS(=O)(=O)c1cc(OC[C@@H](O)CN[C@H]2CC[C@H](c3ccc(C(=O)NNc4ccccc4)cc3)CC2)ccc1O
Reaction time: 48 h

Procedure:
A mixture or 0.166 g of trans-4-[4-(benzyl{(2S)-3-[4-(benzyloxy)-3-(methylsulfonyl)phenoxy]-2-hydroxypropyl}amino)cyclohexyl]-N′-phenylbenzohydrazide (0.226 mmol) and of 0.1 g of 10% palladium-on-charcoal (50% in water) in a mixture of ethanol (3.9 ml) and tetrahydrofuran (2.93 ml) is placed under hydrogen atmosphere and stirred for 48 h. The catalyst is subsequently filtered off and the solvents are evaporated under reduced pressure. The title compound is obtained in the form of a white solid (0.02 g, 16%) after purification on silica gel (eluent: dichloromethane/methanol/aqueous ammonia 99/1/0.1 to 85/15/1.5 gradient in 30 min).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].CN1CCCC1=O.[CH2:27]([O:34][C:35]1[CH:59]=[CH:58][C:57]([O:60][CH2:61][CH2:62]Br)=[CH:56][C:36]=1[C:37]([NH:39][C:40]1[CH:49]=[C:48]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:47]=[CH:46][C:41]=1[C:42]([O:44][CH3:45])=[O:43])=[O:38])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(OCC)(=O)C.O>[CH2:27]([O:34][C:35]1[CH:59]=[CH:58][C:57]([O:60][CH2:61][CH2:62][CH:17]2[CH2:18][CH2:19][N:14]([C:12]([O:11][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:13])[CH2:15][CH2:16]2)=[CH:56][C:36]=1[C:37](=[O:38])[NH:39][C:40]1[CH:49]=[C:48]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:47]=[CH:46][C:41]=1[C:42]([O:44][CH3:45])=[O:43])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCCBr)ccc1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCCC2CCN(C(=O)OC(C)(C)C)CC2)ccc1OCc1ccccc1
Temperature: 90 °C
Reaction time: 0.75 h
Yield: 75.9 %

Procedure:
Potassium carbonate (0.12 g) and 1-(tert-butoxycarbonyl)piperidine (0.15 g) were added to a 1-methyl-2-pyrrolidone (2.0 mL) solution of methyl 2-(2-(benzyloxy)-5-(2-bromoethoxy)benzamido)-4-phenylbenzoate (0.40 g), followed by stirring at 90° C. for 45 minutes. The reaction mixture was cooled to room temperature, and then water and ethyl acetate were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 80-0% hexane/ethyl acetate] to obtain 0.36 g of tert-butyl 4-(2-(4-(benzyloxy)-3-(2-(methoxycarbonyl)-5-phenylphenylcarbamoyl)phenoxy)ethyl)piperidine-1-carboxylate as a white solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[CH2:22]1[C:25]2([CH2:29][CH:28]([OH:30])[CH2:27][O:26]2)[CH2:24][NH:23]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:23]3[CH2:22][C:25]4([CH2:29][CH:28]([OH:30])[CH2:27][O:26]4)[CH2:24]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: OC1COC2(CNC2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1CC2(CC(O)CO2)C1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 5-oxa-2-azaspiro[3.4]octan-7-ol hydrochloride in the presence of TBTU and DIEA to obtain the title compound as yellow oil; MS (EI): m/e=396.5 [MH+].
Reaction SMILES: O1CCCC1.[CH2:6]([Mg]Cl)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[NH4+]>[Cl-].[Zn+2].[Cl-].C1(C)C=CC=CC=1.CN1CCCC1=O>[C:16]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Clc1ccccc1
Reactant: CCCCCCC[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CN1CCCC1=O
Product: CCCCCCCc1ccccc1

Procedure:
A 50-ml four-necked flask was equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser. 1.090 g (8 mmol) of zinc chloride and 4 ml of N-methylpyrrolidinone were weighed in the flask. The flask was purged with argon, followed by stirring. 3.5 ml (7 mmol) of 2M tetrahydrofuran solution of n-heptylmagnesium chloride was added dropwise at 25° C. over a period of 30 minutes, followed by stirring at 25° C. for 30 minutes. The reaction liquid previously obtained was added, followed by stirring at 25° C. for 30 minutes. Further, 0.558 g (5 mmol) of chlorobenzene was added, followed by stirring at 120° C. for 16 hours. After the completion of the reaction, 10 ml of toluene and 10 ml of saturated aqueous ammonium chloride solution were added, followed by separation. The organic phase was purified by column chromatography to afford 0.684 g of 1-phenylheptane (yield: 78 mol % based on chlorobenzene). The identification of the product was made by mass spectroscopy.
Reaction SMILES: [CH:1]([N:4]1[CH:9]2[CH2:10][CH2:11][CH:5]1[CH2:6][C:7](=O)[CH2:8]2)([CH3:3])[CH3:2].N1C=CC=CC=1.Cl.[NH2:20][OH:21]>C(O)C>[CH:1]([N:4]1[CH:9]2[CH2:10][CH2:11][CH:5]1[CH2:6][C:7](=[N:20][OH:21])[CH2:8]2)([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)N1C2CCC1CC(=O)C2
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC(C)N1C2CCC1CC(=NO)C2
Temperature: 23 °C

Procedure:
A mixture of 8-isopropyl-8-aza-bicyclo[3.2.1]octan-3-one (CAS 3423-28-7)(20.0 g, 120 mmol) in ethanol (500 ml) and pyridine (14.5 ml, 179 mmol) with hydroxylamine hydrochloride (8.81 g, 127 mmol) was refluxed for 16 h. Cooled to 23° C., the precipitate was filtered off, washed with diethyl ether leaving a solid, which was partitioned between dichloromethane and sodium carbonate solution, the organic layers dried over sodium sulfate, filtered and the solvents evaporated to give the title compound as a white solid. (17.7 g, 82%), MS: m/e=183.2 (M+H+).
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:27])[CH2:13][CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH3:28]O>Cl.O1CCOCC1.ClCCl>[CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:27])[CH2:13][CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][CH:19]4[CH2:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([O:7][CH3:28])=[O:6]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CO
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of the lithocholic acid 1 (25.1 g, 66.4 mmol) in anhydrous methanol (100 mL), 4M HCl in 1,4-dioxane (100 mL) was added and the reaction mixture stirred at ambient temperature overnight. The reaction mixture became heterogeneous. The reaction mixture was diluted with dichloromethane (300 mL) and the organic layer was washed with saturated NaHCO3 (2×200 mL). The organic layer was concentrated and dried under high vacuum overnight to provide the pure ester as a white solid (25.7 g, 97%). The analytical and spectral data were consistent with that of reported values (Rensen, Patrick C. N.; van Leeuwen, Steven H.; Sliedregt, Leo A. J. M.; Van Berkel, Theo J. C.; Biessen, Erik A. L. Design and Synthesis of Novel N-Acetylgalactosamine-Terminated Glycolipids for Targeting of Lipoproteins to the Hepatic Asialoglycoprotein Receptor. Journal of Medicinal Chemistry (2004), 47(23), 5798-5808.).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][S:10]([NH:13][CH3:14])(=[O:12])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].B.C1COCC1.Cl.[OH-].[Na+]>C1COCC1>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([CH2:9][S:10]([NH:13][CH3:14])(=[O:12])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CNS(=O)(=O)Cc1cccc(C#N)c1
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CNS(=O)(=O)Cc1cccc(CN)c1
Temperature: 100 °C

Procedure:
To a solution of C-(3-cyano-phenyl)-N-methyl-methanesulfonamide (42 mg, 0.2 mmol) in THF (4 mL) is added a solution of BH3−THF in THF (1 M, 1 mL). The mixture is sealed and heated in a microwave reactor at 100° C. for 120 seconds. The mixture is poured into 1 M HCl (20 mL), basified with 3 M NaOH to pH ˜10, extracted with DCM (2×50 mL), dried with Na2SO4, filtered, and concentrated in vacuo to afford C-(3-aminomethyl-phenyl)-N-methyl-methanesulfonamide, which is used directly in the next without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.Cl[C:17]1[CH:22]=[C:21]([O:23][C:24]2[CH:25]=[CH:26][C:27]([C:31]3[C:32]([O:39][CH3:40])=[N:33][C:34]([S:37][CH3:38])=[N:35][CH:36]=3)=[N:28][C:29]=2[CH3:30])[CH:20]=[CH:19][N:18]=1.C([O-])([O-])=O.[K+].[K+]>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.O1CCOCC1.O>[CH3:40][O:39][C:32]1[C:31]([C:27]2[CH:26]=[CH:25][C:24]([O:23][C:21]3[CH:22]=[CH:17][N:18]=[C:19]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)[CH:20]=3)=[C:29]([CH3:30])[N:28]=2)=[CH:36][N:35]=[C:34]([S:37][CH3:38])[N:33]=1
Reactant: COc1nc(SC)ncc1-c1ccc(Oc2ccnc(Cl)c2)c(C)n1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1nc(SC)ncc1-c1ccc(Oc2ccnc(-c3cnn(C)c3)c2)c(C)n1
Temperature: 90 °C
Yield: 98 %

Procedure:
A mixture of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.30 g, 1.44 mmol), 5-(5-((2-chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)-4-methoxy-2-(methylthio)pyrimidine (0.49 g, 1.31 mmol), and K2CO3 (0.54 g, 3.92 mmol) in 5:1 dioxane/water (18 mL) was sparged with Ar, treated with Pd(PPh3)4 (0.15 g, 0.13 mmol), sparged again with Ar and heated at 90° C. for 4 h. The mixture was cooled to RT, treated with satd. NaHCO3, extracted with EtOAc (3×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to obtain 4-methoxy-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-(methylthio)pyrimidine (0.54 g, 98%). 1H NMR (400 MHz, DMSO-d6): δ 8.93 (s, 1H), 8.39 (d, J=5.7 Hz, 1H), 8.28 (s, 1H), 7.99 (d, J=0.7 Hz, 1H), 7.88 (d, J=8.5 Hz, 1H), 7.65 (d, J=8.6 Hz, 1H), 7.30 (d, J=2.4 Hz, 1H), 6.66 (dd, J=5.7, 2.4 Hz, 1H), 4.06 (s, 3H), 3.85 (s, 3H), 2.58 (s, 3H), 2.42 (s, 3H); MS (ESI) m/z: 421.1 (M+H+).
Reaction SMILES: CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[CH3:35][C@@H:36]1[C:40]2[NH:41][C:42](B3OC(C)(C)C(C)(C)O3)=[CH:43][C:39]=2[C:38](=[O:53])[NH:37]1.Br[C:55]1[CH:56]=[CH:57][CH:58]=[C:59]2[C:64]=1[N:63]=[C:62]([NH:65][C:66]([CH3:69])([CH3:68])[CH3:67])[N:61]([CH:70]([CH3:72])[CH3:71])[C:60]2=[O:73].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CO>[C:66]([NH:65][C:62]1[N:61]([CH:70]([CH3:71])[CH3:72])[C:60](=[O:73])[C:59]2[C:64](=[C:55]([C:42]3[NH:41][C:40]4[C@@H:36]([CH3:35])[NH:37][C:38](=[O:53])[C:39]=4[CH:43]=3)[CH:56]=[CH:57][CH:58]=2)[N:63]=1)([CH3:69])([CH3:68])[CH3:67]
Reactant: CC(C)n1c(NC(C)(C)C)nc2c(Br)cccc2c1=O
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: CC(C)n1c(NC(C)(C)C)nc2c(-c3cc4c([nH]3)[C@@H](C)NC4=O)cccc2c1=O
Temperature: 80 °C
Yield: 68.7 %

Procedure:
Argon was bubbled into a mixture of Pd2dba3 (Strem, 7.45 mg, 8.13 μmol), Xphos (Strem; 7.75 mg, 0.016 mmol), (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (705; 0.085 g, 0.325 mmol), 8-bromo-2-(tert-butylamino)-3-isopropylquinazolin-4(3H)-one (0.055 g, 0.163 mmol), potassium phosphate (0.10 g, 0.488 mmol) in 1 mL dioxane and 0.2 mL water for 1 min. The reaction was sealed and heated to 80° C. for 2 h. The reaction was cooled and transferred to a RBF with some MeOH and adsorbed onto 0.7 g silica gel and dried in vacuo. The material was purified by silica gel chromatography (12 g column) using 0-100% 90/10 DCM/MeOH in DCM. The product-containing fractions were concentrated to afford (R)-2-(tert-butylamino)-3-isopropyl-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)quinazolin-4(3H)-one (0.044 g, 0.112 mmol, 69% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.78 (1H, s), 7.84 (2H, ddd, J=14.9, 7.6, 1.6 Hz), 7.59 (1H, s), 7.15 (1H, t, J=7.7 Hz), 6.63 (1H, d, J=1.6 Hz), 5.72 (1H, s), 4.94 (1H, quin, J=6.7 Hz), 4.51 (1H, q, J=6.8 Hz), 3.17 (3H, s), 1.52 (6H, d, J=6.8 Hz), 1.48 (9H, s), 1.36 (3H, d, J=6.7 Hz). m/z (ESI, +ve ion) 394.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[CH:18]1([C:24](Cl)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([C:24]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[NH:9][C:10]4[CH:16]=[CH:15][C:14]([NH:17][C:24]([CH:18]5[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]5)=[O:25])=[CH:13][C:11]=4[N:12]=3)=[CH:6][CH:7]=2)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Nc1ccc(-c2nc3cc(N)ccc3[nH]2)cc1
Reactant: O=C(Cl)C1CCCCC1
Product: O=C(Nc1ccc(-c2nc3cc(NC(=O)C4CCCCC4)ccc3[nH]2)cc1)C1CCCCC1

Procedure:
2-(N-Cyclohexylcarbanoyl-4′-aminophenyl)-6-(cyclohexylcarbanoylamino)-benzimidazole was prepared by Method A from 2-(4-aminophenyl)-6-aminobenzimidazole (0.195 g, 0.87 mmole) and cyclohexylcarbonyl chloride (0.291 ml, 0.319 g, 2.175 mmole). The resulting solid (76.7 mg) was purified by preparative HPLC.